KR20210105388A - Combination therapy with RAF inhibitors and CDK4/6 inhibitors for use in cancer treatment - Google Patents

Abstract

The present invention relates, inter alia, to (a) a Raf inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and (b) CKD4/ 6 to a pharmaceutical combination comprising an inhibitor, in particular ribociclib.

Description

Combination therapy with RAF inhibitors and CDK4/6 inhibitors for use in cancer treatment

The present invention relates to (a) a Raf inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, and (b) a CDK4/6 inhibitor, in particular ribociclib, or a pharmaceutically acceptable salt thereof. Pharmaceutical combinations comprising acceptable salts.

The present invention also relates to such combinations for use in the treatment of cancer; the use of such a combination for the manufacture of a medicament for the treatment of cancer; a method of treating cancer in a subject in need thereof comprising concurrently administering to the subject a therapeutically effective amount of the combination; use of such combinations for the treatment of cancer; and pharmaceutical compositions comprising such combinations.

The present invention also relates to a compound of formula (I) as defined herein for use in combination therapy using a CDK4/6 inhibitor, in particular ribociclib, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof is about Also herein a CDK4/6 inhibitor, in particular ribociclib, or a pharmaceutically acceptable salt thereof for use in combination therapy with a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein salt is provided.

More than 30% of human cancers carry mutations in the mitogen activated protein kinase (MAPK) pathway, the most prevalent of which are RAS or BRAF mutations. The MAPK pathway (also known as the RAS/RAF/CDK4/6/ERK pathway) is an important signaling cascade that drives cell proliferation, differentiation and survival. Dysregulation of this pathway underlies other examples of tumorigenesis, including melanoma (Kirkwood et al, Clin Cancer Res 18(2):555-67, 2012). This pathway, when activated, consists of the RAS small guanidine triphosphate (GTPase), which, when activated, promotes the activation of RAF family proteins (ARAF, BRAF and CRAF, also known as RAF1). Activated RAF protein results in phosphorylation and activation of CDK4/61/2 protein, which in turn phosphorylates and activates extracellular signal regulated kinase (ERK). ERK phosphorylates a variety of substrates, including several transcription factors, and regulates several important cellular activities including proliferation, differentiation, migration, survival and angiogenesis. In addition, RAS or BRAF mutations constitutively activate the cyclin D-CDK4/6 complex, which cooperates with CDK4 activation and causes tumor progression (Chudnovsky Y et al 2005; Monahan KB et al 2010).

There is a high frequency of activating mutations in the MAPK pathway protein in melanoma. RAS mutant melanoma exhibits aggressive behavior, pre-existing at the time of initial diagnosis and with a high rate of metastasis in the brain (Bergamasco et al, Value in Health Journal 19 A347-A766, 2016), thus having a poor prognosis. Response to standard chemotherapy is very limited. A phase 3 clinical study demonstrated some benefits of the CDK4/6 inhibitor binimetinib over standard chemotherapy with dacarbazine, such as an improved overall response rate of 15 to 7%. 402 patients were randomized in a 2:1 manner. A median PFS of 2.8 (95% CI: 2.8 to 3.6) versus 1.5 (1.5 to 1.7), HR 0.62 (0.47 to 0.80) in favor of binimetinib was observed. However, discontinuation rates were high (20% vs. 5%) as a result of adverse events suspected to be related to study drug, and benefits in PFS did not translate to improvements in overall survival (11.0 months (95% CI: 8.9 to 11.0 months) 13.6) versus 10.1 months (7.0 to 16.5) (Dummer et al, Lancet Oncol 18(4):435-445, 2017).

The NRAS gene is mutated in 15-20% of melanomas (a relatively common subtype of melanoma). In melanoma, the majority of activating variants in NRAS occur at codon 61 and less frequently at codons 12 and 13 (Gao et al, Sci Signal, 2013; van Elsas, Recent Results Cancer Res, 1995). The presence of NRAS mutations in melanoma causes a MAPK signaling transition from BRAF to CRAF, initiating downregulated cAMP signaling, enabling CRAF to signal CDK4/6 (Dumaz 2006). Mutations in NRAS exclude alterations in PTEN, suggesting that mutations in NRAS alone may activate signaling through both the MAPK and PI3K pathways (Goel et al, J Invest Dermatol 6(269):pl1, 2006, Davies et al, Clin Cancer Res 15(24): 7538-46, 2009). Compared to other melanoma subtypes, melanomas with NRAS mutations are associated with a worse prognosis (Devitt et al, Pigment Cell Melanoma Res 24(4): 666-72, 2011), and the response to standard chemotherapy is very poor. Limited.

KRAS mutations are frequently found in pancreatic cancer (di Magliano MP & Logsdon CD, Gastroenterology 2013;144(6):1220-9). A study of samples of PDAC patients showed that 93% of all samples carried the KRAS mutation (Biankin et al. Nature 2012; 491, 399-405). KRAS has the same downstream effectors as NRAS. However, there remains a high unmet medical need in both NRAS and KRAS-mutant cancers.

Since the GTPase activity of NRAS has so far eluded the successful design of specific small molecule antagonists, selective pharmaceutical inhibition of NRAS remains a technical challenge. Muρoz-Couselo E, et al, OncoTargets and Therapy, 2017:10 pages 3941-3947 suggest that the combination of MEK inhibitors and immunotherapy is the most promising strategy. However, the efficacy of the current approach has not yet been established.

Recently, it was reported that the pan-Raf inhibitor LY3009120 was used in combination with the CDK4/6 inhibitor abemaciclib to inhibit the proliferation of specific tumor cells having KRAS or BRAF mutations (Chen SH et al, Oncogene, 2018, 37, 821-832). However, LY3009120 inhibits several other kinases, including those that play important roles in cancer, such as the Ephrin receptor, JNK and SRC family members, thus potentially causing off-target toxicity. do.

Thus, effective therapies targeting RAS mutant cancers, including NRAS mutant melanoma and KRAS ductal adenocarcinoma (PDAC), remain an unmet medical need.

It has been found that selective Raf inhibitors, such as ribociclib, a CDK4/6 inhibitor in combination with a compound of formula (I), synergistically inhibited tumor cells in vitro. The combination also resulted in significant tumor regression in patient-derived melanoma xenografts, particularly NRAS mutant melanoma xenografts, and increased median % in preclinical models.

Combination treatment of a compound of formula (I) with ribociclib is well tolerated and results in increased anti-tumor activity compared to single agents in patient-derived tumor xenografts. These data show that the combination activity of a compound of formula (I) with ribociclib is greater in patients suffering from RAS mutant cancers (eg melanoma), in particular NRAS mutant cancers, more specifically NRAS mutant melanomas. indicates that a more sustainable response can be achieved. Importantly, when the compound of formula (I) and ribociclib are used as a single agent, the same dose that produces a very small effect produces a large effect when both agents are combined.

Thus, the combination of a compound of formula (I) with a CDK4/6 inhibitor, in particular ribociclib, or a pharmaceutically active salt thereof, is an activated MAPK pathway, in particular a NRAS-mutant cancer, such as NRAS-mutant melanoma or Larger and more sustainable responses can be achieved in patients with KRAS-mutant cancers, such as KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). The combination therapy also provides few side effects and/or may be more tolerable for patients in need of such therapy.

Compounds of formula (I), which are selective Raf inhibitors together with the CDK4/6 inhibitor ribociclib, can also optimize inhibition of MAPK signaling in NRAS mutant melanoma. Compounds of formula (I) in combination with ribociclib may also prevent the emergence of resistance to a combination of BRAF and CDK4/6 (mitogen-activated protein kinase kinase) inhibitors in NRAS mutant melanoma or KRAS mutant PDAC. can

No targeted therapies are currently available other than clinical studies in patients with NRAS mutant melanoma. The synergistic combination of Raf inhibitors and CDK4/6 inhibitors may exert strong clinical benefit in patients suffering from NRAS mutant cancers, particularly NRAS mutant melanoma.

Accordingly, the present invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the Raf inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof:

[Formula I]

.

.

In another aspect, the present invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein

(i) The Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; and

(ii) The CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides these pharmaceutical combinations for use in the treatment of cancer.

The invention particularly relates to a combination of the invention for use in the treatment of cancer characterized by an activating mutation in the MAPK pathway, and in particular one or more mutations in NRAS or KRAS. In particular, the combinations of the present invention may be useful for the treatment of melanoma, in particular NRAS-mutant melanoma. Additionally, the combinations of the present invention may be useful in the treatment of pancreatic cancer, in particular KRAS-mutant PDAC.

The present invention provides a compound of formula (I) for use in the treatment of cancer by co-administration of a CDK4/6 inhibitor, for example ribociclib, or a pharmaceutically acceptable salt thereof.

The present invention also provides ribociclib, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by co-administration with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides the use of a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, a compound of formula I, for the manufacture of a medicament for the treatment of cancer.

In another aspect, the present invention provides a method for treating cancer in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, which is a compound of formula (I). method of treatment is provided.

The present invention also relates to a method of treating cancer, comprising administering to a subject in need thereof an amount of a combination of the present invention that is concomitantly therapeutically effective against cancer, either simultaneously, separately or sequentially. provides

The invention also provides a pharmaceutical composition or combined formulation comprising a combination of the invention in an amount that is jointly therapeutically effective against cancer, and optionally at least one pharmaceutically acceptable carrier.

