Combination of roginolisib with a malt1-GLS inhibitor

Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, to said subject.

Description

[0001] COMBINATION OF ROGINOLISIB WITH A MALT1 -GLS INHIBITOR

[0002] The present disclosure relates to methods of treating cancer in a patient in need thereof.

[0003] Background

[0004] While much progress has been made in the treatment of cancer, there is increasing demand for targeted therapies and still many cancer patients live with an incurable disease. Accordingly, it is important to continue to find new treatments for patients with incurable cancer that are more effective.

[0005] Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has emerged as a promising therapeutic target in the treatment of cancer (Solsona 2022). It is implicated in the pathogenesis of cancers, where it promotes aberrant activation of the nuclear factor-kappa B (NF-KB) pathway, which is involved in cell survival and proliferation, the acquisition of cancer stem cell properties, metastasis formation, metabolic reprogramming, and the suppression of anti-tumour immune responses. MALT1 is a protease that cleaves various substrates involved in mRNA stability, regulation of NF-KB signalling, adhesion, lymphocyte activation and inflammation (Jaworski and Thome 2016). MALT 1 is also a key regulator of glutamine metabolism.

[0006] Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutaminase (GLS) is an enzyme responsible for catalysing the conversion of the amino acid glutamine into glutamate providing a source of nitrogen for amino acid and nucleotide biosynthesis as well as a source of carbon to replenish the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathways (Jin 2023). Many cancer cells exhibit an increased reliance on glutamine metabolism to meet their energy and biosynthetic needs.

[0007] Although targeting the MALT1-GLS pathway is a promising therapeutic approach, few drugs have been developed. Tumour metabolism is affected by a multitude of microenvironmental factors, including nutrient availability. There are several mechanisms by which cancer cells escape the effects of inhibitors of glutamine metabolism; these include increased metabolic flexibility, uptake of extracellular amino acids via compensatory transporters and macropinocytosis, and expression of nutrient stress-response proteins (Jin 2023).

[0008] The PI3K pathway is frequently activated in cancer cells, making PI3K an attractive therapeutic target in oncology. This has led to a considerable interest in the field for developing inhibitors targeting this pathway (Buchanan 2019). Although many PI3K inhibitors have reached different stages of clinical development, very few PI3K inhibitors have been approved for clinical use. While these agents are effective clinically, their use is associated with a number of serious class-related as well as drug-specific adverse effects. Some of these are thought to be immune-mediated and include cutaneous reactions, severe diarrhoea with or without colitis, hepatotoxicity and pneumonitis. PI3K inhibitors also induce various metabolic abnormalities such as hyperglycaemia and hypertriglyceridaemia. Amongst the myriad disclosures relating to PI3K inhibitor compounds, WO2011 / 058149 describes Tricyclic Pyrazol Amine Derivatives which are PI3K inhibitors and their use for treating autoimmune diseases, inflammatory disorders, multiple sclerosis and other diseases like cancers.

[0009] In view of the above, there is a need in the art for compounds that revert resistance to MALT1-GLS pathway inhibitors and PI3K inhibitors that are better tolerated. Moreover, there is a need in the art for improved ways of treating cancer.

[0010] Summary

[0011] The present invention is directed to a new treatment for patients with cancer. In some embodiments, disclosed is a method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, and a second amount of a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. In the method, the first amount and the second amount together comprise a therapeutically effective amount. The compound of Formula I may be referred to herein as “Compound 1”.

[0012] In some embodiments, disclosed is Compound 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1 , or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, to said subject.

[0013] In some embodiments, disclosed is a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said a MALT1-GLS inhibitor, or a pharmaceutically acceptable salt thereof, and ii) Compound 1, or a pharmaceutically acceptable salt thereof, to said subject.

[0014] A MALT1-GLS pathway inhibitor may inhibit MALT 1 or GLS. This in some of the embodiments above, the MALT1-GLS pathway inhibitor is a MALT 1 inhibitor. In other of the embodiments above, the MALT1-GLS pathway inhibitor is a GLS inhibitor.

