EA047001B1 - DOSAGE FORMS OF ACALABRUTINIB MALEATE - Google Patents

Abstract

The invention relates generally to: (a) solid pharmaceutical dosage forms comprising acalabrutinib maleate; (b) methods of using such pharmaceutical dosage forms to treat B-cell malignancies and/or other conditions; (c) kits comprising such pharmaceutical dosage forms and, optionally, a second pharmaceutical dosage form comprising another therapeutic agent; (d) methods of preparing such pharmaceutical dosage forms; and (e) pharmaceutical dosage forms prepared by such methods.

Description

Field of technology to which the invention relates

The invention relates generally to: (a) solid pharmaceutical dosage forms containing acalabrutinib maleate; (b) methods of using such pharmaceutical dosage forms for the treatment of B cell malignancies and/or other conditions; (c) kits containing such pharmaceutical dosage forms and optionally a second pharmaceutical dosage form containing another therapeutic agent; (d) methods for preparing such pharmaceutical dosage forms and (e) pharmaceutical dosage forms obtained through such methods.

BACKGROUND OF THE INVENTION

Acalabrutinib is a selective covalent inhibitor of Bruton's tyrosine kinase (BTK). It is the active pharmaceutical ingredient in the drug product CALQUENCE®, which has been approved in several countries (including the United States, Canada and Australia) for the treatment of chronic lymphocytic leukemia, small cell lymphocytic leukemia and mantle cell lymphoma. CALQUENCE® is marketed as a capsule dosage form containing 100 mg of acalabrutinib crystalline free base (specifically Form A anhydrous). International Publication WO 2017/002095 reports anhydrous Form A, additional crystalline forms of acalabrutinib free base and crystalline salt forms of acalabrutinib, including, for example, the citrate, fumarate, gentisate, maleate, oxalate, phosphate, sulfate and L-tartrate salts of acalabrutinib . The instructions for use of the drug CALQUENCE® recommend avoiding simultaneous administration with drugs that reduce the acidity of gastric juice, since such drugs may reduce the concentration of acalabrutinib in the blood plasma. Accordingly, there is a need for pharmaceutical dosage forms of acalabrutinib that reduce the potential effects of gastric acid reducers on acalabrutinib plasma concentrations when coadministered with an acalabrutinib dosage form.

Brief description of the invention

In one aspect, the invention provides solid pharmaceutical dosage forms containing from about 75 mg to about 125 mg (equivalent free base weight) of acalabrutinib maleate and at least one pharmaceutically acceptable substance, for oral administration to humans, wherein the dosage form satisfies the following conditions:

at least about 75% of acalabrutinib maleate dissolves in approximately 30 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 75% of acalabrutinib maleate dissolves in about 60 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), a dissolution volume of 900 mL, a dissolution medium consisting of 5 mM phosphate with a pH of 6.8, and a paddle speed of 75 rpm.

In additional aspects, the solid pharmaceutical dosage forms contain from about 75 mg to about 100 mg (equivalent free base weight) of acalabrutinib maleate. In other additional aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate, such as crystalline Form A of acalabrutinib maleate monohydrate.

In another aspect, the present invention provides the above-described solid pharmaceutical dosage forms wherein the dissolution rate of acalabrutinib maleate in a dissolution medium of 5 mM phosphate pH 6.8 is not reduced by more than 20% from its initial dissolution rate after storage dosage form in appropriate packaging for six months at a temperature of 40°C and a relative humidity of 75%.

In another aspect, the present invention provides one or more of the above-described solid pharmaceutical dosage forms, wherein no more than about 5% (w/w) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and a relative humidity of 75%.

In another aspect, the present invention provides one or more of the above-described solid pharmaceutical dosage forms, wherein the dosage form is bioequivalent to Calquence® 100 mg capsules when administered orally to a fasted human subject who has not been administered a gastric acid reducer, wherein a dosage form is bioequivalent provided that the confidence interval for the relative mean _Cmax , AUC( _0-t ) and AUC, _-0-/ , of the dosage form relative to Calquence® 100 mg capsules is in the range of 80 to 125 %.

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In another aspect, the present invention provides one or more of the above-described solid pharmaceutical dosage forms, wherein the dosage form, when administered twice daily to a population of fasted human subjects, satisfies one or more of the following pharmacokinetic conditions for acalabrutinib:

the average C _max in a population of human subjects is from about 400 ng/ml to about 900 ng/ml;

the average AUC( _0-24 ) in a population of human subjects ranges from approximately 350 ng-h/ml to approximately 1900 ng-h/ml; and/or the average AUQ ₀ ->) value in a population of human subjects is from about 350 ng-h/ml to about 1900 ng-h/ml.

In another aspect, the present invention provides one or more of the above-described solid pharmaceutical dosage forms, wherein the dosage form, when administered to a human subject twice daily, provides a median steady state Bruton's tyrosine kinase occupancy value of at least about 90% in peripheral blood mononuclear cells .

In another aspect, the present invention provides one or more of the above-described solid pharmaceutical dosage forms, wherein the dosage form contains acalabrutinib maleate in an amount of from about 15% to about 55% by weight of the dosage form;

at least one diluent in an amount of from about 10% to about 70% by weight of the dosage form;

at least one disintegrant in an amount of from about 0.5% to about 15% by weight of the dosage form and at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

In another aspect, the present invention relates to one or more of the above-described solid pharmaceutical dosage forms, wherein the dosage form contains:

acalabrutinib maleate monohydrate in an amount of from about 30% to about 35% by weight (equivalent weight of free base) of the dosage form;

mannitol in an amount of from about 30% to about 35% by weight of the dosage form;

microcrystalline cellulose in an amount of from about 25% to about 30% by weight of the dosage form;

hydroxypropylcellulose in an amount of from about 3% to about 7% by weight of the dosage form and sodium stearyl fumarate in an amount from about 1% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

Brief description of graphic materials

In fig. Figure 1 shows a representative XRPD diffraction pattern of crystal Form A of acalabrutinib maleate monohydrate.

In fig. Figure 2 shows the dissolution profiles of acalabrutinib phosphate, oxalate, and maleate salts in artificial gastric juice/FaSSIF-V2 media.

In fig. Figure 3 shows the dissolution profiles of the phosphate, oxalate and maleate salts of acalabrutinib in deionized water/FaSSIF-V2 media.

In fig. Figure 4 shows a graph obtained from a dynamic vapor sorption study for the phosphate salt of acalabrutinib.

In fig. Figure 5 shows a graph obtained from thermogravimetric analysis of the phosphate salt of acalabrutinib.

In fig. Figure 6 shows an XRPD diffraction pattern for the phosphate salt of acalabrutinib.

In fig. 7 shows a graph obtained from thermogravimetric analysis of the oxalate salt of acalabrutinib.

In fig. Figure 8 shows a graph obtained from a dynamic vapor sorption study for the oxalate salt of acalabrutinib.

In fig. 9A is a graph obtained from thermogravimetric analysis of the maleate salt of acalabrutinib.

In fig. 9B is a graph obtained from thermogravimetric analysis of acalabrutinib maleate salt performed under an alternative set of conditions.

In fig. 10A shows a graph obtained from a dynamic vapor sorption study for the first sample of acalabrutinib maleate salt.

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In fig. 10B is a graph obtained from a dynamic vapor sorption study of a second, higher quality sample of acalabrutinib maleate salt.

In fig. 11 shows the dissolution profiles of micronized and uncomminuted maleate salts of acalabrutinib in artificial gastric juice/FaSSIF-V2 media.

In fig. 12 shows the dissolution profiles of micronized and unmilled acalabrutinib maleate salts in deionized water/FaSSIF-V2 media.

In fig. Figure 13 shows solubility versus final pH values for acalabrutinib maleate and acalabrutinib free base in various buffer solutions.

In fig. 14 shows the dissolution profiles obtained from the low pH test at extreme dilution conditions for acalabrutinib maleate in the form of tablets T16, T17 and T18 and acalabrutinib free base in the form of capsule C1.

In fig. 15 shows the dissolution profiles obtained from a low ionic strength test at neutral pH under extreme dilution conditions for acalabrutinib maleate tablets T16, T17 and T18.

In fig. 16 shows the dissolution profiles obtained from a high ionic strength test at neutral pH for acalabrutinib maleate in T13 tablet form and acalabrutinib free base in C2 capsule form.

In fig. 17 shows the dissolution profiles obtained in neutral, unbuffered conditions (i.e., under conditions similar to those in the stomach during proton pump inhibitor treatment) for acalabrutinib maleate in tablet form T1 and acalabrutinib free base in capsule form C1.

In fig. 18 shows the dissolution profiles obtained in neutral medium without buffering activity for acalabrutinib maleate in the form of tablet T13 and acalabrutinib free base in the form of capsule C1.

In fig. 19 shows the dissolution profile under pH shift conditions for acalabrutinib maleate in tablet form T19.

In fig. 20 shows the dissolution profiles under pH shift conditions for acalabrutinib maleate in T19 tablet form and acalabrutinib free base in C3 capsule form.

In fig. Figure 21 shows a graph of acalabrutinib cumulative available fraction (%) as a function of time (minutes) for acalabrutinib maleate T19 tablet and acalabrutinib free base capsule C2 when assessed in the TIM-1 system under gastric conditions associated with the acidic gastric compartment , as well as in gastric conditions associated with combined administration with a proton pump inhibitor or acid reducer.

In fig. Figure 22 shows the particle size distribution for acalabrutinib maleate in the form of tablets T10 (D( _V , ₀ , ₉ ) ~ 150 μm), T11 (D( _V , 0, ₉ ) ~ 16 μm), T13 (D( _V , ₀ , 9) ₉ ) ~ 500 µm) and T15 (D( _V , ₀ , ₉ ) ~ 70 µm).

In fig. 23 shows the dissolution profiles in 5 mM sodium phosphate buffer for acalabrutinib maleate tablets T10, T11, T13 and T15 (26 wt% drug loading).

In fig. Figure 24 shows the dissolution profiles in 5 mM sodium phosphate buffer for acalabrutinib maleate tablets T9, T2 and T14 (43 wt% drug loading).

In fig. 25 presents the results of an in vivo study in a dog model measuring AUC values ( _0-24 ) for acalabrutinib free base and acalabrutinib maleate when coadministered with omeprazole.

In fig. 26 shows the dissolution profiles in deionized water for several binary mixtures of disintegrants and acalabrutinib maleate (1:5 ratio).

In fig. 27 shows the dissolution profiles in deionized water for several binary mixtures of lubricants and acalabrutinib maleate (ratio 1:15).

In fig. 28 shows the dissolution profiles in deionized water for the T2 and T3 tablet cores.

In fig. 29 shows the dissolution profiles in a deionized water environment for T6 and T8 tablet cores.

In fig. 30 shows the dissolution profiles in deionized water for T4 and T5 tablet cores.

In fig. 31 provides a schematic overview of the process for preparing acalabrutinib maleate in the form of tablet T21 according to Example 4.

Detailed Description of the Invention

I. Definitions.

Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by one skilled in the art to which this invention belongs.

When ranges are used to describe, for example, quantities, all combinations and subcombinations of ranges and specific embodiments are intended to be included.

Singular forms include plural entities if

- 3 047001 context clearly does not imply otherwise.

The use of the term approximate when referring to a number or numerical range means that the stated number or numerical range is an approximation within the limits of experiment-to-experiment variability (or within the statistical error of the experiment), and thus the number or numerical range may vary. The deviation is typically 0 to 15%, preferably 0 to 10%, more preferably 0 to 5% of the specified number or numerical range. In many cases, the term approximately may include numbers that are rounded to the first significant digit.

The term acalabrutinib refers to the international nonproprietary name (INN) of the compound 4-{8-amino-3-[(2S)-1-(but-2-inoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazine - 1-yl}-N-(iridsh ι2-yl)benzamide, which has the chemical structure shown below:

International Publication No. WO 2013/010868 discloses acalabrutinib (Example 6) and describes the synthesis of acalabrutinib. International publication No. WO 2020/043787 further describes the synthesis of acalabrutinib. International Publication No. WO 2013/010868 and International Publication No. WO 2020/043787 are incorporated by reference in their entirety.

The term acalabrutinib maleate monohydrate refers to crystalline acalabrutinib maleate monohydrate, including crystalline Form A of acalabrutinib maleate monohydrate. Example 6.2 of International Publication No. WO 2017/002095 describes the preparation of crystalline Form A of acalabrutinib maleate monohydrate. International Publication No. WO 2017/002095 is incorporated by reference in its entirety. Acalabrutinib maleate monohydrate Form A may also be referred to by alternative nomenclature as acalabrutinib maleate monohydrate Form 1. Unless otherwise indicated, whenever mentioned in the present invention, the amount of acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate is expressed based on the equivalent weight of acalabrutinib free base. For example, 100 mg refers to 100 mg of acalabrutinib free base or an equivalent amount of acalabrutinib maleate or acalabrutinib maleate monohydrate.

The term ACP-5862 refers to the compound 4-[8-amino-3-[4-(but-2-inoylamino)butanoyl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide, the chemical structure of which is shown below:

ACP-5862 is an active metabolite of acalabrutinib.

The term AUC( _0-24 ) refers to the area under the plasma concentration-time curve from time 0 (time of dosing) to 24 hours after dosing, calculated using the linear trapezoidal method.

The term AUC _(0-/) refers to the area under the plasma concentration-vs.

- 4 047001 time from time 0 (dose administration time) to infinity (yes), calculated using the linear trapezoidal method.

The term BID means twice a day, twice daily or twice a day.

The term _Cmax refers to the maximum observed plasma concentration over the entire sampling period.

The terms co-administration, in combination with, and combination can refer to the administration of two or more therapeutic agents. In one aspect, combination may refer to simultaneous administration (eg, administration of both agents in separate dosage forms, but at substantially the same time). In yet another aspect of the invention, the combination may refer to sequential administration (eg, where a first agent is administered, followed by a delay, followed by the administration of a second or additional agent). When administered sequentially, the delay in administration of the last component should be neither too long nor too short, so as not to lose the beneficial effect of the combination.

Unless the context otherwise requires, the terms contain, contains and containing are used on the basis and express understanding that they are to be interpreted inclusively and not exclusively, and that the applicant intends that each of these words be so interpreted in construing this patent, including number of the claims below.

The term crystalline as applied to acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate refers to the solid state form in which the molecules are arranged to form a distinguishable crystal lattice (i) containing distinguishable unit cells, and (ii) producing diffraction peaks when exposed to x-rays.

The term crystalline purity means the purity of the crystalline form of acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate with respect to the specific crystalline form, as determined by powder x-ray diffraction analytical methods.

The term crystallization as used in the invention may refer to crystallization and/or recrystallization depending on the applicable circumstances associated with the preparation of acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate.

The terms D(o,1) and D( _v , _0,1 ) as used in the invention mean that 10% of the total volume of material in the sample has a particle diameter less than the specified value determined by laser diffraction.

The terms D( _0,5 ) and D( _{v , 0,5} ) as used herein mean that 50% of the total volume of material in the sample has a particle diameter less than the specified value determined by laser diffraction.

The terms D( _0.9 ) and D( _v , ad as used in the invention mean that 90% of the total volume of material in the sample has a particle diameter less than the specified value determined by laser diffraction.

The term pharmaceutically acceptable (eg, in the formulation, a pharmaceutically acceptable diluent or a pharmaceutically acceptable disintegrant) refers to a material that is compatible with administration to a subject, eg, the material does not cause an undesirable biological effect. Examples of pharmaceutically acceptable excipients are described in the Handbook of Pharmaceutical Excipients, Rowe et al., Ed. (Pharmaceutical Press, 7th Ed., 2012).

The pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is intended to include any possible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents, and inert ingredients. Except to the extent that any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with acalabrutinib, acalabrutinib maleate or acalabrutinib maleate monohydrate, their use is provided in the therapeutic compositions of the present invention.

The term Q refers to the amount (Q) of active substance in a sample that dissolves in a given time, expressed as a percentage of the total amount of active substance present in the sample.

The term QD means once daily, once daily, or once daily.

The term _Tmax refers to the time of the maximum observed plasma concentration (Cmax).

The terms treat, treat, and cure refer to alleviating, suppressing, eliminating, reducing the severity, reducing the incidence of, reducing the risk of occurring, or delaying the onset of a condition.

Abbreviations listed in table. 1 below have the meanings shown in this table.

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Table 1

REDUCTION MEANING DC Direct pressing DLBCL Diffuse large B cell lymphoma DVS Dynamic vapor sorption FaSSIF Artificial intestinal juice characteristic of the fasting state G Gram g/mol Gram/mol h Hour HDPE High Density Polyethylene HPLC High performance liquid chromatography kg Kilogram kN Kilonewton l Liter µl Microliter MKM Micrometer µM Micromole mg Milligram(milligrams) ml Milliliter mm Millimeter nM Nanomole NMT Not more than RVRK Physiologically based pharmacokinetic parameters RK Pharmacokinetics (pharmacokinetic parameters) PPI Proton pump inhibitor P-PSD Product particle size distribution XRPD Powder X-ray diffraction RH Relative humidity RPM Rpm RRT Relative retention time TGA Thermogravimetric analysis USP United States Pharmacopoeia weight/weight Weight ratio

II. Solid dosage forms.

The present invention relates in part to solid pharmaceutical dosage forms containing acalabrutinib maleate, in particular crystalline acalabrutinib maleate monohydrate. According to the Biopharmaceutical Classification System (BCS), acalabrutinib is a BCS Class II drug substance, which means it exhibits good penetration but low gastrointestinal solubility. See Pepin, XJH, et al., Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices, European Journal of Pharmaceutics and Biopharmaceutics 142: 435-448 (2019). The bioavailability of BCS Class II drugs, including acalabrutinib, is generally limited by their rate of dissolution and/or solvation. In addition, acalabrutinib free base exhibits pH-dependent solubility, with solubility decreasing as pH increases until the maximum base pK _a (i.e., around pH 6, when acalabrutinib is largely unionized). Increased gastric pH in sub

- 6 047001 patients taking CALQUENCE® (for example, in a subject who is also taking a proton pump inhibitor or other gastric acid reducer) may result in decreased gastric solubility of acalabrutinib and potentially lead to decreased bioavailability and/or increased pharmacokinetic variability acalabrutinib in the same or different subjects. The present invention relates to the unexpected discovery that solid pharmaceutical dosage forms containing acalabrutinib maleate, as described below, are characterized by acceptable physical and pharmacological properties (for example, solubility, stability, processability, pharmacokinetic properties, etc.) and, being essentially bioequivalent to the currently marketed CALQUENCE® capsule dosage form under normal acidic gastric conditions, provide less variability in the pharmacokinetics of acalabrutinib over a wider range of gastric pH conditions. Such solid dosage forms provide an additional therapeutic option for the treatment of conditions including B-cell malignancies such as chronic lymphocytic leukemia, small cell lymphocytic leukemia and mantle cell lymphoma.

In some embodiments, the present invention relates in part to solid pharmaceutical dosage forms containing from about 75 mg to about 125 mg (equivalent free base weight) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient, for oral administration to a human, wherein the dosage form satisfies the following conditions:

at least about 75% of acalabrutinib maleate dissolves in approximately 30 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 75% of acalabrutinib maleate dissolves in about 60 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), a dissolution volume of 900 mL, a dissolution medium consisting of 5 mM phosphate with a pH of 6.8, and a paddle speed of 75 rpm.

The dissolution medium, which is 0.1 N. hydrochloric acid is considered to be representative of the fasting stomach environment, while the 5 mM phosphate dissolution medium, pH 6.8, is considered to be representative of the worst case scenario of the stomach environment treated with a gastric acid reducer. In one aspect, the dosage form satisfies the following conditions:

at least about 75% of acalabrutinib maleate dissolves in approximately 20 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 75% of acalabrutinib maleate dissolves in about 45 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), a dissolution volume of 900 mL, a dissolution medium consisting of 5 mM phosphate with a pH of 6.8, and a paddle speed of 75 rpm. In another aspect, the dosage form satisfies the following conditions:

at least about 80% of acalabrutinib maleate dissolves in approximately 20 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 80% of acalabrutinib maleate dissolves in about 30 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), a dissolution volume of 900 mL, a dissolution medium consisting of 5 mM phosphate with a pH of 6.8, and a paddle speed of 75 rpm. In another aspect, the dosage form satisfies the following conditions:

at least about 80% of acalabrutinib maleate dissolves in approximately 15 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 80% of acalabrutinib maleate dissolves in about 20 minutes when determined in an in vitro dissolution test performed using a test device

- 7 047001 dissolution test USP 2 (paddle stirrer device), dissolution volume 900 ml, dissolution medium 5 mM phosphate pH 6.8 and paddle stirrer speed 75 rpm.

