Combinations of CCT241736 and venetoclax, or of CCT241736, venetoclax and azacitidine for use in the treatment of cancer

Abstract

The present invention provides a compound of Formula (I), or a salt thereof : (I) for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Azacitidine and Venetoclax wherein the three compounds are administered simultaneously, sequentially or separately.

Description

[0001] COMBINATIONS OF CCT241736 AND VENETOCLAX, OR OF CCT241736, VENETOCLAX AND AZACITIDINE FOR USE IN THE TREATMENT OF CANCER

[0002] TECHNOLOGICAL FIELD

[0003] The present invention relates to a particularly advantageous combination therapy of 6-chloro- 7-(4-(4-chlorobenzyl)piperazin-l-yl)-2-(l,3-dimethyl-lHpyrazol-4-yl)-3H-imidazo[4,5- b] py rid i ne, or a salt thereof, especially for use in the treatment or prophylaxis of acute myeloid leukaemia.

[0004] BACKGROUND

[0005] Acute myeloid leukaemia (AML) is a cancer of the myeloid line of blood cells. It is characterized by the rapid growth of proliferative, clonal, and abnormally differentiated cells that build up in the bone marrow and interfere with normal blood cell production.

[0006] AML is the most common form of acute leukaemia in adults and affects about one million people globally, resulting in 147,000 deaths, which accounts for 62% of leukemic deaths. The five-year survival rate of 24% represents the worst survival rate of all acute leukaemias and the 5thworst 5 year survival rate out of all cancers [Sha II is RM et al., Blood Reviews, 2019, 36, 70-87], AML typically affects older adults, with a median age of 68 years at diagnosis.

[0007] Chemotherapy is the primary first-line treatment for patients with AML, and this is divided into phases: induction and consolidation. Induction therapy is usually conducted with continuous-infusion cytarabine with an anthracycline, and the goal is to achieve complete remission of the disease [H. Dbhner et al., New England Journal of Medicine, 2015, 373, 12, 1136 - 1152, DOI: 10.1056 / NEJMral406184], Standard post-remission strategies, referred to as consolidation therapy, are used to eliminate residual undetectable disease with the aim of achieving a cure. Typically, in younger patients (less than 60 years old) an intermediate-dose of cytarabine is used for consolidation therapy, whereas, in older or more fragile patients, hematopoietic-cell transplantation is often used [H. Dbhner et al. (2015)].

[0008] Although it was incurable over 50 years ago, improvements in therapies have resulted in 35 to 40% of people under 60 years old and 5 to 15% of people over 60 years old being cured of the disease [H. Dohner et al. (2015)]. This is coupled with a substantial decrease in treatment- related mortality in recent years [M. Othus et al., Leukemia, 2014, 28, 289-292], However, current intensive curative therapies are generally applicable only to a minority of patients who are younger and fit, and the treatment options available to patients with AML has not changed substantially in more than 30 years. Furthermore, the outcome in older patients who are unable to receive intensive chemotherapy without unacceptable side effects remains dismal, with a median survival of only 5 to 10 months [H. Dbhner et al. (2015)]. Despite advances in treatment in recent years, primary resistance to initial treatment and disease relapse mean that there is still a huge unmet need in the treatment of AML, with the majority of patients still eventually succumbing to the disease.

[0009] Aurora kinases A, B, and C, which are three serine-threonine kinases, are overexpressed in a wide variety of tumour tissues, making them an attractive target for intervention (R. Du et al. Molecular Cancer, 2021, 20, 15, DOI: 10.1186 / sl2943-020-01305-3). Many Aurora kinase inhibitors have been tested, either alone or in combination with a number of different therapeutic agents, within pre-clinical cancer models and clinical trials. For example, Aurora kinase inhibitors are in clinical development for patients with the following cancer types: AML, ovarian cancer, breast cancer, prostate cancer, solid tumours, blood cancer (haematological malignancies), advanced malignancies, leukaemia, myelofibrosis, multiple myeloma, chronic myeloid leukaemia, soft tissue sarcomas, fibrolamellar carcinoma, acute lymphoblastic leukaemia, as reviewed within Du et al. However, Aurora kinase inhibitors display toxicities such as neutropenia, somnolence and mucositis, therefore it would be advantageous for an administration regime to be established that would enable the inhibition of Aurora kinases to be exploited therapeutically, whilst avoiding side effects.

[0010] FLT3, a trans-membrane kinase that belongs to the class III receptor tyrosine kinase (RTK) family, has been found to be highly expressed in AML blasts [D. Stirewalt and J. P. Radich, Nature Reviews Cancer, 2003, 3, 650 - 665], 6-Chloro-7-(4-(4-chlorobenzyl)piperazin-l-yl)-2- (l,3-dimethyl-lHpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (referred to herein as Compound 1) has been shown to have a high activity against Aurora A, B, and C, and FLT3 kinases. The preparation and biological testing of Compound 1 is described in WO 2013 / 190319. The structure of Compound 1 is shown in Scheme 1 below:

[0011]

[0012] Scheme 1 - The structure of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-l-yl)-2-(l,3-dimethyl- lHpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (Compound 1).

[0013] There remains a need for improved chemotherapeutic treatments that provide better outcomes for patients with less toxicity and / or fewer adverse events. Drug resistance continues to be an important clinical problem and therefore there also remains a need for improved chemotherapeutic agents or improved combinations of agents for use as cancer therapies which may generate better treatments for patients with less toxicity and / or fewer adverse events.

[0014] SUMMARY OF THE INVENTION

[0015] The invention provides a compound of Formula (I), or a salt thereof: for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Azacitidine and Venetoclax wherein the three compounds are administered simultaneously, sequentially or separately. The invention further provides a method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject, simultaneously, sequentially or separately, an effective amount of a compound according to Formula (I) and effective amounts of Azacitidine and Venetoclax.

[0016] The invention further provides a compound of formula (I) as described hereinabove for use in the manufacture of a medicament for the treatment and / or prophylaxis of cancer, whereby the compound of formula (I) is administered simultaneously, sequentially or separately in combination with Azacitidine and Venetoclax, to a subject suffering from, or at risk of developing, a cancer.

[0017] The invention further provides a kit comprising appropriate quantities of each of the compound according to Formula (I), Azacitidine and Venetoclax.

[0018] The invention also provides a compound of Formula (I), or a salt thereof: for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Venetoclax wherein the two compounds are administered simultaneously, sequentially or separately.

[0019] The invention further provides a method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject, simultaneously, sequentially or separately, an effective amount of a compound according to Formula (I) and an effective amount of Venetoclax. The invention further provides a compound of formula (I) as described hereinabove for use in the manufacture of a medicament for the treatment and / or prophylaxis of cancer, whereby the compound of formula (I) is administered simultaneously, sequentially or separately in combination with Venetoclax, to a subject suffering from, or at risk of developing, a cancer. The invention further provides a kit comprising appropriate quantities of each of the compound according to Formula (I) and Venetoclax.

[0020] The invention further provides a composition comprising a compound of Formula I, or a salt thereof: and Venetoclax.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] The invention provides a compound of Formula (I), or a salt thereof: for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Azacitidine and Venetoclax wherein the three compounds are administered simultaneously, sequentially or separately.

[0023] The inventors have found that the three compounds act synergistically. The invention therefore enables a lower dose of the compound of Formula (I) to be used than would otherwise be possible in order to achieve an equivalent therapeutic effect. In turn, this provides for an improved treatment option for patients with cancers (for example AML). That is especially advantageous for older or more fragile patients who are more vulnerable to the increased toxicity of existing chemotherapies.

[0024] The dosage of the compound of Formula (I) may be administered as an oral dosage at a dose of from 40 to 200 mg twice per day.

[0025] The invention may be used, for example, in the treatment of a cancer selected from ovarian cancer, breast cancer, prostate cancer, solid tumours (for example, urothelial solid tumours), blood cancers, advanced malignancies, soft tissue sarcomas, fibrolamellar carcinoma, and lung cancer (for example, non-small cell lung cancer). The patients / subjects treated by the current invention for a cancer are generally human patients / subjects.

[0026] The combination treatment of the invention is especially effective in the treatment and / or prophylaxis of a blood cancer. Blood cancers may include, for example, acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, essential thrombocythaemia, hairy cell leukemia, myelodysplastic syndromes, myelofibrosis, myeloma, myeloproliferative neoplasms, polycythaemia vera, and lymphoma. Lymphoma may include, for example, Hodgkin lymphoma, lymphoblastic lymphoma, diffuse large B cell lymphoma, non-Hodgkin lymphoma (for example, mantle cell lymphoma, Burkitt lymphoma), T-cell lymphoma (for example, cutaneous T-cell lymphoma, and anaplastic large cell lymphoma), and small lymphocytic lymphoma. The combination treatment is especially effective in the treatment of acute myeloid leukaemia, myelodysplastic syndromes and chronic myelomonocytic leukaemia, for example acute myeloid leukaemia, for example TP53-mutated acute myeloid leukaemia. As such, the compound of formula (I) and the Azacitidine and the Venetoclax may be administered to, or may be for use in the treatment of, a subject suffering from, or at risk of developing, a cancer, particularly a blood cancer. In the method and use of the invention, the cancer may for example be a blood cancer as described hereinabove, for example acute myeloid leukaemia.

[0027] The strong synergy of the activity of the three compounds has been found in experiments in which AML cells were treated with a series of concentrations of each of the three compounds. Bliss synergy scores of significantly higher than 10 were observed for the combinations of the three drugs at relevant concentrations. More details are provided in the examples section.

[0028] The invention also provides a compound of Formula (I), or a salt thereof: for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Venetoclax, wherein the compounds are administered simultaneously, sequentially or separately.

[0029] The inventors have found that the two compounds act synergistically. The invention therefore enables a lower dose of the compound of Formula (I) to be used than would otherwise be possible in order to achieve an equivalent therapeutic effect. In turn, this provides for an improved treatment option for patients with cancers (for example AML). That is especially advantageous for older or more fragile patients who are more vulnerable to the increased toxicity of existing chemotherapies.

[0030] The dosage of the compound of Formula (I) may be administered as an oral dosage at a dose of from 40 to 200 mg twice per day. The invention may be used, for example, in the treatment of a cancer selected from ovarian cancer, breast cancer, prostate cancer, solid tumours (for example, urothelial solid tumours), blood cancers, advanced malignancies, soft tissue sarcomas, fibrolamellar carcinoma, and lung cancer (for example, non-small cell lung cancer).

[0031] This combination treatment of the invention is especially effective in the treatment and / or prophylaxis of a blood cancer. Blood cancers may include, for example, acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, essential thrombocythaemia, hairy cell leukemia, myelodysplastic syndromes, myelofibrosis, myeloma, myeloproliferative neoplasms, polycythaemia vera, and lymphoma. Lymphoma may include, for example, Hodgkin lymphoma, lymphoblastic lymphoma, diffuse large B cell lymphoma, non-Hodgkin lymphoma (for example, mantle cell lymphoma, Burkitt lymphoma), T-cell lymphoma (for example, cutaneous T-cell lymphoma, and anaplastic large cell lymphoma), and small lymphocytic lymphoma. The combination treatment is especially effective in the treatment of acute myeloid leukaemia, myelodysplastic syndromes and chronic myelomonocytic leukaemia, for example acute myeloid leukaemia, for example TP53-mutated acute myeloid leukaemia.