The present invention also provides: (a) (i) one or more dosage units of a Raf inhibitor selected from the group consisting of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) CDK4/6 Provided is a combined formulation comprising one or more dosage units of an inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a combination of the present invention as an active ingredient, for use in the treatment of cancer such as melanoma and in particular NRAS-mutant melanoma or pancreatic cancer such as KRAS-mutant PDAC, and the present invention in a patient in need of cancer treatment Commercial packages comprising instructions for simultaneous, separate or sequential administration of a combination of the invention are provided.

Various aspects of the invention are described in further detail below. Additional definitions are set forth throughout this specification.

This compound is also referred to herein as “LXH254” or “NVP-LXH254”. Ribociclib is referred to herein as "LEE011" or "NVP-LEE011".
Figure 1: Effect of the combination of a compound of formula (I) and ribociclib on anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in SK-MEL-30 melanoma cell line
Proliferation of ribociclib in combination with a compound of formula I as measured by CyQUANT® direct cell proliferation assay in SK-MEL-30 melanoma cell line carrying co-occurring mutations in NRAS (Q61K) and BRAF (D287H). Combination matrices for inhibition (FIG. 1A), Loewe (ADD) excessive inhibition (FIG. 1B), and growth inhibition (GI) (FIG. 1C) are shown in (FIG. 1A, FIG. 1B, FIG. 1C). In all cases, there is an increase in the concentration of ribociclib along the lower row from right to left and an increase in the concentration of the compound of formula I along the leftmost column from the bottom to the top. All remaining dots on the grid represent % inhibition resulting from the combination of two inhibitors corresponding to a single agent concentration represented by the two axes. The excess inhibition matrix represents the percent inhibition of the experimental value (left grid) above the value predicted from the Loewe dose additivity model, which predicts inhibition due to dose additivity alone (Lehar et. al., 2009). Positive numbers indicate areas of increased synergy and negative numbers indicate areas of antagonism. The Growth Inhibition (GI) scale is based on normalization of experimental inhibition measures using an additional 0 hour vehicle reference level (time of drug addition). The GI scale results in effect values for two different linearly normalized grade fractions with 'breakpoints' at the 0 time level (ie at GI=100%). If the breakpoint is exceeded, the GI value will be greater than 100% (Lehar et al. 2009). ( FIG. 1D ) Western blot analysis of phosphorylated RB1, CDK4/61/2, ERK1/2 and RSK3 after single or combination treatment with ribociclib and a compound of formula I in SK-MEL-20 cells. Drug treatment containing nanomolar (nM) concentration is noted above Western blot image. The duration of drug treatment for all samples was 48 hours. The specific protein probed is shown to the right of each set of panels.
Figure 2: Combination of compound of formula (I) with ribociclib demonstrates improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in IPC-298 melanoma cell line
Antiproliferative effects (Fig. 2a, Fig. 2b, Fig. 2c) and Western analysis of important signaling proteins (Fig. 2d) in the NRAS mutant melanoma cell line IPC298 (NRASQ61L) are shown. The experimental protocol and data points of FIGS. 2A, 2B and 2C are described with respect to FIG. 1 above.
Figure 3: Combination of compound of formula I with ribociclib demonstrates improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in Meljuso melanoma cell line
Antiproliferative effects ( FIGS. 3A , 3B and 3C ) and Western analysis of important signaling proteins ( FIG. 3D ) in the NRAS mutant melanoma cell line Meljuso (NRASQ61L) are shown. The experimental protocol and data points of FIGS. 3A, 3B and 3C are described with respect to FIG. 1 above.
Figure 4: Combination of compound of formula I with ribociclib demonstrates improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in Meljuso melanoma cell line
Antiproliferative effects ( FIGS. 4A , 4B and 4C ) and Western analysis of important signaling proteins ( FIG. 4D ) in the NRAS mutant melanoma cell line SK-MEL-2 (NRASQ61R) are shown. The experimental protocol and data points of FIGS. 4A, 4B and 4C are described with respect to FIG. 1 above.
Figure 5: Anti-tumor activity of compounds of formula (I) and ribociclib against 9 patient-derived NRASmut melanoma tumor xenograft models in mice.
Each bar represents the highest response achieved by each treatment (plotted as mean 3-5 mice/treatment) in an individual patient-derived xenograft (PDX) model. The models for each treatment are plotted from left to right in the following order: HMEX20864, HMEX20744, HMEX4339, HMEX5727, HMEX21124, HMEX3486, HMEX20667, HMEX20585 and HMEX2921.
Figure 6: Kaplan-Meier plot of time at which tumors reached a size of 700 mm 3 during one-day treatment of a compound of formula I, a single agent of ribociclib, or a combination of both.
Treatment was initiated when the mean tumor size of each model was approximately 350 mm 3 , and all animals received continuous daily medication for the duration of the study. The study was terminated when animals were treated for at least 90 days or when tumor size reached 700 mm 3 or greater. The survival curves of the combination groups were statistically significant when compared to each single agent or untreated control group [*p<0.05 log-rank (Mantel-Cox test)].

The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor and (b) a CDK4/6 inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in particular for use in the treatment of cancer provide water.

As used herein, the term "Raf inhibitor" refers to B-Raf protein kinase (also referred to herein as b-RAF, BRAF or b-Raf) and C-Raf protein kinase (herein c-RAF, CRAF) to or adenosine triphosphate (ATP)-competitive inhibitor of c-Raf). Raf inhibitors preferentially inhibit both Raf monomers and Raf dimers.

The compound of formula (I) has the structure:

[Formula I]

.

.

For convenience, the group of compounds and salts thereof are collectively referred to as "compound of formula I" or "compound I", which means that reference to "compound of formula I" or "compound I" in the alternative refers to any of this compound or agent thereof. means that it will refer to a scientifically acceptable salt.

Compounds of formula (I), which are Raf inhibitors, and pharmaceutically acceptable salts thereof, are described in WO2014/151616, which is incorporated herein by reference in its entirety, and methods for its preparation are described, for example, in Example 1156 therein. is described. Compounds of formula (I) are potent and selective inhibitors targeting both BRAF and CRAF kinases with 50% (IC50) values of inhibitory concentrations below nM in biochemical assays, whereas two out of 456 kinases (discoidin domain receptors) It inhibits binding of only tyrosine kinase 1 (DDR1) and platelet-derived growth factor receptor, beta polypeptide (PDGFRβ)) to a similar extent. The compounds of formula (I) have demonstrated efficacy in tumor xenografts in vivo, including a very broad range of MAPK pathway-derived human cancer cell lines and models containing activated lesions within the KRAS, NRAS and BRAF oncogenes. For example, compounds of formula (I) show activity in the low uM range against human pancreatic cancer cell lines expressing mutations in KRAS (WO/2018/203219 A1, Example 1B, Table 2).

The pharmaceutical combination of the present invention further comprises a CDK4/6 inhibitor. The D-cyclin-CDK4/6-RB1 axis is a major effector pathway downstream of MAPK signaling that controls the cell transition from G1 to S phase of the cell cycle.

Suitable CDK4/6 inhibitors for use in the present invention include ribociclib, or a pharmaceutically acceptable salt thereof, and palbociclib, or a pharmaceutically acceptable salt thereof.

CDK4/6 inhibitors useful in the pharmaceutical combinations of the present invention include ribociclib or palbociclib.

Ribociclib (Kisqali®) is an orally bioavailable and highly selective small molecule inhibitor with highly specific inhibitory activity against the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes. A particularly useful salt of ribociclib is its succinate.

The present invention further relates to (a) a Raf inhibitor, which is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and (b) CDK4/6 for simultaneous, separate or sequential use, particularly in the treatment of cancer It relates to a pharmaceutical combination comprising an inhibitor.

Selected terms are defined below and throughout this application. Compounds of the invention are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, the following general definitions apply herein.

As used herein, the term "combination of the present invention" refers to (a) a Raf inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, preferably ribociclib, or Refers to a pharmaceutical combination of pharmaceutically acceptable salts thereof. As used herein, the term "combination of the present invention" also refers to (a) a Raf inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof. It refers to co-administration or co-administration of pharmaceutically acceptable salts. A compound of formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof, are administered simultaneously in a unitary pharmaceutical composition comprising both compounds can be used in the combination according to the present invention. Alternatively, the combination may be administered separately in a sequential manner, each in separate pharmaceutical compositions comprising a Raf inhibitor and a CDK4/6 inhibitor, eg, the Raf inhibitor or the CDK4/6 inhibitor first administered and the remainder administered second. Such sequential administration may be close in time (eg, simultaneously) or distant in time.

As used herein, the singular and similar referents in the context of describing the invention are to be understood to encompass both the singular and the plural unless otherwise indicated herein or otherwise clearly contradicted by context. When the plural form is used for compound, salt, etc., it is also taken to mean a single compound, salt, etc.

The term “or” is used herein to mean the term “and/or” and is used interchangeably with “and/or,” unless the context clearly indicates otherwise.