In some embodiments, the solid pharmaceutical dosage forms of the present invention contain from about 75 mg to about 125 mg of acalabrutinib maleate (equivalent weight of free base). In one aspect, the dosage forms contain from about 75 mg to about 100 mg acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain from about 75 mg to about 80 mg acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain from about 80 mg to about 85 mg acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain from about 85 mg to about 90 mg acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain from about 90 mg to about 95 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain from about 95 mg to about 100 mg acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain approximately 75 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain approximately 80 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain approximately 85 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain approximately 90 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain approximately 95 mg of acalabrutinib maleate (equivalent weight of free base). In another aspect, the dosage forms contain approximately 100 mg of acalabrutinib maleate (equivalent weight of free base).

In some embodiments, acalabrutinib maleate is acalabrutinib maleate monohydrate. In one aspect, acalabrutinib maleate monohydrate is crystalline acalabrutinib maleate monohydrate. In another aspect, crystalline acalabrutinib maleate is crystalline Form A of acalabrutinib maleate monohydrate, characterized by an X-ray powder diffraction pattern containing one or more peaks selected from the group consisting of an X-ray powder diffraction pattern with at least five peaks selected from the group consisting of 5. 3, 9.8, 10.6, 11.6, 13.5, 13.8, 13.9, 14.3, 15.3, 15.6, 15.8, 15.9, 16.6, 17.4, 17.5, 18.7, 19.3, 19.6, 19.8, 20.0, 20.9, 21.3, 22.1, 22.3, 22.7, 23, 2, 23.4, 23.7, 23.9, 24.5, 24.8, 25.2, 25.6, 26.1, 26.4, 26.7, 26.9, 27.1, 27.6, 28.8, 29.5, 30.0, 30.3, 30.9, 31.5, 31.9, 32.5, 34.0 and 35.1, with peak positions measured in °2θ ± 0.2 °2θ. In another aspect, crystalline Form A of acalabrutinib maleate monohydrate is characterized by a powder X-ray diffraction pattern containing peaks at 5.3, 9.8, 10.6, 11.6 and 19.3°2θ ± 0.2°2θ. In another aspect, the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern in FIG. 1. In another aspect, the X-ray powder diffraction pattern of any of the previous embodiments is measured in transmission mode. In another aspect, the X-ray powder diffraction pattern of any of the previous embodiments is measured in reflection mode. In another aspect, crystalline acalabrutinib maleate monohydrate according to any of the previous embodiments has a stoichiometry relative to acalabrutinib that is approximately equivalent to the monohydrate. International publication no. WO 2017/002095 describes the applicable measurement conditions for powder X-ray diffraction.

In some embodiments, the dosage form comprises acalabrutinib maleate, wherein the acalabrutinib maleate is characterized by a crystalline form purity that is at least about 80% by weight of acalabrutinib present in the dosage form. In one aspect, the purity of the crystalline form is at least about 85% by weight. In another aspect, the purity of the crystalline form is at least about 90% by weight. In another aspect, the purity of the crystalline form is at least about 95% by weight. In another aspect, the purity of the crystalline form is at least about 98% by weight. In another aspect, the purity of the crystalline form is at least about 99% by weight. In another aspect, acalabrutinib maleate is acalabrutinib maleate monohydrate. In another aspect, acalabrutinib maleate is Form A of acalabrutinib maleate monohydrate.

In some embodiments, the dosage form comprises acalabrutinib maleate, wherein the acalabrutinib maleate is characterized by a crystalline form purity that is at least about 95% by weight of acalabrutinib present in the dosage form. In one aspect, acalabrutinib maleate is acalabrutinib maleate monohydrate. In another aspect, acalabrutinib maleate is Form A of acalabrutinib maleate monohydrate. In another aspect, the purity of the crystalline form is at least about 96% by weight.

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In another aspect, the purity of the crystalline form is at least about 97% by weight. In another aspect, the purity of the crystalline form is at least about 98% by weight. In another aspect, the purity of the crystalline form is at least about 99% by weight. In additional aspects, acalabrutinib maleate has a crystalline purity that is at least about 95% by weight of the acalabrutinib present in the dosage form and contains less than about 2% by weight of (2Z)-4-[(2S)-2{8-amino) impurity -1-[4-(2-pyridinylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}-1-pyrrolidinyl]-4-oxo-2butenoic acid, which has the chemical structure shown below:

In another aspect, acalabrutinib maleate contains less than about 1.5% by weight of an impurity. In another aspect, acalabrutinib maleate contains less than about 1% by weight of an impurity. In another aspect, acalabrutinib maleate contains less than about 0.5% by weight of an impurity. In another aspect, acalabrutinib maleate is substantially free of impurities.

Selecting a salt of a compound rather than a free form of the compound does not necessarily improve the solubility and absorption of the compound in the gastrointestinal tract to the desired extent. In addition, salts of a compound may vary significantly in physical and other properties affecting the suitability of the salt for use in a pharmaceutical dosage form. For example, the rapid conversion of salt to the relatively insoluble free form in the acidic environment of the stomach, as well as in the intestinal environment of pH 6 to 7.5, may result in precipitation of some of the free form. This precipitation of the free form results in less of the administered dose being available for absorption in the gastrointestinal tract, resulting in lower overall bioavailability of the compound. Surface properties (eg, affecting wettability) and particle size (eg, affecting dissolution rate) are also among the factors that can influence the characteristics of the salt selected for the dosage form.

For example, the citrate, fumarate, gentisate, napadisylate, nitrate, oxalate, phosphate, sulfate and L-tartrate salts of acalabrutinib were found to be unsuitable for use in the solid pharmaceutical dosage forms of the present invention. Citrate, fumarate, gentisate and L-tartrate salts were excluded from consideration based on their pKa values and/or evidence of complex solid state behavior. For example, the napadisylate salt was characterized by difficulties regarding the crystalline state. The nitrate salt has not been adequately manufactured on the required scale and is generally not recommended for use in pharmaceutical products. Oxalate, phosphate, and sulfate salts exhibited complex hydrate behavior and were considered unsuitable for commercial manufacture.

In fact, it was considered unlikely that the initial acalabrutinib maleate samples studied would achieve the solubility and dissolution rate required to overcome the limitations of acalabrutinib free base in patients with elevated gastric pH. In addition, although crystalline Form A of acalabrutinib maleate monohydrate is thermodynamically stable under ambient conditions, it also exhibits solid-state properties that were initially considered challenging for commercial drug product supply.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms wherein the dissolution rate of acalabrutinib maleate in an in vitro dissolution test conducted using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium, representing 5 mM phosphate with a pH of 6.8, and a paddle stirrer speed of 75 rpm, does not decrease by more than 20% of the initial dissolution rate after storing the dosage form in appropriate packaging for six months at a temperature of 40 ° C and relative humidity 75%. In one aspect, the dissolution rate does not decrease by more than 10% of the initial dissolution rate after storage

- 9 047001 dosage form in appropriate packaging for six months at 40°C and 75% relative humidity. In one aspect, the dissolution rate does not decrease by more than 15% of the initial dissolution rate after storing the dosage form in appropriate packaging for six months at 40°C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 5% of the initial dissolution rate after storing the dosage form in appropriate packaging for six months at 40°C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 3% of the initial dissolution rate after storing the dosage form in appropriate packaging for six months at 40°C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 2% of the initial dissolution rate after storing the dosage form in appropriate packaging for six months at 40°C and 75% relative humidity. In another aspect, the dissolution rate does not decrease by more than 1% of the initial dissolution rate after storing the dosage form in appropriate packaging for six months at 40°C and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the packaging is a sealed HDPE bottle containing a desiccant.

In some embodiments, the present invention provides solid pharmaceutical dosage forms wherein no more than about 5% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at a temperature of 40° C and relative humidity 75%. In another aspect, no more than about 3% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and 75% relative humidity. In another aspect, no more than about 2% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and 75% relative humidity. In another aspect, no more than about 1% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and 75% relative humidity. In another aspect, no more than about 0.5% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and 75% relative humidity. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the packaging is a sealed HDPE bottle containing a desiccant. In another aspect, the degradation of acalabrutinib maleate is analyzed using high performance liquid chromatography.

In some embodiments, the present invention provides solid pharmaceutical dosage forms, wherein the dosage form is substantially bioequivalent to Calquence® 100 mg capsules (the composition of which corresponds to the contents of the reference C4 capsule in Table 6 of Example 4) when administered orally to a fasting human subject who is did not administer a drug that reduces the acidity of gastric juice. In one aspect, the dosage form, when administered orally to a fasted human subject who has not been administered a gastric acid reducer, is characterized by a confidence interval of the relative mean _Cmax , AUC( _0-t ), and AUC _0-/ ) of the dosage form relative to to Calquence® 100 mg capsules for acalabrutinib plasma levels ranging from 80 to 125%. In another aspect, the dosage form, when administered orally to a fasted human subject who has not been administered a gastric acid reducer, has a confidence interval of the relative mean value of _Cmax , AUC( _0-t ), and AUC _0-/ , of the dosage form relative to to Calquence® 100 mg capsules for acalabrutinib and its active metabolite ACP-5862 (i.e. 4-[8-amino-3-[4-(but-2inoylamino)butanoyl]imidazo[1,5-a]pyrazine -1-yl]-N-pyridin-2-ylbenzamide) in blood plasma, which ranges from 80 to 125%.

In some embodiments, the present invention provides solid pharmaceutical dosage forms, wherein the dosage form, when administered twice daily to a population of fasted human subjects, satisfies one or more of the following pharmacokinetic conditions for acalabrutinib:

the average C _max in a population of human subjects is from about 400 ng/ml to about 900 ng/ml;

the average AUC( _0-24 ) in a population of human subjects ranges from approximately 350 ng-h/ml to approximately 1900 ng-h/ml; and/or the average AUC( ₀ . ") value in a population of human subjects is from about 350 ng-h/ml to about 1900 ng-h/ml.

In one aspect, the dosage form is administered to populations of human subjects in conjunction with an agent.

- 10 047001 vom, which reduces the acidity of gastric juice.

In some embodiments, the present invention provides solid pharmaceutical dosage forms, wherein the dosage form, when administered to a human subject twice daily (BID), provides a median steady state Bruton's tyrosine kinase occupancy value of at least about 90% in peripheral mononuclear cells. blood. In one aspect, the dosage form, when administered to a human subject twice daily, provides a median steady state Bruton's tyrosine kinase occupancy of at least about 95% in peripheral blood mononuclear cells. In another aspect, the dosage form is administered to a population of human subjects in conjunction with a gastric acid reducing agent.

In some embodiments, the present invention provides solid pharmaceutical dosage forms wherein acalabrutinib maleate is present in an amount of from about 15% to about 55% by weight (equivalent free base weight) of the dosage form. In one aspect, acalabrutinib maleate is present in an amount of from about 25% to about 50% by weight of the dosage form. In another aspect, acalabrutinib maleate is present in an amount of from about 25% to about 45% by weight of the dosage form. In another aspect, acalabrutinib maleate monohydrate is present in an amount of from about 25% to about 40% by weight of the dosage form.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant, and at least one lubricant. In one aspect, the at least one pharmaceutically acceptable excipient contains at least one diluent. In another aspect, the at least one pharmaceutically acceptable excipient contains at least one disintegrant. In another aspect, the at least one pharmaceutically acceptable excipient contains at least one diluent and at least one disintegrant. In another aspect, the at least one pharmaceutically acceptable excipient contains at least one diluent, at least one disintegrant, and at least one lubricant. The interaction(s) of excipients in the dosage form may potentially influence the suitability of the combinations of excipients in the dosage forms of the present invention. Accordingly, the selected combinations of excipients preferably do not significantly affect the suitability of the dosage form for pharmacological use.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the dosage contains at least one diluent, wherein the at least one diluent is present in an amount of from about 10% to about 70% by weight of the dosage form. In one aspect, the at least one diluent is present in an amount from about 20% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount of from about 30% to about 70% by weight of the dosage form. In another aspect, the at least one diluent is present in an amount of from about 40% to about 70% by weight of the dosage form. In another aspect, the weight ratio of acalabrutinib maleate to at least one diluent is from about 1:3 to about 2:1. In another aspect, the weight ratio of acalabrutinib maleate monohydrate to at least one diluent is from about 1:1 to about 1:2.

If available, the selected diluent(s) preferably do not affect the stability of the primary amine moiety of acalabrutinib. In one aspect, the diluent is not prone to react with the primary amine moiety in the Maillard reaction. For example, the diluent is not a reducing sugar such as lactose. In addition, the diluent(s) preferably do not contain a maleic acid remover, such as a metal salt. In one aspect, the diluent(s) do not contain anhydrous dibasic calcium phosphate. Suitable diluents include, for example, sugar alcohols (such as mannitol, sorbitol, maltitol and xylitol), hydrolyzed starches, partially pregelatinized starches and celluloses (such as microcrystalline cellulose and siliconized microcrystalline cellulose) and combinations thereof (such as a combination containing mannitol and starch ).

In some embodiments, the at least one diluent includes a plastic diluent and a friable diluent. A plastic diluent such as microcrystalline cellulose undergoes permanent deformation once the compressive yield stress is exceeded, causing the particles to undergo viscous flow and remain deformed after the compressive force is removed. A brittle diluent such as mannitol undergoes fragmentation during compression, creating new surfaces for particle binding. In one aspect, the dosage form contains a plastic diluent and a friable diluent in a total amount of from about 10% to about

- 11 047001 = 70% by weight of the dosage form; wherein the plastic diluent is present in an amount from about 0% to about 70% by weight of the dosage form; and the fragile diluent is present in an amount of from about 0% to about 50% by weight of the dosage form. If the dosage form is a tablet, the selected ratio of ductile diluent to friable diluent may influence the tensile strength of the tablet. Excess plastic diluent may weaken the tensile strength of the tablet. In one aspect, the w/w ratio. plastic diluent to friable diluent in dosage form is from about 0:100 to about 60:40. In another aspect, the w/w ratio. plastic diluent to friable diluent in dosage form is from about 0:100 to about 60:40, where the dosage form is a tablet having a tensile strength of at least 2.0 MPa.

In some embodiments, the at least one diluent includes mannitol. In one aspect, mannitol is present in an amount from about 10% to about 70% by weight of the dosage form.

In some embodiments, the at least one diluent comprises microcrystalline cellulose. In one aspect, microcrystalline cellulose is present in an amount of from about 5% to about 50% by weight of the dosage form.

In some embodiments, the at least one diluent includes mannitol and microcrystalline cellulose. In one aspect, mannitol is present in an amount from about 0% to about 70% by weight of the dosage form; wherein microcrystalline cellulose is present in an amount of from about 0% to about 50% by weight of the dosage form; and the total amount of mannitol and microcrystalline cellulose is from about 10% to about 70% by weight of the dosage form. In another aspect, the w/w ratio. mannitol and microcrystalline cellulose is from about 0:100 to about 60:40. In another aspect, the w/w ratio. mannitol and microcrystalline cellulose in dosage form is from about 0:100 to about 60:40, where the dosage form is a tablet having a tensile strength of at least 2.0 MPa.

In some embodiments, the present invention provides solid pharmaceutical dosage forms wherein the dosage contains at least one disintegrant and wherein the at least one disintegrant is present in an amount of from about 0.5% to about 15% by weight of the tablet. In one aspect, the at least one disintegrant is present in an amount of from about 1% to about 10% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount of from about 2% to about 8% by weight of the tablet. In another aspect, the at least one disintegrant is present in an amount of from about 3% to about 7% by weight of the tablet. In another aspect, the weight ratio of acalabrutinib maleate (equivalent weight of free base) to at least one disintegrant is from about 2:1 to about 15:1. In another aspect, the weight ratio of acalabrutinib maleate to at least one disintegrant is from about 4:1 to about 10:1.

If available, the selected disintegrant(s) preferably do not provide an ionic disintegrant. In one aspect, the at least one disintegrant does not include sodium starch glycolate and/or croscarmellose sodium. In one aspect, the at least one leavening agent does not include sodium starch glycolate. In another aspect, the at least one disintegrant does not contain croscarmellose sodium. Suitable disintegrants include, for example, hydroxypropyl cellulose, corn starch, microcrystalline cellulose, crospovidone, and combinations thereof. In one aspect, the at least one disintegrant comprises hydroxypropyl cellulose. In another aspect, the at least one disintegrant comprises low-substituted hydroxypropylcellulose.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, where the dosage contains at least one lubricant, and where the at least one lubricant is present in an amount of from about 0.25% to about 4% by weight of the dosage form. In one aspect, the at least one lubricant is present in an amount of from about 1% to about 4% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount of from about 1.5% to about 3.5% by weight of the dosage form. In another aspect, the at least one lubricant is present in an amount of from about 2% to about 3% by weight of the dosage form. In another aspect, the weight ratio of acalabrutinib maleate (equivalent weight of free base) to at least one lubricant is from about 20:1 to about 12:1. In another aspect, the weight ratio of acalabrutinib maleate to at least one lubricant is from about 18:1 to about 14:1.

Suitable lubricants include, for example, sodium stearyl fumarate, stearic

- 12 047001 acid, myristic acid, palmitic acid, sugar esters (such as sorbitan monostearate and sucrose monopalmitate) and combinations thereof. In another aspect, the at least one lubricant comprises sodium stearyl fumarate. In general, magnesium stearate should be avoided as the lubricant of choice.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the dosage form comprises acalabrutinib maleate in an amount of from about 15% to about 55% by weight (equivalent free base weight) of the dosage form;

at least one diluent in an amount of from about 10% to about 70% by weight of the dosage form;

at least one disintegrant in an amount of from about 0.5% to about 15% by weight of the dosage form and at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

In one aspect, the dosage form consists essentially of the above-described components. In additional aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the dosage form contains:

acalabrutinib maleate monohydrate in an amount of from about 20% to about 50% by weight (equivalent weight of free base) of the dosage form;

at least one diluent in an amount of from about 20% to about 70% by weight of the dosage form;

at least one disintegrant in an amount of from about 1% to about 10% by weight of the dosage form and at least one lubricant in an amount from about 1% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

In one aspect, the dosage form consists essentially of the above-described components. In additional aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

In some embodiments, the present invention provides solid pharmaceutical dosage forms, wherein the dosage form comprises acalabrutinib maleate in an amount of from about 25% to about 50% by weight (equivalent free base weight) of the dosage form;

at least one diluent in an amount of from about 30% to about 70% by weight of the dosage form;

at least one disintegrant in an amount of from about 2% to about 8% by weight of the dosage form and at least one lubricant in an amount from about 1.5% to about 3.5% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

In one aspect, the dosage form consists essentially of the above-described components. In additional aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the dosage form comprises acalabrutinib maleate in an amount of from about 25% to about 40% by weight (equivalent free base weight) of the dosage form;

at least one diluent in an amount of from about 40% to about 70% by weight of the dosage form;

at least one disintegrant in an amount of from about 3% to about 7% by weight of the dosage form and at least one lubricant in an amount from about 2% to about 3% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

In one aspect, the dosage form consists essentially of the above-described components. In additional aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

In some embodiments, the present invention provides solid pharmaceutical dosage forms, wherein the dosage form contains acalabrutinib maleate in an amount of about 30% to about 35% by weight (equivalent weight of free base) of the dosage form and mannitol in an amount of about 30% to about 35 % by weight of the dosage form;

- 13 047001 microcrystalline cellulose in an amount of from about 25% to about 30% by weight of the dosage form;

hydroxypropylcellulose in an amount of from about 3% to about 7% by weight of the dosage form and sodium stearyl fumarate in an amount from about 1% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

In one aspect, the dosage form consists essentially of the above-described components. In additional aspects, acalabrutinib maleate is present as acalabrutinib maleate monohydrate.

In some embodiments, the present invention provides solid pharmaceutical dosage forms wherein the acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 500 μM. In one aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 450 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 400 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 350 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 300 μm. In another aspect, acalabrutinib maleate has a D _(v , ₀ , ₉ ) value of from about 20 μm to about 500 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of from about 50 μm to about 450 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of from about 75 μm to about 400 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of from about 75 μm to about 350 μm. In another aspect, acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of from about 100 μm to about 300 μm.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the acalabrutinib maleate satisfies one or more of the following conditions: a D( _v , _0.1 ) value is less than about 20 μm, a D( _v , _0.5 ) value is _less than about 145 μm, and the value of D( _v , ₀ , ₉ ) is less than about 330 μm. In another aspect _, acalabrutinib maleate has a D( _v , _0.5 ) value of less than about ₁₄₅ μm and a D( _v , _0.9 ) value of less than about 330 μm. In another aspect, acalabrutinib maleate has a D( _v , _0.1 ) value of less than about 20 μm, a _D ( _v , _0.5 ) value of less than about 145 μm, and _a D( _v , _0.9 ) value of less than approximately 330 µm.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, where the dosage form is a capsule. In one aspect, the capsule is produced using a method including roller compaction.