[0032] As such, the compound of formula (I) and the Venetoclax may be administered to, or may be for use in the treatment of, a subject suffering from, or at risk of developing, a cancer, particularly a blood cancer. In the method and use of the invention, the cancer may for example be a blood cancer as described hereinabove, for example acute myeloid leukaemia.

[0033] The strong synergy of the activity of the two compounds has been found in experiments in which AML cells were treated with a series of concentrations of each of the two compounds. Bliss synergy scores of significantly higher than 10 were observed for the combinations of the two drugs at relevant concentrations. More details are provided in the examples section.

[0034] Importantly, a strong response has been found in human patients with AML. More details are provided in the experimental section.

[0035] The invention also provides a compound of Formula (I), or a salt thereof: for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Azacitidine, wherein the compounds are administered simultaneously, sequentially or separately. The invention further provides a method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject, simultaneously, sequentially or separately, an effective amount of a compound according to Formula (I) and an effective amount of Azacitidine.

[0036] The invention further provides a compound of formula (I) as described hereinabove for use in the manufacture of a medicament for the treatment and / or prophylaxis of cancer, whereby the compound of formula (I) is administered simultaneously, sequentially or separately in combination with Azacitidine, to a subject suffering from, or at risk of developing, a cancer.

[0037] The invention further provides a kit comprising appropriate quantities of each of the compound according to Formula (I) and Azacitidine.

[0038] The two compounds are especially compatible. The invention may be used, for example, in the treatment of a cancer selected from ovarian cancer, breast cancer, prostate cancer, solid tumours (for example, urothelial solid tumours), blood cancers, advanced malignancies, soft tissue sarcomas, fibrolamellar carcinoma, and lung cancer (for example, non-small cell lung cancer).

[0039] This combination treatment of the invention is especially effective in the treatment and / or prophylaxis of a blood cancer. Blood cancers may include, for example, acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, essential thrombocythaemia, hairy cell leukemia, myelodysplastic syndromes, myelofibrosis, myeloma, myeloproliferative neoplasms, polycythaemia vera, and lymphoma. Lymphoma may include, for example, Hodgkin lymphoma, lymphoblastic lymphoma, diffuse large B cell lymphoma, non-Hodgkin lymphoma (for example, mantle cell lymphoma, Burkitt lymphoma), T-cell lymphoma (for example, cutaneous T-cell lymphoma, and anaplastic large cell lymphoma), and small lymphocytic lymphoma. The combination treatment is especially effective in the treatment of acute myeloid leukaemia, myelodysplastic syndromes and chronic myelomonocytic leukaemia, for example acute myeloid leukaemia, for example TP53-mutated acute myeloid leukaemia.

[0040] As such, the compound of formula (I) and the Azacitidine may be administered to, or may be for use in the treatment of, a subject suffering from, or at risk of developing, a cancer, particularly a blood cancer. In the method and use of the invention, the cancer may for example be a blood cancer as described hereinabove, for example acute myeloid leukaemia. The subject may, for example, be a subject who has had prior treatment with Venetoclax. Such a subject may have developed resistance to Venetoclax. The subject may, for example, be a subject who has not had prior treatment with Venetoclax.

[0041] Compounds for use in the invention

[0042] The compound of Formula (I) is 6-chloro-7-(4-(4-chlorobenzyl)piperazin-l-yl)-2-(l,3-dimethyl- lHpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine. It is known from WO 2013 / 190319 and / or in WO 2021 / 176214 and it can be prepared according to the methods described in those publications.

[0043] For the avoidance of doubt, the compound of formula (I), which is generally represented herein as the tautomeric form on the left below (form A), also includes the tautomeric form on the right below (form B) and it also includes a mixture of the two tautomeric forms. Therefore, it should be understood to the skilled person that the compound represented by formula (I) may also be used in tautomeric form A, in tautomeric form B, or in a mixture of the two tautomeric forms:

[0044]

[0045] Venetoclax has the structure:

[0046] Venetoclax is a BCL-2 inhibitor involved in promoting cellular apoptosis. It has been approved by the FDA for use in the treatment of chronic lymphocytic leukaemia (CLL) since 2016. In Europe, it was also first authorised in 2016. It is sold under the name Venclyxto as film-coated tablets, with each tablet containing 10, 50 or lOOmg of Venetoclax. Venetoclax can also form salts. Accordingly, a salt, e.g. a pharmaceutically acceptable salt, of Venetoclax may be used in the context of the present invention.

[0047] Azacitidine is a nucleoside analogue with the structure:

[0048] It has been approved by the FDA for use in the treatment of myelodysplastic syndrome since 2004. In Europe, it was first authorised in 2008. It is sold under the name Vidaza as a powder for suspension for injection, with each vial containing lOOmg of Azacitidine and instructions to prepare a reconstituted suspension containing 25mg of the drug per mL. Azacitidine may also be referred to 5-Azacitidine, Azacytidine or 5-Azacytidine. All of those names refer to the same compound with the structure as shown above. Azacitidine can also form salts. Accordingly, a salt, e.g. a pharmaceutically acceptable salt, of Azacitidine may be used in the context of the present invention.

[0049] Salts and Solvates

[0050] In some circumstances, it can be beneficial to use a pharmaceutical compound, e.g. the compound of Formula (I), in the form of a salt.

[0051] Salts of the compounds, e.g. the compound of Formula (I), which are suitable for use in the present invention are those wherein a counterion is pharmaceutically acceptable. Such pharmaceutically acceptable salts are described in standard texts on salt formation, see for example: P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA / Wiley-VCH, 2002), or S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66, 1-19. However, salts having non-pharmaceutically acceptable counter-ions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable salts.

[0052] Suitable salts for use according to the invention include those formed with organic or inorganic acids. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C1-C4) alkyl or aryl sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxalic, oxaloacetic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Suitable cations which may be present in salts include alkali metal cations, especially sodium, potassium and calcium, and ammonium or amino cations. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. For the compound of Formula (I), the fumarate salt is especially preferred.

[0053] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, / V- methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri lower alkylamine, for example ethyl, tert butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. Corresponding internal salts may furthermore be formed.

[0054] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted, or from which they are precipitated or crystallized. These complexes are known as "solvates". A "pharmaceutically acceptable solvate" means a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. For example, a complex with water is known as a "hydrate". Solvates, such as hydrates, exist when the drug substance incorporates solvent, such as water, in the crystal lattice in either stoichiometric or non-stoichiometric amounts. Drug substances are routinely screened for the existence of hydrates since these may be encountered at any stage of the drug manufacturing process or upon storage of the drug substance or dosage form. Solvates are described in S. Byrn et al., Pharmaceutical Research, 12(7), 1995, 954-954, and Water-Insoluble Drug Formulation, 2ndedn, R. Liu, CRC Press, page 553, which are incorporated herein by reference. Accordingly, it will be understood by the skilled person that the compounds of the invention, as well as esters, amides, carbamates and / or salts thereof may therefore be present in the form of solvates, and these are also included within the scope of the present invention. Solvates of compounds of the invention, which are suitable for use in medicine, are those wherein the associated solvent is pharmaceutically acceptable. For example, as mentioned above, a hydrate is an example of a pharmaceutically acceptable solvate. However, solvates having non-pharmaceutically acceptable associated solvents may find use as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable esters, amides, carbamates and / or salts thereof.

[0055] Combination treatments

[0056] It has become common practice in the field of oncology to use combinations of anti-cancer treatments to achieve the best overall outcome for a patient. Given the number of different agents available and the possibility of antagonistic action between active compounds or other arising incompatibilities, the development of a successful combination treatment for a particular cancer is a complex task and outcomes are unpredictable.

[0057] MLN8237 (known as Alisertib) is perhaps the Aurora kinase inhibitor that has been studied most widely in the clinic to date. It has been investigated in early stage clinical trials in combinations with docetaxel (https: / / pubmed.ncbi.nlm.nih.gov / 21291867 / ), with Sorafenib (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC6172479 / ), with Gemcitabine (https: / / ascopubs.org / doi / 10.1200 / JCO.2020.38.15_suppl.3589), with Erlotinib (https: / / classic.clinicaltrials.gov / ct2 / show / NCT01471964) and with cytarabine and idarubicin (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC5395112 / ). However, none of those trials of combinations showed sufficient efficacy for the drug to be taken forward to approval alone or in a combination. It has not previously been known to use an Aurora kinase inhibitor together with either or both of Venetoclax and Azacitidine.

[0058] Venetoclax has been used in combination with Azacitidine. However, Saliba et al. 2021 (Cancer Drug Resist., 2021;4(l):125-142. doi: 10.20517 / cdr.2020.95.) described that despite promising results with the pair of compounds, half of patients who responded relapse after a median duration of about 18 months. The authors further noted that "Resistance still constitutes a significant roadblock in the quest to prolong the duration of response".

[0059] It is apparent from these studies that although combination therapies involving Aurora kinase inhibitors have been investigated, there is no particular combination of drugs that shows clear promise of strong efficacy.

[0060] Compositions

[0061] While it is possible for an active pharmaceutical ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition. Accordingly, in the practice of the current invention, pharmaceutical formulations or compositions each comprising one or more of the active compounds and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" materials) are preferred. Pharmaceutical compositions and formulations may take the form of a pharmaceutical composition or formulation as described below.

[0062] Pharmaceutical compositions for use in the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

[0063] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient(s) with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.

[0064] Compositions for use in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient(s); as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient(s) may also be presented as a bolus, electuary or paste.

[0065] A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so to provide slow or controlled release of the active ingredient(s) therein. The compounds of the invention can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising a compound, or compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.

[0066] Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplaryforms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. Also included in such compositions may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such compositions can also include an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e.g. Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Venetoclax may, for example, be provided in the form of a film-coated tablet for oral administration. The compound of Formula (I) may, for example, be provided in the form of a capsule or tablet for oral administration.

[0067] The compounds for use in the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine (cephaline), or phosphatidylcholine (lecithin).

[0068] Compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. For example, Azacitidine may be provided as a lyophilized powder for reconstitution into a suspension for subcutaneous injection.

[0069] Exemplary compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0070] Compositions for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0071] Compositions for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient(s) in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient(s) in a basis such as gelatin and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase® (mineral oil gelled with polyethylene).