"About" and "approximately" generally mean an acceptable degree of error for a measured quantity, taking into account the nature or accuracy of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, and more typically within 5%. When a dosage is described herein as "about" a specific amount, the actual dosage may vary by up to 10% from the stated amount: such use of "about" means that the precise amount of the designated dosage form It is acknowledged that the amount may differ slightly from the intended amount for a variety of reasons without materially affecting the effectiveness.

Where dosages are recited herein in specific amounts, i.e. without the term “about,” the actual dosage may vary by up to 10% (preferably up to 5%) from the stated amount: such use It is acknowledged that the exact amount may differ slightly from the intended amount for a variety of reasons without materially affecting the in vivo effectiveness of the administered compound.

The terms "comprising" and "including" are used herein in their open, non-limiting sense, unless stated otherwise.

"Combination" or "in combination with" or "co-administration" is not intended to mean that the therapies or therapeutic agents must be physically mixed or administered simultaneously and/or formulated for delivery together, although such delivery methods are not intended to be described herein. within the range described in Such combinations of therapeutic agents may be administered concurrently, prior to, or subsequent to one or more other additional therapies or therapeutic agents. The therapeutic agents may be administered in any order. In general, each agent will be administered at a dose and/or time schedule determined for that agent. It will also be understood that the additional therapeutic agents used in this combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that the additional therapeutic agents used in combination will be used at levels not exceeding those used individually. In some embodiments, levels used in combination will be lower than levels used as single agent therapeutics.

The combinations of the present invention have therapeutic or protective functions or both. For example, these molecules can be administered to a human subject to treat and/or prevent various disorders, such as the cancers described herein.

As used herein, the terms "combination", "therapeutic combination" or "pharmaceutical combination" refer to a fixed combination in one dosage unit form, or a non-fixed combination, or combined administration (co-administration). . do.

The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic disease or disorder described herein. Such administration involves co-administration of such therapeutic agents in a substantially simultaneous manner, such as in a single dosage form with fixed proportions of the active ingredients or in separate dosage forms for each active ingredient (eg, capsules and/or intravenous dosage forms). include that Such administration and co-administration also include the use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times. Regardless of whether the active ingredient is administered as a single formulation or as separate formulations, the drug is administered to the same patient as part of the same course of therapy. In any event, the treatment regimen will provide a beneficial effect in treating the condition or disorder described herein.

Within the meaning of the present invention, simultaneous therapeutic use means the administration of at least two active ingredients by the same route and simultaneously or substantially simultaneously.

Within the meaning of the present invention, separate use means in particular the administration of at least two active ingredients simultaneously or substantially simultaneously by different routes.

Sequential therapeutic use means the administration of at least two active ingredients at different times, by the same or different routes of administration. More specifically, the method of administration means that the total administration of one of the active ingredients is carried out before the administration of the other or before the start of the other.

As used herein, the terms “fixed combination,” “fixed dose,” and “single dosage form” refer to a single formulation formulated to deliver to a patient a jointly therapeutically effective amount of two therapeutic agents for the treatment of cancer. refers to a carrier or vehicle or dosage form. A single vehicle is designed to deliver the amount of each agent in association with any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

The term "non-fixed combination" or "kit of parts" means that the therapeutic agents of the combination of the present invention are administered to a patient as separate entities simultaneously, concurrently, or sequentially without specific time limits, provided that such administration requires To provide therapeutically effective levels of the two compounds in the body of a subject. The latter also applies to cocktail therapy, for example the administration of three or more active ingredients.

As used herein, the term "pharmaceutically acceptable" means, within the scope of sound medical judgment, a subject, such as a mammal or Refers to a compound, substance, composition and/or dosage form suitable for contact with human tissue.

As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative ( antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, glidants, sweetening agents, flavoring agents, dyes, and the like, and combinations thereof. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one therapeutic agent administered to a subject, such as a mammal or human, for treating a particular disease or condition affecting the subject. do. The pharmaceutical combinations may be formulated in pharmaceutical compositions suitable for enteral or parenteral administration, such as dragees, tablets, capsules or suppositories, or ampoules. Unless otherwise indicated, these are in a manner known per se, for example by various conventional mixing, grinding, direct compression, granulation, sugar coating, dissolution, lyophilization processes, or by manufacturing techniques readily apparent to those skilled in the art. manufactured. It will be appreciated that the required effective amount may be achieved by administering a plurality of dosage units, so that the unit content of the combination partner contained in individual doses of each dosage form need not in itself constitute an effective amount. The pharmaceutical composition may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60% of the therapeutic agent. One skilled in the art will be able to select one or more of the carriers described above by routine experimentation and without any undue burden in connection with the particular desirable properties of the dosage form. The amount of each carrier used may vary within the ranges customary in the art. The following references disclose techniques and excipients used to formulate oral dosage forms: The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). Such optional additional conventional carriers include the incorporation of one or more conventional carriers into the initial mixture prior to or during granulation, or granules comprising a combination of agents in an oral dosage form or individual formulations of a combination of agents. By combining with one or more conventional carriers, it can be incorporated into oral dosage forms. In the latter embodiment, the combined mixture may be further compounded, such as via a V-blender, and then compressed into, molded into, or encapsulated into a tablet, e.g., a monolithic tablet, or Can be recharged with sachet.

Pharmaceutical compositions may be presented in unit dosage form containing a predetermined amount of the active ingredient per unit dose. In certain embodiments, a unit dose comprises one or more vehicles, each vehicle comprising an effective amount of at least one therapeutic agent in association with pharmaceutically acceptable carriers and excipients. In some embodiments, a unit dose is one or more tablets, capsules, pills, injections, infusions, patches, etc. administered to a patient at the same time. As is known to those skilled in the art, the amount of active ingredient per dose will vary with the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing the active ingredient in a daily dose or sub-dose, or an appropriate portion thereof. Furthermore, such pharmaceutical compositions may be prepared by any method well known in the art of pharmacy.

A pharmaceutical composition of the present invention may comprise a "therapeutically effective amount" or "effective amount" of a compound of the present invention. The term "pharmaceutically effective amount", "therapeutically effective amount" or "clinically effective amount" of a combination of therapeutic agents is observable or clinically significant relative to a baseline of clinically observable signs and symptoms of the disorder treated with the combination. An amount sufficient for the dosage and duration necessary to provide one improvement. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex and weight of the individual. Also, a therapeutically effective amount is one in which the therapeutically beneficial effect is greater than any toxic or adverse effects of the therapeutic agent. A “therapeutically effective dosage” preferably modulates measurable parameters, such as tumor growth rate or disease progression in a desirable manner. The ability of compounds to modulate measurable parameters can be evaluated in animal model systems predictive of efficacy in human tumors to help establish appropriate dosing levels and schedules. Alternatively, these properties of the composition can be assessed by examining the ability of the compound to modulate undesirable parameters using in vitro assays known to the skilled practitioner.

As used herein, the term "conjointly therapeutically active" or "co-therapeutic effect" means that the therapeutic agents may be given concurrently, separately or sequentially, at their preferred time intervals, such that the subject being treated; In particular, it means that humans still exhibit a (preferably synergistic) interaction (co-therapeutic effect). Whether this is true may depend, inter alia, on the blood levels of the compound, indicating that both compounds are present in the blood of the human being treated for at least a certain time interval.

As used herein, the term “agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. It is also understood that an "agent" may be a single compound or a combination or composition of two or more compounds.

The term “cancer” is preferably cancer.

The term “cancer” as used herein refers to a disease characterized by the unwanted, uncontrolled growth of abnormal cells. Cancer cells can spread to other parts of the body either locally or through the bloodstream and lymphatic system. As used herein, the term “cancer” or “tumor” includes malignant as well as precancerous cancers and tumors. The term “cancer” is used herein to mean a wide range of tumors, including all solid and hematologic malignancies.

The term “proliferative disease” or “proliferative disorder” also refers generally to cancer or cancer as defined herein.

"Oral dosage form" includes unit dosage forms prescribed or intended for oral administration.

As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disorder, e.g., a proliferative disorder, or administration of one or more therapies. Refers to amelioration of one or more symptoms, suitably one or more discernible symptoms of a disorder resulting from Refers to the improvement of at least one measurable physical parameter of a proliferative disorder that is not discernible, such as the growth of a tumor In another embodiment, the terms "treat", "treatment" and "treating" refer to In other embodiments, the term refers to inhibiting the progression of a proliferative disorder physically, e.g., by stabilization of an identifiable symptom, physiologically, or both, e.g., by stabilization of a physical parameter. “Treat”, “treatment” and “treating” refer to reduction or stabilization of tumor size or number of cancer cells.

The terms “treat”, “treatment” and “treating” refer to reducing the incidence and severity of adverse events (AEs) and serious AEs (SAEs), including changes in experimental values, vital signs, and electrocardiogram (ECG), in a patient or patient population. includes

The terms “treat”, “treatment” and “treating” refer to, for example, the overall response rate ( ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

Within the meaning of the present disclosure, the term "treat" also means arresting, delaying, and/or reducing the risk of developing or worsening a disease (ie, the period prior to clinical manifestation of a disease). The term “protect” is used herein to mean preventing, delaying, or treating, or suitably all, the development, continuation or exacerbation of a disease in a subject, such as a mammal or human.

