WO2025074090A1

WO2025074090A1 - Combination of cxd101 and an il-15 superagonist to treat proliferative diseases such as cancer

Info

Publication number: WO2025074090A1
Application number: PCT/GB2024/052525
Authority: WO
Inventors: Nicholas La Thangue; Wojciech BARCZAK
Original assignee: Celleron Therapeutics Ltd
Current assignee: Celleron Therapeutics Ltd
Priority date: 2023-10-03
Filing date: 2024-10-02
Publication date: 2025-04-10
Anticipated expiration: 2026-04-03
Also published as: GB202315149D0

Abstract

The present invention provides a combination comprising N-(2-aminophenyl)-4-(1-[(1,3- dimethyl-1H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and an IL 15 superagonist, such as N-803. The combination is suitable for use in the treatment of proliferative disorders, such as cancer.

Description

COMBINATION THERAPY

FIELD OF THE INVENTION

The present invention relates to a novel combination therapy and to the use of this combination therapy for the treatment of proliferative disorders, such as cancer.

BACKGROUND OF THE INVENTION

Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets and key metabolic pathways that are known to be associated with malignancy.

In immunotherapy, cancers may be described in terms of “hot” or “cold”, depending on whether they show signs of inflammation or T-lymphocyte infiltration. Immunogically cold cancers, by virtue of their low mutational burdens, low antigenic loads, and poor recognition by T-lymphocytes and other immune cells, are generally associated with poor response to immune checkpoint inhibitors, such as anti-PD-1/L1 or anti-CTLA4.

Despite numerous advances in the treatment of cancer, there remains a need for new therapies that provide improved therapeutic outcomes.

The present invention was devised with the foregoing in mind.

SUMMARY OF THE INVENTION

Data is presented in the example section herein that shows that the administration of the HDAC inhibitor compound N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101) in combination with the IL-15 superagonist N- 803 results in a significant increase in the anti-tumour response compared to the agents given singly, indeed the combination demonstrated a shrinkage in the tumour mass. It is concluded that there is synergy between CXD101 and the N-803 agents in the treatment of cancer.

Thus, according to the first aspect the present invention relates to a combination comprising N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, and an IL-15 superagonist. Suitably, the CXD101 compound, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with the IL-15 superagonist.

According to the second aspect of the invention there is provided a pharmaceutical product comprising a combination comprising N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, and an IL-15 superagonist.

According to the third aspect of the invention there is provided a pharmaceutical composition comprising a combination of N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, and an IL- 15 superagonist, and one or more pharmaceutically acceptable excipients.

According to the fourth aspect of the invention there is is provided a combination according to the first aspect of the invention, or a pharmaceutical product according to the second aspect of the invention, or a pharmaceutical composition according to the third aspect of the invention for use in therapy. Suitably, the use in therapy is use in the treatment of proliferative disorder, such as cancer.

Suitably, when administered to a subject, the CXD101, or a pharmaceutically acceptable salt thereof, and the IL-15 superagonist are administered separately, sequentially or simultaneously.

According to the fifth aspect of the invention there is provided a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of (i) a combination according to the first aspect of the invention, or (ii) the pharmaceutical product according to the second aspect of the invention, or (iii) the pharmaceutical composition according to the third aspect of the invention.

According to the sixth aspect of the invention there is provided a method of potentiating the immune response against a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of (i) a combination according to the first aspect of the invention, or (ii) the pharmaceutical product according to the second aspect of the invention, or (iii) the pharmaceutical composition according to the third aspect of the invention. Suitably, the tumour is a cancer selected from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer. According to the seventh aspect of the invention there is provided N-(2-aminophenyl)-4-(1- [(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof for use in treating a proliferative disorder in combination with an IL-15 superagonist.

According to the eighth aspect of the invention there is provided an IL- 15 superagonist for use in treating a proliferative disorder in combination with N-(2-aminophenyl)-4-(1-[(1,3- dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof.

According to the ninth aspect of the invention there is provided the use of a combination according to the first aspect of the invention in the manufacture of a medicament for treating a proliferative disorder.

According to the tenth aspect of the invention there is provided the use of N-(2- aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with an IL-15 superagonist

According to the eleventh aspect of the invention there is provided the use of an IL- 15 superagonist in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with N- (2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof.

In particular embodiments or any of the fourth, fifth, seventh, eighth, ninth, tenth or eleventh aspects of the invention the proliferative disorder is cancer, such as a cold cancer. Suitably, the cancer is selected from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer. Suitably, the cancer is a cold cancer.

According to the twelfth aspect of the invetion there is provided a kit comprising two separate formulations to be used together, the formulations being: a first formulation comprising N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient; and a second formulation comprising an IL-15 superagonist and at least one pharmaceutically acceptable excipient.

In a particular embodiment for any of the aspects disclosed herein the IL-15 superagonist is selected from: N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc; preferably, the IL-15 superagonist is N-803.