In some embodiments, the present invention relates to solid pharmaceutical dosage forms, wherein the dosage form is a tablet. In one aspect, the dosage form is a film-coated tablet. In another aspect, the film casing is a stabilizing film casing. In another aspect, the tablet is prepared using a method including direct compression. In another aspect, the tablet is produced using a method including roller compaction. In another aspect, the tablet is prepared using a method including wet granulation. In another aspect, the tablet has a tensile strength of from about 1.5 MPa to about 5.0 MPa. In another aspect, the tablet has a tensile strength of from about 2.0 MPa to about 4.0 MPa. In another aspect, the tensile strength of the tablet does not decrease by more than 10% compared to the original tensile strength after storing the tablet in suitable packaging for six months at a temperature of 40°C and a relative humidity of 75%. In another aspect, the tensile strength of the tablet does not decrease by more than 8% compared to the original tensile strength after storing the tablet in suitable packaging for six months at a temperature of 40°C and a relative humidity of 75%. In another aspect, the tensile strength of the tablet does not decrease by more than 5% compared to the original tensile strength after storing the tablet in suitable packaging for six months at a temperature of 40°C and a relative humidity of 75%. In one aspect, the package is a blister package, such as an aluminum blister. In another aspect, the packaging is a sealed HDPE bottle containing a desiccant.

In some embodiments, the tablet is a coated or uncoated tablet having a core weight of less than about 600 mg. In another aspect, the dosage form is a tablet, coated or uncoated, having a core weight of from about 300 mg to about 500 mg. In another aspect, the dosage form is a tablet, coated or uncoated, having a core weight of from about 350 mg to about 450 mg. In another aspect, the dosage form is a tablet, coated or uncoated, having a core weight of approximately 400 mg.

- 14 047001

III. Methods of treatment.

The present invention also provides methods for treating a BTK-mediated condition in a subject, in particular a human subject suffering from or susceptible to the condition, comprising administering to the subject once or twice daily a solid pharmaceutical dosage form containing acalabrutinib maleate, as described in any of the embodiments of the present invention. In one aspect, a solid pharmaceutical dosage form containing acalabrutinib maleate is administered once daily. In another aspect, a solid pharmaceutical dosage form containing acalabrutinib maleate is administered twice daily.

In one embodiment, the present invention relates to methods of treating a Bcellular hematologic malignancy in a subject, particularly a human subject, suffering from or predisposed to the disease, comprising administering to the subject once or twice daily a solid pharmaceutical dosage form containing acalabrutinib maleate, as described in any of the embodiments of the present invention. In one aspect, a solid pharmaceutical dosage form containing acalabrutinib maleate is administered once daily. In another aspect, a solid pharmaceutical dosage form containing acalabrutinib maleate is administered twice daily.

In some embodiments, the B-cell hematologic malignancy is selected from the group consisting of non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small cell lymphocytic leukemia (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), B-cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenström macroglobulinemia (WM), multiple myeloma, myelodysplastic syndromes and myelofibrosis.

In some embodiments, the B-cell hematologic malignancy is non-Hodgkin's lymphoma. In one aspect, the non-Hodgkin's lymphoma is an aggressive non-Hodgkin's lymphoma. In another aspect, the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma.

In some embodiments, the B cell hematologic malignancy is Hodgkin lymphoma.

In some embodiments, the B-cell hematologic malignancy is selected from the group consisting of mantle cell lymphoma, chronic lymphocytic leukemia, and small cell lymphocytic leukemia.

In some embodiments, the B cell hematologic malignancy is mantle cell lymphoma. In one aspect, mantle cell lymphoma is mantle cell lymphoma. In another aspect, mantle cell lymphoma is mantle cell lymphoma with lymph node involvement. In another aspect, mantle cell lymphoma is diffuse mantle cell lymphoma. In another aspect, the mantle cell lymphoma is a blastoid mantle cell lymphoma.

In some embodiments, the B cell hematologic malignancy is a chronic lymphocytic leukemia.

In some embodiments, the B cell hematologic malignancy is a small cell lymphocytic leukemia.

In some embodiments, the B-cell hematologic malignancy is a diffuse large B-cell lymphoma. In one aspect, the diffuse large B cell lymphoma is selected from the group consisting of primary diffuse large B cell lymphoma, relapsed/refractory diffuse large B cell lymphoma, and transformed diffuse large B cell lymphoma. In another aspect, the diffuse large B cell lymphoma is a primary diffuse large B cell lymphoma. In another aspect, diffuse large B cell lymphoma is relapsed/refractory diffuse large B cell lymphoma. In another aspect, the diffuse large B cell lymphoma is a transformed diffuse large B cell lymphoma. In another aspect, transformed diffuse large B cell lymphoma is Richter's syndrome.

In some embodiments, the diffuse large B cell lymphoma is selected from the group consisting of the subtypes consisting of diffuse large B cell germinal center B cell lymphoma and diffuse large B cell lymphoma of activated B cells. In one aspect, the diffuse large B cell lymphoma is a relapsed/refractory diffuse large B cell lymphoma of germinal center B cells. In another aspect, diffuse large B cell lymphoma is relapsed/refractory diffuse large B cell lymphoma of activated B cells.

In some embodiments, the B cell hematologic malignancy is a follicular lymphoma.

In some embodiments, the B cell hematologic malignancy

- 15 047001 name is Waldenström's macroglobulinemia.

In some embodiments, the B cell hematologic malignancy is B cell acute lymphoblastic leukemia. In one aspect, B cell acute lymphoblastic leukemia is an early pre-B cell acute lymphoblastic leukemia. In another aspect, B cell acute lymphoblastic leukemia is a pre-B cell acute lymphoblastic leukemia. In another aspect, B cell acute lymphoblastic leukemia is an acute lymphoblastic leukemia of mature B cells.

In some embodiments, the B-cell hematologic malignancy is Burkitt's lymphoma. In one aspect, Burkitt's lymphoma is sporadic Burkitt's lymphoma. In another aspect, Burkitt's lymphoma is endemic Burkitt's lymphoma. In another aspect, Burkitt's lymphoma is human immunodeficiency virus-associated Burkitt's lymphoma.

Diagnosis of the specific B cell malignancy that the subject is suffering from can be performed in accordance with standard clinical practice. See, for example, the 2016 World Health Organization (WHO) classification guideline for lymphoid neoplasms or the National Comprehensive Cancer Network (NCCN) classification guideline for non-Hodgkin's lymphoma.

In some embodiments, the human subject has previously received at least one prior chemoimmunotherapy for the treatment of a B cell malignancy. In one aspect, prior chemoimmunotherapy comprises treatment with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). In another aspect, prior chemoimmunotherapy includes treatment with fludarabine, cyclophosphamide and rituximab (FCR). In another aspect, prior chemoimmunotherapy includes treatment with rituximab and bendamustine (BR). In another aspect, prior chemoimmunotherapy includes treatment with chlorambucil and obinutuzumab.

In some embodiments, the human subject has previously received treatment with a BTK inhibitor other than acalabrutinib (eg, ibrutinib or zanubrutinib).

In another embodiment, the present invention relates to the use of solid pharmaceutical dosage forms containing acalabrutinib maleate, as described in any of the embodiments of the present invention, for the treatment of B cell malignancies.

In another embodiment, the present invention relates to the use of solid pharmaceutical dosage forms containing acalabrutinib maleate, as described in any of the embodiments of the present invention, in the manufacture of medicaments for the treatment of Cellular Malignancies.

In some embodiments, a solid pharmaceutical dosage form containing acalabrutinib maleate is administered to a subject along with a gastric acid reducer such as a proton pump inhibitor, an H2 receptor antagonist, or an antacid. In one aspect, co-administration is simultaneous. In another aspect, co-administration is sequential.

In some embodiments, the present invention provides methods for improving the pharmacokinetics of orally administered acalabrutinib over a wider range of gastric acid conditions in a subject with or predisposed to a B-cell hematologic malignancy, comprising administering the subject once (QD) or twice (BID) ) per day of a solid pharmaceutical dosage form containing acalabrutinib maleate, as described in any of the embodiments of the present invention. In one aspect, the method improves and/or reduces the variability of acalabrutinib bioavailability values within the same or different subjects. In another aspect, the method reduces variability in the pharmacokinetic parameters of acalabrutinib within the same or different subjects. In another aspect, the method provides improvement and/or reduction in the variability of acalabrutinib _Cmax values within the same or different subjects. In another aspect, the method improves and/or reduces the variability of acalabrutinib _Tmax values within the same or different subjects. In another embodiment, the method provides improvement and/or reduction in the variability of _HJ-/ acalabrutinib AUC values in the same or different subjects.

In some embodiments, the present invention provides methods for treating a human subject who is infected with SARS-CoV-2 and/or who has coronavirus disease 2019 (COVID-19), comprising administering to the subject a solid pharmaceutical dosage form(s) containing ) acalabrutinib maleate, as described in any of the embodiments of the present invention.

In another embodiment, the present invention relates to the use of solid pharmaceutical dosage forms containing acalabrutinib maleate, as described in any of the variants

- 16 047001 implementation ants, in a human subject who is infected with SARS-CoV-2 and/or who has coronavirus disease 2019 (COVID-19).

In another embodiment, the present invention relates to the use of solid pharmaceutical dosage forms containing acalabrutinib maleate, as described in any of the embodiments of the present invention, in the manufacture of medicinal products for the treatment of a human subject who is infected with SARS-CoV-2 and/or who has have coronavirus disease 2019 (COVID-19).

The methods of the present invention also provide treatment options including co-administration of a solid pharmaceutical dosage form containing acalabrutinib maleate, as described in any of the embodiments of the present invention, with one or more additional therapeutic agents. Accordingly, the dosage forms of the present invention can be administered alone or in combination with one or more additional therapeutic agents. When administered in combination with one or more additional therapeutic agents, the additional therapeutic agent can be administered simultaneously with an acalabrutinib maleate dosage form of the present invention or sequentially with an acalabrutinib maleate dosage form of the present invention. In one aspect, the therapeutic agent is an anti-CD20 antibody. In another aspect, the anti-CD20 antibody is selected from the group consisting of rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab and ublituximab. In another aspect, the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, and ofatumumab. In another aspect, the anti-CD20 antibody is rituximab. In another aspect, the anti-CD20 antibody is obinutuzumab. In another aspect, the anti-CD20 antibody is ofatumumab.

IV. Sets.

The present invention also relates in part to kits containing one or more solid pharmaceutical dosage forms containing acalabrutinib maleate, as described in any of the embodiments of the present invention. The kits may optionally contain one or more additional therapeutic agents and/or instructions for use of the kit. Suitable packaging and accessories for use are known in the art and may be included in the kit. The kits may be provided, sold and/or advertised to health care professionals, including doctors, nurses, pharmacists, pharmaceutical officials, and the like.

In some embodiments, the kit contains a semi-permeable container containing one or more solid pharmaceutical dosage forms containing acalabrutinib maleate. In one aspect, the semi-permeable container is a blister pack.

In some embodiments, the kit contains a substantially impermeable container containing one or more solid pharmaceutical dosage forms containing acalabrutinib maleate. In one aspect, the impervious container is an HDPE bottle with a desiccant.

In some embodiments, the kit contains multiple individual packages, each of which contains a daily dose of solid pharmaceutical dosage forms containing acalabrutinib maleate (eg, a package containing one or two solid dosage forms).

The kits described above are preferably intended for the treatment of B-cell malignancies described herein. For example, in one aspect, the B cell malignancy is non-Hodgkin's lymphoma. In another aspect, the B-cell malignancy is mantle cell lymphoma. In another aspect, the B cell malignancy is a chronic lymphocytic leukemia. In another aspect, the B cell malignancy is a small cell lymphocytic leukemia. In another aspect, the B cell malignancy is a diffuse large B cell lymphoma.

In another embodiment, the kits described above are for use in treating a human subject who is infected with SARS-CoV-2 and/or who has coronavirus disease 2019 (COVID-19).

V. Methods of obtaining.

The present invention also relates to methods for preparing solid pharmaceutical dosage forms containing acalabrutinib maleate described in the present invention, including the methods described in the examples below. Typically, such dosage forms can be prepared using technologies such as, but not limited to, direct mixing, dry granulation (roller compaction), wet granulation (high shear granulation), grinding or sieving, drying (if wet granulation is used), pressing and optionally coating.

VI. A product characterized by the method of its preparation.

The present invention also relates to solid pharmaceutical dosage forms, with

- 17 047001 containing acalabrutinib maleate, obtained in accordance with any of the methods described in the present invention, including the methods described in the examples below.

VII. Examples.

Example 1: Evaluation of acalabrutinib salts.

1. Dissolution study.

The phosphate, oxalate and maleate salts of acalabrutinib were assessed using a two-step in vitro dissolution method known as the pH-shift method. The starting medium was either deionized water or artificial gastric juice containing hydrochloric acid and sodium chloride, and with the pH adjusted to 1.8. After the salts had been in the original medium for 30 min, the medium was then replaced with FaSSIF-V2 medium by adding double strength concentrate to obtain a final pH of 6.5. FaSSIF-V2 medium contained sodium phosphate buffer with sodium chloride, sodium taurocholate and lecithin. Dissolution testing was performed using a USP 2 dissolution tester (with paddle stirrer) operating at 50 rpm at 37 ± 0.5°C, in 250 ml of medium for the first 30 min, and then in 500 ml of medium after shift Dissolution media samples were taken from the aqueous phase at predetermined time points and analyzed by HPLC. In fig. Figures 2 and 3 show the dissolution profiles of the three salts in artificial gastric juice/FaSSIF-V2 medium and deionized water/FaSSIF-V2 medium, respectively. Although the three salts showed generally similar characteristics in low pH artificial gastric juice, the maleate salt showed significantly lower solubility in neutral aqueous media compared to the oxalate and phosphate salts.

2. Study of physical properties.

The physical properties of the phosphate, oxalate and maleate salts of acalabrutinib, including physical stability, crystallinity and particle habit, were studied.

Solid state analysis of the phosphate salt showed a complex behavior of hydrates under environmental conditions, with the solid switching between hydrated forms with one crystalline form converting to a crystalline form with a higher hydrate content at relative humidity (RH) above 20% RH, o as evidenced by the dynamic vapor sorption (DVS) graph in FIG. 4. Thermogravimetric analysis (TGA) showed that the higher hydrate was physically unstable, rapidly dehydrating in less than 10 minutes under isothermal open pan conditions at 40°C, as seen in FIG. 5. The standard TGA further showed that batches of phosphate salts were often heterogeneous in terms of water content and therefore in terms of physical form. X-ray powder diffraction (XRPD) showed that both crystalline forms could be identified, as shown in FIG. 6.

The oxalate salt also exhibited complex hydrate behavior. TGA showed that the hydrate was very labile, as can be seen from FIG. 7. Under isothermal TGA conditions at 35°C, water loss demonstrated a half-life of 4 min and a total weight loss of 3.2% w/w. The loss of water corresponded to approximately one mole of water per mole of oxalate salt. DVS showed conversion of one crystalline form to a higher hydrate content crystalline form at ambient humidity values as seen in FIG. 8. When analyzed by light microscopy for oxalate salt, the habit of very fine needles is shown.

The maleate salt was isolated as a monohydrate. Although isothermal TGA at 50°C showed that the monohydrate dehydrates as shown in FIG. 9A, the dehydration rate was lower than that of phosphate or oxalate salts at lower temperatures of 40 and 35°C, respectively. In fig. 9B shows a TGA plot performed under an alternative set of conditions. DVS plot for maleate salt in FIG. 10A showed that the change in % w/w. water over the entire moisture range was less than that observed for phosphate or oxalate salts. In fig. 10B shows a DVS plot for a higher quality maleate salt sample. The crystal habit of the maleate salt was large and prism-like.

Although the phosphate and oxalate salts showed significantly better dissolution in neutral aqueous media than the maleate salt, the physical properties of the phosphate and oxalate salts presented great challenges in developing a pharmaceutically acceptable formulation containing the acalabrutinib salt.

3. Dissolution of micronized maleate salt.

Due to the formulation difficulties associated with the physical properties of the phosphate and oxalate salts, the maleate salt was retested using the previously described pH shift dissolution method after achieving particle size reduction. Typical mean particle size distributions D( _v , ₀ , ₉ ) for the micronized maleate salt and unmilled maleate salt batches tested were typically about 18 μm and about 446 μm, respectively. Using the same process conditions as described above, a micronized maleate salt sample was tested and demonstrated a dissolution profile that was significantly improved (and to a greater extent than one skilled in the art would expect) compared to an unmilled maleate salt sample. salt. In fig. 11 and 12 show the dissolution profiles of micronized and

- 18 047001 uncomminuted maleate salt in artificial gastric juice/FaSSIF-V2 medium and deionized water/FaSSIF-V2 medium, respectively.

Example 2. Assessment of solubility of acalabrutinib maleate.

The solubility of acalabrutinib maleate was measured in unbuffered medium and was approximately 3 mg/mL at pH 4, with a calculated pHmax of 4.11. Additionally, it was determined that in unbuffered media with an initial pH of above pH 4 to approximately pH 11, acalabrutinib maleate buffers its surface pH to a value in the range of 3.8 to 5 and that the solubility of acalabrutinib maleate in unbuffered media from pH 4 to pH 11 remains at a level of about 3 mg/ml. In contrast, the solubility of acalabrutinib free base in unbuffered media decreases to less than approximately 0.1 mg/mL as the pH approaches pH 6.

In addition, the solubility of acalabrutinib maleate was measured in buffered solutions representative of the media used to dissolve acalabrutinib maleate in tablet form. It was found that the final pH was also influenced by the presence of acalabrutinib maleate and, depending on the buffer used, acalabrutinib maleate was able to become supersaturated compared to the free base at an equivalent final pH or exhibit solubility values close to that of the free base at an equivalent final pH . For example, acalabrutinib maleate in supersaturated acetate buffer at pH 4.5 exhibits a solubility that is significantly greater than that of the free base at pH 4.5. In phosphate buffer, adjustment of phosphate concentration and hence pH provided control of the final pH and final solubility of acalabrutinib maleate, but the values observed under all conditions were close to those of acalabrutinib free base at an equivalent final pH. In fig. 13 depicts solubility versus final pH values for acalabrutinib maleate and acalabrutinib free base in various buffer solutions.

Example 3. Physicochemical properties of acalabrutinib maleate monohydrate.

Some physicochemical properties of acalabrutinib maleate monohydrate were determined, which are presented in table. 2 below.

table 2

PROPERTY MEANING Structure Acalabrutinib maleate monohydrate Molecular mass (g/mol) 465.51 (free base), 599.61 (salt) Physical form Crystalline, salt to base ratio = 1.29. pKa (s) Maleic acid (1.83(A), 6.07(A)) + Free base (3.54(V), 5.77(V) and 12.1(A)) LogP/LogD (with pH) 2.0 Melting point Start at 150°C (thermal decomposition after loss of water) Own solubility 3 mg/ml (at pH 4, salt) 48 µg/ml (at pH 8, free base) Solubility at pH 4 (mg/ml) 3 Own penetrating power (cm/s) 5.4 10' ⁴ Churn Potential In vitro Vmax = 79.6 10' ⁶ μg.s' ¹ , Km = 5. 97 μM Unbound fraction ( _fu ) 2.6% Density (g/ml) (molecular mass/molar volume) 1.359 g/ml (salt) 1.36 g/ml (free base) Diffusivity in water (x1E-9 m ² /s) 0.646 (calculated for free base at 37°C) The ratio of content in blood and blood plasma 0.787

- 19 047001

Example 4: Acalabrutinib maleate in tablet form.

Tablets containing acalabrutinib maleate monohydrate and various excipients were prepared by either direct compression or roller compaction and are further described below. Tablets produced by direct compression were uncoated, while tablets produced by roll compaction were film coated. All tablets obtained contained a unit dose equivalent to approximately 100 mg of acalabrutinib maleate monohydrate.

A. Tablets obtained by direct compression.

Tablets having the compositions indicated in table. 3 and 4 were obtained by direct compression. Before pressing the tablets, all components except the lubricant were mixed, then sifted through a sieve and mixed again. The sifted lubricant was added to the mixture, then the lubricant was distributed throughout the mixture by further mixing. Compression of the tablets was performed using a suitable tablet press and tooling appropriate to the target compression weight of the tablet. In cases where additional lubricant was required for the tablets (ie, when jamming or sticking of the punch was observed), additional lubricant was applied to the outside of the tablet mold.