The term “subject” or “patient” as used herein is intended to include an animal suffering from or suffering from cancer, or any disorder that directly or indirectly involves cancer. Examples of subjects include mammals such as humans, apes, monkeys, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In a preferred embodiment, the subject is a human, such as a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer.

The terms “inhibition”, “inhibitor” or “antagonist” include a decrease in the activity of a particular parameter, eg, a given molecule or pathway. For example, inhibition of the activity of a targeted kinase (Raf or CDK4/6) by 5%, 10%, 20%, 30%, 40% or more is encompassed by this term. Thus, inhibition can be 100%, but not necessarily 100%.

As used herein, "salt" (meaning "or salts thereof" or "salt thereof") is a free compound of the present invention, either alone or in a combination, such as a compound of formula I or CDK4/6 which is a Raf inhibitor. It may be present in a mixture with an inhibitor, preferably ribociclib, and is preferably a pharmaceutically acceptable salt. For example, such salts are formed from compounds of the combinations of the present invention having a basic nitrogen atom, preferably as acid addition salts with organic or inorganic acids, in particular as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt that retains the biological effectiveness and properties of the compound and which is typically biologically or otherwise desirable. Compounds can form acid addition salts by the presence of amino groups.

A list of suitable salts can be found in "Remington's Pharmaceutical Sciences" , 20th ed., Mack Publishing Company, Easton, Pa., (1985); New version: "Remington: the science and practice of pharmacy" , 22nd ed., Pharmaceutical Press, London (2012); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2011).

For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are used (where applicable in the form of pharmaceutical preparations) and are therefore preferred. In light of the close relationship between the novel compound in its free form and in its salt form, including salts that can be used as intermediates, for example, in the purification and identification of the novel compound, any reference to the free compound corresponds appropriately It is understood to also refer to salts and excipients. The salts of the compounds used in the combinations of the present invention are preferably pharmaceutically acceptable salts; Pharmaceutically acceptable salts that form suitable counterions are known in the art. Unless otherwise specified or specified herein, reference to a therapeutic agent useful in a pharmaceutical combination provided herein includes both the free base of the compound and all pharmaceutically acceptable salts of the compound.

As used herein, the term "synergistic effect" refers to two agents, for example, to produce an effect greater than the simple addition of each drug effect administered alone, for example, an effect indicating the progression of cancer or a symptom thereof. For example, it refers to the action of a compound of formula I, which is a Raf inhibitor, or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof.

In one embodiment, the combination of the present invention comprises (a) a Raf inhibitor, or a pharmaceutically acceptable salt thereof, which is a compound of formula (I): and (b) a CDK4/6 inhibitor:

[Formula I]

.

.

In one embodiment, the combination of the present invention comprises (a) a compound of formula (I) that is a Raf inhibitor, or a pharmaceutically acceptable salt thereof, and (b) ribociclib and palbociclib, and a pharmaceutically acceptable salt thereof CDK4/6 inhibitors selected from:

[Formula I],

.

.

The CDK4/6 inhibitor is preferably ribociclib or a pharmaceutically acceptable salt thereof.

The combination of the present invention may be effective in the treatment of cancer, as it showed increased depth and durability of tumor responses compared to single agent therapy in cell lines and human xenograft models (see Examples). Accordingly, the present invention provides a CDK4/6 inhibitor, and in particular ribociclib, or Provided are compositions and methods using a Raf inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable salt thereof.

Preferably, these therapeutic agents are administered in therapeutically effective dosages that, when combined, provide a beneficial effect. The present invention relates to a combination of the present invention useful for separate, simultaneous or sequential administration to a subject in need thereof, particularly for treating cancer. The invention as defined alternatively relates in particular to a combination of the invention for use in the treatment of cancer.

Cancer is multifactorial. Under certain circumstances, therapeutic agents with different mechanisms of action may be combined. However, contemplation of any combination of therapeutic agents with different modes of action does not necessarily result in a combination with a beneficial effect, nor is it necessarily interpreted as a clinical benefit for a patient suffering from a particular cancer.

In the present invention, administration of a combination of the present invention results in a more advantageous effect, e.g., a synergistic or improved anti-proliferative effect, e.g. with respect to delaying or inhibiting the progression of cancer or a symptom thereof. is expected, and may also provide additional beneficial effects such as any one or more of the following: fewer side effects compared to any therapy in the prior art or compared to monotherapy using any one of the combination partners , such as skin-related toxicity (eg rash) and gastrointestinal toxicity (eg diarrhea), improved tolerability, higher quality of life and reduced morbidity.

The therapeutic agents of the combination of the present invention may be administered individually, simultaneously or sequentially to a subject in need of such treatment. Preferably, these therapeutic agents are administered in therapeutically effective dosages that, when combined, provide a beneficial effect. Accordingly, in one embodiment of the present invention, the COMBINATION OF THE INVENTION is for use in the treatment of cancer, in particular a cancer as described herein.

The term “cancer” is used herein to mean a broad spectrum of tumors, including all solid and hematologic malignancies. The cancer may be early, intermediate or late stage cancer. The cancer may be locally advanced or metastatic cancer.

The cancer treated by the combination therapies described herein may be a cancer that may have progressed following criteria of treatment or for which no effective standard of care exists.

In one embodiment, the cancer is melanoma.

Combinations of the present invention include cancers, such as cancers carrying one or more mitogen-activated protein kinase (MAPK) pathway alterations, such as NRAS mutant tumors, and in particular at least one of Ras as described herein. It is particularly useful for the treatment of tumors expressing gain-of-function mutations and/or at least one gain-of-function mutation of Raf as described herein.

NRAS mutant cancers or tumors. The NRAS mutation of interest may be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. The term “ NRAS-mutant ” tumor or cancer refers to any tumor displaying a mutated NRAS protein, in particular a gain-of-function NRAS-mutant; especially any G13R, Q61K, Q61L, Q61R, NRAS-mutant tumor. Thus, NRAS-mutant melanoma includes melanomas having at least one NRAS mutation corresponding to Q61K, Q61L or Q61R. The cancer may be a NRAS QG13R-mutant melanoma. Also included are KRAS mutant cancers or tumors. The KRAS mutation of interest may be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. The term “KRAS-mutant” tumor or cancer includes any tumor that displays a mutated KRAS protein. The cancer may be early, intermediate or late stage cancer. The cancer may be locally advanced or metastatic cancer.

In other embodiments, the cancer is resistant or refractory to standard of care.

In another embodiment, the cancer is resistant or refractory to standard of care with dacarbazine.

In another embodiment the cancer is resistant or refractory to treatment with a MEK inhibitor.

In another embodiment, the cancer is resistant or refractory to treatment with an immunotherapeutic treatment comprising therapy with one or more checkpoint inhibitors.

In another embodiment, the cancer is resistant or refractory to treatment with a cytotoxic agent, such as nitrosourea and/or mitomycin C.

In one embodiment, the cancer is characterized by at least one mutation selected from the group comprising a NRAS protein.

In one embodiment, the cancer is characterized by a NRAS mutation.

In one embodiment, the COMBINATION OF THE INVENTION relates to a method of treating cancer, in particular melanoma.

Combinations of the present invention may be particularly useful for treating NRAS-mutant melanoma.

In one embodiment, the cancer is characterized by at least one mutation selected from the group comprising a KRAS protein.

In one embodiment, the cancer is characterized by a KRAS mutation.

In one embodiment, the COMBINATION OF THE INVENTION relates to a method of treating cancer, in particular pancreatic cancer.

Combinations of the present invention may be particularly useful for treating KRAS-mutant PDACs.

In one embodiment, a therapeutically effective amount of the invention comprising (a) a Raf inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein; and (b) a CDK4/6 inhibitor. Provided herein is a method of treating cancer in a subject in need thereof comprising administering a pharmaceutical combination. In a preferred embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

In an embodiment, in a subject in need of treatment for cancer comprising the step of simultaneously, separately or sequentially administering to the subject in need thereof a combination of the present invention in an amount concomitantly therapeutically effective for said cancer herein. A method of treating cancer is provided, wherein the combination of the present invention comprises (a) a Raf inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein; and (b) a CDK4/6 inhibitor. do. In a preferred embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention relates, inter alia, to a method for the treatment of a cancer that carries at least one mitogen-activated protein kinase (MAPK) pathway alteration. In one embodiment, the invention relates to a method of treating cancer characterized by at least one mutation in NRAS. In another embodiment, the invention relates to a method of treating cancer characterized by at least one mutation in KRAS. In one embodiment, the present invention relates to the use of a combination of the present invention for the manufacture of a medicament for the treatment of cancer, in particular a cancer as described herein. In one embodiment, the COMBINATION OF THE INVENTION is for use in the manufacture of a medicament for the treatment of cancer.

In a further embodiment, the invention relates to the use of a combination of the invention for the manufacture of a medicament for the treatment of cancer characterized by a gain-of-function mutation in the MAPK pathway.

In one embodiment, a combination or composition provided herein, or both, exhibits a synergistic effect.

Accordingly, in one aspect, the present invention provides a method for enhancing the efficacy of an anti-cancer compound by using it in combination with another anti-cancer compound, in particular, a compound of formula (I), or a pharmaceutically acceptable salt thereof, as a single agent (monotherapy); or a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof, to provide enhanced efficacy achievable by administering a similar dose of one of the CDK4/6 inhibitors. Provided is a method of using a Raf inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof.