Preferred, suitable, and optional features of any one particular aspect of the present invention described herein are also preferred, suitable, and optional features of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

A “pharmaceutically acceptable salt” of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), refers to any salt form suitable for pharmaceutical use. Examples of pharmaceutically acceptable salts include an acid-addition salt of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin- 4-yl)benzamide (CXD101/zabadinostat), for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoracetic, formic, citric methane sulfonate or maleic acid.

References herein to N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt thereof, include, where appropriate, any isomeric, tautomeric, polymorphic, amorphous and solvate (e.g. hydrate) forms of the inhibitors. N-(2-aminophenyl)-4-(1-[(1,3- dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), may also be administered in the form of a prodrug which is broken down in the human or animal body to release the active inhibitor. Examples of pro-drugs include in vivo cleavable ester derivatives of the inhibitors that may be formed at a carboxy group or a hydroxy group in an inhibitor compound and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in an inhibitor compound. Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter s “Design and Application of Pro-drugs”, by H. Bundgaard p. US- 191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

References herein to the N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof, being administered “in combination with” an IL-15 superagonist, or vice versa, unless otherwise stated otherwise, include the agents being administered sequentially, separately or simultaneously with one another.

As used herein “simultaneous administration” refers to therapy in which the both agents (e.g., N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4- yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof, and IL-15 superagonist) are administered at the same time, suitably as a monotherapy.

As used herein “sequential administration” means that one agent is administered after the other, however, the time period between the administration of each agent is such that both agents are capable of acting therapeutically concurrently. Thus, administration "sequentially" may permit one agent to be administered within seconds, minutes, or a matter of hours after the other provided the circulatory half-life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts. The time delay between the administration of the agents may vary depending on the exact nature of the agents, the interaction there between, and their respective half-lives.

As used herein, "separate administration" means that one agent is administered after the other, however, the time period between administration is such that the first administered agent is no longer present a therapeutically effective amount when the second agent is administered. Accordingly, the two agents exert their therapeutic effects separately. Nevertheless, the overall therapeutic effect observed when the two agents separately act therapeutically may be greater than either agent used alone.

As used herein the “subject(s)” and/or “patient(s)”, suitably refer to mammals (e.g., humans and non-human mammals such as livestock (cows, sheep, goats) or companion animals (cats, dogs, horses, rabbits). Suitably, the subject(s) and/or patient(s) are human(s).

As used herein, a “pharmaceutical product” refers to a product comprising a pharmaceutical. For instance, examples of a pharmaceutical product include a medical device, a pharmaceutical composition and a kit of parts suitably comprising one or more devices, containers and/or pharmaceuticals.

As used herein, the term "potentiate," means that any of the mentioned activities of the compound embodied herein, are, e.g., increased, enhanced, promoted. Potentiation can increase activity more than 1-fold, 2-fold, 3-fold, 5-fold, 10-fold, 100-fold, etc., over baseline values.

N-(2-aminophenyl)-4-(1-K1,3-dimethyl-1H-pyrazol-4-yl)methvHpiperidin-4- vDbenzamide (CXD101/zabadinostat). CXD101/zabadinostat (previously known as AZD9468) is a Class l-selective histone deacetylase (HDAC) inhibitor with specificity for Class I isoforms HDAC1 (62 nM IC50), HDAC2 (570 nM IC50), and HDAC3 (550 nM IC50), and no activity (>2500 nM) against HDAC Class II¹.

The chemical name of CXD101/zabadinostat is N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H- pyrazol-4-yl)methyl]piperidin-4yl)benzamide. It has a molecular weight of 403.52, and formula C24H29N50. CXD101/zabadinostat is a white or off-white crystalline solid. It is dibasic with a pKas of 3.2 and 9. It displays pH-dependent solubility, with a solubility of 0.5 mg/mL to >20 mg/mL across the pH range 1 to 8 at 25°C. The melting point of CXD101/zabadinostat is approximately 172°C. The UV absorbance maxima are 199 and 229 nm.

The structure of CXD101/zabadinostat is shown below:

The compound is described in W02007045844 (AstraZeneca).

The CXD101/zabadinostat compound is suitably administered orally, optionally in the form of a tablet or capsule (for example, a tablet or capsule containing 0.25 to 40 mg of CXD101/zabadinostat, such as 0.5 mg to 30 mg, 0.5 to 20 mg, 0.5 to 10 mg, or 0.5 to 5 mg). Typically, the dosage for the CXD101/zabadinostat compound will be 0.5-40 mg per day optionally in a divided dose, such as 1-30 mg per day optionally in a divided dose, 1-20 mg per day optionally in a divided dose, or 1-10 mg per day optionally in a divided dose.

Suitably, the CXD101/zabadinostat compound is adminstered twice daily.

The ortho-aminoanilide or benzamide group on zabadinostat sequesters the Zn²⁺ ion required for the hydrolysis and removal of the acetyl group from lysine residues, preventing substrate deacetylation. As such, zabadinostat is chemically distinct from earlier generations of less selective pan-HDAC inhibitors, such as vorinostat, belinostat and panobinostat, which bind Zn²⁺ ions through their hydroxamic acid groups ².

Zabadinostat is being investigated as a treatment for late-stage cancers, including relapsed or refractory lymphoma, microsatellite stable colorectal cancer, and hepatocellular carcinoma, the most common form of liver cancer.