Table 3 COMPOSITION OF TABLETS OBTAINED BY DIRECT PRESSING Component T1 T2 technical specifications T4 T5 (g/lot (g/batch (g/batch (g/lot (g/batch ) ) ) ) I) EB18- EB18- EB18- EB18- EB18- 254510 396006 396008 432106 431408 Acalabrutinib maleate 10 ^a 14.835 ^b 14.835 ^b 16.125 ^b 16.125 ^b Lactose monohydrate 25.96 Not Not Not Not applicable applicable applicable apply O O O MO Microcrystalline Not 23.4025 17.94 25.4375 19.5 cellulose applicable O Mannitol Not 8.05 20.9875 8.75 22.8125 applicable O Dibasic phosphate Not 7,475 Not 8.125 Not calcium, anhydrous applicable applicable apply O O MO Sodium starch glycolate 1.92 Not Not Not Not applicable applicable applicable apply O O O MO Hydroxypropyl cellulo Not 2.875 2.875 3.125 3.125 for with low degree applicable substitution O Magnesium stearate 0.57 0.8625 0.8625 Not Not applicable apply O MO G liceryl dibehenate Not Not Not 0.9375 0.9375 applicable applicable applicable O O O ^a Micronized acalabrutinib maleate. ^b Acalabrutinib maleate particle size, D V, 0.9) « 70 µm.

- 20 047001

Table 4

COMPOSITION OF TABLETS OBTAINED BY DIRECT COMPRESSION Component TB (g/batch) EB18432407 T7 (g/party) EB19021246 T8 (g/batch) EB18431421 T9 (g/batch) EB19033106 T10 (g/batch) EB19033107 tn (g/party) EB19- 033101 T12 (g/batch) EB19033108 T13 (g/batch) EB19033109 T14 (g/batch) EB19033110 T15 (g/batch) EB19021245 Acalabrutinib maleate 16.125 ^a 12.9 ^a 16.125 ^a 21.5 ^a 15.48 ^b 7.74 ^e 21.5 ^b 15.48“ 21.5" 12.9 ^a Microcrystalline I'm pulp 24.5 19.6 18,563 AND 17.82 8.91 AND 17.82 AND 14.9 Mannitol 8.75 7 22.8125 13.5 21.9 10.95 13.5 21.9 13.5 18.3 DPCA 8.125 6.5 Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable Hydroxypropylcellulose with low degree of substitution 3.125 2.5 3.125 2.5 3 1.5 2.5 3 2.5 2.5 Sodium stearyl fumarate 1.875 1.5 1.875 1.5 1.8 0.9 1.5 1.8 1.5 1.5

^a Particle size of acalabrutinib maleate, D( _v , 0.9) « 70 µm.

^b Particle size of acalabrutinib maleate, D( _v , 0.9) « 150 µm.

^c Particle size of acalabrutinib maleate, D( _v , 0.9) « 16 µm.

^d Particle size of acalabrutinib maleate, D( _v , 0.9) « 500 µm.

B. Tablets obtained by roller compaction.

Tablets having the compositions indicated in table. 5 was obtained by roller compaction. All components, except the lubricant, were mixed. The intragranular portion of the lubricant was sieved and then added to the mixture, then the lubricant was distributed throughout the mixture by further mixing. The mixture with the lubricant distributed in it was subjected to compaction with rollers to form belts, which were then crushed into granules. The extragranular portion of the lubricant was sieved and then added to the granules, then distributing the lubricant into the granules by further mixing. The tablet cores were compressed to a target compression weight of 400 mg and a force of 14 kN using a compression tool to produce oval shaped tablets measuring 13 x 7.5 mm. The resulting tablet cores were film-coated, and the weight gain due to the coating suspension was 3-4%.

- 21 047001

Table 5

COMPOSITION OF FILM COATED TABLETS, OBTAINED USING ROLLER COMPACTION Component T16 (kg/lot) TAAV T17 (kg/lot) TAAS T18 (kg/lot) TAAD T19 (kg/lot) EB19144101 T20 (g/batch) EB19079701 Acalabrutinib maleate 12.9 ^a 12.9 ^b 12.9 ^e 1000 ^d 241.9 ^e Microcrystalline cellulose 10.9 10.9 10.9 845 202.5 Mannitol 13.2 13.2 13.2 1023.3 245.6 Hydroxypropylcellulose with low degree of substitution 2 2 2 155 37.5 Sodium stearyl fumarate (intragranular part) 0.2 0.2 0.2 15.5 3.8 Sodium stearyl fumarate (extragranular part) 0.8 0.8 0.8 58 18.8 Film casing (% weight gain) 3.4 3.7 3.7 4.0 Not applicable

^a Particle size of acalabrutinib maleate, D ₍ v, _0.9 ) ~ 260 µm.

^b Particle size of acalabrutinib maleate, D ₍ v, ₀ , ₉ ) « 98 µm.

^c Particle size of acalabrutinib maleate, D ₍ v, ₀ , ₉ ) « 270 µm.

^d Particle size of acalabrutinib maleate, 50:50 mixture D ₍ v, ₀₉ ) 70 µm and D ₍ v, ₀₉₎ 150 µm.

^e Particle size of acalabrutinib maleate, D ₍ v, ₀₉ ) « 70 µm.

C. Capsules obtained by roller compaction.

In addition to the tablets described above, reference capsules containing acalabrutinib free base and having the compositions indicated in Table 1 were prepared. 6 and were used in the next few examples. All components, except the lubricant, were mixed, then sifted through a sieve and mixed again. The sifted lubricant was added to the mixture, then the lubricant was distributed throughout the mixture by further mixing. The mixture with the lubricant distributed therein was fed into a roller press and the resulting tape was then crushed to produce granules suitable for encapsulation. The sieved extragranular lubricant was mixed with acalabrutinib granules, which, after distributing the lubricant therein, were encapsulated into size 1 hard gelatin capsules to a target fill weight of 240 mg (ie, 100 mg acalabrutinib free base).

- 22 047001

Table 6

COMPOSITION OF CAPSULES OBTAINED BY ROLLER COMPACTION Component C1 (kg/batch) W025985 C2 (kg/batch) W026394 SZ (kg/lot) WO27180 C4 (kg/lot) L0505009 Acalabrutinib 10.951 ^a 10.951 ^b 11.130 ^e 11.765“ Silicated microcrystalline cellulose 7.227 7.227 7,324 7.655 Partially pregelatinized starch 7.227 7.227 7,324 7.655 Sodium starch glycolate 0.657 0.657 0.666 0.696 Magnesium stearate (intragranular) 0.109 0.109 0.111 0.116 Magnesium stearate (extragranular) 0.109 0.109 0.111 0.114 Total Capsule Filling Weight in Size 1 Blue-Yellow Gelatin Capsules 240 mg 240 mg 240 mg 240 mg

a Particle size of acalabrutinib free base, D( _v , ₀ , ₉ ) ~ 365 μm.

^b Particle size of acalabrutinib free base, D( _v , ₀ , ₉ ) « 392 µm.

^c Particle size of acalabrutinib free base, D( _v , ₀ , ₉ ) « 394 µm.

^d Particle size of acalabrutinib free base, D( _v , ₀ , ₉ ) « 377 µm.

D. Film-coated tablet, T21.

An additional example of a film-coated dosage form (T21) is described in table. 7 below.

- 23 047001

Table 7

ACALABRUTINIB MALEATE, FILM-COATED TABLETS (T21) COMPONENTS % WEIGHT/VE WITH QUANTITY (MG/TABLET) FUNCTION KLAS WITH TABLET CORE Acalabrutinib maleate monohydrate Form A 32.25 129.0* Active substance Mannitol 33.00 132.0 Filler Pearlit ol 200SD Microcrystalline cellulose 27.25 109.0 Filler Avicel PHI 02 Hydroxypropyl cellulo with a low degree of substitution 5.00 20.0 Baking powder LH-31 Sodium stearyl fumarate 0.50 2.0 Intragranular e lubricating substance PRUV SSF Sodium stearyl fumarate 2.00 8.0 Extragranular lubricant Tablet core weight 400.0 SHELL PILLS Aquarius Preferred VRRZ13095 3.5 14.0 Film casing Ashlan d Nominal weight coated tablets shell 414.0

* equivalent weight of 100 mg free base.

Example 5 In vitro dissolution profile assessment.

In vitro dissolution studies were performed to evaluate the dissolution profiles of acalabrutinib maleate formulations under low pH conditions and under elevated pH conditions. The pH conditions were selected to mimic gastric pH conditions when the tablet was administered alone (low pH conditions) or in combination with a proton pump inhibitor or acid reducer (high pH conditions). Details of dissolution studies are provided below.

1. Testing dissolution in 0.1N. HCL at low pH.

In fig. 14 shows the dissolution profiles obtained from the low pH test at extreme dilution conditions for acalabrutinib maleate in the form of tablets T16, T17 and T18 and acalabrutinib free base in the form of capsule C1. Dissolution testing was carried out in 900 ml of dissolution medium containing 0.1 N. hydrochloric acid using a USP 2 dissolution tester (with paddle stirrer) operating at 50 rpm and 37 ± 0.5°C. Dissolution media samples were collected from the aqueous phase at predetermined time points and analyzed by either HPLC or UV/visible spectroscopy. The results show that, under low pH conditions, acalabrutinib maleate in tablet form and acalabrutinib free base in capsule form have similar dissolution profiles.

2. Dissolution testing in 5 mM phosphate pH 6.8 at neutral pH, low ionic strength.

In fig. Figure 15 shows dissolution profiles obtained from a low ionic strength test at neutral pH at extreme dilution conditions for acalabrutinib maleate tablets.

- 24 047001

T16, T17 and T18. Dissolution testing was performed in 900 ml of dissolution medium containing 5 mM sodium phosphate adjusted to pH 6.8 and using a USP 2 dissolution test apparatus (with paddle stirrer) operating at 75 rpm and a temperature of 37 ± 0 .5°C. Dissolution media samples were collected from the aqueous phase at predetermined time points and analyzed by UV/visible spectroscopy. The results indicate that these tablet versions of acalabrutinib maleate, when tested under elevated pH conditions, essentially maintained the dissolution profile exhibited under low pH conditions.

3. Dissolution testing in 50 mM phosphate pH 6.8 at neutral pH, high ionic strength.

In fig. 16 shows the dissolution profiles obtained from a high ionic strength test at neutral pH for acalabrutinib maleate in T13 tablet form and acalabrutinib free base in C2 capsule form. Dissolution testing was carried out in 900 ml of dissolution medium containing 50 mM sodium phosphate adjusted to pH 6.8 and using a USP 2 dissolution test apparatus (with paddle stirrer) operating at 75 rpm and a temperature of 37 ± 0 .5°C. Dissolution media samples were taken from the aqueous phase at predetermined time points and analyzed by HPLC. The results showed an improved dissolution profile under elevated pH conditions for acalabrutinib maleate in tablet form compared to acalabrutinib free base in capsule form.

4. Testing for dissolution in water.

In fig. 17 shows the dissolution profiles obtained in a neutral environment without buffering activity (ie, under conditions similar to those in the proton pump inhibitor-treated stomach) for acalabrutinib maleate in tablet form T1 and acalabrutinib free base in capsule form C1. Dissolution testing was performed in 300 mL of dissolution medium containing deionized water and using a USP 2 dissolution test apparatus (with paddle stirrer) operating at 50 rpm and 37 ± 0.5°C. Dissolution media samples were taken from the aqueous phase at predetermined time points and analyzed by HPLC.

In fig. 18 shows the dissolution profiles obtained in neutral medium without buffering activity for acalabrutinib maleate in the form of tablet T13 and acalabrutinib free base in the form of capsule C1. Dissolution testing of the T13 tablet was performed in a volume of 900 ml of dissolution medium containing deionized water and using a USP 2 dissolution test device (with paddle stirrer) operating at 75 rpm and a temperature of 37 ± 0.5 °C and compared with reference tablet C1, for which testing was carried out in 300 ml and at 50 rpm. Dissolution media samples were taken from the aqueous phase at predetermined time points and analyzed by HPLC.

The results presented in Fig. 17 and 18 showed an improved dissolution profile under elevated pH conditions for acalabrutinib maleate in tablet form compared to acalabrutinib free base in capsule form.

5. Test with biorelevant medium.

The dissolution of acalabrutinib maleate in T19 tablet form was assessed under gastric conditions associated with the acidic gastric compartment, as well as under gastric conditions associated with combined administration with a proton pump inhibitor or an acid-reducing agent. The initial medium used was either artificial gastric juice containing hydrochloric acid and sodium chloride and with the pH adjusted to 1.8, or a low buffering medium designed to replicate the conditions in the proton pump inhibitor treated stomach (see Segregur D., et al., Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes, J. Pharm. Set, 108(11): 2461-3477 (2019). The PPI buffer was maleate based and contained sodium chloride adjusted to pH 6. After the T19 tablet had been in the original medium for 30 min, the medium was changed to FaSSIF-V2 medium by adding double strength concentrate to obtain a final pH of 6. 5. FaSSIF-V2 medium contained sodium phosphate buffer with sodium chloride, sodium taurocholate and lecithin. Dissolution testing was performed using a USP 2 dissolution tester (with paddle stirrer) operating at 75 rpm at 37 ± 0.5°C in 250 mL for the first 30 min and then in 500 mL after shear. Dissolution media samples were taken from the aqueous phase at predetermined time points and analyzed by HPLC. After shifting the pH to FaSSIF-V2 for both starting media, acalabrutinib (at a dose equivalent to 100 mg free base) did not precipitate or become supersaturated for at least another 90 min, as seen in FIG. 19.

In a separate dissolution test, acalabrutinib maleate in T19 tablet form and acalabrutinib free base in C3 capsule form were evaluated under the same pH shift conditions described above using simulated gastric juice pH 1.8 as the starting medium. In fig. 20 presents results which show that under biorelevant conditions corresponding to those in the fasted stomach, maleate in tablet form has dissolution characteristics in

- 25 047001 in vitro, which are comparable to those for the free base in capsule form.

Overall, the results of in vitro dissolution tests indicate that the dissolution profiles of acalabrutinib maleate tablets obtained when tested under low pH conditions and when tested under elevated pH conditions are substantially comparable, further suggesting that such tablets, when administered alone or at coadministration with a proton pump inhibitor or acid reducer are bioequivalent.

Example 6. Estimation in the TIM-1 model.

The study was conducted using the TNO TIM-1 (TIM-1) system, an important tool in the testing cascade designed to uncover the mechanisms underlying in vitro product performance and demonstrate the clinical relevance of the selected in vitro method. The TIM-1 system has previously been described in detail in the literature. See, for example, Barker, R., et al., Application and validation of an advanced gastrointestinal in vitro model for the evaluation of drug product performance in pharmaceutical development, J. Pharm. Sci., Volume 103, Issue 11, 15, Pages 3704-3712 (September 2014). The TEMI-1 system is a multi-component dynamic system that uses environments, volumes, pH and fluid dynamics relevant to an in vivo system to mimic conditions found in the adult upper gastrointestinal tract. The system also simulates absorption runoff through hollow fiber ultrafiltration. Everything from volumes, media composition, emptying rates, temperature and pH are dynamically controlled by the computer, allowing the determination of various physiological states of subjects, such as fasting, feeding or other more complex disease states.

Specifically, this study was conducted in the TIM-1 system to evaluate the relative performance of acalabrutinib maleate, T19 tablet, and acalabrutinib free base, C2 capsule, evaluated under gastric conditions associated with the acidic gastric compartment, as well as under gastric conditions associated with combined administration with a proton pump inhibitor or acid reducer. The conditions chosen were representative of those in humans with gastric pHs of 2 and 6. Gastric emptying rates were set to fast to represent the most challenging scenario for the formulations in terms of pH shifts. This means that the t1/ ₂ value for the stomach compartment was 15 min, which is typical of the in vivo scenario in a fasting adult. The TIM-1 system was dosed with the study device and the selected protocol was performed for 300 min. The system was then operated automatically and samples from the compartments where absorption occurs were collected and analyzed every 60 min by HPLC.

In fig. 21 demonstrated that the performance of acalabrutinib maleate in tablet form was equivalent to that of acalabrutinib free base in capsule form under low pH conditions (pH 2). It also demonstrated that the performance of acalabrutinib maleate in tablet form was not affected by high pH conditions (pH 6) and did not precipitate during the pH shift that occurred during gastric emptying into the duodenum.

Example 7: Effect of particle size and drug loading on dissolution rate.

A study was conducted to evaluate the effect of drug particle size and drug loading on the in vitro dissolution of acalabrutinib maleate tablets. The tablets evaluated contained acalabrutinib maleate (equivalent to 100 mg free base) with a particle size D( _v , ₀ , ₉ ) (measured by laser diffraction) ranging from 16 to 500 μm and a drug loading of either 26 wt.% or 43 wt. .%. Dissolution testing was performed in 900 mL of 5 mM sodium phosphate buffer using a USP 2 dissolution tester (with paddle stirrer) operating at 75 rpm and 37 ± 0.5°C.

The study evaluated acalabrutinib maleate in the form of T9, T10, T11, T12, T13, T14 and T15 tablets. The drug particle size and drug loading for each tablet variant are summarized in Table 1. 8 below.

- 26 047001

Table 8

Tablet T9 EB19033106 T10 EB19033107 T11 EB19033101 T12 EB19033108 T13 EB19033109 T14 EB19033110 T15 EB19021245 Particle size D(v, 0.9) (µm) 70 150 16 150 500 500 70 Drug load (wt%) 43 26 26 43 26 43 26

In fig. 22 further shows the particle size distribution for acalabrutinib maleate in the form of T10, T11, T13 and T15 tablets. The tablets evaluated for drug loading effects were acalabrutinib maleate tablets T10, T11, T13 and T15 (drug loading 26 wt%) and acalabrutinib maleate tablets T9, T2 and T14 (drug loading 43 wt%). .%) respectively. In fig. 23 and 24 show the results of dissolution testing of acalabrutinib maleate tablets T10, T11, T13 and T15 (26 wt% drug load) and acalabrutinib maleate tablets T9, T12 and T14 (43 wt% drug load), respectively. The dissolution rate of the tablet generally decreased as the particle size of acalabrutinib maleate increased, although this observation was not true for the tablet with the smallest particle size of acalabrutinib (T11). One possible explanation for the different results for T11 tablets is that the dissolution rate, which was high at the initial time points, decreased due to the lack of wettability of the drug. In vitro dissolution rates of acalabrutinib maleate in the form of tablets with particle size distribution values in the D _(V0.9 ) range from 70 to ₅₀₀ μm under the conditions studied were relatively constant as drug loading increased from 26 to 43 wt.%.

Example 8 GastroPlus Modeling and Acalabrutinib Simulation.

A software modeling and simulation study was performed to predict the effects of acalabrutinib in humans following administration of acalabrutinib maleate tablets from Example 7 (ie, T10, T11, T13, and T15). The tablet dissolution rate data obtained in Example 7 was used to obtain a lot-specific particle size distribution (P-PSD) for each tablet variant according to the methodology described by Pepin, et al. (Pepin, X.J.H., et al., Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modeling of drug product dissolution to derive a P-PSD for PBPK model input, Eur. J. Pharm. Biopharm., 142 :421-434 (2019)), and the measured solubility was 2.144 mg/ml. The resulting PPSD values were then used as input to the PBPK model described by Pepin et al. (Pepin, X.J.H., et al. Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices, Eur. J. Pharm. and Biopharm., 142: 435–448 (2019)) to predict human exposure to acalabrutinib for each tablet variant.

The results of the simulation study predicted that all T10, T11, T13 and T15 tablets under acidic gastric conditions with the equivalent of 100 mg free base had mean AUC and _Cmax values that were comparable to the mean AUC and _Cmax values of the reference free base acalabrutinib in the form of a C4 capsule. In table 9 below provides a summary of the estimated mean exposure values for acalabrutinib maleate in tablet form and the relationship between these estimated values and the corresponding values for the reference acalabrutinib free base in capsule form. The exposure factor for the T11 tablet was close to the lower limit of bioequivalence, possibly due to a slower dissolution rate due to wettability issues.