[0015] In some embodiments, the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway. In some of these embodiments, the cancer is a cancer ameliorated by MALT 1 inhibition. In other of these embodiments, the cancer is a cancer ameliorated by the inhibition of GLS.

[0016] In some embodiments, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukaemia, lymphoma, multiple myeloma (including Morbus Waldenstrom), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer and colorectal cancer. For example, the cancer may be melanoma, lymphoma, myelofibrosis, non-small cell lung cancer or mesothelioma. In some cases, melanoma is advanced or metastatic melanoma or ocular / uveal melanoma.

[0017] Advanced or metastatic melanoma may be histologically confirmed, unresectable Stage III or IV melanoma. In some cases, the cancer is B cell lymphoma. In some cases, the cancer is T cell lymphoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma.

[0018] In some embodiments the cancer is a solid tumour.

[0019] In some embodiments the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease.

[0020] In some embodiments the cancer is lymphoma. In some embodiments the cancer is cutaneous T cell leukemia or cutaneous T cell lymphoma. In some embodiments the cancer is cutaneous T-cell lymphoma.

[0021] In some embodiments the cancer is peripheral T cell lymphoma.

[0022] In some embodiments the cancer is mantle cell lymphoma.

[0023] In some embodiments, disclosed is a pharmaceutical product comprising i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

[0025] The combination of Compound 1 and a MALT1-GLS pathway inhibitor may be synergistic, and / or may otherwise result in improved treatment outcomes or patient prognosis, for example the reduction of side effects and improved tolerability, when compared to current monotherapies or combination therapies. This may result from Compound 1 blocking survival pathways that are activated once MALT1-GLS pathway inhibitors are given and vice versa.

[0026] Brief Description of the Drawings

[0027] Figure 1 shows the dose response data of the combination of Compound 1 and MALT1 inhibitor safimaltib in the HH cell line, a cutaneous T-cell lymphoma cell line.

[0028] Figure 2 shows the dose response data of the combination of Compound 1 and MALT1 inhibitor safimaltib in the SP53 cell line, a mantle cell lymphoma cell line.

[0029] Figure 3 shows the dose response data of the combination of Compound 1 and GLS inhibitor telaglenastat in the HH cell line, a cutaneous T-cell lymphoma cell line.

[0030] Figure 4 shows the dose response data of the combination of Compound 1 and GLS inhibitor telaglenastat in the SP53 cell line, a mantle cell lymphoma cell line. Detailed Description

[0031] Compound 1 is example 339 in WO2011 / 058149, which document is incorporated herein by reference in its entirety. Its structure is according to Formula I: Formula I

[0032] In IIIPAC nomenclature, the above Compound 1 may be referred to as 6-Fluoro-3- (morpholin-4-ylcarbonyl)-1-[4-(morpholin-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3- c]pyrazole 5,5-dioxide. Alternatively, the structural formula shown above may be described as [6-fluoro-1-(4-morpholin-4-yl-methylphenyl)-5,5-dioxo-4,5-dihydro-1H-5A6- thiochromeno[4,3-C]pyrazol-3-yl]-morpholin-4-yl-methanone.

[0033] Compound 1 can be prepared and characterized as described in published patent application WO 2011 / 058149 A1 (see compound 339 on p. 69; the preparation on p. 303- 307; and the characterization on p. 481 with p. 414-418), which information is specifically incorporated herein by reference.

[0034] Based on the process disclosed in WO 2011 / 058149 A1 , the authors of Haselmayer 2014 describe a five-step preparation procedure for the compound. This procedure starts with reaction of 8-fluoro-2,3-dihydro-4Hthiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinylbenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid, followed by saponification of the ethyl ester into the corresponding acid and subsequent coupling with morpholine to yield the compound of formula I.

[0035] Alternatively, the intermediate of the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. The benzoic acid is reduced using borane-THF complex and the thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. Saponification of the ethyl ester into the corresponding acid and chlorination of both the acid and alcohol with excess thionyl chloride in the presence of dimethylformamide and subsequent coupling with morpholine then yields Compound 1.