[0072] Preferred unit dosage compositions are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient(s). For effective and convenient dosing, the invention also provides a composition, such as a unit dosage composition, comprising two or all three of the active ingredients described herein in combination. For example, the invention provides a composition, for example a composition for oral administration, comprising both the compound of Formula I and Venetoclax in combination. Since both the compound of Formula I and Venetoclax are normally administered orally to a patient, a combined composition containing both ingredients, e.g. a composition for oral administration, may be a particularly effective and convenient way to administer those compounds to a patient in the context of a method of treatment as disclosed herein. Similarly, the invention also provides a composition comprising both the compound of Formula I and Azacitidine in combination as well as a composition comprising the compound of Formula I, Venetoclax and Azacitidine in combination. Since the compound of Formula I, Venetoclax and Azacitidine can all be administered orally to a patient, a combined composition containing the compound of Formula I and Azacitidine or all three ingredients, e.g. a composition for oral administration, may be a particularly effective and convenient way to administer those compounds to a patient in the context of a method of treatment as disclosed herein. Such combined compositions may be for use in the treatment or prophylaxis of cancer or for use in the manufacture of a medicament for the treatment or prophylaxis of cancer as described herein.

[0073] It should be understood that in addition to the ingredients particularly mentioned above, the compositions for use in the invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include flavouring agents.

[0074] The compounds for use in the invention also find use in combination with radiation therapy for the treatment of cancer.

[0075] Kits

[0076] As mentioned above, the invention provides a kit comprising appropriate quantities of each of the compounds according to Formula (I), Azacitidine and Venetoclax. The three compounds used in the treatment of the current invention are to be administered in a coordinated manner. It is therefore convenient to provide them in a kit comprising the three compounds. Typically, they are administered separately. For example, the compound according to Formula (I) is administered in the form of a tablet or a hard capsule, Azacitidine is administered by subcutaneous or intravenous injection (so may be provided as a dry powderfor reconstitution) and Venetoclax is administered in the form of a film-coated tablet. A kit of the invention may provide suitable quantities of the three drugs for a cycle of treatment, or for multiple cycles of treatment. Further details regarding treatment cycles are provided below.

[0077] As mentioned above, the invention provides a kit comprising appropriate quantities of each of the compounds according to Formula (I) and Venetoclax. The two compounds used in the treatment of the current invention are to be administered in a coordinated manner. It is therefore convenient to provide them in a kit comprising the two compounds. Typically, they are administered separately. For example, the compound according to Formula (I) is administered in the form of a tablet or a hard capsule and Venetoclax is administered in the form of a film-coated tablet.

[0078] A kit of the invention may provide suitable quantities of the two drugs for a cycle of treatment, or for multiple cycles of treatment. Further details regarding treatment cycles are provided below.

[0079] As mentioned above, the invention provides a kit comprising appropriate quantities of each of the compounds according to Formula (I) and Azacitidine. The two compounds used in the treatment of the current invention are to be administered in a coordinated manner. It is therefore convenient to provide them in a kit comprising the two compounds. Typically, they are administered separately. For example, the compound according to Formula (I) is administered in the form of a tablet or a hard capsule and Azacitidine is administered by subcutaneous or intravenous injection (so may be provided as a dry powder for reconstitution).

[0080] A kit of the invention may provide suitable quantities of the two drugs for a cycle of treatment, or for multiple cycles of treatment. Further details regarding treatment cycles are provided below.

[0081] Treatments

[0082] The compounds of the invention as described hereinabove, find use in the treatment and / or prophylaxis of cancer in a patient, for example the treatment and / or prophylaxis of blood cancers. The amounts of each compound, which is required to achieve a therapeutic effect will vary with the particular route of administration and the characteristics of the subject (i.e. the patient) under treatment, for example the species, age, weight, sex, medical conditions, the particular disease or condition and its severity, and other relevant medical and physical factors. An ordinarily skilled physician can readily determine and administer an effective amount of a compound of formula (I) and Azacitidine and Venetoclax as described hereinabove required for treatment or prophylaxis of a cancer.

[0083] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may be at least 18 years old, at least 30 years old or at least 40 years old, for example at least 50 years old, or at least 60 years old.

[0084] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may have previously been administered Venetoclax. In other words, said subject or patient has been treated with Venetoclax prior to commencing a combination treatment of the present invention.

[0085] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may not have previously been administered Venetoclax. In other words, said subject or patient has not been treated with Venetoclax prior to commencing a combination treatment of the present invention.

[0086] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may have previously been administered Azacitidine. In other words, said subject or patient has been treated with Azacitidine prior to commencing a combination treatment of the present invention.

[0087] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may not have previously been administered Azacitidine. In other words, said subject or patient has not been treated with Azacitidine prior to commencing a combination treatment of the present invention.

[0088] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may have previously been administered Venetoclax and Azacitidine. In other words, said subject or patient has been treated with Venetoclax and Azacitidine prior to commencing a combination treatment of the present invention.

[0089] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may not have previously been administered Venetoclax and Azacitidine. In other words, said subject or patient has not been treated with Venetoclax and Azacitidine prior to commencing a combination treatment of the present invention.

[0090] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may have previously been administered cytarabine. In other words, said subject or patient has been treated with cytarabine prior to commencing a combination treatment of the present invention.

[0091] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may not have previously been administered cytarabine. In other words, said subject or patient has not been treated with cytarabine prior to commencing a combination treatment of the present invention.

[0092] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer): (i) may have altered expression of a gene; or (ii) may carry a mutation in a gene, wherein in either case said gene is selected from the group consisting of TP53, an IDH gene (e.g. IDH1 or IDH2), DDX41, FLT3 (including ITD and TKD), KIT, NPM1, CEBPA, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR, ANKRD26, BCL2, BCORL1, CALR, CBL, CUX1, DNMT3A, ETNK1, ETV6, GATA1, GATA2, GNB1, JAK2, KMT2A, KRAS, MPL, MYC, NF1, NRAS, PHF6, PPM1D, PRPF8, PTPN11, RAD21, SETBP1, SF1, SMC3, STAT3, STAT5B, TET2, WT1, ZRSR2 and a combination thereof, for example a TP53 expression alteration or mutation, an IDH1 expression alteration or mutation, a FLT3 expression alteration or mutation, a RUNX1 expression alteration or mutation, an NPMl expression alteration or mutation, a DDX41 expression alteration or mutation, a TP53 / IDH2 double expression alteration / double mutation, a TP53 / FLT3 double expression alteration / double mutation, a TP53 / NRAS double expression alteration / double mutation or an NRAS / WT1 double expression alteration / double mutation. The altered gene expression may be an increase or a decrease in expression level, which leads to an increase or decrease in expression of the related protein. The mutations may be a gain of function mutations or loss of function mutations, i.e. the mutation may increase or decrease (e.g. abolish) the activity of the gene and its associated protein. Since the subject or patient as referred to herein is generally a human patient or subject, the references to genes herein should be understood as referring to human genes.

[0093] The subject or patient who is the object of the invention as described hereinabove (i.e. the subject or patient to whom the compounds of the invention are administered for the purpose of treating or preventing cancer) may be wildtype for a gene selected from the group consisting of TP53, an IDH gene (e.g. IDH1 or IDH2), DDX41, FLT3 KIT, NPMl, CEBPA, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR, ANKRD26, BCL2, BCORL1, CALR, CBL, CUX1, DNMT3A, ETNK1, ETV6, GATA1, GATA2, GNB1, JAK2, KMT2A, KRAS, MPL, MYC, NF1, NRAS, PHF6, PPM1D, PRPF8, PTPN11, RAD21, SETBP1, SF1, SMC3, STAT3, STAT5B, TET2, WT1, ZRSR2 and a combination thereof.

[0094] The compounds of the invention as described hereinabove may for example be administered as a parenteral or oral dosage. Parenteral administration includes intravenous (into a vein, for example a central or a peripheral vein, bolus or infusion), intra-arterial (into an artery, for example a central or a peripheral artery), intraosseous infusion (into the bone marrow), intramuscular (into muscle), intradermal (into the dermis), and subcutaneous (under the skin) administration. In one preferred embodiment, the dosage of the present invention is administered intravenously or intra-arterially, and more preferably by intravenous infusion (for example central intravenous infusion or peripheral intravenous infusion). The compound of formula (I) as described hereinabove may be administered in an amount of about 40 mg to 250 mg per administration, for example about 50 mg to about 75 mg per administration. For example, in an amount of about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg or 250 mg per administration. For example, the compound of formula (I) may be administered in an amount of about 50 mg to 200 mg per administration, for example about 50 mg to about 100 mg per administration, for example 75 to 150 mg per administration, for example 80 to 120 mg per administration, for example 100 mg per administration. The compound may be administered in those amounts once or twice per day, for example twice per day. For example, the compound may be administered in a daily dose of from about 10 mg to 500 mg or of from about 50 mg to about 150 mg, for example a daily dose of from about 50 mg to about 200 mg, for example a daily dose of from about 50 mg to about 100 mg, for example about 100 mg per administration, administered twice daily making a total daily dose of about 200 mg. The compound may be administered, for example as an oral dosage, at a dose of from about 40 to 200 mg twice per day, e.g. 100 mg twice per day. Thus, the dosage of the compound of Formula (I) may be administered as an oral dosage at a dose of from 40 to 200 mg twice per day. For example, compound of formula (I) may be administered for the duration of a treatment. Alternatively, it may be administered in the first portion of a treatment cycle. For example, compound of formula (I) may be administered on days 1 to 14, or on days 1 to 21, or on days 1 to 28 of a 28 day treatment cycle. The compound of formula (I) may be administered orally. The dose amounts of the compound of Formula (I) specified herein refer to the mass of the compound administered excluding any salt element.

[0095] Venetoclax as described hereinabove may be administered in an amount of about 50 mg to 800 mg per administration. For example, in an amount of about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg per administration. For example, Venetoclax may be administered in an amount of about 50 mg to about 100 mg per administration, or about 50 mg to about 80 mg per administration or about 100 mg to 800 mg per administration, for example about 100 mg to about 400 mg per administration, for example about 100 mg to about 200 mg per administration, for example 200 to 600 mg per administration, for example 300 to 500 mg per administration, for example 100 mg per administration, for example 200 mg per administration, for example 400 mg per administration. The compound may be administered in those amounts once per day or twice per day, for example once per day. For example, Venetoclax may be administered at a dose from about 50 mg to about 100 mg, from about 50 mg to about 80 mg or from about 50 to 500 mg, once per day, for example about 400 mg, once per day. At the start of the first treatment cycle, it may be beneficial to use a lower dose, for example 100 mg on the first day and 200 mg on the second day. For example, Venetoclax may be administered on each day of a treatment cycle, for example each day of a 28 day treatment cycle. Venetoclax may be administered orally. The dose amounts of Venetoclax specified herein refer to the mass of the compound administered excluding any salt element.