A further benefit provided by the present invention is that lower doses of the therapeutic agents of the combinations of the present invention may be used, for example, the dosages may often be lower as well as may be applied less frequently, or lower doses of the therapeutic agent may be used. It may be that the therapeutic agent of the combination of the present invention can be used to reduce the incidence of side effects observed with one of the combination partners alone.

In some embodiments, the compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof, is It may be administered as a therapeutic dose or at lower therapeutic doses compared to single agent dose levels. In certain embodiments, the concentration or dosage of one therapeutic agent necessary to achieve inhibition, e.g., growth inhibition or tumor shrinkage, is such that when the other therapeutic agent is used or administered in combination with the first therapeutic agent, each therapeutic agent is administered separately. lower than the case In certain embodiments, in combination therapy, the concentration or dosage of one therapeutic agent necessary to achieve inhibition, e.g., growth inhibition, is greater than the therapeutic dose as monotherapy, e.g., 10-20%, 20-30% , 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90% lower.

In determining a synergistic interaction between one or more components, the optimal range for effect and the absolute dose range for each component for effect are different w/w ratio ranges and doses for patients in need of treatment with the components. It can be clearly measured by administering to In the case of humans, the complexity and cost of conducting clinical studies on patients may make it impractical to use this type of trial as a primary model for synergy. However, observations of synergy in certain experiments can predict effects in other species, and existing animal models can be used to further quantify synergistic effects. Observation of synergy in one species can predict effects in another species, and, as described herein, using animal models, synergistic effects can be measured, and the results of these studies also indicate pharmacokinetics/pharmacodynamics. By application of the (PK/PD) method, it can be used to predict the range of effective dose ratios and absolute doses and plasma concentrations required in other species. Established correlations between tumor models and effects seen in humans suggest that synergy in animals can be demonstrated, for example, by xenograft models or in appropriate cell lines. Established test models can reveal that the combinations of the present invention result in the beneficial effects described herein. A person skilled in the art is fully capable of selecting relevant test models to demonstrate these beneficial effects. The pharmaceutical activity of the combinations of the invention may be demonstrated, for example, in clinical studies or in in vivo or in vitro test procedures, as essentially described herein.

Administration of a combination (ie, administration of one therapeutic agent with another combination partner, i.e., “co-administration”) is the administration of the combination in a single dosage form or unit dosage form, simultaneous but separate administration of the separate agents of the combination, or a combination sequential administration by any suitable route of separate formulations of water. Each combination partner of the combination of the present invention is administered individually at different times during the course of treatment, or sequentially in any order or together in divided or single combination form, eg, simultaneously or jointly in a therapeutically effective amount. , preferably in a synergistically effective amount, eg, in daily or intermittent (ie, not daily) dosages corresponding to the amounts described herein.

A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the methods, treatments, combinations and compositions disclosed herein is a strong inhibitor of BRAF and CRAF. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 200-1200 mg, about 300-1000 mg, about 400-800 mg, or about 500-600 mg (e.g., 1 once daily) in a total daily dose. The compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg or about 1200 mg in total It may be administered in one dose. In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a total daily dose selected from about 200 mg, 400 mg, 600 mg, 800 mg and 1200 mg.

The total dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered once a day, or may be divided into two doses, each dose of the compound of formula (I) administered twice a day, the actual dosage and The time of administration depends on the age, weight and sex of the patient; the extent and severity of the cancer being treated; and the judgment of the treating physician. Preferably, the total dose of the compound of formula (I) is administered once daily. In another preferred embodiment, the total dose of the compound of formula (I) is administered twice daily.

As part of the combination according to the invention the CDK4/6 inhibitor is administered in a therapeutically effective amount to a subject in need of treatment.

In a preferred embodiment, the total daily dose of ribociclib, a CDK4/6 inhibitor, or a pharmaceutically acceptable salt thereof, administered daily as part of a combination according to the invention in a subject in need thereof is about an amount selected from 100 mg to about 600 mg; Suitably, the amount will be selected from about 200 mg to about 400 mg per day. In a preferred embodiment, ribociclib, or a pharmaceutically acceptable salt thereof, is administered in a daily dose selected from about 100 mg, about 200 mg, about 400 mg and about 600 mg. Alternatively, the total dose may be divided into two doses administered twice daily.

In particular, the following daily doses are conceivable:

When a dose or dosage is referred to herein, the stated amount refers to the amount of the therapeutic agent. For example, when a 200 mg dose of ribociclib is administered and ribociclib is administered in a tablet containing ribociclib succinate, the tablet will contain the same ribociclib succinate as 200 mg ribociclib. .

In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, ribociclib is prepared for administration via oral delivery and may be used in salt form, eg, succinate form. In some embodiments, the compound is prepared in tablet form for oral administration. Tablets can be produced in various dosages for flexible administration.

The dose of ribociclib, or a pharmaceutically acceptable salt thereof, may be administered once a day, or twice a day, or three times a day, or four times a day. The total daily dose of ribociclib or a pharmaceutically acceptable salt thereof may be administered once or twice a day.

For example, as part of a combination therapy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered in a total daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg or about 1200 mg. and ribociclib may be administered, for example, in the form of succinate, in a total daily dose selected from about 100 mg, about 200 mg, about 400 mg and about 600 mg. The daily dose of a compound of formula (I) may be administered once or twice per day. Thus, a dose of about 200 mg of the compound of formula I may be administered twice per day (total daily dose of about 400 mg), and a dose of about 100 mg or about 200 mg of ribociclib may be administered once per day. have. Alternatively, a dose of about 200 mg of the compound of formula I may be administered twice per day (total daily dose of about 400 mg), and a dose of about 100 mg or about 200 mg of ribociclib is administered twice per day. can be

Alternatively, the compound of formula I may be administered at 600 mg twice daily (b.i.d or BID) and ribociclib at 600 mg once daily. The compound of formula (I) may also be administered at 400 mg twice daily (BID) and ribociclib at 200 mg once daily.

The compound of formula (I) is preferably administered continuously, ie without a washout period.

The CDK4/6 inhibitor may be administered continuously, ie, without interruption during the treatment period, or with a washout period.

For example, a CDK4/6 inhibitor, eg, ribociclib or a pharmaceutically acceptable salt thereof, may be administered for 3 weeks and discontinued for 1 week, or administered for 2 weeks and discontinued for 2 weeks; Preferably, it can be administered in 3 weeks administration and 1 week interruption. In particular, the following therapies may be used according to the present invention.

For example, the compound of formula (I) may be given once or twice a day without a drug washout period, and a CDK4/6 inhibitor (eg, ribociclib, or a pharmaceutically acceptable salt thereof) is administered for 3 weeks. and 1 week interruption.

In the contemplated drug regimen, the total daily dose of the compound of formula (I) and the CDK4/6 inhibitor is as described above and throughout this specification.

For example, a dose of 400 mg or 600 mg of a compound of formula (I) may be given once or twice daily, preferably twice a day, and a dose of 200 mg of ribociclib once daily , 3 weeks of dosing and 1 week interruption.

For example, a dose of 600 mg of a compound of formula (I) may be given once or twice a day, preferably twice a day, and a dose of 600 mg of ribociclib is given once a day, for 3 weeks. It may be given as a dosing and one week interruption.

A compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof, may be used together according to the method disclosed herein. Both compounds can be administered for 2 days, 3 days, 4 days, 5 days, 6 days as the treatment of the present invention is deemed appropriate by the treating physician and further guided using the methods described herein to determine suitable dosages and dosing frequencies. They may be administered together or separately, depending on the intended dosage and frequency of administration, as it is contemplated that they may continue for days, 1 week, 2 weeks, 3 weeks, 4 weeks, or 4 weeks or more. The frequency of administration may vary depending on the compound used and the particular condition being treated. In general, the use of a dosage that is minimal enough to provide an effective treatment is preferred and will depend on the age, weight, and sex of the patient; the extent and severity of the cancer being treated; and the judgment of the treating physician. Patients can be monitored for treatment efficacy using assays suitable for the condition being treated, generally familiar to those skilled in the art.

Combinations of the present invention that obtain efficacy without toxicity (i.e., a compound of formula I, or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof) Optimal ratios, individual and combination dosages and concentrations of the combination partners of the subject's age, weight, general health, sex and diet; time of administration and route of administration; and other medications the subject is taking. Optimal dosages can be established using routine tests and procedures well known in the art. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.

The therapeutic agents of the combinations of the present invention may be administered by any suitable route. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient of the combination and the location of the cancer to be treated. In addition, each of the therapeutic agents may be administered by the same or different routes, and a therapeutic agent, for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably ribociclib, or its It will be appreciated that pharmaceutically acceptable salts may be formulated together into a pharmaceutical composition.

A compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof, may be used together as disclosed herein. The two therapeutic agents of the combination of the present invention may be administered together (simultaneously), sequentially or separately.

Furthermore, it is not critical whether the compounds are administered in the same dosage form, eg, one compound may be administered topically and the other compound administered orally. Suitably, both therapeutic agents are administered orally. The compounds may be administered in the same or different dosage forms.