[0036] Compound 1 may be provided as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Some pharmaceutically acceptable salts of Compound 1 are described in W02014 / 121901, which is incorporated by reference in its entirety.

[0037] As used herein, Compound 1 is provided as an anhydrous hemifumarate salt (formula illustrated). Its synthesis and characterisation are described in W02014 / 121901 (page 4). It is referred to as solid form A1. A hemifumarate hydrate (H1) has also been identified. The anhydrous hemifumarate salt used is crystalline and has a powder X-ray peak list as described in W02014 / 121901. It will be appreciated that the findings of the invention are not limited to use of this solid form, although it is preferred.

[0038] Accordingly, in some cases Compound 1 is administered as the hemifumarate salt (Formula la). However, it will be understood that the invention is not so limited, and other solid forms (for example, other pharmaceutically acceptable salts) are envisaged.

[0039] Haselmayer 2014 also describes the characterisation of the compound as highly selective PI3K5 inhibitor. Tarantelli 2022 and Johnson 2023 further describe the activity of Compound 1 in lymphoma cell lines and Carlo-Stella 2022 reports the data on the first dose cohort of the clinical study of Compound 1 in FL patients (NCT04328844).

[0040] MALT1 , or Mucosa- Associated Lymphoid Tissue Lymphoma Translocation Protein 1 , is a protease encoded by the MALT1 gene. MALT1 is a member of an evolutionarily conserved superfamily of caspase-like proteins and is involved in the CARMA1-Bcl10 pathway of antigen-induced nuclear factor KB (NF-KB) activation (Ruefli-Brasse 2003). GLS, or glutaminase, is a downstream target of MALT1 and an amidohydrolase enzyme that generates glutamate from glutamine (Xia 2020).

[0041] MALT1-GLS pathway inhibitors include but are not limited to safimaltib, ABBV-525, ONO- 7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231 , MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg- Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0042] In some embodiments the MALT1-GLS pathway inhibitor is a MALT1 inhibitor selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231 , MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX- 317, and Val-Arg-Pro-DL-Arg-Fluoromethylketone.

[0043] In some embodiments the MALT1-GLS pathway inhibitor is a MALT1 inhibitor and is safimaltib.

[0044] In some embodiments the MALT1-GLS pathway inhibitor is a GLS inhibitor selected from IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0045] In some embodiments the MALT1-GLS pathway inhibitor is a GLS inhibitor and is telaglenastat.

[0046] Safimaltib (also referred as JNJ-67856633 or JNJ-6633) is an orally bioavailable potent, selective and allosteric MALT 1 inhibitor (Hamp 2021). It is under development for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and diffuse large B-cell lymphoma (NCT03900598). Safimaltib has the following structure:

[0047] The IUPAC name of safimaltib is 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2- (trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide. This compound, and methods to make it, its crystalline polymorph as well as specific pharmaceutical formulations are disclosed in LIS2018 / 0170909, WO2020 / 169736 and W02020 / 169738 incorporated by reference herein in its entirety.

[0048] ABBV-525 is a selective, orally bioavailable MALT1 inhibitor. It is under development for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and diffuse large B-cell lymphoma (NCT05618028).

[0049] ONO-7018 (also referred as CTX-177) is a potent, selective, orally bioavailable MALT1 inhibitor (Morishita 2022). It is under development for the treatment of relapsed or refractory non-Hodgkin's lymphoma or chronic lymphocytic leukemia (NCT05515406).

[0050] SGR-1505 is a selective, orally bioavailable MALT 1 inhibitor. It is under development for the treatment of relapsed or refractory B-cell lymphomas (NCT05544019). It has the structure:

[0051] MPT-0118 is a selective, orally bioavailable MALT1 inhibitor. It is under development for the treatment of advanced or metastatic refractory solid tumors (NCT04859777).