A Phase I clinical trial (NCT01977638) conducted in late-stage cancer patients unresponsive to conventional therapy found that zabadinostat treatment resulted in anti-cancer responses for follicular lymphoma (FL), classic Hodgkin lymphoma (HL), and peripheral T-cell lymphoma (PTCL). The most common Grade 3 and above treatment-related adverse events (TRAE) were neutropenia (17%), thrombocytopenia (11%) and leukopenia (5%). Serious adverse events (SAE) were infrequent, and included neutropenic fever (3%), fatigue (1.5%), anorexia (<1%), diarrhoea (<1%), and bronchial infection (<1%). No treatment-related deaths occurred on study. The recommended Phase 2 dose (RP2D) was found to be 20 mg twice daily (b.i.d.) ¹.

A single-arm Phase II clinical trial (NCT03993626) combining zabadinostat and nivolumab showed that it was effective in treating metastatic microsatellite-stable (MSS) colorectal cancer patients who had progressed despite receiving at least two lines of systemic anticancer therapies. The combination therapy was well tolerated with the most frequent Grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although single cases of pneumonitis, hypothyroidism and hypopituitarism were seen. There were also no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months with a 95% confidence interval of 5.13-10.22 months. The study met its primary endpoint demonstrating anti-tumour efficacy in 3rd line and above MSS colorectal cancer ³.

Experiments conducted in mice showed that zabadinostat treatment altered their tumour microenvironment (TME), attracting CD4+ and CD8+ tumour-infiltrating T lymphocytes, and enhancing anti-tumour activity, especially when combined with immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA4 ⁴.

Further experiments in human and murine colorectal cancer cell lines and tumour samples showed that zabadinostat treatment resulted in changes to the expression of immune- relevant genes, in particular, those that are linked to antigen processing (MHC class I and MHC class II genes) and natural killer (NK) cell-mediated cytotoxicity ⁴.

Additional studies also provided evidence that zabadinostat increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue, enhanced the activity of DCs, and CD4 and CD8 T lymphocytes, and enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. The results concluded that zabadinostat functions as systemic regulator of adaptive immunity with the potential to augment diverse therapeutic agents that act through the immune system (Liu et al. The HDAC Inhibitor zabadinostat is a systemic regulator of adaptive immunity. Communications Biology. 6(102), 2023).

Cytokines, IL-15 superagonists

Interleukin- 15 (IL-15) is a member of the common receptor gamma chain (yc) family, which is a group of cytokines with broad pleiotropic activity on both the innate and adaptive immune systems.

IL-15 signals through a receptor complex composed of the IL-2/IL-15 receptor (CD122) and the common yc receptor subunit (CD132) ⁵.

IL-15Ra is not a signalling receptor for IL-15 but is critical for IL-15 biological activity ⁶.

Due to its high affinity for IL-15, the IL-15Ra transmembrane receptor binds intracellularly to IL-15, facilitating its trafficking and cell surface expression as I L-15/I L-15Ra heterodimer complexes, which can also be cleaved from the cell surface ⁶.

Primarily expressed by activated monocytes, macrophages, and dendritic cells, membranebound I L-15/I L-15Ra complexes are presented in trans to cells that express the receptor complex ⁵.

As such, IL-15 preferentially stimulates activation, proliferation, survival, and cytotoxicity of NK and CD8+ T cell populations, including regulation of memory CD8+ T cell homeostatic proliferation and survival ⁵.

Although un-associated IL-15 is not found naturally in vivo, soluble recombinant (r) IL-15 was initially examined for therapeutic potential. In multiple murine carcinoma models, rlL-15 promoted significant anti-tumour efficacy associated with enhanced CD8+ T and NK cell function ⁷.

The efficacy of rlL-15 is limited by its short half-life due to instability, ranging from <1 hour in mice and 2.5 to 12 hours in patients depending on the route of administration [7-9], and IL- 15Ra availability in vivo. To improve the therapeutic potential of IL-15 therapy, several types of I L- 15/I L- 15Ra complexes were developed.

As used herein the term “IL-15 superagonist or IL-15 superagonist complex” refers to a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, in this case, the IL-15 receptor.

There are four main soluble structurally distinct IL-15 superagonists in clinical development¹⁵:

1. heterodimeric (het) IL-15,

2. receptor-linker-IL-15 (RLI),

3. IL-15/IL-15Ra-Fc; and

4. N-803 (formerly ALT-803)

N-803 is described in WO2018183821 (Aitor Bioscience Corporation) and US 8163,879 (Aitor Bioscience Corporation).

Het IL-15 is described in WO2015103928 (SHANGHAI HENGRUI PHARMACEUTICAL CO., LTD and JIANGSU HENGRUI MEDICINE CO., LTD).

Receptor-linker-IL-15 (RLI) is described in WO2012175222 (Cytune and INSERM).

IL-15/IL-15Ra-Fc is described in WO2019204592 (Xencor Inc.).

Any IL-15 superagonist may be used in the aspects of the invention described herein.