[0096] Azacitidine as described hereinabove may be administered in an amount of about 10 mg to 200 mg per administration. For example, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per administration. In some instances, a dose is determined based on the patient's body weight or the patient's body surface area. For example, the Azacitidine may be administered in an amount from 25 to 150 mg / m2or from 25 to 60 mg / m2per administration. For example, 30 mg / m2, 35 mg / m2, 40 mg / m2, 45 mg / m2, 50 mg / m2, 55 mg / m2, 60 mg / m2, 65 mg / m2, 70 mg / m2, 75 mg / m2, 80 mg / m2, 85 mg / m2, 90 mg / m2, 95 mg / m2, 100 mg / m2, 110 mg / m2, 120 mg / m2, 130 mg / m2, and 140 mg / m2per administration. For example, Azacitidine may be administered in an amount of about 30 to 130 mg / m2, for example about 30 to about 75 mg / m2, for example about 30 to about 50 mg / m2, for example to 50 to 100 mg / m2, for example 60 to 90 mg / m2, for example 70 to 80 mg / m2, for example 75 mg / m2per administration. The compound may be administered in those amounts once per day. For example, Azacitidine may be administered at a dose from about 25 to about 150 mg / m2or 25 to 60 mg / m2once per day. For example, Azacitidine may be administered for the duration of a treatment. Alternatively, it may be administered in the first portion of a treatment cycle. For example, Azacitidine may be administered on days 1 to 7 of a 28 day treatment cycle. The dose amounts of Azacitidine specified herein refer to the mass of the compound administered excluding any salt element. The compound of Formula (I) and Venetoclax may be administered orally. The compound of Formula (I) and Venetoclax may be administered orally and Azacitidine may be administered parenterally, e.g. by subcutaneous injection. All three compounds may be administered orally. The compounds may be administered as part of a treatment cycle. In a treatment cycle, the first administration is on day 1 of the cycle, wherein the cycle lasts X days. X may be, for example, from 1 to 42, for example from 2 to 28 days. Preferably, the treatment cycle is 28 days. The compounds maybe administered on the days mentioned above.

[0097] A compound of formula (I) as described herein above may be administered once daily or twice daily, as part of the treatment cycle. For example, the compound of formula (I) may be administered twice daily for every day of the treatment cycle. For example, the compound of formula (I) may be administered twice daily on days 1-28 of a cycle of 28 days.

[0098] Venetoclax as described herein above may be administered once daily or twice daily, as part of the treatment cycle. For example, Venetoclax may be administered once daily for every day of the treatment cycle. For example, Venetoclax may be administered once daily on days 1-28 of a cycle of 28 days.

[0099] Azacitidine as described herein above may be administered once daily or twice daily, as part of the treatment cycle. For example, Azacitidine may only be administered every day for 7 consecutive days starting on any of days 1-4 of the treatment cycle. For example, Azacitidine may be administered every day for the first 7 days of the treatment cycle. For example, Azacitidine may be administered on days 1 - 7 only of a cycle of 28 days.

[0100] The cycle may be repeated one or several times depending on the category, class or stage of the cancer to be treated. For example, the cycle may be repeated from 1 to 100 times, for example from 2 to 50 times, for example 1 to 12 times, for example 8 to 40 times, for example 8 or 16 times. For example, the compounds may be administered in 28 day cycles until disease progression has ceased or unacceptable toxicity levels are reached. An ordinarily skilled physician or clinician can readily determine the number of cycles required to prevent, counter or arrest the progress of the cancer.

[0101] A compound of Formula (I), Venetoclax, and Azacitidine, as described hereinabove, may be used simultaneously, sequentially or separately. For example, the individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

[0102] A compound of Formula (I) and Venetoclax, as described hereinabove, may be used simultaneously, sequentially or separately. For example, the individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

[0103] A compound of Formula (I) and Azacitidine, as described hereinabove, may be used simultaneously, sequentially or separately. For example, the individual components of such combinations can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

[0104] In the combination treatment of the invention in which a compound of Formula (I), Venetoclax, and Azacitidine are administered, the doses may be as follows:

[0105] - 50 to 75 mg of the compound of formula (I) per administration,

[0106] - 50 to 100 mg of Venetoclax per administration, and

[0107] - 40 to 60 mg / m2of Azacitidine per administration; or

[0108] - 50 to 150 mg of the compound of formula (I) per administration,

[0109] - 50 to 600 mg of Venetoclax per administration, and

[0110] - 40 to 90 mg / m2of Azacitidine per administration; or

[0111] - 75 to 150 mg of the compound of formula (I) per administration,

[0112] - 200 to 600 mg of Venetoclax per administration, and - 60 to 90 mg / m2of Azacitidine per administration.

[0113] Preferably, the doses are as follows:

[0114] - 80 to 120mg of the compound of formula (I) per administration,

[0115] - 300 to 500 mg of Venetoclax per administration, and

[0116] - 70 to 80 mg / m2of Azacitidine per administration.

[0117] For example, the doses are as follows:

[0118] - 100 mg per of the compound of formula (I) per administration,

[0119] - 400 mg of Venetoclax per administration, and

[0120] - 75 mg / m2of Azacitidine per administration.

[0121] For example, in such dosage regimens, the compound of formula (I) is administered on days 1 to 14, or on days 1 to 21, or on days 1 to 28 of a 28 day treatment cycle, Venetoclax is administered on each day of a treatment cycle, for example each day of a 28 day treatment cycle, and Azacitidine is administered for the duration of a treatment or for the first portion of a treatment cycle (for example, on days 1 to 7 of a 28 day treatment cycle).

[0122] For example, in such dosage regimens, when the compound of formula (I) is administered on a particular day of a treatment cycle, it is administered twice per day; when Venetoclax is administered on a particular day of a treatment cycle, it is administered once per day and when Azacitidine is administered on a particular day of treatment cycle, it is administered once per day.

[0123] In the combination treatment of the invention in which a compound of Formula (I) and Venetoclax are administered, the doses may be as follows:

[0124] - 50 to 75 mg of the compound of formula (I) per administration, - 50 to 100 mg of Venetoclax per administration; or

[0125] - 50 to 150 mg of the compound of formula (I) per administration,

[0126] - 50 to 600 mg of Venetoclax per administration; or

[0127] - 75 to 150 mg of the compound of formula (I) per administration, and

[0128] - 200 to 600 mg of Venetoclax per administration.

[0129] Preferably, the doses are as follows:

[0130] - 80 to 120mg of the compound of formula (I) per administration, and

[0131] - 300 to 500 mg of Venetoclax per administration.

[0132] For example, the doses are as follows:

[0133] - 100 mg per of the compound of formula (I) per administration, and

[0134] - 400 mg of Venetoclax per administration.

[0135] For example, in such dosage regimens, compound of formula (I) is administered on days 1 to 14, or on days 1 to 21, or on days 1 to 28 of a 28 day treatment cycle, and Venetoclax is administered on each day of a treatment cycle, for example each day of a 28 day treatment cycle.

[0136] For example, in such dosage regimens, when the compound of formula (I) is administered on a particular day of a treatment cycle, it is administered twice per day and when Venetoclax is administered on a particular day of a treatment cycle, it is administered once per day.

[0137] In the combination treatment of the invention in which a compound of Formula (I) and Azacitidine are administered, the doses may be as follows:

[0138] - 50 to 75 mg of the compound of formula (I) per administration, and - 40 to 60 mg / m2of Azacitidine per administration; or

[0139] - 50 to 150 mg of the compound of formula (I) per administration, and

[0140] - 40 to 90 mg / m2of Azacitidine per administration; or

[0141] - 75 to 150 mg of the compound of formula (I) per administration, and

[0142] - 60 to 90 mg / m2of Azacitidine per administration.

[0143] Preferably, the doses are as follows:

[0144] - 80 to 120mg of the compound of formula (I) per administration, and

[0145] - 70 to 80 mg / m2of Azacitidine per administration.

[0146] For example, the doses are as follows:

[0147] - 100 mg per of the compound of formula (I) per administration, and

[0148] - 75 mg / m2of Azacitidine per administration.

[0149] For example, in such dosage regimens, compound of formula (I) is administered on days 1 to 14, or on days 1 to 21, or on days 1 to 28 of a 28 day treatment cycle, and Azacitidine is administered for the duration of a treatment or for the first portion of a treatment cycle (for example, on days 1 to 7 of a 28 day treatment cycle).

[0150] EXAMPLES

[0151] Example 1: Preparation of Compound 1

[0152] The compound of formula (I), shown below, can be prepared according to the methods described in WO 2013 / 190319 and / or in WO 2021 / 176214.

[0153]

[0154] Example 2: Obtaining IC50 Values for Kinase Inhibitors Within Cell-Free Assay

[0155] Cell-Free Kinase Inhibition Assays

[0156] This assay is based on the transfer of33P-la be lied phosphate from ATP to the kinase substrate. Proteins and peptides in the HotSpot™ assay are captured via spotting of the reaction mix on a filter membrane.

[0157] The kinase assay was performed as described within Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity [T. Anastassiadis et al., Nature Biotechnol., 2011, 29, 11, 1039 - 1045, DOI: 10.1038 / nbt.2017],

[0158] Kinase Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCb, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO

[0159] Required cofactors are added individually to each kinase reaction.

[0160] Reaction Procedure

[0161] 1. Prepare substrate in freshly prepared Reaction Buffer.

[0162] 2. Deliver any required cofactors to the substrate solution above.

[0163] 3. Deliver kinase into the substrate solution and gently mix.

[0164] 4. Deliver compounds in 100% DMSO into the kinase reaction mixture and incubate for 20 min at room temperature.

[0165] 5. Add lOuM33P-ATP into the reaction mixture to initiate the reaction.

[0166] 6. Incubate for 2 hours at room temperature. 7. Detect kinase activity by P81 filter-binding method.

[0167] Results

[0168] Compound 1 is a multi-kinase inhibitor that primarily targets aurora kinases, followed by

[0169] FLT3: Table 1. IC50 values for Compound 1 with Aurora and FLT3 kinases.

[0170] Example 3: In vitro evaluation of Compound 1 alone or in combination with 5-Azacytidine and Venetoclax in PBMC cells prepared from patients with Acute Myeloid Leukaemia by Cell Titer Gio Cell Viability Analysis.

[0171] 5-Azacytidine and Venetoclax

[0172] 5-Azacytidine (CAS: 320-67-2) and Venetoclax (CAS: 1257044-40-8) can be obtained from commercial sources. Preparation of Cells

[0173] The PBMC cells were prepared in accordance with procedures that are well known within the art.

[0174] Human Leukapheresis Sample Processing and Cryopreservation

[0175] Leukapheresis from AML patients were collected in a pheresis bag and transported to the lab for further processing within 2 hours of sample collection. Briefly, cells were transferred in 50ml Falcon tubes (Fisher) and diluted with PBS, 2% (v / v) fetal bovine serum (FBS, Gemini Bio). After centrifugation (300 x g) for 5 minutes at 20°C, red blood cells were lysed using ammonium chloride (Stem Cell Technologies) and cells were washed and resuspended in PBS, 2% (v / v) FBS for counting. Cells were then aliquoted and frozen at an appropriate cell concentration in a mix 1:1 of PBS 2% (v / v) FBS and 14% (v / v) dimethyl sulfoxide (Fisher), 4% Hetastarch (NovaPlus), and 4% bovine serum albumin (Gemini Bio). Cell vials (Abdos) were placed at -80 °C overnight and transferred into liquid nitrogen freezer for long-term conservation.