[0052] RGT-068A is a potent, selective and oral bioavailable MALT1 inhibitor. RGT-068A has the following structure:

[0053] XL114 (also referred as AUR 104) is a selective, orally bioavailable MALT1 inhibitor. It is under development for the treatment of Non-Hodgkin’s lymphoma (NCT05144347). MLT-943 is a selective, orally bioavailable MALT1 inhibitor. MLT-943 has the following structure:

[0054] IPN60090 is an orally active and highly selective inhibitor of GLS (Soth 2020). It is under development for the treatment of advanced solid tumors (NCT03894540). IPN60090 has the following structure:

[0055] Telaglenastat (also referred as CB-839) is an orally active and highly selective inhibitor of GLS. It is under development for the treatment of several solid tumors especially in combinations with other treatments. Telaglenastat has the following structure:

[0056] Definitions

[0057] The language “pharmaceutical composition” includes compositions comprising an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent, wherein the active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a MALT 1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. The language “pharmaceutically acceptable excipient, carrier or diluent” includes compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as ascertained by one of skill in the art. In some embodiments, the pharmaceutical compositions are in solid dosage forms, such as capsules, tablets, granules, powders or sachets. In some embodiments, the pharmaceutical compositions are in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizing agents, co-solvents, or carriers. A sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or suspension in a non-aqueous diluent, carrier or co-solvent, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents. The pharmaceutical compositions could be a solution for iv bolus / infusion injection or a lyophilized system (either alone or with excipients) for reconstitution with a buffer system with or without other excipients. The lyophilized freeze-dried material may be prepared from non-aqueous solvents or aqueous solvents. The dosage form could also be a concentrate for further dilution for subsequent infusion.

[0058] The language “treat,” “treating” and “treatment” includes the reduction or inhibition of tumour cells of a haematological malignancy in a subject, amelioration of one or more symptoms of a haematological malignancy in a subject, or the slowing or delaying of progression of a haematological malignancy in a subject. The language “treat,” “treating” and “treatment” also includes the reduction or inhibition of the growth of a tumour or proliferation of cancerous cells in a subject.

[0059] The language “inhibit”, “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0060] The term “subject” includes warm-blooded mammals, for example, primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject is suffering from cancer.

[0061] The language “therapeutically effective amount” includes that amount of Compound 1 and that amount of a MALT1-GLS pathway inhibitor which together will elicit a biological or medical response in a subject, for example, the reduction or inhibition of tumour cells; amelioration of symptoms of cancer; or the slowing or delaying of progression of cancer. In some embodiments, the language “therapeutically effective amount” includes the amount of Compound 1 and a MALT1-GLS pathway inhibitor together that is effective to at least partially alleviate, inhibit, and / or ameliorate cancer or inhibit tumour cells and / or reduce or inhibit the proliferation of cancerous cells in a subject. In some embodiments, disclosed is a method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of Compound 1 or a pharmaceutically acceptable salt thereof, and a second amount of a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. In the method, the first amount and the second amount together comprise a therapeutically effective amount.

[0062] In some embodiments, disclosed is Compound 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1 , or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, to said subject.

[0063] In some embodiments, disclosed is a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, and ii) Compound 1, or a pharmaceutically acceptable salt thereof, to said subject.

[0064] In some embodiments, disclosed is the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, to said subject.

[0065] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are administered separately, sequentially or simultaneously in a treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is continuously administered in the treatment cycle and a MALT 1 inhibitor or a pharmaceutically acceptable salt is also continuously administered in the treatment cycle.

[0066] In some embodiments the MALT1-GLS pathway inhibitor is selected from safimaltib, MPT- 0118, ABBV-525, ONO-7018, SGR-1505, RGT-068A, XL114, MLT-943, INP60090, telaglenastat. In further embodiments the MALT1-GLS pathway inhibitor is safimaltib. In further embodiments the MALT1-GLS pathway inhibitor is telaglenastat.