Thus, in one embodiment, one or more doses of a compound of formula I, or a pharmaceutically acceptable salt thereof, is combined with one or more doses of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof. administered simultaneously, sequentially or separately.

In one embodiment, multiple doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially or separately with multiple doses of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof. is administered with

In one embodiment, multiple doses of a compound of formula I, or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially or concurrently with a single dose of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof, or administered individually.

In one embodiment, a single dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or concurrently with multiple doses of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof; administered individually.

In one embodiment, a single dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially with a single dose of a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof. or administered individually.

In all the above embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered initially, or a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof, may be administered first. can

In one embodiment, (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, suitably ribociclib, or a compound thereof, for use in the methods of the invention herein Pharmaceutical compositions comprising pharmaceutically acceptable salts are provided. In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable diluents, excipients or carriers. Carriers, diluents or excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof. These elements of the pharmaceutical composition used may be presented as separate pharmaceutical combinations or may be formulated together into one pharmaceutical composition. The combinations disclosed herein may be administered together in a single composition or may be administered separately in two or more different compositions, such as a composition or dosage form as described, wherein the components are in the same dosage form by any suitable route; or in separate formulations, alone, eg, as indicated above, or in combination with one or more pharmaceutically acceptable carriers.

Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject being treated; Each unit, in association with the required pharmaceutical carrier, contains a predetermined amount of an active compound calculated to produce the desired therapeutic effect (eg, a compound of formula I, or a pharmaceutically acceptable salt thereof, or a CDK4/6 inhibitor, suitable preferably contains ribociclib, or a pharmaceutically acceptable salt thereof The unit dosage form may also be a fixed combination.

An effective dosage of each of the combination partners may require more frequent administration of one of the therapeutic agents compared to the other therapeutic agent in the combination. Accordingly, to allow for proper dosing, the packaged pharmaceutical product contains one or more dosage forms containing the combination of compounds, and one therapeutic agent of the combination of the present invention but not the other therapeutic agent of the combination of the present invention. It may contain one or more dosage forms that do not

When the combination partner used in the combination of the present invention is applied in the form marketed as a single drug, their dosage and administration mode, unless otherwise stated, shall be in accordance with the information provided on the package insert of each commercially available drug. can

Thus, to allow for proper dosing, the packaged pharmaceutical product includes one or more dosage forms containing a combination of agents, and one or more dosage forms containing one of the therapeutic agents of the combination but not the other therapeutic agents of the combination. may contain.

Also, one or more other elements: instructions; other reagents for use with the combinations of the present invention; a device or other material for preparing a compound for administration, such as a mixing vessel; pharmaceutically acceptable carriers; Combination kits comprising as therapeutic agents a combination of the invention for simultaneous, separate or sequential administration as described herein, together with a device or other material for administration to a subject, such as a syringe, are within the scope of the invention. .

The term “combination kit” or “kit of parts” as used herein refers to a pharmaceutical composition or composition for use according to the present invention. When the compounds are both administered simultaneously, the combination kit comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitable in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions Preferably, it may contain ribociclib, or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt thereof. A compound of formula (I) or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof When the acceptable salts are not administered at the same time, the combination kit is suitable for a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages Preferably, it will contain ribociclib or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, a kit of parts comprising: (a) (i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, diluent and/or carrier A Raf inhibitor compound selected from the group consisting of, and (b) a CDK4/6 inhibitor, preferably ribociclib, or a pharmaceutically acceptable salt thereof is provided together with a pharmaceutically acceptable excipient, diluent or carrier, is provided in a form suitable for sequential, separate and/or simultaneous administration. Combination kits may also be provided with instructions, such as dosage and administration instructions. These dosages and instructions for administration may be of the kind provided to the physician, for example by means of the drug label, or may be of the kind provided by the physician, such as instructions for the patient.

Other features, objects and advantages of the invention will become apparent from the description and drawings and from the claims.

The following examples illustrate the invention described above; They are not intended to limit the scope of the invention in any way. The beneficial effects of the pharmaceutical combinations of the present invention can be determined by other test models so known to those skilled in the art.

Example

Example 1: Enhanced Combination Effect of CDK4/CDK6 Inhibition and RAF Inhibition in NRAS Mutant Melanoma Cell Lines

Way

A compound of formula I (NVP-LXH254) and ribociclib (NVP-ribociclib) were synthesized, and a compound stock solution of ribociclib was prepared in DMSO to a final concentration of 10 mM. For combination plots, serial dilutions of the working stock in 3-fold increments (2-fold increments for ribociclib) in the appropriate cell culture medium were used for NVP-LXH254 and 10 µM to 1.5 nM for NVP-Ribociclib ( Final assay concentrations ranging from 10 μM to 39 nM (in the form of succinate) were achieved.

SK-MEL-2 cells were purchased from the American Center for Microbial Conservation (ATCC), MEL-JUSO cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), MM415 cells were purchased from Cell Bank Australia, and IPC-298 and SK-MEL-30 cells were obtained from GNF. IPC-298, MEL-JUSO, MM415 and SK-MEL-30 cells were cultured in RPMI medium (ATCC), and SK-MEL-2 cells were cultured in EMEM medium (ATCC) supplemented with 10% fetal bovine serum (Gibco). Incubated and incubated at 37° C./5% CO 2 . For combinatorial activity, cells were seeded in 80 μl of medium in 96-well plates (Corning #3904) at 5,000 cells per well and incubated overnight prior to compound addition. Compound stocks (10×) were freshly prepared in appropriate culture medium and manually added to the plate by motorized multichannel pipette to generate a complete 10×10 combination matrix grid. In a minimum of 3 duplicate wells, quantification of the combination effect after 72 hours as well as the number and viability of cells upon compound addition was performed using a fluorescence-based DNA-binding proliferation assay, i.e., CyQUANT® Direct (Thermo #C35011 according to the manufacturer's protocol). ) was evaluated by Combination data analysis was performed using the internal Novartis software, Combination Analysis Module. The present application used the Loewe dose additivity model to calculate a weighted synergistic score for each dose substrate that modulates for dose sampling and coverage, and a weight in favor of the combination effect at high inhibition levels (Lehar et al. ., 2009).

Cells were plated in 6-well dishes (#3506, Corning, NY) at a density of 0.5×10 6 cells per well. One day after plating, the lines were treated with the single agent ribociclib at 200, 400 and 800 nM and the combination of the compound of formula I (300 nM) for 48 hours. RIPA Lysis Buffer (#89900, Thermo Fisher, Waltham, MA) containing a protease inhibitor (#87785, Thermo Fisher, Waltham, MA) and a phosphatase inhibitor (#78420, Thermo Fisher, Waltham, MA) cells were harvested from Proteins were separated on 4-12% Bis-Tris NuPAGE SDS gels (#WG1403B×10, Life Technologies, Carlsbad, CA) and the Trans-Blot Turbo System (Bio-Rad, Hercules, CA) was run. was transferred to nitrocellulose. 1:1000 dilution of antibody recognizing pRB (#8516, Cell Signaling Technology, Beverly, MA), pCDK4/61/2 (#9154, Cell Signaling Technology, Beverly, MA), pERK1/2 ( #4730, Cell Signaling Technology, Beverly, MA), and pRSK (#9348, Cell Signaling Technology, Beverly, MA) and a 1:5000 dilution of antibody-recognized β-actin (#AM4302, Life Technologies, CA) The protein was detected using the Carlsbad, Main. Protein levels were detected using anti-mouse-HRP or anti-rabbit-HRP secondary antibodies and SuperSignal West Femto (#34096, Thermo Scientific) on a GE Image Quant LAS 4000 imaging system (GE Healthcare, Woburn, MA). , Waltham, MA) or Dura Chemiluminescent substrate (#34076, Thermo Scientific, Waltham, MA).

result

The combination of the compound of formula I and ribociclib demonstrated improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in SK-MEL-30 melanoma cell line ( FIG. 1 ). The SK-MEL-30 melanoma cell line carries consistent mutations in NRAS (Q61K) and BRAF (D287H).

The combination of a compound of formula I and ribociclib demonstrated improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in the IPC-298 melanoma cell line ( FIG. 2 ). The IPC-298 melanoma cell line carries the NRAS mutation (NRASQ61L).

The combination of the compound of formula I and ribociclib demonstrated improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in Meljuso melanoma cell line ( FIG. 3 ). The Meljuso melanoma cell line carries the NRAS mutation (NRASQ61L).

The combination of a compound of formula I and ribociclib demonstrated improved anti-proliferative and phospho-Rb inhibitory effects compared to single treatment in Meljuso melanoma cell line ( FIG. 4 ).

Example 2: Efficacy of the combination of a compound of formula (I) and ribociclib in xenografts from NRAS mutant melanoma patients

The effect of selective dual RAF and CDK4/6 inhibition in vivo was studied by combining a compound of formula I and ribociclib in melanoma xenografts from nine NRAS mutant patients.

Way

Animals and Maintenance Conditions Outbred outbred athymic (nu/nu) female mice (athymic nude-nu") (Charles River, Indianapolis) Novartis with ad libitum access to food and water at least 3 days prior to manipulation. The animals were acclimatized to the NIBR facility (Table 1).