In a preferred embodiment, the I L-15 superagonist for use in any of the aspects of the invention described herein is N-803.

N-803 (also known as ALT-803) is an IL-15 superagonist in clinical development with therapeutic potential against solid cancers and haematological malignancies. It consists of an IL-15 superagonist mutein (IL-15N72D) and a dimeric IL-15 receptor alpha (I L-15Ra)/Fc fusion protein. In vitro, N-803 increased human NK-mediated cytotoxicity against B cell lymphoma, head and neck, lung, and breast carcinoma cells, including in the presence of cetuximab (anti- EGFR) or avelumab (anti-PD-L1) ⁸.

N-803 restricted tumour growth and improved the median overall survival (mOS) of mice with colon and breast tumours, among others ¹¹.

Given the current clinical results, IL- 15 superagonists appear to have an advantage over rlL- 15 in mediating immune effects, specifically, greater expansion of NK and CD8+ T cells, without inducing significant toxicity.

This is most likely due to increased stability/half-life and bioactivity of IL- 15 superagonists versus rlL-15.

N-803 is currently being investigated in clinical trials to treat patients with bladder cancer, myeloma, melanoma and other relapsed hematological malignancies. It is well characterised clinically and is described as well tolerated with no dose-limiting toxicity.

IL-15 heterodimer (hetlL-15) comprises a complex of the IL-15 chain with the IL-15 receptor alpha (IL-15Ra) chain. It closely resembles the natural form of the cytokine produced in vivo.

IL-15/IL-15Ra-Fc comprises a pre-association of IL-15, IL-15Ra, and the Fc portion of human lgG1, which enhances the activities of IL-15 in vivo. It greatly enhances the proliferation of NK cells and CD8 T lymphocytes.

Receptor-linker-IL-15 (RLI) is a fusion molecule of human IL-15 covalently linked to the human IL-15Ra sushi+ domain. It is currently assessed in clinical trials as a treatment for patients with advanced/metastatic solid cancer.

In particular embodiments, the IL-15 superagonist for use in the present invention is selected from N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc. The preferred IL-15 superagonist is N-803.

Combination Therapy

The present invention resides in the recognition that N-(2-aminophenyl)-4-(1-[(1,3-dimethyl- 1H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat) and the IL15 superagonist N-803 act synergistically in an art recognised mouse colon cancer model. Indeed, as shown in the examples the combination was capable of effectively shrinking the tumour volume. Based on their mode of action, it is expected that other IL-15 superagonists will also act syergistically with CXD101.

Thus, the combination treatment or therapy of the present invention has the potential to provide better outcomes in cancer patients.

According to the first aspect the present invention relates to a combination comprising N-(2- aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, and an IL-15 superagonist.

Suitably, the CXD101 compound, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with the IL-15 superagonist.

In particular embodiments, the IL-15 superagonist is selected from N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc. The preferred IL-15 superagonist is N-803.

In a particular embodiment, the IL-15 superagonist is N-803.

In particular embodiments, the N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered at dosage of 20mg to 40mg per day.

In particular embodiments, the wherein N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered at dosage of 10 to 20 mg twice a day.

In particular embodiments, the N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered for 2 to 8 consecutive days in a two or three period and this dosing schedule is optionally repeated.

In particular embodiments, the wherein N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered for 5 consecutive days in a two or three week period and this dosing schedule is optionally repeated.

In particular embodiments, the N-803 is administered subcutaneously, at a clinical dosage between 0.9 mg to 1.1 mg, on Days 1 and 15 of a 15-day treatment cycle.

This may be combined with zabadinostat (CXD101), which is administered orally, at a clinical dosage of 20 mg, twice daily, between Days 1 to 5, of a 15-day treatment cycle. The combination of N-803 and zabadinostat, in terms of dosage, route and regimen, may be altered, modified, or combined with other agents, if required to improve on the safety or efficacy of the treatment.

Pharmaceutical Products

According to the second aspect of the invention there is provided a pharmaceutical product comprising a combination of N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, and an IL-15 superagonist.

In a particular embodiment, the IL-15 superagonist is N-803.

In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solavte thereof, and the IL-15 superagonist. The separate formulations of N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof, and the IL- 15 superagonist, may be administered sequentially, separately and/or simultaneously.

In another embodiment the pharmaceutical product is a kit of parts which comprises: a first container comprising N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4- yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier; and a second container comprising an IL-15 superagonist; and a container means for containing said first and second containers.

In one embodiment, the pharmaceutical product may comprise a one or more unit dosage forms (e.g. vials, tablets or capsules in a blister pack). In one embodiment, one unit dose comprises N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4- yl)benzamide (CXD101/zabadinostat) compound, or a pharmaceutically acceptable salt or solvate thereof, and and the other unit dosage form is the IL- 15 superagonist. In another embodiment, the unit dosage form comprises both the N-(2-aminophenyl)-4-(1-[(1,3- dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat) compound, or a pharmaceutically acceptable salt or solvate thereof, and the IL-15 superagonist (e.g., N-803).

Suitably, the CXD101 compound, or a pharmaceutically acceptable salt or solvate thereof, is administered orally and the IL-15 superagonist (e.g., N-803) is administered parenterally.