[0067] The term “continuous” or “continuously” refers to administration of a therapeutic agent, e.g. Compound 1 , at regular intervals without stopping or interruption, i.e., no void day. By “void day”, it is meant a day when a therapeutic agent is not administered.

[0068] A “cycle”, “treatment cycle” or “dosing schedule”, as used herein, refers to a period of combination treatment that is repeated on a regular schedule. For example, the treatment can be given for one week, two weeks, or three weeks wherein Compound 1 and a MALT 1- GLS pathway inhibitor are administered in a coordinated fashion. In some embodiments, a treatment cycle is about 1 week to about 3 months. In some embodiments, a treatment cycle is about 5 days to about 1 month. In some embodiments, a treatment cycle is about 1 week to about 3 weeks. In some embodiments, a treatment cycle is about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0069] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are administered to the human subject in one or more treatment cycles, e.g., a treatment course. A “treatment course” comprises multiple treatment cycles, which can be repeated on a regular schedule, or adjusted as a tapered schedule as the patient’s disease progression is monitored. For example, a patient's treatment cycles can have longer periods of treatment and / or shorter periods of rest at the beginning of a treatment course (e.g., when the patient is first diagnosed), and as the cancer enters remission, the rest period lengthens, thereby increasing the length of one treatment cycle. The period of time for treatment and rest in a treatment cycle, the number of treatment cycles, and the length of time for the treatment course can be determined and adjusted throughout the treatment course by the skilled artisan based on the patient’s disease progression, treatment tolerance, and prognosis. In some embodiments, the method comprises 1 to 10 treatment cycles. In some embodiments, the method comprises 2 to 8 treatment cycles.

[0070] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle.

[0071] Dosage

[0072] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in tablet dosage form. In some embodiments, Compound 1 as the hemifumarate salt is administered in a dose of 40 mg per day. In some embodiments Compound 1 as the hemi-fumarate salt is administered in a dose of 80 mg per day.

[0073] In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is in tablet dosage form. In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is in capsule dosage form. In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and 1 g per day.

[0074] In some embodiments, a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered as an intravenous (IV) infusion.

[0075] In some embodiments, Compound 1 and a MALT1-GLS pathway inhibitor are taken together on an empty stomach, with no food two hours before, and one hour after.

[0076] In some embodiments, Compound 1 is taken on an empty stomach, with no food two hours before, and one hour after, and the MALT1-GLS pathway inhibitor is taken with food, so either at least two hours before, or one hour after Compound 1.

[0077] In some embodiments, the MALT1-GLS pathway inhibitor is dosed twice daily.

[0078] In some embodiments, disclosed is a pharmaceutical product comprising i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof, and a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof, and a MALT1- GLS pathway inhibitor or a pharmaceutically acceptable salt thereof are present separate dosage forms.

[0079] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV- 525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT- 748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg- Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0080] In some embodiments the MALT1-GLS pathway inhibitor is safimaltib.

[0081] In some embodiments, disclosed is a pharmaceutical product comprising i) Compound 1 , or a pharmaceutically acceptable salt thereof, and ii) safimaltib, or a pharmaceutically acceptable salt thereof. In some embodiments Compound 1 or a pharmaceutically acceptable salt thereof and safimaltib or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments Compound 1 or a pharmaceutically acceptable salt thereof and safimaltib or a pharmaceutically acceptable salt thereof are present as separate dosage forms.

[0082] In some embodiments the MALT1-GLS pathway inhibitor is telaglenastat.

[0083] In some embodiments, disclosed is a pharmaceutical product comprising i) Compound 1 , or a pharmaceutically acceptable salt thereof, and ii) telaglenastat or a pharmaceutically acceptable salt thereof. In some embodiments Compound 1 or a pharmaceutically acceptable salt thereof and telaglenastat or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments Compound 1 or a pharmaceutically acceptable salt thereof and telaglenastat or a pharmaceutically acceptable salt thereof are present as separate dosage forms.