[0176] Human Cells

[0177] All patient samples were procured after informed consent and deidentified in accordance with IRB-approved protocols. White blood cells were obtained via leukapheresis from AML patients in blast crisis. Mononuclear cells were separated by density gradient centrifugation (400 x g), 30 minutes at 20°C, (Ficoll Paque Plus), washed and then red blood cells lysed using Ammonium Chloride (Stem Cell Technologies). Cells were resuspended in appropriate volume of PBS 2% (v / v) fetal bovine serum (Gemini Bio) for cell counting using a Nexcelom Cell Counter. After final centrifugation (300 x g for 5 minutes at 20°C), cells were then aliquoted and frozen at an appropriate cell concentration in a mix 1:1 of PBS 2% FBS and 14% dimethyl sulfoxide (Fisher), 4% Hetastarch (NovaPlus), and 4% bovine serum albumin (Gemini Bio). Cell vials (Abdos) were placed at -80°C overnight and transferred into liquid nitrogen freezer for long-term conservation.

[0178] Experimental Design

[0179] After thawing, cells were washed with serum free AML basal media and centrifuged at 300g for5 minutes. The pellets were resuspended in AMLVitroScreen media (Champions Oncology) and stored within 37°C / 5% CO2 incubator to maintain the AML cells for dosing. Cells were treated with test agents and controls as outlined below. For each test sample, the single agent and / or combination treatment were set up in 96 well plates in duplicate or triplicate with 3 wells of each in-plate positive control; 5 pM Cytarabine or 10% (v / v) DMSO and 3 wells of vehicle negative control. DMSO was adjusted to 0.1% (v / v) final concentration in all wells.

[0180] Table 2. Treatment of cells with control and test compounds. The dilution scheme for Compound 1 - Group 4 above:

[0181] Table 3. Dilution scheme for Compound 1 (Group 4 in Table 2). Protocol

[0182] Human AML patient cells obtained by leukapheresis were seeded at a density of 20,000 cells / 100 pl per well in black, flat bottomed 96 well plates in AML VitroScreen media (Champions Oncology) on Day 0. Test compounds, diluted in the same media were added to wells on Day 0 along with cell plating according to the experimental design using a Tecan D300e digital dispenser.

[0183] Triplicate wells treated with Cytarabine (5,000 nM) or media with 10% DMSO (v / v) were used as a positive control, while triplicate wells of Media + vehicle 0.1% DMSO (v / v) were used as negative control. DMSO was adjusted to 0.1% (v / v) in all treatment wells. Plates were kept in 37°C / 5% CO? incubator throughout the duration of the experiment. Following 6 days incubation with compounds, cell viability was tested using the Cell Titer Gio assay (Promega), as per the manufacturer's instructions.

[0184] Plates were removed from incubator and equilibrated to room temperature up to 30 minutes. 50 pl of 2D Cell Titer Gio reagent was added to each well and incubated at room temperature for 10 minutes to stabilize luminescent signal. Luminescence was recorded using Tecan plate reader. Data was recorded as a change in Relative Luminescence Units (RLU) in response to different drug concentrations as luminescence read is directly proportional to cell viability.

[0185] Data Analysis

[0186] Data from each readout was analysed using Bliss synergy analysis method as described within the SynergyFinder website [https: / / synergyfinder.fimm. fi / synergy / synfin_docs / #welcome, Accessed May 2024]:

[0187] The Bliss independence model assumes a stochastic process in which two drugs elicit their effects independently, and the expected combination effect can be calculated based on the probability of independent events. Thus, Bliss synergy score, SBHSS, is defined as:

[0188] ( ( EA \ ( EB\ ( EN\ \

[0189] SRH^ = EA R n- 100 1 - 1 - — 1 - — ... 1 - — ,

[0190] Bllss A’B.N\ \ 100 / \ 100 / \ 100 / /

[0191] Here, terms 1 — represent probabilities that drugs A,B,...,N do not inhibit the target. Thus, multiplication of these terms results in the probability that none of the drugs inhibit the target. Subtracting this probability from 1, 1 — 1 gives the probability that at least one of the drugs inhibits the target, which is equivalent to the Bliss effect.

[0192] The Bliss effect can also be represented with equivalent extended formula, as a combination of individual drug effects and their interactions:

[0193] Although both formulas may look different, they are mathematically equivalent and will yield the same value for the Bliss effect. For example, for a 3-drug combination, with each drug responses equal to e.g. EA = 35% inhibition, EB = 57% inhibition, EN = 44% inhibition, and combination effect EA,B N = 93% inhibition, based on probabilistic equation, Bliss synergy score (SBHSS) equals to:

[0194] ^Biiss — 93 100 = 8.652

[0195] The extended formula provides exactly the same results:

[0196] = 8.652

[0197] Viability data from each individual patient sample were averaged and plotted with the variable X- and Y-axes as indicated in each table below. The average Bliss synergy responses from these data are indicated in each table below. Generally speaking, when the synergy score is less than -10 the interaction between two drugs is likely to be antagonistic, whereas if the score is from

[0198] -10 to 10 the interaction between two drugs is likely to be additive and larger than 10, the interaction between two drugs is likely to be synergistic.

[0199] Further information regarding Bliss synergy analysis can be found in: Statistical determination of synergy based on Bliss definition of drugs' independence (E. Demidenko and T. Miller, PLOS ONE, 2019, 14, 11, e0224137).

[0200] Results and Conclusion

[0201] The average bliss values and the mean viability values are shown for all cells below, with different combinations of Compound 1, 5-Azacitidine, and Venetoclax.

[0202]

[0203] Table 4. Ex vivo cell viability assay for all samples (n = 30), measured using a Cell Titer Gio assay kit. Average bliss values for each combination are shown, along with the mean viability values in parentheses. Concentrations of 5-Azacitidine and Compound 1 are shown on the x- and y-axis, respectively. The concentration of Venetoclax is fixed at 30 nM.

[0204] Table 5. Ex vivo cell viability assay for all samples (n = 30), measured using a Cell Titer Gio assay kit. Average bliss values for each combination are shown, along with the mean viability values in parentheses. Concentrations of Venetoclax and Compound 1 are shown on thex- and y-axis, respectively. The concentration of 5-Azacitidine is fixed at 2 pM.

[0205]

[0206] Table 6. Ex vivo cell viability assay for FLT3-mut and NPMl-wt. cells (n = 2), measured using a Cell Titer Gio assay kit. Average bliss values for each combination are shown, along with the mean viability values in parentheses. Concentrations of 5-Azacitidine and Compound 1 are shown on the x- and y-axis, respectively. The concentration of Venetoclax is fixed at 30 nM.

[0207] Table 7. Ex vivo cell viability assay for FLT3-mut, NPMl-wt. cells (n = 2), measured using a Cell Titer Gio assay kit. Average bliss values for each combination are shown, along with the mean viability values in parentheses. Concentrations of Venetoclax and Compound 1 are shown on the x- and y-axis, respectively. The concentration of 5-Azacitidine is fixed at 2 pM.

[0208]

[0209] Table 8. Ex vivo cell viability assay for FLT3 = WT cells (n = 5), measured using a Cell Titer Gio assay kit. Average bliss values for each combination are shown, along with the mean viability values in parentheses. Concentrations of 5-Azacitidine and Compound 1 are shown on the x- and y-axis, respectively. The concentration of Venetoclax is fixed at 30 nM.

[0210] Table 9. Ex vivo cell viability assay for FLT3 = WT cells (n = 5), measured using a Cell Titer Gio assay kit. Average bliss values for each combination are shown, along with the mean viability values in parentheses. Concentrations of Venetoclax and Compound 1 are shown on thex- and y-axis, respectively. The concentration of 5-Azacitidine is fixed at 2 pM.

[0211] The results show that Compound 1 cell killing activity is independent of FLT3 mutation status and synergizes with venetoclax and azacitidine. The cell killing effect may be more pronounced in FLT3 mutant cells. Example 4: In vitro evaluation of inhibition by Compound 1 alone or in combination with Venetoclax in MV4;11 and M0LM13 cells by flow cytometry

[0212] The cells used in the experiment were:

[0213] MV4;11 leukaemia cells

[0214] MV4;11 leukaemia cells resistant to Venetoclax

[0215] M0LM13 AML cells.

[0216] MV4;11 leukaemia cells resistant to Venetoclax were prepared by treating MV4;11 cells with Venetoclax, causing them to develop acquired resistance to Venetoclax (see for example Yamatani et al., Translational Oncology, 2022, 18, 101354 for a general description of the method for preparing resistant cells). The drug was removed 2-3 days before the treatment.

[0217] The Culture media was: RPMI1640+10%FBS+l% Penicillin / Streptomycin.

[0218] Treatment protocol:

[0219] 1. Prepare 4X stocks for drugs of the interest. Use culture media as the solvent.

[0220] 2. In a 96 well plate load 50 pL of drug of interest into each well.

[0221] 3. For mono-drug treatment wells, add additional 50 pL of culture media. For no-treatment control, add 100 pL culture media.

[0222] 4. Using Vi-cell to calculate viable cell number and percentage. Prepare cells at 0.4 xlO6cells / ml, >95% viability, using culture media for necessary dilutions.

[0223] 5. Load 100 pL of prepared cell stocks from step 4 to the 96-well plate prepared in step 3. Incubate a 5% CO2 incubator at 37°C for desired experiment time length.

[0224] Final set up:

[0225] Dual treatment: 50 pL drug A +50 pL drug B +100 pL AML cells

[0226] Mono treatment: 50 pL drug A or B +50 pL media + 100 pL AML cells

[0227] Control: 100 pL media + 100 pL AML cells. Measurements:

[0228] Annexin V binding buffer: lOmM HEPES, 150mM NaCI, 2.5mM CaCI2, pH 7.4, in PBS.

[0229] Annexin V-Cy5 BD Pharmingen, cat#559934.

[0230] 7-AAD: Millipore Sigma, A9400-1MG.

[0231] Counting beads: Spherotech, ACFP-70-10.

[0232] Staining buffer: Annexin V binding buffer, 28 pL Annexin V -Cy5 (1:10 diluted from stock) + 10 pL 7-AAD (50 pg / mL).

[0233] Counting buffer: Annexin V binding buffer, 25 pL counting beads per ml.

[0234] The measurements were obtained as follows:

[0235] 1. By the day of measurement, take 60 pL of cell culture from the treatment plate, transfer into a U-bottom 96 well plate for the flow cytometry analysis.

[0236] 2. Centrifuge at 400xg for 5 mins, then aspirate extra cell culture from the plate. Wash cells with PBS for twice.

[0237] 3. In each well, load 60 pL staining buffer, and incubator in room temperature for 30 mins, avoid light.

[0238] 4. Centrifuge at 400xg for 5 mins, then aspirate extra staining buffer. Wash with PBS for twice.

[0239] 5. Load 60 pL of counting buffer into each well. The plate is ready for the flow cytometry analysis.