In one embodiment, the pharmaceutical product is a pharmaceutical composition.

According to the twelfth aspect of the invention there is provided a kit comprising two separate formulations to be used together, the formulations being: a first formulation comprising N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient; and a second formulation comprising an IL-15 superagonist and at least one pharmaceutically acceptable excipient.

Suitably, the CXD101/zabadinostat agent is administered orally.

Suitably, the IL-15 superagonist agent is administered pareterally, e.g, intravenously, intramuscularly or subbcutaneously.

In one embodiment the pharmaceutical product or kit of parts further comprises means for facilitating compliance with a dosage regimen, for instance instructions detailing how to administer the combination.

Pharmaceutical compositions

In particular embodiments, the IL-15 superagonist is selected from N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc. The preferred IL-15 superagonist is N-803. In a particular embodiment, the IL-15 superagonist is N-803.

The pharmaceutical compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

Suitably, the pharmaceutial composition is in a form suitable for administration orally, such as in a tablet, capsule, solution or the like, or by injection, for example for subcutaneous, intramuscular, intradermal, or in a form suitable for intranasal administration.

The pharmaceutical compositions of the invention will typically be for parenteral administration when the agent is proteinaceous in nature. The IL- 15 superantagonist is proteinaceous.

The pharmaceutical compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration.

An effective amount of a combination of an N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, or an IL- 15 superagonist for use in the combination therapy of the invention is an amount sufficient to treat a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. When the proliferative condition is cancer, the effective amount of a combination of an N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, or an IL-15 superagonist for use in the combination therapy of the invention may also be an amount sufficient to slow tumour growth, halt tumour growth or reduce the tumour mass. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. For example, a formulation intended for subcutanous administration to humans will generally contain, for example, from 0.1 mg to 1 g of active agent (more suitably from 0.5 to 2 mg, for example from 0.9 to 1.1 mg, or 15 pg/kg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

The size of the dose for therapeutic purposes of a combination of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

In using a combination of the invention for therapeutic purposes it will generally be administered with a therapeutically effective dose of the particular I L-15 superagonist selected. These dosages are known in the art and will vary from one agent to another. The dosage may, for example, be in the range of 0.1 mg/kg to 30 mg/kg body weight. The doing schedule will also vary from one I L-15 superagonist complex agent to another. Suitable doing schedules are known in the art.

The CXD101 compound is suitably administered orally, optionally in the form of a tablet or capsule (for example, a tablet or capsule containing 10mg of CXD101). Typically, the dosage for the CXD101 compound will be 20-40mg per day. Suitably, the daily dose is administered in divided doses, with a twice daily dosing schedule being generally preferred. CXD101 is suitably dosed for 2 to 8 consecutive days, more suitably 3 to 7 consecutive days and most suitably for 5 consecutive days over a two or three week period. This dosing schedule can be repeated on a two or three week cycle throughout the duration of therapy.

In an embodiment, the CXD101 compound is administered at a dosage of 10-20mg twice daily for 3 to 7 consecutive days of a two or three week cycle and the therapy is continued for the duration of the therapy.

In a particular embodiment, the CXD101 compound is administered at a dosage of 10-20mg twice daily for 5 consecutive days of a two or three week cycle (i.e. 5 days of treatment followed by 9 days with no treatment in a two week cycle and 16 days without treatment in a three week cycle) and the therapy is continued for the duration of the therapy.

In a particular embodiment, the N-803 superagonist is administered at a dosage of 0.5 to 2 mg on Days 1 and 15 of a 15-day cycle and the therapy is continued for the duration of the therapy. Both the dosage and treatment days may be modified, altered, or combined with other agents based on clinical assessment of addition benefit to safety, efficacy, or ease of administration.

Therapeutic Uses

According to the fourth aspect of the invention there is provided a combination as herein described, a pharmaceutical product as herein desribed, or a pharmaceutical composition as herein described for use in therapy.

In one aspect, the present invention relates to a combination as herein described, a pharmaceutical product as herein described, or a pharmaceutical composition as herein described for for use in the treatment of a proliferative disorder.

In one aspect, the present invention relates to a combination comprising N-(2-aminophenyl)- 4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, and an IL- 15 superagonist as defined herein, for use in the treatment of a proliferative disorder.

Suitably, the present invention relates to a combination as herein described, a pharmaceutical product as herein described, or a pharmaceutical composition as herein described for for use in the treatment of a proliferative disorder in a subject.

The term "proliferative disorder" is used herein to refer to an unwanted, uncontrolled and abnormal cellular proliferation, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, benign, pre- malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, bladder, kidney, bone, nerves and skin.

In an embodiment of the invention, the proliferative disorder is a benign disorder, such as, for example, neuroblastoma or fibrosis. The anti-proliferative effects of the combination therapy of the present invention has particular application in the treatment of human cancers.