[0084] In some embodiments, the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway. In some of these embodiments, the cancer is a cancer ameliorated by MALT 1 inhibition. In other of these embodiments, the cancer is a cancer ameliorated by the inhibition of GLS.

[0085] In some embodiments, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukaemia, lymphoma, multiple myeloma (including Morbus Waldenstrom), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer and colorectal cancer. For example, the cancer may be melanoma, lymphoma, myelofibrosis, non-small cell lung cancer or mesothelioma. In some cases, melanoma is advanced or metastatic melanoma or ocular / uveal melanoma.

[0086] Advanced or metastatic melanoma may be histologically confirmed, unresectable Stage III or IV melanoma. In some cases, the cancer is B cell lymphoma. In some cases, the cancer is T cell lymphoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma.

[0087] In some embodiments the cancer is lymphoma. In some embodiments the cancer is a solid tumour.

[0088] In some embodiments the cancer is cutaneous T cell leukemia or cutaneous T cell lymphoma. In some embodiments the cancer is cutaneous T-cell lymphoma.

[0089] In some embodiments the cancer is peripheral T cell lymphoma.

[0090] In some embodiments the cancer is mantle cell lymphoma.

[0091] Without wishing to be bound by theory, the combination of Compound 1 and a MALT1-GLS pathway inhibitor may be beneficial for patients not responding or refractory to either Compound 1 or the MALT1-GLS pathway inhibitor. In addition, the combination of Compound 1 and a MALT1-GLS pathway inhibitor may deepen the response to either Compound 1 or the MALT 1-GLS pathway inhibitor or make the response more durable. Furthermore, the combination of Compound 1 and a MALT1-GLS pathway inhibitor may allow for dose reductions of the MALT1-GLS pathway inhibitor resulting in improved tolerability and quality of life.

[0092] Methods of the invention

[0093] As described in more detail below, the present inventors have surprisingly found that the combination of Compound 1 with MALT1-GLS pathway inhibitors has synergistic effects on the proliferation of cancer cell lines. Thus, a combination therapy with improved antiproliferative activity can be provided.

[0094] Secondly, the present inventors surprisingly found that the synergistic anti-tumour activity of the combination of Compound 1 with MALT1-GLS pathway inhibitors is not limited to a specific malignancy. Thus, a combination therapy with improved therapeutic activity across multiple malignancies can be provided. Additionally, the present inventors surprisingly found that the combination of Compound 1 with MALT1-GLS pathway inhibitors results in tumour cell killing that is not observed with either inhibitor alone. Thus, a combination that can reduce tumour burden can be provided. Furthermore, the present inventors surprisingly found that the combination of Compound 1 with MALT1-GLS pathway inhibitors has synergistic effects already at sub-therapeutic doses. Thus, a combination with improved tolerability may be provided.

[0095] Examples

[0096] The compounds of the application will now be further explained by reference to the following non-limiting examples.

[0097] Example 1. Efficacy of Compound 1 combined with MALT1-GLS pathway inhibitor safimaltib in an in vitro assay using the cutaneous T-cell lymphoma (CTCL) cell line HH and the mantle cell lymphoma (MCL) cell line SP53

[0098] HH (CRL-2105) and SP53 cells were exposed to increasing doses of Compound 1, to increasing doses of safimaltib (JNJ-67856633), and to increasing doses of the combination of Compound 1 and safimaltib. Safimaltib was used at a maximum concentration of 20 pM, following an eight fold dose response design based on 1:2 compound dilutions plus an untreated control. Compound 1 was used at a maximum concentration of 10 pM, following an eight fold dose response design based on 1:3 compound dilutions plus an untreated control.