[0240] Flow cytometry:

[0241] Data were collected at 240 pL / min for 10s. CytoFLEX flow cytometer was used for the data collection.

[0242] The results:

[0243] The mean % inhibition of growth and the average bliss values are shown below for the three cell types, with different combinations of Compound 1 and Venetoclax. For MV4;11 cells:

[0244] Table 10: Ex vivo cell inhibition assay for MV4;11 cells. Average bliss values for each combination are shown, along with the mean inhibition values in parentheses. Concentrations of Compound 1 and Venetoclax are shown on the x- and y-axis respectively.

[0245] For MV4;llres cells: Table 11: Ex vivo cell viability assay for MV4;llRes cells. Average bliss values for each combination are shown, along with the mean inhibition values in parentheses. Concentrations of Compound 1 and Venetoclax are shown on the x- and y-axis respectively. For MOLM-13 cells:

[0246] Table 12: Ex vivo cell viability assay for MOLM-13. Average bliss values for each combination are shown, along with the mean inhibition values in parentheses. Concentrations of

[0247] Compound 1 and Venetoclax are shown on the x- and y-axis respectively.

[0248] The results show that Compound 1 has good cell killing activity in all three tested cell types. The bliss scores show that Compound 1 synergizes with venetoclax. The synergy effect in cell killing appears to be most pronounced in the venetoclax-resistant cells, MV4;11 res.

[0249] Example 5: Human Clinical Trial Study

[0250] The clinical trial is a Phase l / lla, modular, multi-arm, multi-centre, open-label, FIH.

[0251] The design consists of a core study protocol and individual modules, as follows:

[0252] • Module 1: Monotherapy using Compound of Formula (I) dosing in patients with R / R AML, CMML or MDS: dose escalation and dose optimization.

[0253] • Module 2: Compound of Formula (I) in combination with Venetoclax and Azacitidine in patients with R / R and newly diagnosed AML. Module 1: Monotherapy dosing in patients with AML, CMML or MPS

[0254] Module 1 is a first-in-human (FIH) single and multiple ascending dose (MAD) study, to investigate safety, tolerability, PK and PD and to define the maximum tolerated dose (MTD) and / or RP2D in patients with pathologically confirmed / documented AML or MDS as defined by the 2017 European LeukaemiaNet (ELN) recommendations, or CMML as defined by World Health Organization (WHO) criteria, who have relapsed from or are refractory to previous therapy. A standard 3+3 dose escalation design is proposed of approximately 10 cohorts.

[0255] Once the MTD has been identified in Module 1, recruitment of approximately 9-18 additional patients may be initiated in order to obtain further safety and efficacy data for identification of the optimal dose and schedule to take forward into Module 2.

[0256] Dose Escalation:

[0257] The initial dosing of patients in the dose-escalation part of the study is staggered, with at least a 1-week interval between the first 2 patients treated at each dose level. The integrated response system (IRS) is used to control patient allocation to treatment and ensure the dosing intervals and cohort recruitment complies with the protocol.

[0258] Cycle 1:

[0259] Each cycle of treatment is 28 days. For Cycle 1, daily dosing is initiated for 14 days out of 28. Daily dosing may be increased from 14 days out of 28 up to a maximum of 28 out of 28 days (smaller increments guided by safety, PK and PD data) in subsequent cohorts if, in the opinion of the Safety Management Committee (SMC), the safety, tolerability and PK data support further daily dosing. Where a cohort has increased the number of days dosing to more than 14 days per cycle or amended to a BID dosing regime, with no safety or tolerability issues during the first cycle, as judged at the SMC Meetings patients in previous cohorts may have their dosing amended in line with the increased number of days or BID dosing regime, if the investigator deems it in the best interest of the patient after consultation with the Medical Monitor. Safety parameters, including neutrophil, lymphocyte and platelet counts are carefully monitored. If, after 14 days continuous dosing with Compound 1, the SMC consider that the patient would benefit from a dose-free period, for the recovery of bone marrow or other toxicities, a period of up to 14 days with no dosing may occur. The dose of Compound 1 and / or schedule (for example a 14 days on / 14 days off, 21 days on, 7 days off or 28 days dosing) may be modified based on emerging safety and available PK and PD data.

[0260] Patients enrolled in each cohort are observed for Dose Limiting Toxicities (DLTs) for a period of 1 cycle (28 days) with Compound 1 being dosed QD on days 1-14 in cycle 1, but with the potential to extend dosing to 21 or 28 days in subsequent cycles. Dose escalation or de- escalation decisions is determined following review of all available safety, PK, and efficacy data from cycle 1. The key decisions of dose escalation or de-escalation and identification of the MTD and / or the RP2D are made by the SMC and occur during the SMC Meetings, which are held once all patients in a given dosing cohort have completed the DLT evaluation period. All dosing decisions are agreed upon and documented in the SMC meeting minutes. The SMC includes participating Investigators (or suitable delegate), the Sponsor Medical Monitor and statistician (if required). The data package reviewed by the SMC is cleaned on an ongoing basis, and all AE / serious adverse event (SAE) and DLT data are source data verified and cleaned as much as possible before each SMC review. The completeness and cleaning status of the data shared prior to and during SMC meetings (e.g., reviewed internally by Ellipses Pharma, source data verified, investigator's account for late incoming data, and open queries for critical safety data) are documented in the SMC meeting presentation and minutes.

[0261] Patients who do not complete the DLT assessment period for reasons other than toxicity may be replaced after consultation with the Medical Monitor. For the purpose of toxicity evaluation, patients must have received >80% of the Cycle 1 dose and have completed 28 days of observation (DLT period), unless missed doses are due to Compound 1-related toxicity.

[0262] Each cohort enrols 3 patients until the dose level is reached at which the toxicity meets the criteria for DLT, at which point the cohort is expanded to enrol six patients. Thereafter dose escalation is completed according to a "3+3" dose escalation design to determine the MTD.

[0263] If deemed necessary by the SMC, additional patients may be included to make informed dosing decisions. In each module, the frequency of dosing, any washout and dosing staggering interval between patients may change based upon emerging data as reviewed and agreed by the SMC, without the requirement to submit a substantial amendment to the protocol. The frequency of PK sampling may also be modified based on SMC review of PK data and may include up to three additional PK samples of 4 ml within any given cycle, in order to better characterize the PK profile.

[0264] Dose Optimization:

[0265] Upon the identification of the Maximum Tolerated Dose (MTD), following review of the PK, safety and efficacy data, approximately 9-18 additional patients may be recruited to collect further safety and efficacy data, and to further characterize the dose selection and appropriate schedule:

[0266] (1) Further expansion of the preceding dose levels may be initiated at a different dosing schedule

[0267] (2) Exploration of additional dose levels which are intermediate, between the preceding dose levels and the MTD

[0268] (3) Intra-patient dose escalation cohorts may be explored

[0269] These cohorts may open in parallel. Safety parameters are carefully monitored as per the Schedule of Events. Each cohort enrols 3 patients initially, whom are observed for DLTs during the first cycle (28 days). Patients who do not complete the DLT assessment period for reasons other than toxicity may be replaced after consultation with the Medical Monitor. For the purpose of toxicity evaluation, patients must have received >80% of the Cycle 1 dose and have completed 28 days of observation, unless missed doses are due to Compound 1-related toxicity. If a toxicity meets the criteria for DLT during this period, the cohort may be expanded to enrol six patients. PK / PD data are also reviewed on an ongoing basis for all patients and cohorts may be expanded should the SMC deem that additional data is required in order to supporting selecting the appropriate dose for Module 2.

[0270] The SMC meets following completion of the dose optimization cohorts and reviews the data in totality in order to select the doses and appropriate schedule to be explored in Module 2.

[0271] Module 1 of this protocol was initiated with the objective of establishing the safety of Compound 1 as a monotherapy and establishing an appropriate dose to take forward into subsequent modules. In order to achieve this objective, a broad population of mostly heavily pre-treated patients with relapsed refractory (R / R) AML, myelodysplastic syndrome (MDS) or chronic myelomonocytic leukaemia (CMML) with / without FLT3 mutations were included.

[0272] As per the Investigator's Brochure (IB) cut-off date (28 July 2024), 46 patients (20 female / 26 male) were enrolled across 9 different cohorts. Median age 72 years, range 25-84. Patients presented with R / R AML (33), CMML (2) or MDS (11). Eleven (11) patients had FLT3 mutated AML at the point of entry (10 having FLT3 internal tandem duplication (ITD) mutations, and 1 having a FLT3 tyrosine kinase domain (TKD) mutation - both mutations cause constitutive activity of the mutant FLT3 protein). Patients were administered doses ranging from 40 mg to 170 mg, once daily (QD) or twice daily (BID), with different schedules, across 7 cohorts (Table

[0273] 10). The median number of prior treatments was 2 (range: 1-6). Twelve (12) patients received a prior FLT3 inhibitor including midostaurin, gilteritinib or sorafenib and 8 / 12 patients received >2 prior FLT3 inhibitors. Three (3) patients received prior autologous stem cell transplant (ASCT). Compound 1 was administered in the form of its fumarate salt (the indicated dose being the weight of compound excluding the fumarate). It was provided as a hard capsule for oral administration.

[0274] The outcome of the dosing cohorts for Module 1 is presented in Table 13 below:

[0275]

[0276] Table 13. Summary of dosing cohorts and key data from Module 1. Abbreviations: BID = twice daily; QD = once daily; SD = stable disease; CRMRD- = complete remission with minimal residual disease; DLTs = dose limiting toxicides. Across all cohorts, 26 patients achieved stable disease (SD). One patient achieved complete remission with minimal residual disease confirmed by flow cytometry, as known in the art. This patient completed treatment on cycle 15, day 15 and maintained transfusion independence for 10 months. One patient achieved morphologic leukaemia-free state on cycle 2, day 1, and remained on the trial until cycle 4, day 22 when they discontinued the trial due to thrombocytopenia. In addition, 5 patients (11%) experienced a > 50% reduction in peripheral blasts during treatment.

[0277] Thus, the maximum tolerated dose (MTD) was identified as 150 mg BID 28 / 28 days, with 2 patients experiencing dose-limiting toxicities (DLTs) identified as Grade 3 somnolence and ataxia, and Grade 3 encephalopathy. Module 2A - Treatment with Compound 1 and Venetoclax:

[0278] 1. Patient criteria:

[0279] The following eligibility criteria are used to select patients for whom protocol treatment is appropriate. Patients must meet all of the following inclusion criteria to be eligible for inclusion in the treatment study:

[0280] 1. Male or female patients aged > 18 years of age, at the time of informed consent, with histological or cytological confirmation of Acute Myeloid Leukemia (AML). (Median age of patients enrolled was 67.)

[0281] 2. Ability to understand and provide written informed consent before any study-specific procedures, sampling, or analyses, including access to archival tumor tissue.

[0282] 3. Ability to swallow and retain oral medication.

[0283] 4. Sufficient life expectancy to allow the patient to complete at least 1 cycle (28 days) of the treatment period.

[0284] 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 at screening.