In particular, the combination therapy of the present invention will be useful for treating any human cancer in which immune cells, such as Natural Killer cells or T lymphocytes are lacking or display low activity, or in the case of cold tumours, in which the lack of antigenic presentation results in poor detection by such immune cells. This includes any cancer that has been unresponsive or responded poorly to therapy comprising either an IL-15-based agent (such as IL-15 or IL-15 superagonist) or N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101).

Suitably, the proliferative disorder is cancer.

In particular embodiments of the invention, the anti-tumour effects of the combination therapy of the present invention has particular application in the treatment and/or prevention of a wide range of cancers including, but not limited to, non-solid tumours such as leukaemia, for example acute myeloid leukaemia, multiple myeloma, haematologic malignancies or lymphoma, and also solid tumours and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, oesophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumours and haematological malignancies.

Suitably, the cancer is selected from the group consisting of: leukaemia, lymphoma, multiple myeloma, lung cancer, liver cancer, breast cancer, head and neck cancer, neuroblastoma, thyroid carcinoma, skin cancer (including melanoma), oral squamous cell carcinoma, urinary bladder cancer, Leydig cell tumour, biliary cancer, such as cholangiocarcinoma or bile duct cancer, brain cancer, pancreatic cancer, colon cancer, colorectal cancer and gynaecological cancers, including ovarian cancer, endometrial cancer, fallopian tube cancer, uterine cancer and cervical cancer, including epithelia cervix carcinoma. In suitable embodiments, the cancer is leukaemia and can be selected from the group consisting of acute lymphoblastic leukaemia, acute myelogenous leukaemia (also known as acute myeloid leukaemia or acute non-lymphocytic leukaemia), acute promyelocytic leukaemia, acute lymphocytic leukaemia, chronic myelogenous leukaemia (also known as chronic myeloid leukaemia, chronic myelocytic leukaemia or chronic granulocytic leukaemia), chronic lymphocytic leukaemia, monoblastic leukaemia and hairy cell leukaemia. In further preferred embodiments, the cancer is acute lymphoblastic leukaemia. In a suitable embodiment the cancer is lymphoma, which may be selected from the group consisting of: Hodgkin’s lymphoma; non-Hodgkin lymphoma; Burkitt’s lymphoma; and small lymphocytic lymphoma.

In particular embodiments, the cancer is a cold cancer.

A cold cancer, also known as a cold tumour, is an abnormal, uncontrolled tissue growth (neoplasm) that has the ability or potential to spread to secondary sites (metastasize) and is difficult to detect by immune cells (for example, T-lymphocytes and Natural Killer cells). Cold cancers are characterised by low mutational burdens, low antigenic loads, and poor NK and T-cell infiltration. Usually, they show low or no response to immune therapy agents, such as checkpoint inhibitors, for example, anti-PD1/L1 or anti-CTLA4 therapies.

In particular embodiments, the cancer is is selected from from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.

Suitably the treatment of such cancers may achieve effective treatment of the cancer by preventing or treating the development of the cancer, by preventing or treating the progression of the cancer, by preventing or treating the recurrence of the cancer, by preventing or treating the propagation (including metastasis) of the cancer or by shrinking/reducing the tumour mass.

In particular embodiments of any aspect wherein the CXD101 , or a pharmaceutically acceptable salt thereof, and IL-15 superagonist are administered to a subject the agents act synergistically in the treatment of the subject, e.g., in the treatment of a proliferative disease such as cancer. In particular embodiments the agents are capable of shriking the tumour mass when administered as a combination therapy.

According to one aspect of the invention there is provided a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination comprising N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and an IL-15 superagonist. According to another aspect of the invention there is provided a method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of an IL-15 superagonist (IL-15SA), wherein the CXD101 , or a pharmaceutically acceptable salt or solvate thereof, and the IL- ISSA are administered simultaneously, separately or sequentially.

Suitably, the proliferative disorder is cancer.

In particular embodiments, the cancer is a cold cancer.

According to the sixth aspect of the invention there is provided a method of potentiating the immune response to a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination a combination comprising N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and an IL-15 superagonist. According to an aspect of the invention there is provided a method of of potentiating the immune response to a tumour in a subject in need thereof comprising administering to said subject a therapeutically effective amount of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of an IL-15 superagonist (IL- ISSA), wherein the CXD101 , or a pharmaceutically acceptable salt or solvate thereof, and the IL-15SA are administered simultaneously, separately or sequentially.

According to another aspect of the invention there is provided a method of potentiating the immune response to a tumour, the method comprising administering to a patient receiving treatment with an IL- 15 superagonist a therapeutically effective amount of N-(2-aminophenyl)- 4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof. I a paricular embodiment, the amount of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof administered is effective to enhance the immune response of the IL-15 superagonist.

In particular embodiments, the CXD101 , or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with the and the IL-15SA.

As indicated above, the IL- 15 superagonist may be any IL- 15 superagonist as defined in any of the embodiments herein.

In a particular embodiment for any of the aspects herein, the IL-15 superagonist, such as N- 803, is administered parenterally, such as intravenously.

In a particular embodiment for any of the aspects herein, the CXD101 , or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

According to the seventh aspect of the invetion there is provided N-(2-aminophenyl)-4-(1- [(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof for use in treating a proliferative disorder in combination with an IL-15 superagonist.