Statements Regarding Animal Welfare Animals were handled in accordance with Novartis NIBR ACUC regulations and guidelines.

Test Compounds and Formulations: Compounds of formula I (in free base form) were dosed p.o. (oral) with MEPC4 vehicle (45% Cremophor RH40 + 27% PEG400 + 18% corn oil glycerides + 10% ethanol). The compound of formula I was formulated at 5 mg/ml. Ribociclib succinate was administered p.o. (oral) in a vehicle of 0.5% methyl cellulose; Ribociclib was formulated at 7.5 mg/ml.

Development of a patient-derived xenograft (PDX) model in nude mice

HMEX5727, HMEX3486, HMEX20667, HMEX2921, HMEX20864, HMEX20585, HMEX4339, HMEX20744 and HMEX21124 patient-derived tumor xenografts (PDX) were propagated in nude mice by serial passage of tumor slurries. Briefly, fragments of new tumors from previous passages were homogenized using a Gentle MACS dissociator (MACS (Miltenyi Biotec, #120-005-331)) and tissue grinder (Chemglass lifeSciences #CLS-5020-085). Passage through, dilute in PBS and mix with equal volume of Matrigel™ Matrix (Corning #354234).Then, 200 μl of tumor slurry is subcutaneously implanted in the right flank of female nude mice.Tumor volume is transferred to caliper and was calculated using the following formula: Tumor volume (V _t ) (mm 3 ) = (l×w2)/2, where l is the longest axis of the tumor and w is perpendicular to l. Mice were monitored twice/week for growth, weight and physical condition.

Efficacy Study Design in the PDX Model

The efficacy study design for all models is shown in Table 2. The test formulation was dosed at a dose volume of 10 ml/kg, which was adjusted according to body weight. Tumor dimensions and body weights were collected at randomization and twice weekly for the duration of the study. Mice were randomized into treatment groups (n=3 to 5/group) when the mean tumor volume was approximately 350 mm 3 , and treated with tumor outgrowth (tumor volume >/= 700 mm 3 ) or until approximately 90 days. The percent change in tumor volume for all models was determined by comparing the change in tumor volume to its baseline at time t. The best response was the minimum of the percent change in tumor volume for t≧10 days. When untreated control mice were sacrificed, two mice from each group were also sacrificed and tumors were collected for future pharmacodynamic (PD) analysis. Efficacy was performed with 3 mice/group after this time point.

data analysis

Body weight: The percent change in body weight _{was calculated as (BW present-} BW _onset )/(BW _onset )×100%. Data are presented as % change in mean body weight from the date of initiation of treatment±SEM.

Tumor Volume: The percent change in tumor volume was determined by comparing the change in tumor volume to its baseline at time t using the formula: % tumor volume change = ΔV _t = 100%×((V _t - V _onset )/ V _onset ). The best response was the minimum of _{ΔV t for t≥10 days.}

here,

ΔV _t = change in tumor volume

V _t = tumor volume in the drug-treated (or untreated) group on a given study day;

V volume in drug-treated (or untreated) group on the day of _{initiation of dosing.} The best response >/= -30% was considered tumor regression.

Kaplan-Meier survival plots were generated using GraphPad Prism software for individual mice that reached an endpoint of tumor size greater than or equal to 700 mm 3 . Statistical analysis of the significance between groups was performed using the log-rank (Mantle-Cox) test. p<0.05 was considered significant.

Results: Efficacy of the combination of a compound of formula I and ribociclib in a patient-derived NRAS mutant melanoma xenograft model in nude mice

The antitumor efficacy of compounds of formula I when used in combination with ribociclib was determined using a melanoma xenograft model from nine NRAS mutant patients in nude mice: HMEX5727 (NRASQ61K), HMEX3486 (NRASQ61K), HMEX20667 (NRASQ61R). ), HMEX2921 (NRASQ61R), HMEX20585 (NRASQ61R), HMEX20864 (NRASQ61R), HMEX21124 (NRASQ61H), HMEX20744 (NRASQ61K) and HMEX4339 (NRASQ61R). Mice were treated for approximately 90-100 days or until tumor size reached 700 mm 3 or greater in each group. Percent change in tumor volume (best response), percentage change in body weight and survival are reported in Table 3, FIGS. 5 and 6 .

compound of formula I + dosed at 50 mg/kg bid The combined activity of ribociclib, and compound of formula I plus 75 mg/kg qd (ribociclib) resulted in tumor regression in 44% of test models. In comparison, neither a single formulation of compound I at 50 mg/kg bid nor a single formulation of ribociclib dosed at 75 mg/kg qd achieved tumor regression in any of the models tested (Table 3 and Figure 3). 5). In addition, the combination of compound of formula (I) + ribociclib resulted in significantly increased median survival compared to each single agent or untreated control ( FIG. 6 ).

Both single agent and combination treatments were very well tolerated as judged by the lack of weight loss according to the model. One mouse treated with the compound of formula (I) was sacrificed at an earlier time point due to weight loss.

Conclusion and discussion

The in vivo activity of the compound of formula I+ribociclib combination in NRAS mutant melanoma was profiled in a panel of melanoma xenografts from 9 NRAS mutant patients. The combined activity of Compound I+Ribociclib dosed at 50 mg/kg bid (Compound of Formula I)+75 mg/kg qd (Ribociclib) resulted in tumor regression in 44% of test models. In comparison, neither a single formulation of compound I at 50 mg/kg bid nor a single formulation of ribociclib dosed at 75 mg/kg qd achieved tumor regression in any of the models tested. In addition, the combination of compound of formula (I)+ribociclib was well tolerated and resulted in a significantly increased median percent survival compared to each single agent or untreated control. A strong synergy of the CDK4/6 inhibitor ribociclib with the compound of formula I was observed in melanoma xenografts from NRAS mutant patients, leading to significant tumor regression and increased median survival percentage in a preclinical model. Collectively, these data indicate that the combination of a compound of formula (I)+ribociclib can achieve a larger and more sustainable response in NRAS mutant melanoma patients.

Example 3: Phase Ib, open-label, multicenter study of a compound of formula I in combination with ribociclib in patients with NRAS mutant melanoma

The purpose of the study was to characterize the safety and tolerability of the dual combination of a compound of formula I and ribociclib in patients with NRAS mutant melanoma, and to identify recommended doses.

The primary endpoints are:

(1) Safety: Serious AEs (SAE), including changes in incidence and severity of adverse events (AEs) and experimental values, vital signs and electrocardiogram (ECG), dose limiting toxicity (DLT) during cycle 1 (dose escalation alone) occurrence and characteristics of

(2) Tolerability: Discontinuation, reduction of dose, and dose intensity.

The secondary objectives and endpoints are as follows:

(a) To evaluate the preliminary antitumor activity of a compound of formula (I) in combination with ribociclib. Overall response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Dose Expansion Part Only: Overall Survival (OS), Plasma Concentrations and Induced PK Parameters

(b) Characterization of the pharmacokinetic (PK) profile of a compound of formula (I) and ribociclib in combination. Changes from baseline in the PD marker DUSP6 in tumor tissue.

(c) To evaluate the pharmacodynamic (PD) effect of a compound of formula (I) and ribociclib (DUSP6) in combination in tumors

The exploratory objectives and endpoints are as follows:

(a) To evaluate genetic alterations in a number of cancer-associated genes in tumor samples (tumors and plasma (circulating free DNA (cfDNA))) to assess their relationship with the development of clinical outcome/resistance, disease progression and clinical Genetic alterations of a number of cancer-associated genes found in tumor samples at baseline and post-dose, including their relationship to outcome endpoints.

(b) To further evaluate the PD effect of a compound of formula (I) in combination with ribociclib. Changes from baseline for PD markers in blood (eg, DUSP6).

(c) To evaluate the drug-drug interaction (DDI) between a compound of formula (I) and ribociclib. Compounds of Formula I and Ribociclib Plasma Concentrations and Induced PK Parameters.

(d) To study how cfDNA alterations respond to genetic alterations in recorded and (when available) newly obtained tumor samples. Differences in genetic alterations measured in both tumors and plasma samples as surrogate tissues from the same patient at a given time point (pre-dose and post-dose).

This is a multicenter, open-label, phase Ib dose escalation study, the next expansion part. A compound of formula (I) in combination with ribociclib will be administered to melanoma patients carrying an NRAS mutation. Study treatment is taken until the patient experiences unacceptable toxicity, and progressive disease and/or treatment is discontinued at the investigator's or patient's discretion or due to withdrawal of consent. The cycle is set to 28 days.

Inclusion Criteria: Adult (age 18 years or older) melanoma patients diagnosed with locally advanced or metastatic NRAS-mutant melanoma who progressed according to standard of care or for which no effective standard of care does not exist, tolerated, appropriate, or equivalent to study treatment Patients considered to be eligible to participate in this study. Presence of NRAS mutations in tumor tissue prior to study treatment as determined by regional laboratories or Novartis-designated central laboratories or written documentation of KRAS, BRAF or RAS mutations. The Eastern Cooperative Tumor Group (ECOG) performance status is 2 or less. The patient must have a biopsyable disease site and be willing to undergo a new tumor biopsy at baseline and during treatment in accordance with the treating institution's own guidelines and requirements for these procedures. The presence of at least one measurable lesion according to RECIST v1.1 is required.