[0285] 6. In the opinion of the investigator, all other relevant medical conditions must be wellmanaged and stable for at least 28 days prior to first administration of study drug.

[0286] 7. Patients with pathologically confirmed / documented Acute Myeloid Leukemia (AML) or Myelodysplastic syndrome (MDS), as defined by the 2022 European LeukaemiaNet (ELN) recommendations, or CMML, as defined by World Health Organization (WHO) criteria, who have relapsed from or are refractory to previous therapy and have failed all (or are not eligible for / intolerant to) available approved therapies for their disease.

[0287] All cohorts are initially enriched with patients with AML harboring certain genetic alterations, including but not limited to TP53, RUNX1 and NPM1 alterations.

[0288] Some of the patients had received Venetoclax as prior therapy, whereas some had not received Venetoclax as prior therapy. 2. Treatment regimen

[0289] The subjects are administered Compound 1 and Venetoclax.

[0290] Compound 1 is provided in hard capsules for oral administration. The compound is in the form of its fumarate salt, and each capsule provides the equivalent of 20mg or 50mg of the active ingredient, Compound 1. The capsules also contain D-a-TPGS.

[0291] Venetoclax is supplied as lOOmg film-coated tablets for oral administration.

[0292] Compound 1 should be taken on an empty stomach (at least 2 hours after and 1 hour before meals) and at approximately the same time each day. Capsules should be swallowed whole, with water if necessary, and not chewed. Venetoclax tablets should be taken with a meal and swallowed whole with water at approximately the same time each day. Therefore, the Compound 1 dosing must occur first on an empty stomach, followed by venetoclax dosing with a meal. The tablets should not be chewed, crushed, or broken before swallowing.

[0293] Compound 1 and Venetoclax are dosed in cycles, each cycle consisting of 28 days. The dosing amounts are as follows:

[0294] Table 14. Dosing cycles and amounts of Compound 1 and Venetoclax 3. Assessments

[0295] Baseline Characteristics:

[0296] Prior to starting the trial, each subject undergoes a medical screening assessment, and the following are checked: Informed consent; Demography; Inclusion / exclusion criteria; Medical history and cancer history; Prior anti-cancer therapy; Prior / concomitant medications; Adverse events (from consent); Full physical examination including height and weight; ECOG performance status; Vital signs; 12-lead ECG (triplicate); Bone Marrow examination; Hematology panel; Coagulation Tests; Chemistry panel (potassium, uric acid, phosphorus, calcium, and creatinine) is assessed, and pre-existing abnormalities corrected prior to initiation of treatment); Urinalysis; Serum pregnancy test (women of childbearing potential); Serum FSH test (postmenopausal women to confirm menopausal status); Next Generation Sequencing (NGS) e.g. DNA Seq, RNA Seq and mutation profiling (blood or bone marrow); Exploratory Blood Banking Sample (Blood PBMCs and Plasma); Exploratory Bone Marrow Banking Sample.

[0297] In particular, the data to be collected at screening includes general patient demographics, relevant medical history and current medical conditions, diagnosis and extent of cancer, details of prior anti-cancer treatments and procedures, prior medications (up to 4 weeks before starting dosing), concomitant medications and any other assessments done for determining eligibility for inclusion in the study. Prior anti-cancer therapies including medications, transplants, radiotherapy, and surgery are to be recorded in the eCRF (electronic Case Report Form).

[0298] The following details on the patient's diagnosis are collected in the eCRF:

[0299] • If the AML (or MDS or CMML) is de novo, or secondary to antecedent hematological disorders (MPN, MDS, Aplastic anemia) or secondary to treatment (therapy related AML, t- AML) e.g. alkylating chemotherapy, radiation

[0300] • Prognostic cytogenetic risk group (ELN 2022)

[0301] FLT3 mutation status Bone Marrow Examination:

[0302] Bone marrow aspirates are collected to assess response criteria and exploratory biomarkers at screening (within 30 days of first dose) the end of each cycle (taken pre-dose on Day 1 (± 7 days) from Cycle 2 onwards). If a bone marrow aspirate cannot be obtained, an optional trephine biopsy is requested. Where a bone marrow aspirate and a trephine are completed at the same visit, both the aspirate and trephine results are reported in the eCRF (one as an unscheduled assessment). Where a bone marrow aspirate is collected, the sample is used to assess blast counts and other assessments.

[0303] The bone marrow aspirate tube drawn (or biopsy if trephine performed) is analyzed locally for the following:

[0304] • Bone marrow to assess blast counts (to include blast percentage and number of cells counted in the differential), cell ula rity and morphological dysplasia

[0305] • Bone marrow flow cytometry / immunophenotyping, where available, to include leukemia cells (percentage)

[0306] • Cytogenetics

[0307] • Molecular genetics (KIT, FLT3 (including ITD and TKD), NPM1, CEBPA, IDH1, IDH2, TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR, ANKRD26, BCL2, BCORL1, CALR, CBL, CUX1, DDX41, DNMT3A, ETNK1, ETV6, GATA1, GATA2, GNB1, JAK2, KMT2A, KRAS, MPL, MYC, NF1, NRAS, PHF6, PPM1D, PRPF8, PTPN11, RAD21, SETBP1, SF1, SMC3, STAT3, STAT5B, TET2, WT1 and ZRSR2).

[0308] Cytogenetics and molecular genetic bone marrow samples are assessed at Screening and End of Treatment visits, other samples from visits are taken and stored but may not be analyzed. Bone marrow aspirates (or trephines) samples are taken from patients at every cycle until CR is achieved for 2 subsequent response criteria assessments, and then the frequency is reduced to every 3 cycles if the full blood count normalizes or approximates normality (red blood cell and platelet transfusion independence for >1 month and Hb >10g / dL, Neutrophils > 1.0 x 109 / L, Platelets >100 x 109 / L). If a patient achieves a CRi with incomplete recovery for 2 subsequent response criteria assessments, of neutrophils (< 1.0 x 109 / L) and / or platelets (< 1.0 x 109 / L) and / or remains dependent on transfusion of red blood cells and / or platelets, bone marrow aspirates collection are reduced to every 2 cycles.

[0309] Bone Marrow Blast

[0310] Bone marrow was collected and processed according to the procedures described in the International Journal of Laboratory Hematology guidelines for the standardization of bone marrow specimens and reports (S.-H. Lee et al., Int. Jnl. Lab. Hem. 2008, 30, 349-364) and in the UCSF Pathology Guide for Bone Marrow Specimen Collection (https: / / pathology.ucsf.edu / sites / pathology.ucsf.edu / files / 2020-01 / visual-bone-marrow- guideline-UCSF-Pathology.pdf).

[0311] Bone marrow aspirate specimens were typically used to determine the blast cell percentage. Aspirate specimens were prepared by drawing the aspirate into a tube containing isotonic EDTA solution to achieve a desired concentration of EDTA.

[0312] Bone marrow smears were prepared immediately following aspiration. To prepare the smears, a drop of aspirate was placed on the middle of a slide and a second slide was placed on top of the slide comprising the bone marrow-comprising particles. The two slides were moved in opposite directions to complete the smear, and then the slides were separated in the direction of the long axis of the slide at a steady speed to prevent cell distortion.

[0313] Following the preparation of the bone marrow smear, the percentage of bone marrow blast was determined by counting the cells under magnification.

[0314] When samples cannot be taken via aspiration, bone matter trephine specimens may be obtained (and processed accordingly), or the bone marrow blast percentage can be determined by flow cytometry. However, a discrepancy can arise between specimens that are analysed morphologically and specimens that are analysed via flow cytometry (M. Yogarajah et al., Blood, 2019, 134, Supplement_l: 5441). Response Criteria Category Assessment:

[0315] Response Criteria are determined using the criteria set below, which are based on Cheson criteria (Cheson et al, 2003) for AML together with ELN Response Criteria (Dohner et al, 2017) and for MDS / CMML (Cheson et al, 2006).

[0316] The response for a patient with AML is collected at Day 1 of each cycle, using the following categories:

[0317] For Complete Remission (CR), all of the following must be achieved:

[0318] • Absolute neutrophil count (ANC) > 1000 / mm3 or > 1.0 x 109 / L

[0319] • Platelet count > 100,000 / mm3 or >100 x 109 / L

[0320] • Absence of circulating blasts and blasts with Auer rods

[0321] • Bone marrow < 5% blasts

[0322] • Absence of extramedullary disease

[0323] • Independent of transfusions (Note: Hemoglobin concentration or hematocrit has no bearing on remission status)

[0324] For Complete Remission with Incomplete Hematologic Recovery (CRi), all of the following must be achieved:

[0325] • ANC < 1000 / mm3or < 1.0 x 109 / L OR platelet count < 100,000 / mm3or < 100 x 109 / L

[0326] • Absence of circulating blasts and blasts with Auer rods

[0327] • Bone marrow < 5% blasts

[0328] • Absence of extramedullary disease

[0329] • Independent of transfusions (Note: Hemoglobin concentration or hematocrit has no bearing on remission status)

[0330] For Complete Remission with Incomplete Platelet Recovery (CRp), all of the following must be achieved:

[0331] Absolute neutrophil count (ANC) > 1000 / mm3 • Platelet count < 100,000 / mm3or <100 x 109 / L provided that patients are platelet transfusion independent

[0332] • Absence of circulating blasts and blasts with Auer rods

[0333] • Bone marrow < 5% blasts

[0334] • Absence of extramedullary disease

[0335] • Independent of transfusions (Note: Hemoglobin concentration or hematocrit has no bearing on remission status)

[0336] For Partial Remission (PR), all of the following must be achieved:

[0337] • ANC > 1.0 x 109 / L

[0338] • platelet count >100 x 109 / L

[0339] • Bone marrow blast percentage 5% - 25% and a decrease of pre-treatment bone marrow blast percentage by at least 50%.

[0340] • Independent of transfusions (Note: Hemoglobin concentration or hematocrit has no bearing on remission status)

[0341] For Stable Disease (SD):

[0342] • Absence of CR, CRi, CRp, PR; and criteria for progressive disease not met.

[0343] For Progressive Disease (PD):

[0344] • Evidence for an increase in bone marrow blast percentage and / or increase of absolute blast counts in the blood (>50% increase in marrow blasts over baseline (a minimum 15% point increase is required in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% over at least 3 months; without at least a 100% improvement in ANC to an absolute level (>0.5 x 109 / L [500 / pL], and / or platelet count to >50 x 109 / L [50 OOO / pL] nontransfused);

[0345] Or

[0346] • >50% increase in peripheral blasts (WBC x % blasts) to >25 x 109 / L (>25 OOO / pL) Or

[0347] • New extramedullary disease

[0348] Safety and Tolerability:

[0349] The safety is monitored by assessing physical examination, vital signs, ECG, weight, ECOG performance status, hematology, chemistry, urinalysis, as well as collecting AEs at every visit. In particular, haemoglobin, neutrophil, lymphocyte and platelet counts are monitored at every visit. Adverse Events are graded according to CTCAE Version 5.