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Table 9

Conditions The consignment Parameter Average value S D Correlation with standard Sour L0505009 Predicted AUC(0t) (ng-h/ml) 700 21 5 1 Free base Sour EB 19- 021245 Predicted AUC(0t) (ng-h/ml) 679 20 1 0.97 D90=70 µm Sour EB 19- 033101 Predicted AUC(0t) (ng-h/ml) 630 17 1 0.9 D90=16 µm Sour EB 19- 033107 Predicted AUC(0t) (ng-h/ml) 675 19 8 0.96 D90=150 µm Sour EB 19- 033109 Predicted AUC(0t) (ng-h/ml) 662 18 9 0.95 D90=500 µm Sour L0505009 Predicted Cmax (ng/ml) 649 29 9 1 Free base Sour EB 19- 021245 Predicted Cmax (ng/ml) 614 27 6 0.95 D90=70 µm Sour EB 19- 033101 Predicted Cmax (ng/ml) 534 22 9 0.82 D90=16 µm Sour EB 19- 033107 Predicted Cmax (ng/ml) 607 27 0 0.93 D90=150 µm Sour EB 19- 033109 Predicted Cmax (ng/ml) 586 25 6 0.9 D90=500 µm

Similar results from the simulation study predicted that all T10, T11, T13 and T15 tablets under neutral to acidic gastric pH conditions at the equivalent of 100 mg free base would have average AUC and Cmax values that were essentially consistent across the pH range , compared to the average AUC and Cmax values for reference acalabrutinib free base C4 capsule over the same pH range. The simulation study supported the conclusion that the effect of acid reducers on acalabrutinib exposure may be significantly reduced compared to that of the reference free base acalabrutinib capsule C4, with acalabrutinib maleate tablet maintaining bioequivalence over a pH range of sour to neutral. In table Table 10 below provides a summary of the estimated mean exposure values for acalabrutinib maleate in tablet form and the relationship between these estimated values and the corresponding values for the reference acalabrutinib free base in capsule form.

- 28 047001

Table 10

D90 (µm) Conditions Parameter Average value S D Relation to acidic conditions 70 EB 19-021245 - Sour Predicted AUC(0t) (ng-h/ml) 679 20 1 70 EB 19-021245 - Neutral Predicted AUC(0t) (ng-h/ml) 655 18 4 0.96 16 EB19-033101 - Sour Predicted AUC(0t) (ng-h/ml) 630 17 1 16 EB19-033101 - Neutral Predicted AUC(0t) (ng-h/ml) 594 15 1 0.94 150 EB19-033107 - Sour Predicted AUC(0t) (ng-h/ml) 675 19 8 150 EB19-033107 - Neutral Predicted AUC(0t) (ng-h/ml) 637 17 2 0.94 500 EB19-033109 - Sour Predicted AUC(0t) (ng-h/ml) 662 18 9 500 EB19-033109 - Neutral Predicted AUC(0t) (ng-h/ml) 611 15 6 0.92 Free base L0505009- Sour Predicted AUC(0t) (ng-h/ml) 700 21 5 Free base L0505009- Neutral Predicted AUC(0t) (ng-h/ml) 259 58 0.37 70 EB 19-021245 - Sour Predicted Cmax (ng/ml) 614 27 6 70 EB 19-021245 - Neutral Predicted Cmax (ng/ml) 571 24 4 0.93 16 EB19-033101 - Predicted Swipe 534 22

- 29 047001

Sour (ng/ml) 9 16 EB19-033101 - Neutral Forecastnr. Cmax (ng/ml) 473 19 4 0.89 150 EB19-033107 - Sour Predicted Cmax (ng/ml) 607 27 0 150 EB19-033107 - Neutral Predicted Cmax (ng/ml) 539 22 0 0.89 500 EB19-033109 - Sour Predicted Cmax (ng/ml) 586 25 6 500 EB19-033109 - Neutral Predicted Cmax (ng/ml) 495 19 3 0.85 Free base L0505009- Sour Predicted Cmax (ng/ml) 649 29 9 Free base L0505009- Neutral Predicted Cmax (ng/ml) 138 38 0.21

Example 9: In vivo study in dogs.

An in vivo study was conducted to evaluate coadministration of acalabrutinib maleate and omeprazole compared with coadministration of acalabrutinib free base and omeprazole in a canine model. In the study, previously dosed Beagle dogs were administered capsules containing 100 mg acalabrutinib free base, with or without pretreatment with 10 mg omeprazole, and _{acalabrutinib AUC (0.24 )} values were measured. In addition, the same dogs, after an appropriate washout period, were administered size 13 capsules containing a binary mixture of acalabrutinib maleate (100 mg equivalent weight) and 200 mg microcrystalline cellulose, both with and without omeprazole pretreatment, and AUC( _{0- 24} ) acalabrutinib. The results of the study are presented in Fig. 25. When acalabrutinib maleate was administered in capsule form (equivalent weight to 100 mg free base) with pretreatment with omeprazole, exposure was maintained comparable to that of acalabrutinib free base in capsule form without pretreatment with omeprazole.

Example 10: Evaluation of excipients and combinations of excipients.

A study was conducted to evaluate the suitability of certain excipients and combinations of excipients in the formulation of acalabrutinib maleate dosage form.

A. Leavening agents.

Binary mixtures of disintegrants and acalabrutinib maleate (1:5 ratio) were prepared and evaluated in in vitro dissolution testing. Binary mixtures and acalabrutinib maleate control were dissolved in 250 mL deionized water using a USP 2 dissolution tester (with paddle stirrer) at 37 ± 0.5°C and 75 rpm. After time point 120 minutes, the paddle speed was increased to 250 rpm, and after 135 minutes, the pH was adjusted to pH 1.8-2 to provide increased solubility to determine if any undissolved material remained. The binary mixtures tested were sodium starch glycolate/acalabrutinib maleate (1:5 ratio), croscarmellose sodium/acalabrutinib maleate (1:5 ratio), and low-substituted hydroxypropylcellulose/acalabrutinib maleate (1:5 ratio).

The results are shown in Fig. 26. Only the acalabrutinib maleate control and the low-substituted hydroxypropylcellulose/acalabrutinib maleate mixture (1:5 ratio) did not show a significant increase in dissolution after increasing paddle speed or adding acid, indicating complete dissolution was achieved. For croscarmellose sodium/acalabrutinib maleate (1:5 ratio) and croscarmellose sodium/acalabrutinib maleate (1:5 ratio) a significant increase in dissolution was demonstrated when acidity was adjusted, demonstrating that complete release may be an issue at higher pH levels and suggests that an excipient/drug interaction may have occurred, possibly caused by conversion

- 30 047001 converting acalabrutinib maleate into a less soluble form, such as the free base.

B. Lubricants.

Binary mixtures of lubricants and acalabrutinib maleate (1:15) were prepared and evaluated in in vitro dissolution tests under the same conditions described above for the disintegrant mixtures. The binary mixtures tested were glyceryl dibehenate/acalabrutinib maleate (1:15), magnesium stearate/acalabrutinib maleate (1:15), and sodium stearyl fumarate/acalabrutinib maleate (1:15).

The results are shown in Fig. 27. Control acalabrutinib maleate, glyceryl dibehenate/acalabrutinib maleate (1:15), and sodium stearyl fumarate/acalabrutinib maleate (1:15) did not show a significant increase in dissolution after increasing paddle speed or adding acid, suggesting achieving complete dissolution. For magnesium stearate/acalabrutinib maleate (1:15), a significant increase in dissolution was observed with increasing paddle speed and adjusting acidity, demonstrating that complete release may be an issue at higher pH levels and suggesting that excipient interaction /drug substance may be caused by the conversion of acalabrutinib maleate to a less soluble form, such as the free base. Additionally, when evaluating binary products resulting from the compaction of magnesium stearate and acalabrutinib maleate, such binary products resulting from compaction showed increased degradation of acalabrutinib compared to acalabrutinib maleate alone.

C. Thinner.

Direct compression tablet cores containing diluent, disintegrant, lubricant and acalabrutinib maleate were prepared and evaluated in in vitro dissolution tests under the same conditions as described above for the disintegrant mixtures. Each tablet core contained either microcrystalline cellulose/mannitol or microcrystalline cellulose/anhydrous dibasic calcium phosphate/mannitol as a diluent. The specific tablet core tested contained: (1) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low-substituted hydroxypropylcellulose, magnesium stearate and acalabrutinib maleate (T2), (2) microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose, magnesium stearate and acalabrutinib maleate (T3), (3) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low-substituted hydroxypropylcellulose, sodium stearyl fumarate and acalabrutinib maleate (T6), (4) microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose, stearyl fumarate sodium and acalabrutinib maleate (T8), (5) microcrystalline cellulose, anhydrous dibasic calcium phosphate, mannitol, low-substituted hydroxypropylcellulose, glyceryl dibehenate and acalabrutinib maleate (T4) or (6) microcrystalline cellulose, mannitol, low-substituted hydroxypropylcellulose, glyceryl dibehenate and acalabrutinib maleate (T5).

The results are shown in Fig. 28 (T2 and T3 tablet cores), FIG. 29 (T6 and T8 tablet cores) and FIG. 30 (T4 and T5 tablet cores). For all mixtures tested, the presence of anhydrous dibasic calcium phosphate resulted in a greater increase in dissolution when acidity was adjusted, suggesting an interaction of anhydrous dibasic calcium phosphate with acalabrutinib maleate. In contrast, no significant increase was observed for mixtures not containing anhydrous dibasic calcium phosphate. Additionally, when evaluating binary products resulting from the compaction of anhydrous dibasic calcium phosphate and acalabrutinib maleate, such binary products resulting from compaction showed increased degradation of acalabrutinib compared to acalabrutinib maleate alone.

Example 11. Evaluation of the stability of acalabrutinib maleate in tablet form.

A. Stability of T19 tablet.

A stability study was conducted to evaluate acalabrutinib maleate tablets (T19) under open storage conditions and in the following three packages:

packaging in bulk: aluminum multilayer foil package, 4-layer, tear-off, 185x280 mm (60 tablets per package);

110 ml HPDE bottle with induction seal and container of 1 g silica gel desiccant (60 tablets per bottle);

110ml HPDE bottle with induction seal and container of 2g silica gel desiccant (60 tablets per bottle).

The storage conditions investigated in the stability study are detailed in Table. 11 below.

- 31 047001

Table 11

CONDITION THE FINAL POINT OF TIME 25°C/60% RH 156 weeks 30°C/75% RH 156 weeks Exposure to light 10 days 40°C/75% RH 26 weeks 30°C/75% RH (opened) 4 weeks 40°C/75% RH (opened) 4 weeks 50°C 13 weeks

As of the 26 week time point, the following data were available.

Description: No changes in the appearance of any of the samples.

Analysis: No trends in the analysis data were observed in any sample tested.

Organic impurities:

for samples that were stored in appropriate packaging (HDPE bottle with desiccant or aluminum bag containing bulk product), the impurity level met the specification limit of 0.7% for specified impurities and no more than 0.2% for unspecified impurities;

storage for four weeks at 40°C and 75% relative humidity resulted in increased levels of 4-{2-[(2S)-1-(2-butinoyl)-2-pyrrolidinyl]-5-carbamidoyl-1H-imidazol- 4-yl}X-(2-pyridinyl)benzamide, the content of which exceeded the specification limit of not more than 0.2%; all other impurities met the specification limits: 0.7% for specified impurities and 0.2% for unspecified impurities.

Enantiomeric purity: All samples met the criteria (>99.6%) of the method at the start time point and the 26 week time point.

Dissolution (0.1N HCl): No trends were observed in any of the samples; all samples met specification (Q = 80% after 20 min).

Dissolution (pH 6.8): No trends were observed in any of the samples; all samples corresponded to Q = 80% after 20 min.

Water content: No trends were observed in any of the samples stored with desiccant or in bulk packaging; All samples stored open showed an increase in water content after 4 weeks, with the largest increase observed in the sample stored at 40°C/75% RH.

Water activity: No trends were observed in the results. Microbiological quality: all results were within specification (Pharm Eur/USP).

Based on the data obtained, it was concluded that an aluminum pouch containing the bulk product was suitable to provide adequate shelf life in bulk and it was concluded that an HDPE bottle containing a desiccant was suitable to provide adequate shelf life for the tested acalabrutinib maleate in in the form of film-coated tablets. B. Additional stability assessments.

A stability study was conducted to evaluate the chemical stability of acalabrutinib maleate in the form of T2 and T3 tablets and the following general observations were made:

the presence of anhydrous dibasic calcium phosphate promoted the formation of 4-{8-amino3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]-pyrazin-1-yl}-N-(2-pyridinyl)-benzamide and RRT 0.05;

the presence of magnesium stearate promoted the formation of 4-{2-[(2S)-1-(2-butinoyl)-2-pyrrolidinyl]-5-carbamidoyl-1H-imidazol-4-yl}-N-(2-pyridinyl)-benzamide and RRT 0.82;

the presence of microcrystalline cellulose promoted the formation of 4-{3-[(2S)-1-acetoacetyl-2-pyrrolidinyl]-8-aminoimidazo[1,5-a]pyrazin-1-yl}-X-(2-pyridinyl)benzamide, RRT 0.82 and RRT 0.05.

A limited stability study was conducted evaluating limited data for acalabrutinib maleate tablets T7 and T15 and the following observations were made:

the main destruction products were 4-{3-[(2S)-1-acetoacetyl-2-πpyrrolidinyl]-8aminoimidazo[1,5-a]pyrazin-1-yl}-X-(2-pyridinyl)benzamide, RRT 0 82, and 4-{2-[(2S)-1-(2-butinoyl)-2pyrrolidinyl]-5-carbamidoyl-III-imidazol-4-yl}-X-(2-pyridinyl)benzamide;

increased levels of 4-{3-[(2S)-1-acetoacetyl-2-pyrrolidinyl]-8-aminoimidazo[1,5-a]pyrazin-1yl}-X-(2-pyridinyl)benzamide and compounds with RRT 0, 82 were higher than those observed for acalabrutinib maleate T2 and T3 tablets;

- 32 047001 moisture appears to be a significant contributor to the formation of the compound with an RRT of 0.82, but can probably be controlled by appropriate packaging.

Example 12. Preparation of acalabrutinib maleate.

A. Conversion of acalabrutinib free base to acalabrutinib maleate

Acalabrutinib (18 kg, 1.0 molar equivalent) in tetrahydrofuran (162 L, 9.0 relative volume) and water (9 L, 0.5 relative volume) was heated to 50°C and filtered. Tetrahydrofuran (9 L, 0.5 relative volume) was used as a line flushing agent. Maleic acid (5 kg, 1.1 molar equivalents) in tetrahydrofuran (68 L, 3.75 relative volumes) was added at 50°C, followed by a line flush with tetrahydrofuran (5 L, 0.25 relative volumes). The mixture was seeded with acalabrutinib maleate (18 mg, 0.001 relative weight), kept for 1 hour at 50°C and then cooled to 20°C over 1 hour and held for 1 hour before circulating the wet mixture through the mill. grinding to achieve the required particle size distribution. The product was then filtered and washed with tetrahydrofuran (36 L, 2.0 relative volume) and then dried under a stream of nitrogen (relative humidity >20%) at 40°C to give acalabrutinib maleate (20.4 kg, 88%) in monohydrate form.

B. Conversion of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide to acalabrutinib maleate

In an alternative method for preparing acalabrutinib maleate, the maleate salt was prepared without intermediate isolation of acalabrutinib free base. To a mixture of 4-{8-amino-3-[(2S)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide (15.0 g, 1 .0 molar equivalent) and triethylamine (13.2 ml, 2.6 molar equivalent) in tetrahydrofuran (80 ml, 5.3 relative volume), add 2-butynic acid (3.3 g, 1.1 molar equivalent) to tetrahydrofuran (15 ml, 1.0 relative volume) (over 1 hour), and after 8 minutes, propylphosphonic anhydride (53% w/w in ethyl acetate) (23.7 g, 1.1 molar equivalent) in tetrahydrofuran (15 ml, 1.0 relative volume). The mixture was stirred until the reaction was complete. The mixture was quenched with water (30 ml, 2.0 relative volume), the aqueous phase was separated and discarded. The remaining organic phase was passed through a filter with the line flushed with tetrahydrofuran (7 ml, 0.5 relative volume). The mixture was then heated to 50°C and treated with maleic acid (8 g, 1.9 molar equivalent) in tetrahydrofuran (59 ml, 3.9 relative volume). The mixture was seeded with acalabrutinib maleate (15 mg, 0.001 relative weight), then cooled to 20°C for 5 hours, filtered and washed three times with ethanol (30 ml, 2.0 relative volume), then with t-butyl methyl ether (58 ml, 3 .9 relative volume), then filter dried for 30 min to obtain acalabrutinib maleate (16 g, 74%) as monohydrate.

Analysis of the product by Method B above showed the presence of an impurity, (27)-4-[(28)-2-{8-amino1-[4-(2-pyridinylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3- yl}-1-pyrrolidinyl]-4-oxo-2-butenoic acid, which was not observed in the product prepared by Method A. This impurity was present in an amount that would potentially require an impurity toxicity specification for regulations

- 33 047001 new registration of acalabrutinib maleate in the form of a tablet, formulated using a medicinal substance obtained by method B.

Example 13. Preparation of acalabrutinib maleate in tablet form.

In fig. 31 is a schematic overview of the process for preparing acalabrutinib maleate in tablet form T21 from Example 4. Specifically, acalabrutinib maleate, mannitol, microcrystalline cellulose and low-substituted hydroxypropylcellulose are added to a suitable diffusion mixer and mixed together. The intragranular portion of sodium stearyl fumarate is added to the powders and mixed before compaction with rollers. By compacting the mixture with a lubricant distributed in it with rollers, tapes are obtained. The belts are then ground into granules by passing the belts through a suitable mill. The granules are mixed with the extragranular portion of sodium stearyl fumarate using a suitable diffusion mixer. The granules with the lubricant distributed therein are compressed into tablet cores using a suitable tablet press. An orange film coating suspension is prepared and applied to tablet cores using a conventional film coating method.

Example 14: Relative bioavailability study.

An open-label, sequential, randomized, phase 1 study of a single dose of acalabrutinib maleate tablets was conducted in healthy subjects to evaluate relative bioavailability, proton pump inhibitor (rabeprazole) effect, meal effect, and particle size effect. The study is divided into two parts of the study. Part 1 of the study is designed to test the relative bioavailability of acalabrutinib maleate in tablet form compared to acalabrutinib free base in capsule form as a preliminary study to inform the design of part 2 of the study. Part 1 of the study is also designed to test the effect of proton pump inhibitor (PPI) and the effect of food intake on exposure to acalabrutinib maleate tablets. Following review of the safety and pharmacokinetic data from Part 1, the study will continue in Part 2 of the study. Part 2 of the study is designed to examine the effect of drug particle size variations on the exposure of acalabrutinib maleate tablets and the relative bioavailability of acalabrutinib maleate tablets versus solution.

The results of the study will provide information on the pharmacokinetic and pharmacodynamic profiles of acalabrutinib maleate tablets to be evaluated.

A. Study design.

Objectives of Part 1 of the Study.

Primary goal.

To evaluate the relative bioavailability of acalabrutinib maleate tablet versus acalabrutinib free base capsule when administered on an empty stomach.

Secondary goals.

To evaluate the pharmacokinetic profile of ACP-5862 acalabrutinib maleate tablet compared with acalabrutinib free base capsule when administered in the fasted state.

To evaluate the effects of the proton pump inhibitor rabeprazole on the pharmacokinetic profiles of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablet.

To evaluate the effect of food intake on the pharmacokinetic parameters of acalabrutinib and its metabolite (ACP-5862) obtained after administration of acalabrutinib maleate tablet.

To evaluate the safety and tolerability of single doses of acalabrutinib maleate tablet in healthy subjects.

To measure the pharmacodynamic parameter of BTK receptor occupancy for acalabrutinib maleate in tablet form and acalabrutinib free base in capsule form in isolated PBMCs.

Research objectives.

Assess differences in exposure by H. pylon breath test status (present or absent).

Collect pH information using SmartPill and use this information as input to the PBPK model to calculate individual in vivo dissolution.

Objectives of Part 2 of the Study.

Primary goal.

To evaluate the effect of drug particle size on the bioavailability of acalabrutinib maleate tablets.

Secondary goals.

To evaluate the effect of drug particle size on the pharmacokinetic profile of ACP5862 acalabrutinib maleate tablets.

To compare the pharmacokinetics of acalabrutinib maleate tablets and acalabrutinib oral solution in healthy subjects.

To evaluate the safety and tolerability of single doses of acalabrutinib maleate tablets.

- 34 047001 with different drug particle size distribution in healthy subjects.

To evaluate the safety, tolerability, taste, and odor of single doses of acalabrutinib oral solution in healthy subjects.

Part 1. Study design.

Part 1 of the study is an open-label, randomized, crossover, three-treatment, four-treatment, single-center study of the relative bioavailability, PPI effect, and meal effect of acalabrutinib maleate in the novel tablet formulation in healthy subjects (men or women without reproductive potential).

Part 1 of the study includes:

screening period with a maximum duration of 28 days;

three treatment periods during which subjects will reside at the center from before dinner on the day before dosing (day -1) until at least 48 hours after dosing and being discharged on the morning of day 3; and a follow-up visit 7 to 10 days later.