Exclusion criteria:

(a) Prior treatment with a RAF inhibitor (including any BRAF inhibitor and Raf inhibitor) or a CDK4/6 inhibitor.

(b) Treatment with any of the following anti-cancer therapies prior to the initial dose of study treatment within the stated time frame:

(i) 4 weeks or less for radiotherapy or 2 weeks or less for limited field radiation for remission prior to the first dose of study treatment.

(ii) Half-life of 4 weeks or less or 5 or less (whichever is shorter) for chemotherapy or biological therapy (excluding immunotherapy) or continuous or intermittent small molecule therapy or any other study agent.

(iii) 4 weeks or less for any immunotherapeutic treatment comprising an immune checkpoint inhibitor.

(iv) 6 weeks or less for cytotoxic agents with major delayed toxicity, such as nitrosourea and mitomycin C.

(c) History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulation syndrome).

(d) Any medical condition that, in the investigator's judgment, prevents a patient from participating in a clinical study because of safety concerns or compliance with clinical study procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or administration of study treatment or interfere with the interpretation of study results will cause the investigator to determine that the patient is inappropriate for the study. do.

(e) strong inhibitors and/or inducers of CYP3A and CYP2C8; inhibitors or inducers of UGT2B7; substrates and inhibitors of UGT1A1; substrates of CYP2C8, CYP2C9 and CYP3A with narrow therapeutic indices; and patients on treatment with medications known to cause hepatotoxicity and known to be sensitive substrates of the herbal medicine CYP3A, which cannot be discontinued 7 days prior to initiation of study treatment and for the duration of the study.

(f) Patients receiving non-interruptible proton pump inhibitors (PPIs) 3 days prior to the start of study treatment and for the duration of the study.

(g) Patients with malignancies other than those being treated in this study. Exceptions to this exclusion criterion include: malignancies that were treated within 2 years prior to study treatment and did not recur; completely resected basal cell and squamous cell skin cancer; and any type of carcinoma completely resected in situ.

Clinical efficacy was assessed by measuring overall response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) according to RECIST version 1.1, and overall survival (OS) (dose expansion portion only). will evaluate

Data from a dose split efficacy study in Calu-6 xenografts showed that, across different dose levels, compounds of Formula I had similar levels when dosed QD (qd) and when fractionated twice daily (BID). showed that the antitumor activity of These results support the investigation of QD or BID dosing regimens in the clinic.

Potential symptomatic assessments of clinical efficacy including ORR, PFS and OS assessments will be performed.

All patients enrolled during the dose escalation part of the study will be assigned to receive a compound of Formula I in combination with ribociclib to evaluate the safety and tolerability of the combination.

Dose escalation for each trial regimen will be guided by a Bayesian logistic regression model (BLRM) based on Cycle 1 DLT data.

BLRM/BHLRM is a well-established method for estimating MTD in cancer patients. Adaptive BLRM/BHLRM will be guided by the principle of escalation with overdose control (EWOC) to control the risk of DLT in future patients under study. The use of the Bayesian response adaptation model for small datasets has been approved by EMEA (“Guidelines for Clinical Trials in Small Populations”, February 13, 2007) and endorsed by numerous publications (Babb et al 1998, Neuenschwander). et al 2008, Neuenschwander et al 2010]), its development and appropriate use is an aspect of FDA's Critical Path Initiative.

Patients enrolled in this expansion part will be treated with the recommended dose combination (MTD or lower dose combination) of a compound of Formula I and ribociclib.

To evaluate safety (including dose-DLT relationships) and tolerability of the combination; Dose(s) and regimen(s) for use in dose expansion will be identified based on a review of these data. The information available on PK, PD and preliminary anti-tumor activity will also guide recommended doses for expansion.

cure

Study treatment will be administered on a fasting 28-day dosing cycle.

Oral tablets and capsules are administered as daily doses given over a 28-day cycle.

Investigators or responsible field personnel should instruct patients to take exactly the study medication as prescribed to facilitate compliance.

Patients should inform study sergeant staff of any missed or delayed doses.

If treatment is discontinued at the discretion of the investigator or patient and/or if the patient withdraws consent, the patient may discontinue study treatment earlier due to acceptable toxicity, progressive disease.

The following table lists the starting doses and transient dose levels for the individual study drugs (not combinations) that can be evaluated during this trial.

The MTD(s) for any combination are less likely to cause a DLT (<25% posterior probability) in at least 33% of treated patients in the first cycle of compound of Formula I and ribociclib treatment during the escalation part of the study. ) as the highest dose combination for that combination.

The RD is less than or equal to the MTD and, from the investigator and Novartis study staff point of view, would be the dose with the most appropriate adverse-benefit assessment based on a review of safety and tolerability, PK, PD, and activity information. Note that there is a possibility that the MTD may not be reached in some situations.

The CDK4/6 inhibitor may be administered continuously, ie, without interruption during the treatment period, or with rest periods.

For example, a CDK4/6 inhibitor, eg, ribociclib or a pharmaceutically acceptable salt thereof, may be administered for 3 weeks and discontinued for 1 week, or administered for 2 weeks and discontinued for 2 weeks; Preferably, it can be administered in 3 weeks administration and 1 week interruption. In particular, the following therapies may be used in accordance with the present invention.

Claims (26)

A pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the Raf inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof:
[Formula I]

. A pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. According to claim 1,
(i) the Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; and
(ii) the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, a pharmaceutical combination. 4. A pharmaceutical combination according to any one of claims 1 to 3 for use in the treatment of cancer. 5. The pharmaceutical combination according to claim 4, wherein the cancer has a NRAS mutation. 5. The pharmaceutical combination according to claim 4, wherein the cancer has a KRAS mutation. The pharmaceutical combination according to claim 4 or 5, wherein the cancer is melanoma. The pharmaceutical combination according to claim 7, wherein the cancer is a mutant melanoma, preferably a NRAS mutant melanoma. 9. The method of claim 8, wherein the melanoma is a NRAS mutation G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. A pharmaceutical combination expressing at least one mutation selected from the group consisting of. 7. The pharmaceutical combination according to claim 4 or 6, wherein the cancer is pancreatic cancer, for example pancreatic ductal adenocarcinoma (PDAC). The pharmaceutical combination according to claim 10 , wherein the cancer is a mutant pancreatic cancer, for example a mutant PDAC, preferably a KRAS mutant PDAC. 12. The method of claim 11, wherein the PDAC is KRAS mutants G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. A pharmaceutical combination expressing at least one mutation selected from the group consisting of. 13. The pharmaceutical combination according to any one of claims 4 to 12, wherein the two compounds or a pharmaceutically acceptable salt thereof are administered separately, simultaneously or sequentially. 14. The pharmaceutical combination according to any one of claims 4 to 13, wherein one or both compounds or pharmaceutically acceptable salts thereof are administered orally. 15. The method according to any one of claims 4 to 14, wherein the Raf inhibitor or a pharmaceutically acceptable salt thereof is about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg. , 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg or 1600 mg in total daily dose. 16. The pharmaceutical combination according to any one of claims 4 to 15, wherein the Raf inhibitor is administered once a day or twice a day. 17. The pharmaceutical combination according to any one of claims 4 to 16, wherein the Raf inhibitor is administered continuously for the duration of the treatment. 18. The method according to any one of claims 4 to 17, wherein the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg; A pharmaceutical combination administered in a total daily dose of 450 mg, 500 mg, 550 mg or 600 mg. 19. The pharmaceutical combination according to any one of claims 4 to 18, wherein the CDK4/6 inhibitor is administered once a day or twice a day. 20. The pharmaceutical combination according to any one of claims 4 to 19, wherein the CDK4/6 inhibitor is administered with a drug-free period, eg 3 weeks of administration and 1 week of interruption. 4. The NRAS mutation of any one of claims 1 to 3, wherein the NRAS mutation is G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H. , Q61P, Q61E, a mutant melanoma expressing at least one mutation, or preferably a NRAS mutant melanoma, or a KRAS mutation G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D , G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, Q61E mutant pancreatic cancer expressing at least one mutation, for example a mutant PDAC, preferably KRAS For use in the treatment of mutant PDAC, wherein the Raf inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg bid, and the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is A pharmaceutical combination administered at a daily dose of about 600 mg qd. 4. The NRAS mutation of any one of claims 1 to 3, wherein the NRAS mutation is G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H. , Q61P, Q61E, a mutant melanoma expressing at least one mutation, or preferably a NRAS mutant melanoma, or a KRAS mutation G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D , G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, Q61E mutant pancreatic cancer expressing at least one mutation, for example a mutant PDAC, preferably KRAS For use in the treatment of mutant PDAC, wherein the Raf inhibitor or a pharmaceutically acceptable salt thereof is continuously administered at a daily dose of about 600 mg bid, the CDK4/6 inhibitor, or a pharmaceutically acceptable salt thereof A possible salt is administered at a daily dose of about 600 mg qd, 3 weeks on and 1 week off. Use of a pharmaceutical combination according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of cancer. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to any one of claims 1 to 3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by co-administration with ribociclib or a pharmaceutically acceptable salt thereof:
[Formula I]

. Ribociclib or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by co-administration with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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