According to the eighth aspect of the invention there is provided an IL- 15 superagonist for use in treating a proliferative disorder in combination with N-(2-aminophenyl)-4-(1-[(1 ,3- dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof. In a particular embodiment, the IL-15 superagonist is N- 803. According to the ninth aspect of the invention there is provided the use of a combination comprising N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4- yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and an IL- 15 superagonist in the manufacture of a medicament for treating a proliferative disorder. In a particular embodiment, the IL-15 superagonist is N-803.

According to the tenth aspect of the invention there is provided the use of N-(2- aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with an IL-15 superagonist. In a particular embodiment, the IL-15 superagonist is N-803.

According to the eleventh aspect of the invention there is provided the use of an IL- 15 superagonist in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with N- (2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the IL- 15 superagonist is N-803.

The combination therapy may be in the form of a combined formulation for simultaneous administration of the therapeutically active components or they may be administered as separate formulations. The separate formulations may be administered sequentially, separately or simultaneously.

In one embodiment the separate formulations of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt thereof, and the IL-15 superagonist are administered simultaneously (optionally repeatedly).

In one embodiment the separate formulations of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt thereof, and the IL-15 superagonist are administered sequentially (optionally repeatedly).

In one embodiment the separate formulations of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H- pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt thereof, and the IL-15 superagonist are administered separately (optionally repeatedly).

The skilled person will understand that where the separate formulations of N-(2- aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt thereof, and an IL-15 superagonist (e.g., N-803) are administered sequentially or serially that this could be administration of N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4- yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof, followed by the IL-15 superagonist or IL-15 superagonist followed by N-(2- aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof.

Where the administration of the separate formulations of N-(2-aminophenyl)-4-(1-[(1 ,3- dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof, and an IL-15 superagonist is sequential or separate, the delay in administering the second formulation should not be such as to lose the beneficial effect of the combination therapy.

Routes of Administration

N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl)benzamide (CXD101/zabadinostat), or a pharmaceutically acceptable salt or solvate thereof may be administered to a subject by any appropriate or convenient route of administration, whether systemically/peripherally or topically (i.e. , at the site of desired action).

Routes of administration for CXD101 include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

CXD101/zabadinostat is suitably administered orally. Suitably, routes of administration for the IL-15 supergonist include intravenous, subcutaneous, intramuscular, intradermal, or intranasal. As the IL-15 superagonist is proteinaceous, parenteral administration, including intravenous, is particularly suitable.

Combinations with additional

The combination treatment defined herein may be applied as the sole therapy for the treatment of the specified condition or it may involve, in addition to the combination therapy of the present invention, one or more additional therapies (including treatment with another therapeutic agent, surgery or other therapeutic interventions).

Typically, the other therapeutic agent used in combination with the combination therapy of the present invention will be one or more therapeutic agents used as the standard of care for the treatment or prevention of the disease, condition, or disorder concerned. The other therapeutic agent may include, for example, another drug used for the treatment of the condition concerned, or an agent that modulates the biological response to the combination therapy of the invention.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

The combination therapy of the present invention is particularly suitable for treating a proliferative disease or disorder. Accordingly, the antiproliferative combination therapy defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may further include one or more of the following categories of anti-tumour agents:- other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), A/-(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as A/-(3-chloro- 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), /V-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-A/-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AM N 107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)]; vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the combination therapy of the invention, conventional surgery or radiotherapy or chemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the combination therapy of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a combination therapy of the invention as defined hereinbefore, and another anti-tumour agent.

According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour), comprising a combination therapy of the invention as defined hereinbefore, and any one of the anti-tumour agents listed herein above.

DESCRIPTION OF DRAWINGS

Embodiments of the invention will be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1A. Depicts the experimental design showing dosing regimen.

Figure 1B. Shows mean tumour volumes of female Balb/c mice implanted with Colon26 cells and then treated with control, N-803, zabadinostat, or combination. Error bars represent standard deviation.

Figure 1C. Shows tumour volumes of individual female Balb/c mice implanted with Colon26 cells and then treated with control, N-803, zabadinostat, or combination.

Figure 1D. Provides boxplots that represent mean tumour volumes at Day 13 of individual female Balb/c mice implanted with Colon26 cells and then treated with control, N-803, zabadinostat, or combination. **, P < 0.01 ; ***, P < 0.001 ; ***, P < 0.0001.

Figure 1 E. Shows relative body weight changes of female Balb/c mice implanted with Colon26 cells and then treated with control, N-803, zabadinostat, or combination. Error bars represent standard deviation. Examples

Example 1 - Assessment of the in vivo anti-tumour activity of N-803, an IL-15 superagonist complex, and CXD101 , the HDAC inhibitor zabadinostat, alone and in a combination treatment in the murine colon cancer model Colon26.

Objectives

This experiment was set up to assess the in vivo anti-tumour activity of the histone deacetylase (HDAC) inhibitor CXD101, the IL-15 superagonist complex N-803, as single agents as well as in a combination treatment in the murine colon cancer model Colon26 grown subcutaneously in Balb/c mice.