There will be a minimum washout period of 7 days between each acalabrutinib administration. Each subject will receive three of the following four treatments over three treatment periods in a fasted or postprandial state. Subjects will be randomized to receive either treatment A or B in treatment periods 1 and 2, followed by treatment C or D in treatment period 3. The 100 mg acalabrutinib maleate tablet (option 1) is characterized by tablet composition T21 (see Example 4, Table 7), in which the medicinal substance is characterized by a particle size D _(v , ₀ , ₉ ) of no more than 218 μm.

Treatment A: 100 mg acalabrutinib free base capsule, administered under fasting conditions (> 10 hours)*.

Treatment B: 100 mg acalabrutinib maleate tablet (option 1), fasted (> 10 hours)*.

Treatment C: 100 mg acalabrutinib maleate in tablet form (option 1), after meals*,**.

Treatment D: rabeprazole 20 mgx1 (fasting) 2 hours before 100 mg acalabrutinib maleate tablet (option 1)* and after pre-administration of rabeprazole 20 mg BID (with food) on days -3, -2 and -1.

*Each subject will be administered the SmartPill with 120 mL of still water, followed immediately by a single oral dose of acalabrutinib maleate in tablet form (Treatment B, C, or D) or acalabrutinib free base in capsule form (Treatment A), administered with 120 mL still water, followed by sampling for PK assessment within 24 hours.

* *Subjects will begin eating a high-fat meal (per FDA) 30 minutes prior to SmartPill/100 mg acalabrutinib maleate tablet administration. Subjects will be required to consume food within 25 minutes; however, SmartPill/IMP should be administered 30 minutes after the start of the meal.

Part 2. Study design.

Part 2 of this study will be an open-label, single-center, randomized, 4-treatment, 4-treatment relative bioavailability crossover study to determine the particle size effect on the PK of a single dose of acalabrutinib maleate tablet in healthy subjects (male or non-fertile female).

Part 2 of the study includes:

screening period with a maximum duration of 28 days;

four treatment periods during which subjects will reside at the center from pre-dinner on the day before dosing (Day -1) until at least 48 hours post-dose and being discharged on the morning of Day 3; and a follow-up visit 7 to 10 days later.

There will be a minimum washout period of at least 3 days between each acalabrutinib administration.

Each subject will receive the following treatments:

treatment A: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach;

Treatment B: 100 mg acalabrutinib maleate in tablet form (option 2), on an empty stomach;

treatment C: 100 mg acalabrutinib maleate in tablet form (option 3), on an empty stomach; Treatment D: 100 mg acalabrutinib solution in the fasted state.

100 mg acalabrutinib maleate tablet (Option 1) contains drug substance having an intermediate particle size, while 100 mg acalabrutinib maleate tablet form (Option 2) contains drug substance having a smaller particle size, and 100 mg acalabrutinib maleate tablet form (option 3) contains a medicinal substance characterized by a large particle size. In particular, 100 mg acalabrutinib maleate in tablet form is characterized by the composition of the T21 tablet (see example 4, table 7), where option 1 contains the drug

- 35 047001 a substance characterized by a particle size D( _v , ₀ , ₉ ) of not more than 218 μm, option 2 contains a medicinal substance characterized by a particle size D( _v , ₀ , ₉ ) of not more than 160 μm, and option 3 contains a medicinal substance , characterized by a particle size D( _v , ₀ , ₉ ) of no more than 319 μm.

Expected duration of the study.

In Part 1, each subject will participate in the study for approximately 7-8 weeks. In Part 2, each subject will participate in the study for approximately 6-7 weeks.

Target population of the study.

Part 1 of the study will include a total of 28 healthy male and female subjects aged 18 to 55 years (inclusive) to ensure a minimum of 24 evaluable subjects. Part 2 of the study will include a total of 24 healthy male and female subjects aged 18 to 55 years (inclusive), to ensure 20 evaluable subjects at the end of the last treatment period.

Outcome assessment endpoints.

Pharmacokinetic endpoints.

Serial venous blood samples will be obtained to determine plasma concentrations of acalabrutinib and its metabolite (ACP-5862). Whenever possible, the pharmacokinetic parameters of acalabrutinib and the metabolite ACP-5862 will be assessed using plasma concentrations.

Parts 1 and 2:

primary PK parameters: _Cmax , AUC _last , AUCinf of acalabrutinib;

secondary PK parameters: C _max , AUC _last , AUCinf ACP-5862; acalabrutinib and ACP-5862: AUC _0-12 , AUClast, AUCmf, %AUCextrap, Cmax, t1/2, tmax, Kel, F _re i, CL/F (initial only), Vz/F (initial only), ACP ratio -5862 (metabolite) and acalabrutinib (original) (M/P) for C _max , AUC _last , AUC _in f.

If necessary, additional PK parameters can be defined. Safety and tolerability endpoints.

Variables to assess safety and tolerability will include:

adverse events/serious adverse events;

laboratory tests (hematology, clinical biochemistry, coagulation and urinalysis);

physical examination;

electrocardiogram (ECG in 12 leads);

vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature);

assessment of taste and smell (part 2 only).

Exploratory endpoints (part 1).

Acalabrutinib and ACP-5862: Repeated measures analysis of covariance (ANCOVA) will be used to analyze PK parameters (AUC _last , AUC _inf and C _max ) and to evaluate differences in exposure according to pH and gastric emptying rate using an appropriate statistical procedure.

Profiles of temperature, pH and pressure throughout the gastrointestinal tract; Gastric pH immediately (first point measured) following dosing of acalabrutinib-based products (Part 1 only).

Breath test status for H.pylorl.

Statistical methods part 1.

To assess the relative bioavailability of acalabrutinib maleate tablet versus acalabrutinib free base in the capsule form in the fasted state, the key PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared in Treatment B (acalabrutinib) versus A (acalabrutinib free base). in capsule form). Analyzes will be performed using a linear mixed-effects ANOVA model using the natural logarithm of C _max , AUC _last , AUC _inf as the response variables, sequence, period, treatment as a fixed effect, and volunteer entered into sequence as a random effect. After inverse transformation from the logarithmic scale, geometric means along with CI (2-sided 95%) for AUCinf·, AUC _last and _Cmax will be estimated and presented. Geometric mean ratios along with CI (2-sided 90%) will also be estimated and presented.

To evaluate the effects of the proton pump inhibitor rabeprazole on acalabrutinib and its metabolite (ACP-5862), PK profiles obtained after administration of acalabrutinib maleate tablet, the main PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared during treatment D (rabeprazole) compared with those in treatment B (acalabrutinib), from the same analysis of variance (ANOVA) model.

To evaluate the effect of food intake on acalabrutinib and its metabolite (ACP-5862), PK profiles obtained after administration of acalabrutinib maleate tablets, the main PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared during treatment D (rabeprazole) according to compared with B (acalabrutinib), from the same ANOVA model.

Statistical methods part 2.

- 36 047001

To evaluate the effect of drug particle size on the bioavailability of acalabrutinib maleate tablets, the key PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared for treatment B (less than target) versus A (target), C (more than target) compared to A (target value) and C (greater than target value) versus B (less than target value), and analyzes will be performed using a linear mixed effects analysis of variance model using the natural logarithm of Cmax, AUC _inf and AUC _last as the variables response, sequence, period, treatment as a fixed effect, and volunteer entered into sequence as a random effect. After inverse transformation from the logarithmic scale, geometric means along with CI (2-sided 95%) for AUC _inf , AUC _last and C _max will be estimated and presented. Geometric mean ratios along with CI (2-sided 90%) will also be estimated and presented.

To compare the PK of acalabrutinib maleate tablets and acalabrutinib oral solution, key PK parameters of acalabrutinib and its metabolite, ACP-5862, will be compared between treatments D (solution) and A (target) from the same ANOVA model.

Statistical methods part 1 and part 2.

In addition, the 90% CI for the difference in median tmax will be calculated and presented using the same comparisons from the ANOVA. Median differences and 90% confidence intervals will be tabulated for each comparison and analyte.

The results are expected to demonstrate that coadministration of PPI or other acid reducers with acalabrutinib maleate tablets does not alter the exposure of acalabrutinib and ACP-5862.

B. Research results.

Pharmacokinetic parameters.

Results from Part 1 showed that acalabrutinib maleate tablet (Option 1) and acalabrutinib capsule had similar bioavailability.

The mean pharmacokinetic exposure parameters ( _Cmax and AUC) of acalabrutinib and the ACP-5862 metabolite were similar following oral administration of acalabrutinib maleate tablet (Option 1) compared with acalabrutinib capsule in the fasted state. Relative bioavailability was approximately 91% and 98% for acalabrutinib _Cmax and AUC, respectively, and approximately 100% and 103-104% for ACP-5862 _Cmax and AUC, respectively.

Co-administration of PPI (rabeprazole) with acalabrutinib maleate in tablet form (option 1) did not have a clear effect on the pharmacokinetic parameters of acalabrutinib and the ACP-5862 metabolite. Cmax was slightly lower (geometric mean difference ~24%) and AUCs were slightly higher (geometric mean difference ~14-17%) for acalabrutinib. The Cmax of ACP-5862 was approximately 30% lower, with comparable AUCs in the presence and absence of PPI.

For acalabrutinib maleate tablet (Option 1), food intake reduced acalabrutinib and ACP-5862 Cmax by approximately 54% and 36%, respectively, but had no effect on overall AUC values.

Because there was no difference in BTK occupancy across treatments, and inter-subject variability (geometric CV%) of acalabrutinib and ACP-5862 Cmax values was up to approximately 81%, the observed differences in Cmax values are unlikely to have a clinically significant impact.

Summary data on pharmacokinetic parameters of blood plasma from part 1 of the study are presented in table. 12-16 below.

- 37 047001

Table 12

Part 1. Summary of pharmacokinetic parameters. in plasma for acalabrutinib

Parameter (unit) Statistical indicators A (N=30) B (N=29) C (N=14) D (N=14) Stach (ng/ml) Geometric mean Geometric CV% 541.6 41.06 504.9 49.88 255.6 46.52 371.9 81.44 AUCinf (h ng/ml) Geometric mean Geometric CV% 569.9 25.55 559.5 34.63 528.7 18.20 694.1 39.74 AUClast (h ng/ml) Geometric mean Geometric CV% 565.7 25.41 556.2 34.73 525.7 18.34 669.7 40.54 tmax (h) Median value Min, Max 0.75 0.48, 2.02 0.73 0.25, 1.53 2.00 0.25, 4.00 ι,οι 0.23, 3.00 ΐ1/2λζ (h) Average value SD 1.954 2,031 1.515 0.6280 1,347 0.3991 2,863 2,313 CL/F (l/h) Average value SD 180.9 46.45 188.7 64.41 192.0 34.22 154.4 61.75 Vz/F (l) Average value SD 469.3 332.5 386.8 135.9 373.9 134.8 583.6 456.9

A: 100 mg acalabrutinib in capsule form, on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

C: 100 mg acalabrutinib maleate in tablet form (option 1), after meals.

D: 20 mg rabeprazole QD (fasting) 2 hours before administration of 100 mg acalabrutinib maleate tablet (option 1) and after preadministration of 20 mg rabeprazole BID (with food) on days -3, -2 and -1.

BID - twice a day; CV - coefficient of variation; Max - maximum; Min - minimum;

M is the number of subjects in the sample for PK analysis; QD - once a day; SD - standard deviation.

- 38 047001

Table 13

Part 1. Summary of pharmacokinetic parameters in blood plasma for the metabolite ACP-5862

Parameter (unit) Statistical indicators A (N=30) B (N=29) C (N=14) D (N=14) Stach (ng/ml) Geometric mean Geometric CV% 533.7 37.21 538.5 42.19 358.4 33.19 365.3 56.45 AUCinf (h ng/ml) Geometric mean Geometric CV% 1625 24.14 1672 24.84 1644 17.13 1783 28.71 AUClast (h ng/ml) Geometric mean Geometric CV% 1534 24.58 1575 25.87 1532 17.36 1656 29.58 tmax (h) Median value Min, Max 1.00 0.73, 3.00 0.80 0.50, 2.98 2.98 0.98, 4.02 1.75 0.52, 6.00 ΐ1/2λζ (h) Average value SD 7,824 1.558 8,152 1,287 7,945 1.439 7,848 1,579 M:P [AUC] Geometric mean Geometric CV% 2,756 21.06 2,890 25.32 3,007 17.89 2,484 22.32 M:R [Stah] Geometric mean Geometric CV% 0.9526 27.67 1.031 32.12 1.356 30.17 0.9496 37.94

A: 100 mg acalabrutinib in capsule form, on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

C: 100 mg acalabrutinib maleate in tablet form (option 1), after meals.

D: 20 mg rabeprazole QD (fasting) 2 hours before administration of 100 mg acalabrutinib maleate tablet (option 1) and after preadministration of 20 mg rabeprazole BID (with food) on days -3, -2 and -1.

BID - twice a day; CV - coefficient of variation; Max - maximum; Min - minimum;

M is the number of subjects in the sample for PK analysis; QD - once a day; SD - standard deviation.

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Table 14

Part 1. Statistical comparisons of pharmacokinetic parameters to assess relative bioavailability

Analyst Parameter (unit) Treatment N η Geometries European LSM 95%CI Pairwise comparison(B/A) Ratio e(%) 90%CI CV% for comparisons between groups CV% for comparisons within the group Akalabruti nib Stach (ng/ml) A IN thirty 29 29 556.2 503.3 (471.7, 655.7) (426.9, 593.5) 90.50 (79.42, 103.1) 33.5 29.8 AUCinf (chng/ml) A IN thirty 29 29 571.4 559.4 (510.1, 640.3) (499.2, 626.8) 97.90 (91.62, 104.6) 26.6 14.9 AUClast (h ng/ml) A IN thirty 29 29 567.2 556.1 (506.1, 635.6) (496.2, 623.2) 98.05 (91.77, 104.8) 26.6 14.9 ASR-5862 Stach (ng/ml) A IN thirty 29 29 537.4 536.5 (463.4, 623.2) (462.6, 622.2) 99.84 (91.94, 108.4) 35.5 18.6 AUCinf (h ng/ml) A IN thirty 29 29 1615 1673 (1472, 1773) (1525, 1837) 103.6 (100.1, 107.3) 23.5 7.8 AUClast (h ng/ml) A IN thirty 29 29 1525 1576 (1385, 1679) (1431, 1735) 103.3 (99.86, 106.9) 24.4 7.6

A: 100 mg acalabrutinib in capsule form, on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

Only subjects with a valid PK parameter in both treatments were considered in the statistical analysis.

The result is based on a linear mixed-effects ANOVA of the log-transformed PK parameter with sequence, period, treatment as fixed effects, and subject entered into sequence as a random effect. The geometric mean ratio and the corresponding 90% CI are inversely transformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also inversely transformed. ANOVA - analysis of variance; CI - confidence interval; LSM - average value determined by the least squares method; N is the number of subjects in the sample for PK analysis; n is the number of subjects included in the statistical comparative analysis; PK - pharmacokinetic parameters.

Table 15

Part 1. Statistical comparison of pharmacokinetic parameters to evaluate the effect of PPI

Analyst Parameter (unit) Treatment N η Geometric eLSM 95%CI Pairwise comparison(D/B) Ratio (%) 90% CI Akala- Stakh IN 29 486.9 (338.2, 700.9) brutinib (ng/ml) D 14 14 371.9 (258.3, 535.5) 76.39 (54.88, 106.3) AUCinf IN 29 591.1 (466.9, 748.4) (h ng/ml) D 14 14 694.1 (548.2, 878.7) 117.4 (105.4, 130.8) AUClast IN 29 587.8 (462.6, 746.9) (h ng/ml) D 14 14 669.7 (527.0, 850.9) 113.9 (101.4, 128.0) ASR- Stakh IN 29 523.6 (390.7, 701.9) 5862 (ng/ml) D 14 14 365.3 (272.5, 489.6) 69.76 (51.31, 94.86) AUCinf IN 29 1770 (1491.2101) (h ng/ml) D 14 14 1783 (1502.2117) 100.7 (93.26, 108.8) AUClast IN 29 1666 (1397, 1985) (h ng/ml) D 14 14 1656 (1389,1973) 99.40 (90.81, 108.8)

B: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

D: 20 mg rabeprazole QD (fasting) 2 hours before administration of 100 mg acalabrutinib maleate tablet (option 1) and after preadministration of 20 mg rabeprazole BID (with food) on days -3, -2 and -1.

Only subjects with valid PK parameters in both treatments were considered in the statistical analysis.

- 40 047001

The result is based on a linear mixed-effects ANOVA on the log-transformed PK parameter with sequence, treatment as fixed effects, and subject within sequence as a random effect. The geometric mean ratio and the corresponding 90% CI are inversely transformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also inversely transformed. ANOVA - analysis of variance; BID - twice a day; CI - confidence interval; LSM - average value determined by the least squares method; N is the number of subjects in the sample for PK analysis; n is the number of subjects included in the statistical comparative analysis; PK - pharmacokinetic parameters; QD - once a day.

Table 16

Part 1. Statistical comparisons of pharmacokinetic parameters to assess the effect of food intake.

Anal IT Parameter (unit) Treatment N η Geometric LSM 95%CI Pairwise comparison (C/B) Ratio (%) 90% CI Akal abruti nib Stakh (ng/ml) IN WITH 29 14 14 555.4 255.6 (446.2, 691.4) (205.3, 318.1) 46.01 (35.92, 58.95) AUCinf (h ng/ml) IN With 29 14 14 541.2 528.7 (483.0, 606.5) (471.9, 592.5) 97.69 (87.19, 10.5) AUClast (h ng/ml) V With 29 14 14 538.2 525.7 (480.0, 603.4) (468.9, 589.4) 97.69 (87.18, 10.5) ASR- 5862 Stakh (ng/ml) V With 29 14 14 560.6 358.4 (469.4, 669.5) (300.1, 428.1) 63.94 (54.15, 75.49) AUCinf (h ng/ml) V With 29 14 14 1617 1644 (1470, 1778) (1495, 1809) 101.7 (96.90, 106.7) AUClast (h ng/ml) V With 29 14 14 1531 1532 (1387, 1691) (1388, 1692) 100.1 (95.47, 104.9)

B: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

C: 100 mg acalabrutinib maleate in tablet form (option 1), after meals.

Only subjects with valid PK parameters in both treatments were considered in the statistical analysis.

The result is based on a linear mixed-effects ANOVA on the log-transformed PK parameter with sequence, treatment as fixed effects, and subject within sequence as a random effect. The geometric mean ratio and the corresponding 90% CI are inversely transformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also inversely transformed. ANOVA - analysis of variance; CI - confidence interval; LSM - average value determined by the least squares method; N is the number of subjects in the sample for PK analysis; n is the number of subjects included in the statistical comparative analysis; PK - pharmacokinetic parameters.

- 41 047001

Results from Part 2 of the study showed that acalabrutinib maleate particle size did not have a significant effect on the pharmacokinetics of acalabrutinib and ACP-5862 across the particle size range evaluated. After administration, options 1, 2 and 3 resulted in comparable pharmacokinetic parameters of exposure.

The mean pharmacokinetic exposure parameters (Cmax and AUC) of acalabrutinib and the metabolite ACP-5862 were similar after oral administration of acalabrutinib maleate in the form of tablets with different particle sizes (options 1, 2 and 3). The 90% CIs for geometric mean ratios were similar or ranged from 80% to 125%.

Acalabrutinib solution had a higher Cmax and comparable AUC compared to acalabrutinib maleate tablet (Option 1). Relative bioavailability was approximately 122% and 102% for acalabrutinib Cmax and AUC, respectively, and approximately 124% and 106-107% for ACP-5862 Cmax and AUC, respectively.

Summary data on plasma pharmacokinetic parameters from part 2 of the study are presented in Table. 17-21.

Table 17

Part 2. Summary of plasma pharmacokinetic parameters for acalabrutinib

Parameter (unit) Statistical indicators A (N=24) V (N=24) C (N=24) ^a D (N=24) Stach (ng/ml) Geometric mean 596.5 543.3 602.2 727.2 Geometric CV% 44.29 56.12 60.51 44.90 AUCinf (h ng/ml) Geometric mean 667.2 616.1 632.7 677.0 Geometric CV% 32.91 33.01 30.00 36.84 AUClast (h ng/ml) Geometric mean 662.9 612.8 628.7 673.5 Geometric CV% 33.27 33.21 30.14 36.99 trnax (h) Median value 0.50 0.75 0.50 0.50 Min, Max 0.25, 1.50 0.25, 3.00 0.25, 2.00 0.25, 1.00 ΐ1/2λζ (h) Average value 1,768 1,364 1,794 1.685 SD 0.7369 0.4352 0.7305 0.7755 CL/F (l/h) Average value 157.4 170.4 164.1 156.9 SD 49.95 54.44 42.61 57.76 Vz/F (l) Average value 400.8 334.8 414.6 378.8 SD 245.8 193.1 191.8 222.5

^f The summary data includes data for 23 subjects; in one subject, all concentrations were not quantifiable and therefore pharmacokinetic parameters could not be calculated.