[0350] Pharmacokinetic Assessments:

[0351] PK blood samples are taken for PK analysis of the compound of Formula (I). The compound is measured in plasma.

[0352] Results:

[0353] At a preliminary stage of Module 2A, 7 patients have been dosed and evaluated. In those patients, two patients have achieved complete remission (CR) and are transfusion independent, and one patient achieved morphologic leukaemia-free state (MLFS), indicating a successful reduction of leukemia to undetectable levels and effective disease control (Table 15). Of these three patients, the patient who achieved MLFS (Patient 2) had received Venetoclax treatment prior to their inclusion in the trial; the patients who achieved complete remission (Patients 1 and 6) had received no prior Venetoclax treatment. Patients 3 and 5, who both achieved stable disease with the Module 2A treatment, had received Venetoclax treatment prior to their inclusion in the trial.

[0354]

[0355] Table 15. Summary of patient outcomes for Module 2A combination treatment (status at 4 November 2024). Abbreviations: PD = progressive disease; SD = stable disease; CR = complete remission. * - Patient response unknown as bone marrow was not evaluable. Subsequent analysis of patient response at the time of writing:

[0356] Patient 1 is on treatment at cycle 16 and remains in complete remission. Patient 3 continued treatment until the end of cycle 8 day 8 and achieved stable disease as a best response. Patient 6 continued treatment until cycle 6 day 22 and achieved complete remission as a best response.

[0357] A significant bone marrow blast reduction was observed in the patients dosed in the Module 2A treatment (Table 16), which correlates with the positive responses observed by the patients.

[0358] Table 16. Bone marrow smear blast percentage data recorded from patients dosed as part of the Method 2A combination treatment. Disc. = Discontinued. *Data acquired by flow cytometry.

[0359] Without being bound by a particular theory, the inventors believe that the blast data indicates that the treatment is working by killing blast cells, potentially via apoptosis.

[0360] Surprisingly, an effect is seen in the blast percentage data in patients who have received prior treatment with Venetoclax alone.

[0361] Module 2B - Treatment with Compound 1, Venetoclax and Azacitidine:

[0362] 1. Patient criteria:

[0363] As for Module 2A set out above, except that criterion 7 is replaced by:

[0364] 7B. Patients with relapsed / refractory FLT3 wildtype AML. In Part B, newly diagnosed patients unfit for intensive chemotherapy, may also be recruited.

[0365] As in Module 2A, all cohorts are initially enriched with patients with AML harboring certain genetic alterations, including but not limited to TP53, RUNX1 and NPM1 alterations.

[0366] 2. Treatment regimen

[0367] The subjects are administered Compound 1, Venetoclax and Azacitidine.

[0368] Compound 1 is provided in hard capsules for oral administration. The compound is in the form of its fumarate salt, and each capsule provides the equivalent of 20mg or 50mg of the active ingredient, Compound 1. The capsules also contain D-a-TPGS.

[0369] Venetoclax is supplied as lOOmg film-coated tablets for oral administration.

[0370] Azacitidine is supplied as a 25 mg / mL powder for suspension for injection. Each vial contains 100 mg azacitidine. After reconstitution, each mL of suspension contains 25mg azacitidine. The recommended starting dose of Azacitidine for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg / m2of body surface area.

[0371] Compound 1 should be taken on an empty stomach (at least 2 hours after and 1 hour before meals) and at approximately the same time each day. Capsules should be swallowed whole, with water if necessary, and not chewed. Venetoclax tablets should be taken with a meal and swallowed whole with water at approximately the same time each day. Therefore, the Compound 1 dosing must occur first on an empty stomach, followed by Venetoclax dosing with a meal. The tablets should not be chewed, crushed, or broken before swallowing. The recommended starting dose of Azacitidine for the first treatment cycle is injected either subcutaneously or intravenously, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle). There is no defined timing of injection of azacitidine in relation to the oral dosing of Compound 1 and Venetoclax. Compound 1, Venetoclax and Azacitidine are dosed in cycles, each cycle consisting of 28 days. The dosing amounts are as follows:

[0372] Table 17. Cycles and dosage amounts of Compound 1, Venetoclax and Azacitidine

[0373] 3. Assessments

[0374] Assessments are carried out as above for Module 2A.

Claims

CLAIMS1. A compound of Formula (I), or a salt thereof:for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Azacitidine and Venetoclax wherein the three compounds are administered simultaneously, sequentially or separately.2 The compound for use as claimed in claim 1, wherein the compound of Formula (I) is administered to the patient in a daily dose of from about 10 mg to 500 mg, for example from about 50 mg to about 150 mg.3 The compound for use as claimed in any of the preceding claims, wherein the dosage of the compound of Formula (I) is administered at a dose of from 40 to 200 mg twice per day.4 The compound for use as claimed in any of the preceding claims, wherein the dosage of Venetoclax is administered at a dose from 50 to 500 mg once per day, for example from about 50 mg to about 100 mg once per day.5 The compound for use as claimed in any of the preceding claims, wherein the dosage of Azacitidine is administered at a dose from 25 to 150 mg / m2once per day, for example from about 40 to about 60 mg / m2once per day.6 The compound for use as claimed in any of the preceding claims, wherein the dosage of the compound of Formula (I) is administered orally.The compound for use as claimed in any of the preceding claims, wherein the dosage of the compound of Formula (I) and Venetoclax are administered orally, and Azacitidine is administered by subcutaneous injection. The compound for use as claimed in any of the preceding claims, wherein the dosage of the compound of Formula (I) is taken each day of a treatment with a cycle length of 28 days. The compound for use as claimed according to claim 8, wherein the dosage of the compound of Formula (I) is administered twice daily on days 1 - 28 of a cycle of 28 days. The compound for use as claimed according to claim 8 or 9, wherein the dosage of Venetoclax is administered once daily on days 1 - 28 of a cycle of 28 days. The compound for use as claimed according to any one of claims 8 to 10, wherein the dosage of Azacitidine is administered on days 1 - 7 only of a cycle of 28 days. The compound for use as claimed according any one of claims 8 to 11, wherein the cycle is repeated from 1 to 12 times. The compound for use as claimed according to any of the preceding claims, wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, solid tumours (for example, urothelial solid tumours), blood cancers, advanced malignancies, soft tissue sarcomas, fibrolamellar carcinoma, lung cancer (for example, non-small cell lung cancer). The compound for use as claimed according to claim 13, wherein the cancer is a blood cancer. The compound for use as claimed according to claim 14, wherein the blood cancer is selected from acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, essential thrombocythaemia, hairy cell leukaemia, myelodysplastic syndromes, myelofibrosis,myeloma, multiple myeloma, myeloproliferative neoplasms, polycythaemia vera, and lymphoma.

16. The compound for use as claimed according to claim 15, wherein the lymphoma is selected from Hodgkin lymphoma, lymphoblastic lymphoma, diffuse large B cell lymphoma, nonHodgkin lymphoma (for example, mantle cell lymphoma and Burkitt lymphoma), T-cell lymphoma (for example, cutaneous T-cell lymphoma and anaplastic large cell lymphoma), and small lymphocytic lymphoma.

17. The compound for use as claimed according to claim 15, wherein the cancer is selected from acute myeloid leukaemia, for example TP53-mutated acute myeloid leukaemia, myelodysplastic syndrome and chronic myelomonocytic leukaemia.

18. The compound for use as claimed according to any of the preceding claims, wherein the compound of Formula (I) is administered as the fumarate salt.

19. Use of a compound of Formula (I), or a salt thereof:in the manufacture of a medicament for the treatment of a cancer, wherein, in the treatment of the cancer, the compound of Formula (I) is administered simultaneously, sequentially or separately with Azacitidine and Venetoclax.

20. A method of treating a cancer in a subject in need thereof comprising administering to the subject a compound of Formula (I), or a salt thereof:wherein the compound of Formula (I) is administered with Azacitidine and Venetoclax wherein the compounds are administered simultaneously, sequentially or separately.

21. A compound of Formula (I), or a salt thereof:for use in the treatment or prophylaxis of a cancer, wherein the compound of Formula (I) is administered in combination with Venetoclax wherein the two compounds are administered simultaneously, sequentially or separately.

22. The compound for use as claimed in claim 21, wherein the compound of Formula (I) is administered to the patient in a daily dose of from about 10 mg to 500 mg, for example from about 50 mg to about 150 mg.

23. The compound for use as claimed in claims 21 or 22, wherein the dosage of the compound ofFormula (I) is administered at a dose of from 40 to 200 mg twice per day.

24. The compound for use as claimed in claims 21 to 23, wherein the dosage of Venetoclax is administered at a dose from 50 to 500 mg once per day, for example from about 50 mg to about 100 mg once per day.

25. The compound for use as claimed in claims 21 to 24, wherein the dosage of the compound of Formula (I) is administered orally.

26. The compound for use as claimed in claims 21 to 25, wherein the dosage of the compound of Formula (I) and Venetoclax are administered orally.

27. The compound for use as claimed in claims 21 to 26, wherein the dosage of the compound of Formula (I) is taken each day of a treatment with a cycle length of 28 days.

28. The compound for use as claimed according to claim T1 , wherein the dosage of the compound of Formula (I) is administered twice daily on days 1 - 28 of a cycle of 28 days.

29. The compound for use as claimed according to claim 1 or 28, wherein the dosage of Venetoclax is administered once daily on days 1 - 28 of a cycle of 28 days.

30. The compound for use as claimed according any one of claims T1 to 29, wherein the cycle is repeated from 1 to 12 times.

31. The compound for use as claimed according to claim 21 to 30, wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, solid tumours (for example, urothelial solid tumours), blood cancers, advanced malignancies, soft tissue sarcomas, fibrolamellar carcinoma, lung cancer (for example, non-small cell lung cancer).

32. The compound for use as claimed according to claim 31, wherein the cancer is a blood cancer.

33. The compound for use as claimed according to claim 32, wherein the blood cancer is selected from acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocyticleukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, essential thrombocythaemia, hairy cell leukaemia, myelodysplastic syndromes, myelofibrosis, myeloma, multiple myeloma, myeloproliferative neoplasms, polycythaemia vera, and lymphoma34. A compound for use as claimed according to claim 33, wherein the lymphoma is selected from Hodgkin lymphoma, lymphoblastic lymphoma, diffuse large B cell lymphoma, non-Hodgkin lymphoma (for example, mantle cell lymphoma and Burkitt lymphoma), T-cell lymphoma (for example, cutaneous T-cell lymphoma and anaplastic large cell lymphoma), and small lymphocytic lymphoma.

35. The compound for use as claimed according to claim 33, wherein the cancer is selected from acute myeloid leukaemia, for example TP53-mutated acute myeloid leukaemia, myelodysplastic syndrome and chronic myelomonocytic leukaemia.

36. The compound for use as claimed according to claims 21 to 35, wherein the compound of Formula (I) is administered as the fumarate salt.

37. A composition comprising a compound of Formula I, or a salt thereof:and Venetoclax.

38. A composition as claimed in claim 37, further comprising Azacitidine.

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