Female Balb/c mice were treated by subcutaneous unilateral injection of colon26 cells as follows: ell injection conditions

Group assignment and therapy schedule

*Based on last body weight measurement

Vehicle x: 5% DMSO, 0.5% Tween80 in wfi

Vehicle i: PBS

Tumour volume at randomisation was between 50-100 mm³.

Dosing starts within 24h of randomization.

Observation period: max. 6 weeks total experimental duration included. Read out was body weights and tumour volumes [mm3] by calliper measurement three times weekly.

Results are shown in Figures 1 B-E. Whilst CXD101 and N-803 as single agents could slow/reduce the tumour growth in the mice, the combination of the two shrunk the tumour volumes demonstrating a synergistic effect with combination index = 0.57 and synergistic effect (CI<0.85) (see Fig 1 D).

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.

The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law.

References

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Claims

1. A combination comprising N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and an IL- 15 superagonist.

2. The combination according to claim 1, wherein the N-(2-aminophenyl)-4-(1-[(1,3- dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101) compound, or a pharmaceutically acceptable salt or solvate thereof, is administered simultaneously, separately or sequentially with the IL-15 superagonist.

3. The combination according to claim 1 or 2, wherein the IL-15 superagonist is selected from N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc.

4. A combination according to any one of claims 1 to 3, wherein N-(2-aminophenyl)-4- (1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered at dosage of 20mg to 40mg per day.

5. A combination according to any one of claims 1 to 4, wherein N-(2-aminophenyl)-4- (1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered at dosage of 10 to 20 mg twice a day.

6. A combination according to any one of claims 1 to 5, wherein N-(2-aminophenyl)-4- (1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered for 2 to 8 consecutive days in a two or three period and this dosing schedule is optionally repeated.

7. A combination according to any one of claims 1 to 5, wherein N-(2-aminophenyl)-4- (1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, is administered for 5 consecutive days in a two or three week period and this dosing schedule is optionally repeated.

8. A pharmaceutical product comprising a combination according to any one of claims 1 to 7.

9. A pharmaceutical composition comprising a combination according to any one of claims 1 to 7, and one or more pharmaceutically acceptable excipients.

10. A combination according to any one of claims 1 to 7, or a pharmaceutical product according to claim 8, or a pharmaceutical composition according to claim 9 for use in therapy.

11. A combination according to any one of claims 1 to 7, or a pharmaceutical product according to claim 8, or a pharmaceutical composition according to claim 9 for use in the treatment of a proliferative disorder, optionally wherein the proliferative disorder is cancer, such as wherein the cancer is selected from from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.

12. A method of treating of a proliferative disorder in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination according to any one of claim 1 to 7, optionally wherein the proliferative disorder is cancer, such as cancer selected from from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.

13. A method of potentiating the immune response to a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination according to any one of claims 1 to 7.

14. The method according to claim 12 or 13, wherein the IL- 15 superagonist is administered intravenously.

15. The method according to any one of claims 12 to 14, wherein the CXD101, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

16. N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4- yljbenzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof for use in treating a proliferative disorder in combination with an IL-15 superagonist, optionally wherein the IL-15 superagonist is setected from: N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL- 15/1 L-15Ra-Fc.

17. CXD101 , or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 16, wherein the proliferative disorder is cancer, optionally wherein the cancer is selected from from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.

18. An IL-15 superagonist for use in treating a proliferative disorder in combination with N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, optionally wherein the IL-15 superagonist is setected from: N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL- 15/1 L-15Ra-Fc.

19. The IL-15 superagonist for use according to claim 18, wherein the proliferative disorder is cancer, optionally wherein the cancer is selected from from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.

20. Use of a combination according to any one of claims 1 to 7 in the manufacture of a medicament for treating a proliferative disorder.

21. Use of N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1 H-pyrazol-4-y1)methyl]piperidin-4- yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administration with an IL-15 superagonist, optionally wherein the IL-15 superagonist is setected from: N-803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc.

22. Use of an IL- 15 superagonist in the manufacture of a medicament for treating a proliferative disorder, wherein the medicament is for simultaneous, separate or sequential administeration with N-(2-aminophenyl)-4-(1-[(1 ,3-dimethyl-1 H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt thereof, optionally wherein the IL-15 superagonist is setected from: N-803, het-IL-15, receptor-linker- IL-15 (RLI), and IL-15/IL-15Ra-Fc.

23. The use according to any one of claims 20 to 22, wherein the proliferative disorder is cancer, optionally wherein the cancer is selected from from lung, colorectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.

24. A kit comprising two separate formulations to be used together, the formulations being: a first formulation comprising N-(2-aminophenyl)-4-(1-[(1,3-dimethyl-1H-pyrazol-4- y1)methyl]piperidin-4-yl)benzamide (CXD101), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient; and a second formulation comprising an IL-15 superagonist and at least one pharmaceutically acceptable excipient.

25. The kit according to claim 24, wherein the IL-15 superagonist is selected from: N- 803, het-IL-15, receptor-linker-IL-15 (RLI), and IL-15/IL-15Ra-Fc.