A: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 2), in the fasted state.

C: 100 mg acalabrutinib maleate in tablet form (option 3), on an empty stomach.

- 42 047001

D: 100 mg acalabrutinib solution in the fasted state.

CV - coefficient of variation; Max - maximum; Min - minimum; M is the number of subjects in the sample for pharmacokinetic analysis; PK - pharmacokinetic parameters; SD - standard deviation.

Table 18

Part 2. Summary of pharmacokinetic parameters in blood plasma for the metabolite ACP-5862

Parameter (unit) Statistical indicators A (N=24) V (N=24) C (N=24) ^a D (N=24) Stach (ng/ml) Geometric mean Geometry of cells CV% 536.5 39.38 532.8 33.25 594.5 33.65 662.6 26.54 AUCinf (h ng/ml) Geometric mean Geometric CV% 1746 24.46 1775 24.80 1792 25.78 1845 26.79 AUClast (h ng/ml) Geometric mean Geometric CV% 1653 24.97 1674 25.69 1702 26.03 1762 27.08 tmax (h) Median value Min, Max 0.77 0.48, 2.02 0.88 0.50, 3.00 0.75 0.48, 3.50 0.74 0.48, 1.52 ΐ1/2λζ (h) Average value SD 7,668 1.035 7,856 1.755 7,406 1.005 7,130 1.145 M:P [AUC] Geometric mean Geometric CV% 2,529 25.04 2.785 24.62 2,738 25.00 2.635 23.30 M:R [Stah] Geometric mean Geometric CV% 0.8695 29.87 0.9480 39.18 0.9544 36.26 0.8809 25.13

^g The summary data includes data for 23 subjects; in one subject, all concentrations were not quantifiable and therefore pharmacokinetic parameters could not be calculated.

A: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 2), in the fasted state.

C: 100 mg acalabrutinib maleate in tablet form (option 3), on an empty stomach.

D: 100 mg acalabrutinib solution in the fasted state.

CV = coefficient of variation; Max = maximum; Min = minimum; M=number of subjects in the pharmacokinetic analysis sample; PK = pharmacokinetics; SD = standard deviation.

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Table 19

Part 2: Statistical comparison of acalabrutinib pharmacokinetic parameters to evaluate the particle size effect

Parameter (unit) Treatment N η Geometric LSM 95%CI Pairwise comparisons Pair Ratio (%) 90%CI Stach (ng/ml) A 24 596.5 (489.9, 726.4) IN 24 24 543.3 (446.2, 661.6) V/A 91.08 (79.35, 104.5) A 24 599.0 (484.5, 740.5) WITH 24 23 600.1 (485.5, 741.9) S/A 100.2 (82.95, 121.0) IN 24 536.7 (425.8, 676.4) WITH 24 23 599.7 (475.9, 755.9) s/v 111.8 (90.67, 137.7) AUCinf (h ng/ml) A 24 667.2 (583.4, 763.0) IN 24 24 616.1 (538.7, 704.6) V/A 92.35 (85.64, 99.58) A 24 674.5 (590.3, 770.8) WITH 24 23 631.9 (553.0, 722.1) S/A 93.68 (85.37, 102.8) IN 24 622.1 (545.6, 709.2) With 24 23 630.7 (553.2, 719.0) S/W 101.4 (94.20, 109.1) AUClast (h ng/ml) A 24 662.9 (579.0, 758.9) IN 24 24 612.8 (535.3, 701.7) V/A 92.46 (85.72, 99.72) A 24 670.1 (585.8, 766.6) WITH 24 23 627.9 (548.9, 718.3) S/A 93.71 (85.35, 102.9) IN 24 618.8 (542.3, 706.0) With 24 23 626.7 (549.3, 715.0) S/W 101.3 (94.08, 109.1)

A: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 2), in the fasted state.

C: 100 mg acalabrutinib maleate in tablet form (option 3), on an empty stomach.

In one subject on treatment C, all concentrations were not quantifiable and therefore pharmacokinetic parameters could not be calculated.

The result is based on a linear mixed-effects ANOVA of the log-transformed PK parameter with sequence, period, treatment as fixed effects, and subject entered into sequence as a random effect. The geometric mean ratio and the corresponding 90% CI are inversely transformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also inversely transformed. ANOVA - analysis of variance; CI - confidence interval; LSM - average value determined by the least squares method; N is the number of subjects in the sample for PK analysis; n is the number of subjects included in the statistical comparative analysis; PK - pharmacokinetic parameters.

- 44 047001

Table 20

Part 2: Statistical Comparison of ACP-5862 Pharmacokinetic Parameters to Evaluate the Particle Size Effect

Parameter (unit) Treatment N η Geometric eLSM 95%CI Pairwise comparisons Pair Ratio(%) 90%CI Stach (ng/ml) A 24 536.5 (463.1, 621.6) IN 24 24 532.8 (459.9, 617.2) V/A 99.30 (88.73, 111.1) A 24 537.7 (461.5, 626.5) WITH 24 23 593.0 (509.0, 691.0) S/A 110.3 (97.02, 125.4) IN 24 528.5 (457.9, 609.8) WITH 24 23 594.2 (514.9, 685.7) s/v 112.4 (103.1, 122.7) AUCinf (h ng/ml) A 24 1746 (1574, 1936) IN 24 24 1775 (1600, 1968) V/A 101.7 (98.39 105.0) A 24 1746 (1566, 1946) WITH 24 23 1788 (1604, 1993) S/A 102.4 (98.78, 106.2) IN 24 1774 (1589, 1980) With 24 23 1789 (1603, 1997) S/W 100.9 (97.11, 104.8) AUClast A 24 1653 (1486, 1839) (h ng/ml) IN 24 24 1674 (1505, 1862) V/A 101.3 (97.60, 105.1) A 24 1653 (1481, 1845) WITH 24 23 1699 (1522, 1896) S/A 102.8 (98.74, 107.0) IN 24 1673 (1495, 1872) With 24 23 1700 (1519, 1902) S/W 101.6 (97.52, 105.9)

A: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

B: 100 mg acalabrutinib maleate in tablet form (option 2), in the fasted state.

C: 100 mg acalabrutinib maleate in tablet form (option 3), on an empty stomach.

In one subject on treatment C, all concentrations were not quantifiable and therefore pharmacokinetic parameters could not be calculated.

The result is based on a linear mixed-effects ANOVA of the log-transformed PK parameter with sequence, period, treatment as fixed effects, and subject entered into sequence as a random effect. The geometric mean ratio and the corresponding 90% CI are inversely transformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also inversely transformed. ANOVA - analysis of variance; CI - confidence interval; LSM - average value determined by the least squares method; N is the number of subjects in the sample for PK analysis; n is the number of subjects included in the statistical comparative analysis; PK - pharmacokinetics.

- 45 047001

Table 21

Part 2. Statistical comparisons of pharmacokinetic parameters to assess relative bioavailability

Anal IT Parameter P (unit) Treatment N η Geometric LSM 95%CI Pairwise comparison(D/A) Ratio (%) 90% CI Akal abruti nib Stakh (ng/ml) A D 24 24 24 596.5 727.2 (501.3, 710.0) (611.1, 865.5) 121.9 (U6.7, 139.3) AUCinf (h ng/ml) A D 24 24 24 667.2 677.0 (577.2, 771.2) (585.7, 782.6) 101.5 (95.30, 108.1) AUClast (h ng/ml) A D 24 24 24 662.9 673.5 (572.9, 766.9) (582.1, 779.2) 101.6 (95.32, 108.3) ASR- 5862 Stakh (ng/ml) A D 24 24 24 536.5 662.6 (469.3, 613.4) (579.6, 757.6) 123.5 (U9.9, 138.8) AUCinf (h ng/ml) A D 24 24 24 1746 1845 (1567, 1944) (1657, 2055) 105.7 (U2.7, 108.8) AUClast (h ng/ml) A D 24 24 24 1653 1762 (1482, 1844) (1580, 1966) 106.6 (U3,2, 1U,2)

A: 100 mg acalabrutinib maleate in tablet form (option 1), on an empty stomach.

D: 100 mg acalabrutinib solution in the fasted state.

The result is based on a linear mixed-effects ANOVA on the log-transformed PK parameter with sequence, treatment as fixed effects, and subject within sequence as a random effect. The geometric mean ratio and the corresponding 90% CI are inversely transformed and presented as percentages. The geometric LSM and the corresponding 95% CI are also inversely transformed. ANOVA - analysis of variance; CI - confidence interval; LSM - average value determined by the least squares method; N is the number of subjects in the sample for PK analysis; n is the number of subjects included in the statistical comparative analysis; PK - pharmacokinetic parameters.

Pharmacodynamic parameters.

Part 1 of the study examined BTK receptor occupancy by acalabrutinib when administered as capsules or tablets. The results showed that at all post-dose time points (4, 12 and 24 hours) similar VTC occupancy was observed after tablets and capsules were administered. In addition, food intake or PPI administration had no effect on BTK occupancy by the tablet formulation.

Research.

Gastric pH was found to have no effect on the effects of acalabrutinib maleate from 100 mg aka

- 46 047001 labrutinib maleate is in the form of film-coated tablets, and therefore the in vivo dissolution of the tablets is not sensitive to gastric pH.

Safety.

Overall, no new safety concerns were identified with acalabrutinib maleate 100 mg film-coated tablets and the new formulation was well tolerated.

Example 15. Bioequivalence assessment.

An open-label, randomized, two-way crossover bioequivalence study in healthy subjects was conducted to evaluate the bioequivalence of acalabrutinib maleate tablet (study formulation) and acalabrutinib free base capsule (reference formulation). The study is designed to demonstrate, in accordance with regulatory requirements, that acalabrutinib maleate in tablet form and acalabrutinib free base in capsule form are bioequivalent.

Study title:

An open-label, randomized, 2-treatment, 2-period phase 1 crossover study in healthy subjects to evaluate the bioequivalence of acalabrutinib tablet and acalabrutinib capsule.

Rationale for the study:

Acalabrutinib is a Biopharmaceutical Classification System (BCS) Class II drug (high penetration, low solubility) that exhibits two major dissociation constants over the physiological pH range. The solubility of acalabrutinib decreases with increasing pH. At a pH below 4, the drug is highly soluble. However, in patients taking acid-lowering agents (i.e., pH greater than 4), the solubility of the drug in the stomach/intestinal tract is insufficient to ensure complete solubilization and absorption of the drug. Previous observations in a phase I study (ACE-HV-112 study) showed that 100 mg acalabrutinib capsules followed by 40 mg omeprazole (a proton pump inhibitor (PPI)) administered once daily (qd) resulted in a 43% reduction in AUC and 72% reduction in C _max compared to those when dosing the drug under normal acidic pH conditions.

At a dose equivalent to 100 mg free base, acalabrutinib maleate tablet (AMT) exhibits pH-independent release in vitro, unlike acalabrutinib capsule form (i.e., Calquence). The results of the relative bioavailability study (see Example 14) demonstrated that the systemic exposure of acalabrutinib and its active metabolite ACP-5862 after administration of AMT was similar in the presence or absence of PPI and comparable to that observed with the administration of 100 mg acalabrutinib capsule. This bioequivalence study is designed to confirm that AMT 100 mg eliminates the effect of PPI on the pharmacokinetics (PK) of acalabrutinib in humans.

Planned number of subjects.

Approximately 64 subjects (about 32 per treatment sequence) will be randomized to ensure at least 52 evaluable subjects (26 per sequence) at the end of Treatment Period 2.

Objectives of the study.

Primary goal.

Demonstrate the bioequivalence of AMT and acalabrutinib capsule administered in the fasted state.

Secondary goals.

To compare the pharmacokinetic profile of ACP-5862, the active metabolite of acalabrutinib, after administration of AMT and acalabrutinib capsule.

To compare the safety and tolerability of single doses of AMT and acalabrutinib capsule.

Research goal:

measure the pharmacodynamics (PD) of acalabrutinib.

Research plan.

This study will be a multicenter, open-label, randomized, phase I crossover bioequivalence study with 2 sequences, 2 treatments, 2 periods, with single doses of acalabrutinib administered orally to healthy subjects at approximately three study sites in the United States. The study is designed to demonstrate the bioequivalence of AMT (Treatment A) compared to commercially available acalabrutinib capsule (Treatment B) in the fasted state.

The study will include:

Visit 1: screening period up to 28 days before first dose;

visit 2: two treatment periods:

subjects will be admitted to the study site on day -2 of treatment period 1 to confirm eligibility before the first dose; compliance criteria

- 47 047001 vaniyams will be confirmed on day -1 of each treatment period;

on Day 1 of Treatment Periods 1 and 2, subjects will be administered the assigned treatment (A or B) as randomized, followed by a washout of at least five days between Treatment Periods 1 and 2;

Subjects will be discharged from the study center on the morning of Day 3 of Treatment Period 2 after completion of scheduled study assessments;

visit 3: follow-up visit/early termination visit 7-10 days after the last IMP administration.

If a follow-up visit/termination visit is required, part or all of a telemedicine visit may be performed in lieu of a center visit if necessary (lab tests, ECGs, and tympanic temperature measurements will not be performed during a telemedicine visit). The term telehealth visit refers to virtual or video visits. During a civil crisis, natural disaster, or public health crisis such as the COVID-19 pandemic, in-center visits may be replaced by a telehealth visit if permitted by local/regional guidelines. Having telemedicine contact with subjects will allow information on adverse events (AEs) and concomitant treatments to be collected as required by the study, which will be recorded and documented.

Subjects will be randomized to receive either treatment sequence 1 (AB) or treatment sequence 2 (BA). AMT is characterized by the composition of the T21 tablet (see example 4, table 7), in which the medicinal substance is characterized by a particle size D( _v , _0>9) of no more than 218 μm.

Treatment A: AMT, 100 mg, on an empty stomach.

Treatment B: 100 mg acalabrutinib capsule in fasting state.

Subjects will receive fixed single doses of acalabrutinib on two occasions in the fasted state.

Expected duration of the study.

Each subject will participate in the study for approximately six weeks.

Target population of the study.

Healthy adult male and female subjects aged 18 to 55 years (inclusive), body mass index from 18.5 to 30 kg/ ^m2 inclusive, non-smokers; women should be without reproductive potential.

Test and reference compounds

Test composition Reference composition Compound: Acalabrutinib maleate tablet (T21 tablet) Acalabrutinib capsule (commercially available) Dosage/concentration: 100 mg 100 mg Dose: 100 mg (equivalent to 100 mg free base) 100 mg Route of administration: Oral Oral Mode: Single dose Single dose

Outcome assessment endpoints.

Safety and tolerability endpoints.

Adverse events.

Laboratory tests (hematology, coagulation, clinical biochemistry and urinalysis).

Physical examination.

Electrocardiogram (ECG).

Vital signs (systolic blood pressure [BP], diastolic BP, pulse, respiratory rate, tympanic temperature).

Pharmacokinetic endpoints.

Primary PK parameters:

acalabrutinib - AUC _inf , AUClast, Cmax.

Secondary PK parameters:

acalabrutinib - tmax, t _1/2 Xz, MRT, Xz, CL/F, Vz/F;

ACP-5862 - AUCinf, AUClast, Cmax, tmax, t1/2 Xz, MRT, Xz, M:P[AUC], M:P[Cmax].

Statistical methods.

All statistical analyzes and compilation of tables, figures and lists will be performed using

- 48 047001 SAS® version 9.4 or later.

Data sets for analysis.

The safety analysis set will include data from all subjects who received at least one dose in Treatment Period 1 and for whom any post-dose safety data are available. The PK analysis set will consist of data from all subjects in the safety analysis set for which there is at least one quantifiable post-dose concentration of acalabrutinib without significant protocol deviations or adverse events that are considered to affect the data analysis RK. The randomized set will consist of data from all subjects randomized to participate in the study.

Presentation and analysis of safety and tolerability data.

All safety data (planned and unplanned) will be presented in data sheets. Continuous variables will be summarized using descriptive statistics (number of subjects [n], mean, standard deviation [SD], minimum, median, maximum) by treatment. Categorical variables will be summarized in frequency tables (frequency and proportion) by treatment. The security variable analysis will be based on the security analysis set.

Adverse events will be summarized by system organ class (SOC) and preferred term using the current version of the dictionary, the Medical Dictionary of Regulatory Activities (MedDRA). Data tables and lists will be provided for vital signs, clinical laboratory tests, and ECGs. Any new or worsening clinically significant abnormality on the physical examination compared to the baseline assessment will be reported as an adverse event. Clinical laboratory data will be presented in units provided by the clinical laboratory and in International System of Units units.

Presentation of pharmacokinetic data.

Lists for blood sampling times for PK will be provided, as well as resulting sampling time deviations. For each analyte, plasma concentrations and PK parameters will be summarized according to treatment. Diagnostic PK parameters will be summarized and presented in lists. The tables will be based on the PK assay set. Data from subjects excluded from the PK analysis set will be included in data sheets but not in descriptive statistics or inferential statistics. For each analyte, the individual plasma concentration versus actual time will be plotted on linear and semi-log scales with all treatments superimposed on the same plot and separate plots for each subject. Cumulative individual plasma concentrations versus actual time will be displayed on linear and semi-logarithmic scales, with separate plots for each treatment and analyte. The geometric mean plasma concentration as a function of nominal sampling time will be plotted on a linear scale (-/+ geometric standard deviation) and a semi-logarithmic scale (geometric standard deviation not shown) with all treatments superimposed on the same same figure, and separate figures for each analyte. All plots will be based on the PK assay set, except for individual subject plots, which will be based on the safety assay kit.

Statistical analysis of pharmacokinetic data.

Bioequivalence will be assessed between treatment A: AMT (test) treatment B: acalabrutinib capsule (reference) based on the PK assay kit. Analyzes will be performed using a linear mixed-effects ANOVA model using the natural logarithm of _Cmax , AUC _last , and AUC _inf for acalabrutinib as response variables, with sequence, period, treatment as fixed effects, and subject entered into sequence as random effect. After inverse transformation from the logarithmic scale, geometric means along with confidence intervals (CI) (2-sided 95%) for C _max , AUC _last and AUCinf will be estimated and presented. Geometric mean ratios along with CI (2-sided 90%) will also be estimated and presented. In addition, %CVs for between-group comparisons and for within-group comparisons will be estimated and presented for _Cmax , AUC _inf and AUC _last for acalabrutinib and ACP-5862, respectively.

Bioequivalence criteria.

If the 90% CI for the log-transformed geometric mean ratio Cmax and AUC _last or AUC _inf between test and reference are entirely within 80.00 and 125.00%, the two treatments are concluded to be bioequivalent. Statistical analysis to establish bioequivalence will be performed by pooling PK data across all study sites.

- 49 047001

Presentation and analysis of pharmacodynamic data.

The results of the exploratory determination of the PD parameter (BTK receptor occupancy) will be listed and summarized accordingly based on the pharmacokinetic assay set.

Determining the sample size.

Based on a bioequivalence range of 80.00 to 125.00% for _Cmax and AUC _inf for acalabrutinib, intrasubject CV of 29.8% for _Cmax and 15.1% for AUC _inf (study ACE-HV-115) and mean ratio test/reference 0.95, 52 evaluable subjects needed to achieve 90% power.

Overall, a total of 64 subjects would provide at least 95% power to conclude bioequivalence for each of the C _max and AUC _inf , respectively.

VIII. Embodiments.

Embodiment 1. A solid pharmaceutical dosage form containing from about 75 mg to about 125 mg (equivalent free base weight) of acalabrutinib maleate and at least one pharmaceutically acceptable excipient, for oral administration to humans, wherein the dosage form satisfies the following conditions: (i ) at least about 75% of acalabrutinib maleate dissolves in approximately 30 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0.1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and (ii) at least about 75% of acalabrutinib maleate dissolves in approximately 60 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium , which is 5 mM phosphate with a pH of 6.8 and a paddle stirrer speed of 75 rpm.

Embodiment 2. The dosage form of Embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 75% of acalabrutinib maleate dissolves in about 20 minutes when determined in an in vitro dissolution test conducted using a dissolution testing device USP 2 (device with paddle stirrer), dissolution volume 900 ml, dissolution medium, which is 0.1 N. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and (ii) at least about 75% of acalabrutinib maleate dissolves in approximately 45 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium , which is 5 mM phosphate with a pH of 6.8 and a paddle stirrer speed of 75 rpm.

Embodiment 3. The dosage form of Embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 80% of acalabrutinib maleate dissolves in about 20 minutes when determined in an in vitro dissolution test conducted using a dissolution testing device USP 2 (device with paddle stirrer), dissolution volume 900 ml, dissolution medium, which is 0.1 N. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and (ii) at least about 80% of acalabrutinib maleate dissolves in approximately 30 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium , which is 5 mM phosphate with a pH of 6.8 and a paddle stirrer speed of 75 rpm.

Embodiment 4. The dosage form of Embodiment 1, wherein the dosage form satisfies the following conditions: (i) at least about 80% of acalabrutinib maleate dissolves in about 15 minutes when determined in an in vitro dissolution test conducted using a dissolution testing device USP 2 (device with paddle stirrer), dissolution volume 900 ml, dissolution medium, which is 0.1 N. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and (ii) at least about 80% of acalabrutinib maleate dissolves in approximately 20 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium , which is 5 mM phosphate with a pH of 6.8 and a paddle stirrer speed of 75 rpm.

Embodiment 5. The dosage form of any one of embodiments 1-4, wherein acalabrutinib maleate is acalabrutinib maleate monohydrate.

Embodiment 6. The dosage form of Embodiment 5, wherein acalabrutinib maleate monohydrate is crystalline Form A.

Embodiment 7. The dosage form of any one of embodiments 1 to 6, wherein the at least one pharmaceutically acceptable excipient is selected from at least one diluent, at least one disintegrant and at least one lubricant.

- 50 047001

Embodiment 8. The dosage form of any one of embodiments 1-7, wherein the dissolution rate of acalabrutinib maleate in the dissolution medium of 5 mM phosphate pH 6.8 is not reduced by more than 20% from the initial dissolution rate after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and a relative humidity of 75%.

Embodiment 9. The dosage form of any one of embodiments 1-7, wherein the dissolution rate of acalabrutinib maleate in the dissolution medium of 5 mM phosphate pH 6.8 is not reduced by more than 10% from the initial dissolution rate after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and a relative humidity of 75%.

Embodiment 10. The dosage form of any one of embodiments 1-7, wherein the dissolution rate of acalabrutinib maleate in the dissolution medium of 5 mM phosphate pH 6.8 is not reduced by more than 5% from the initial dissolution rate after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and a relative humidity of 75%.

Embodiment 11. The dosage form of any one of embodiments 1-7, wherein the dissolution rate of acalabrutinib maleate in the dissolution medium of 5 mM phosphate pH 6.8 is not reduced by more than 2% from the initial dissolution rate after storage of the dosage form in appropriate packaging for six months at a temperature of 40°C and a relative humidity of 75%.

Embodiment 12. The dosage form of any one of embodiments 1-11, wherein no more than about 5% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at 40°C and relative humidity 75%.

Embodiment 13. The dosage form of any one of embodiments 1-11, wherein no more than about 2% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at 40°C and relative humidity 75%.

Embodiment 14. The dosage form of any one of embodiments 1-11, wherein no more than about 1% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months at 40°C and relative humidity 75%.

Embodiment 15. The dosage form of any one of embodiments 1-11, wherein no more than about 0.5% (wt/wt) of acalabrutinib maleate present in the dosage form is destroyed after storage of the dosage form in appropriate packaging for six months. at a temperature of 40°C and a relative humidity of 75%.

Embodiment 16. The dosage form of any one of Embodiments 1-15, wherein the dosage form is bioequivalent to Calquence® 100 mg capsules when administered orally to a fasting human subject who has not been administered a gastric acid reducer, wherein the dosage form is bioequivalent provided that the confidence interval of the relative mean _Cmax , AUC( _0t ) and AUC _0-/ , of the dosage form with respect to Calquence® 100 mg capsules is in the range of 80 to 125%.

Embodiment 17. The dosage form of any one of embodiments 1-15, wherein the dosage form, when administered twice daily to a population of fasted human subjects, satisfies one or more of the following pharmacokinetic conditions for acalabrutinib: (i) the mean C _max in population of human subjects is from about 400 ng/ml to about 900 ng/ml; (ii) the average AUC( _0-24 ) in the population of human subjects is from approximately 350 ng-h/ml to approximately 1900 ng-h/ml; and/or (iii) the average AUC _0-/ ) in the population of human subjects is from about 350 ng-h/ml to about 1900 ng-h/ml.

Embodiment 18. The dosage form of Embodiment 17, wherein the dosage form is administered to a population of human subjects in conjunction with a gastric acid reducer.

Embodiment 19. The dosage form of any one of embodiments 1-18, wherein the dosage form, when administered to a human subject twice daily, provides a median steady-state Bruton's tyrosine kinase occupancy value of at least about 90% in peripheral blood mononuclear cells.

Embodiment 20. The dosage form of any one of embodiments 1-18, wherein the dosage form, when administered to a human subject twice daily, provides a median steady-state Bruton's tyrosine kinase occupancy value of at least about 95% in peripheral blood mononuclear cells.

Embodiment 21. The dosage form of Embodiment 19 or 20, wherein the drug

- 51 047001 the natural form is administered to populations of human subjects together with an agent that reduces the acidity of gastric juice.

Embodiment 22. The dosage form of any one of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of from about 15% to about 55% by weight (equivalent free base weight) of the dosage form.

Embodiment 23. The dosage form of any one of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of from about 20% to about 50% by weight (equivalent free base weight) of the dosage form.

Embodiment 24. The dosage form of any one of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of from about 25% to about 50% by weight (equivalent free base weight) of the dosage form.

Embodiment 25. The dosage form of any one of embodiments 1-21, wherein acalabrutinib maleate is present in an amount of from about 25% to about 40% by weight (equivalent free base weight) of the dosage form.

Embodiment 26. The dosage form of any one of embodiments 1-25, wherein the at least one pharmaceutically acceptable excipient includes at least one diluent.

Embodiment 27. The dosage form of Embodiment 26, wherein the at least one diluent is present in an amount of from about 10% to about 70% by weight of the dosage form.

Embodiment 28. The dosage form of Embodiment 26, wherein the at least one diluent is present in an amount of from about 20% to about 70% by weight of the dosage form.

Embodiment 29. The dosage form of Embodiment 26, wherein the at least one diluent is present in an amount of from about 30% to about 70% by weight of the dosage form.

Embodiment 30. The dosage form of Embodiment 26, wherein the at least one diluent is present in an amount of from about 40% to about 70% by weight of the dosage form.

Embodiment 31. The dosage form of any one of embodiments 26-30, wherein the at least one diluent does not affect the stability of the primary amine moiety of acalabrutinib.

Embodiment 32. The dosage form of any one of embodiments 26-30, wherein at least one diluent is lactose-free.

Embodiment 33. The dosage form of any one of embodiments 26-32, wherein the at least one diluent does not include a maleic acid scavenging agent.

Embodiment 34. The dosage form of any one of embodiments 26-33, wherein at least one diluent does not include anhydrous dibasic calcium phosphate.

Embodiment 35. The dosage form of any one of embodiments 26-34, wherein at least one diluent includes a plastic diluent and a friable diluent.

Embodiment 36. The dosage form of Embodiment 35, wherein the w/w ratio. plastic diluent and brittle diluent is from about 0:100 to about 60:40.

Embodiment 37. The dosage form of Embodiment 35 or 36, wherein (i) wherein the at least one diluent comprises a plastic diluent and a friable diluent in a total amount of from about 10% to about 70% by weight of the dosage form; (ii) the plastic diluent is present in an amount of from about 0% to about 70% by weight of the dosage form; and (iii) the fragile diluent is present in an amount of from about 0% to about 50% by weight of the dosage form.

Embodiment 38. The dosage form of any one of embodiments 26-34, wherein at least one diluent comprises mannitol.

Embodiment 39. The dosage form of any one of embodiments 26-34, wherein at least one diluent comprises microcrystalline cellulose.

Embodiment 40. The dosage form of any one of embodiments 26-34, wherein at least one diluent comprises mannitol and microcrystalline cellulose.

Embodiment 41. The dosage form of Embodiment 40, wherein the w/w ratio. mannitol and microcrystalline cellulose is from about 0:100 to about 60:40.

Embodiment 42. The dosage form of Embodiment 38, wherein mannitol is present in an amount of from about 10% to about 70% by weight of the dosage form.

Embodiment 43. The dosage form of Embodiment 39, wherein microcrystalline cellulose is present in an amount of from about 5% to about 50% by weight.

- 52 047001 weight of the dosage form.

Embodiment 44. The dosage form of Embodiment 40, wherein (i) mannitol is present in an amount of from about 0% to about 70% by weight of the dosage form; (ii) microcrystalline cellulose is present in an amount of from about 0% to about 50% by weight of the dosage form; and (iii) the total amount of mannitol and microcrystalline cellulose is from about 10% to about 70% by weight of the dosage form.

Embodiment 45. The dosage form of any one of embodiments 26-44, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) and at least one diluent is from about 1:3 to about 2:1.

Embodiment 46. The dosage form of any one of embodiments 26-44, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) and at least one diluent is from about 1:1 to about 1:2.

Embodiment 47. The dosage form of any one of embodiments 1-46, wherein the at least one pharmaceutically acceptable excipient comprises at least one disintegrant.

Embodiment 48. The dosage form of Embodiment 47, wherein the at least one disintegrant is present in an amount of from about 0.5% to about 15% by weight of the tablet.

Embodiment 49. The dosage form of Embodiment 47, wherein the at least one disintegrant is present in an amount of from about 1% to about 10% by weight of the tablet.

Embodiment 50. The dosage form of Embodiment 47, wherein the at least one disintegrant is present in an amount of from about 2% to about 8% by weight of the tablet.

Embodiment 51. The dosage form of Embodiment 47, wherein the at least one disintegrant is present in an amount of from about 3% to about 7% by weight of the tablet.

Embodiment 52. The dosage form of any one of embodiments 47-51, wherein the at least one disintegrant does not include an ionic disintegrant.

Embodiment 53. The dosage form of any one of embodiments 47-51, wherein the at least one disintegrant does not include sodium starch glycolate.

Embodiment 54. The dosage form of any one of embodiments 47-53, wherein at least one disintegrant does not contain croscarmellose sodium.

Embodiment 56. The dosage form of any one of embodiments 47-54, wherein the at least one disintegrant comprises a non-ionic disintegrant.

Embodiment 57. The dosage form of any one of embodiments 47-56, wherein at least one disintegrant comprises hydroxypropyl cellulose.

Embodiment 58. The dosage form of any one of embodiments 47-56, wherein the at least one disintegrant comprises low-substituted hydroxypropylcellulose.

Embodiment 59. The dosage form of any one of embodiments 47-59, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) to the at least one disintegrant is from about 2:1 to about 15:1.

Embodiment 60. The dosage form of any one of Embodiments 47-59, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) to the at least one disintegrant is from about 4:1 to about 10:1.

Embodiment 61. The dosage form of any one of embodiments 1-60, wherein the at least one pharmaceutically acceptable excipient includes at least one lubricant.

Embodiment 62. The dosage form of Embodiment 61, wherein the at least one lubricant is present in an amount of from about 0.25% to about 4% by weight of the dosage form.

Embodiment 63. The dosage form of Embodiment 61, wherein the at least one lubricant is present in an amount of from about 1% to about 4% by weight of the dosage form.

Embodiment 64. The dosage form of Embodiment 61, wherein the at least one lubricant is present in an amount of from about 1.5% to about 3.5% by weight of the dosage form.

Embodiment 65. The dosage form of Embodiment 61, wherein the at least one lubricant is present in an amount of from about 2% to about 3% by weight of the dosage form.

Embodiment 66. The dosage form of any one of embodiments 61-65,

- 53 047001 where at least one lubricant does not contain magnesium stearate.

Embodiment 67. The dosage form of any one of embodiments 51-66, wherein the at least one lubricant does not include glyceryl dibehenate.

Embodiment 68. The dosage form of any one of embodiments 61-67, wherein the at least one lubricant comprises sodium stearyl fumarate.

Embodiment 69. The dosage form of any one of embodiments 61-68, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) to the at least one lubricant is from about 20:1 to about 12:1.

Embodiment 70. The dosage form of any one of embodiments 61-68, wherein the weight ratio of acalabrutinib maleate (equivalent weight of free base) to the at least one lubricant is from about 18:1 to about 14:1.

Embodiment 71. The dosage form of any one of embodiments 1-70, wherein the at least one pharmaceutically acceptable excipient comprises at least one diluent, at least one disintegrant, and at least one lubricant.

Embodiment 72. The dosage form of Embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of from about 15% to about 55% by weight (equivalent free base weight) of the dosage form; (ii) at least one diluent in an amount of from about 10% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of from about 0.5% to about 15% by weight of the dosage form; and (iv) at least one lubricant in an amount from about 0.25% to about 4% by weight of the dosage form ; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

Embodiment 73. The dosage form of Embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of from about 20% to about 50% by weight (equivalent free base weight) of the dosage form; (ii) at least one diluent in an amount of from about 20% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of from about 1% to about 10% by weight of the dosage form and (iv) at least one lubricant in an amount from about 1% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

Embodiment 74. The dosage form of Embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of from about 25% to about 50% by weight (equivalent free base weight) of the dosage form; (ii) at least one diluent in an amount of from about 30% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of from about 2% to about 8% by weight of the dosage form; and (iv) at least one lubricant in an amount from about 1.5% to about 3.5% by weight of the dosage form ; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

Embodiment 75. The dosage form of Embodiment 7, wherein the dosage form contains: (i) acalabrutinib maleate in an amount of from about 25% to about 40% (equivalent weight of free base) by weight of the dosage form; (ii) at least one diluent in an amount of from about 40% to about 70% by weight of the dosage form; (iii) at least one disintegrant in an amount of from about 3% to about 7% by weight of the dosage form and (iv) at least one lubricant in an amount from about 2% to about 3% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

Embodiment 76. The dosage form of Embodiment 7, wherein the dosage form comprises: (i) acalabrutinib maleate in an amount of about 30% to about 35% by weight (equivalent free base weight) of the dosage form; (ii) mannitol in an amount of from about 30% to about 35% by weight of the dosage form; (iii) microcrystalline cellulose in an amount of from about 25% to about 30% by weight of the dosage form; (iv) hydroxypropylcellulose in an amount of from about 3% to about 7% by weight of the dosage form; and (v) sodium stearyl fumarate in an amount from about 1% to about 4% by weight of the dosage form; and wherein the sum of the individual quantities constitutes 100% of the total weight of the dosage form.

Embodiment 77. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 500 μm.

Embodiment 78. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D _(v , ₀ , ₉ ) value of less than about 450 μm.

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Embodiment 79. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 400 μm.

Embodiment 80. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _v ) value of 0.9 of less than about 350 μM.

Embodiment 81. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of less than about 300 μm.

Embodiment 82. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _v , 0.9) value of from about 20 μm to about 500 μm.

Embodiment 83. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _v , ₀ , ₉ ) value of from about 50 μm to about 450 μm.

Embodiment 84. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _{v , 0.9 )} value of from about 75 μm to about 400 μm.

Embodiment 85. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D _{(vθ , 0.9 )} value of from about 75 μm to about 350 μm.

Embodiment 86. The dosage form of any one of embodiments 1-76, wherein the acalabrutinib maleate has a D( _{v , 0.9 )} value of from about 100 μm to about 300 μm.

Embodiment 87. The dosage form as in any one of embodiments 1-86, wherein the dosage form is a capsule.

Embodiment 88. The capsule of Embodiment 87, wherein the capsule is produced by a method including roller compaction.

Embodiment 89. The dosage form of any one of embodiments 1-86, wherein the dosage form is a tablet.

Embodiment 90. The dosage form of any one of embodiments 1-86, wherein the dosage form is a film-coated tablet.

Embodiment 91. The tablet of embodiment 89 or 90, wherein the tablet is produced by a process including direct compression.

Embodiment 92. The tablet of embodiment 89 or 90, wherein the tablet is produced by a process including roller compaction.

Embodiment 93. The tablet of any one of embodiments 89-92, wherein the tablet has a tensile strength of from about 1.5 MPa to about 5.0 MPa.

Embodiment 94. The tablet of any one of embodiments 89-92, wherein the tablet has a tensile strength of from about 2.0 MPa to about 4.0 MPa.

Embodiment 95. The tablet of any one of embodiments 89-94, wherein the tensile strength of the tablet does not decrease by more than 10% from the original tensile strength after storing the tablet in the blister pack for six months at a temperature of 40° C. and a relative humidity of 75 %.

Embodiment 96. The tablet of any one of embodiments 89-94, wherein the tensile strength of the tablet does not decrease by more than 8% of the original tensile strength after storing the tablet in the blister pack for six months at a temperature of 40° C. and a relative humidity of 75 %.

Embodiment 97. The tablet of any one of embodiments 89-94, wherein the tensile strength of the tablet does not decrease by more than 5% from the original tensile strength after storing the tablet in the blister pack for six months at a temperature of 40° C. and a relative humidity of 75 %.

Embodiment 98. A method of treating a BTK-mediated condition in a subject suffering from or predisposed to the condition, comprising administering to the subject once or twice daily a solid pharmaceutical dosage form of any one of Embodiments 1-97.

This written description uses examples to disclose the present invention and to enable any person skilled in the art to practice the present invention, including preparing and using any of the disclosed salts, substances or compositions and performing any of the disclosed methods or processes. The patentable scope of an invention is determined by the claims and may include other examples that come to mind to those skilled in the art. Such other examples are intended to be within the scope of the claims if they contain elements that do not differ from the literal statements of the claims, or if they include equivalent elements with immaterial differences from the literal statements of the claims. Although the preferred implementation options

Claims (6)

While the embodiments of the present invention are shown and described in this specification, such embodiments are presented by way of example only and are not intended to limit the scope of the invention in any other way. Various alternatives to the described embodiments may be used in the practice of the present invention. The section headings used in this section and throughout the invention are not intended to be limiting. All of the above references (patent and non-patent) are incorporated by reference into this patent application. The discussion of these references is intended only to summarize the statements made by their authors. No reference (or part of any reference) is intended to be prior art (or prior art as a whole). Applicants reserve the right to challenge the accuracy and currency of references cited. CLAIM 1. A solid pharmaceutical tablet containing approximately 100 mg (equivalent free base weight) of acalabrutinib maleate for oral administration to humans, wherein the tablet contains acalabrutinib maleate in an amount of from about 15% to about 55% by weight of the core (equivalent free base weight) of the tablet; the tablet contains one or more diluents in an amount of from about 10% to about 70% by weight of the tablet core, wherein the one or more pharmaceutically acceptable diluents is selected from the group consisting of sugar alcohols, hydrolyzed starches, partially pregelatinized starches, celluloses, and combinations thereof; the tablet contains one or more disintegrants in an amount of from about 0.5% to about 15% by weight of the tablet core, wherein the one or more pharmaceutically acceptable disintegrants is selected from the group consisting of hydroxypropylcellulose, corn starch, microcrystalline cellulose, crospovidone, and combinations thereof; the tablet contains one or more lubricants in an amount of from about 0.25% to about 4% by weight of the tablet core; the sum of the amount of acalabrutinib maleate, the amount of all diluents, the amount of all disintegrants and the amount of all lubricants is 100% of the total weight of the tablet core; and where the tablet satisfies the following conditions: at least about 75% of acalabrutinib maleate dissolves in approximately 30 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 75% of acalabrutinib maleate dissolves in about 60 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), a dissolution volume of 900 mL, a dissolution medium consisting of 5 mM phosphate with a pH of 6.8, and a paddle speed of 75 rpm. 2. A tablet according to claim 1, where the tablet satisfies the following conditions: at least about 80% of acalabrutinib maleate dissolves in approximately 15 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), 900 mL dissolution volume, dissolution medium being 0 ,1n. hydrochloric acid, and the rotation speed of the paddle mixer is 50 rpm; and at least about 80% of acalabrutinib maleate dissolves in about 20 minutes when determined in an in vitro dissolution test performed using a USP 2 dissolution test device (paddle device), a dissolution volume of 900 mL, a dissolution medium consisting of 5 mM phosphate with a pH of 6.8, and a paddle speed of 75 rpm. 3. A tablet according to claim 1 or 2, wherein acalabrutinib maleate is crystalline Form A of acalabrutinib maleate monohydrate. 4. A tablet according to any one of claims 1 to 3, wherein the dissolution rate of acalabrutinib maleate in the dissolution medium, which is 5 mM phosphate with a pH of 6.8, does not decrease by more than 20% compared to the initial dissolution rate after storing the tablet in blister packaging for six months at a temperature of 40°C and a relative humidity of 75%. 5. The tablet according to any one of claims 1 to 4, wherein not more than about 5% (w/w) of acalabrutinib maleate present in the tablet is destroyed after storing the tablet in the blister pack for six months at a temperature of 40° C. and relative humidity 75%. 6. A tablet according to any one of claims 1 to 5, wherein the tablet is bioequivalent to a 100 mg capsule of acalarutinib free base when administered orally to a fasted human subject who is not -