[0099] Cells were incubated for 72 hours at 37°C and 5% CO2. The antiproliferative effect of single and combination treatments were determined by adding 20 pL MTT [3-(4,5-dimethylthiazolyl- 2)-2, 5-diphenyltetrazoliumbromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well and the plates were incubated at 37°C for 4 hours, followed by adding 50 pL of sodium dodecyl sulfate (SDS) (250 pM SDS, 0,21% fuming HCI) lysis buffer. The lysed cells were kept overnight, and then the absorbance was read at 570 nm using the Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effect of the combinations was determined according to the Chou-Talalay Combination Index (Cl) (Chou 2008, Chou 2010) and calculated with the Synergy R package (Lee 2007). The effect of the combinations was defined as strongly synergistic for Cl values below < 0.3, synergistic for Cl values between 0.3 and 0.9, additive for Cl values between 0.9 and 1.1 , and antagonistic for Cl values > 1.1.

[0100] Data from two representative experiments is shown Figures 1 and 2. The combination of Compound 1 and safimaltib in HH is synergistic with a median Cl value of 0.48. The combination of Compound 1 and safimaltib in SP53 is synergistic with a median Cl value of 0.66.

[0101] Example 2. Efficacy of Compound 1 combined with MALT1-GLS pathway inhibitor telaglenastat in an in vitro assay using the cutaneous T-cell lymphoma (CTCL) cell line HH and the mantle cell lymphoma (MCL) cell line SP53

[0102] HH (CRL-2105) and SP53 cells were exposed to increasing doses of Compound 1, to increasing doses of telaglenastat, and to increasing doses of the combination of Compound 1 and telaglenastat. Telaglenastat was used at a maximum concentration of 10 pM, following an eight fold dose response design based on 1:3 compound dilutions plus an untreated control. Compound 1 was used at a maximum concentration of 10 pM, following an eight fold dose response design based on 1:3 compound dilutions plus an untreated control.

[0103] Cells were incubated for 72 hours at 37°C and 5% CO2. The antiproliferative effect of single and combination treatments were determined by adding 20 pL MTT [3-(4,5-dimethylthiazolyl- 2)-2, 5-diphenyltetrazoliumbromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well and the plates were incubated at 37°C for 4 hours, followed by adding 50 pL of sodium dodecyl sulfate (SDS) (250 pM SDS, 0,21% fuming HCI) lysis buffer. The lysed cells were kept overnight, and then the absorbance was read at 570 nm using the Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effect of the combinations was determined according to the Chou-Talalay Combination Index (Cl) (Chou 2008, Chou 2010) and calculated with the Synergy R package (Lee 2007). The effect of the combinations was defined as strongly synergistic for Cl values below < 0.3, synergistic for Cl values between 0.3 and 0.9, additive for Cl values between 0.9 and 1.1 , and antagonistic for Cl values > 1.1.

[0104] Data from two representative experiments is shown Figures 3 and 4.

[0105] The combination of Compound 1 and telaglenastat in HH is synergistic with a median Cl value of 0.47. The combination of Compound 1 and safimaltib in SP53 is strongly synergistic with a median Cl value of 0.16. Table 1. Cl values for the combination of Compound 1 and MALT1-GLS pathway inhibitors in different cancer cell lines

[0106] Summary of Chou-Talalay combination index (<0.3, strong synergism; 0.3-0.9, synergism;

[0107] 0.9-1.1 additive effect), conf. int. = confidence interval. References

[0108] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

[0109] Statements

[0110] 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, and a second amount of a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0111] 2. The method according to statement 1, wherein the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway.

[0112] 3. The method according to statement 1 or 2 wherein the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease.

[0113] 4. The method according to statement 1 or 2 wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0114] 5. The method according to statement 1 or 2 wherein the cancer is a solid tumour.

[0115] 6. The method according to any of statements 1 to 5, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, M LT-231, M LT-748, M LT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0116] 7. The method according to any one of statements 1 to 6, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day. 8. The method according to any one of statements 1 to 8, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and 1 g per day.

[0117] 9. The method according to any one of statements 1 to 8, wherein the MALT1-GLS pathway inhibitor is safimaltib, or a pharmaceutically acceptable salt thereof.

[0118] 10. A method according to any one of statements 1 to 8, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

[0119] 11. A compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, to said subject.

[0120] 12. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 11, wherein the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway.

[0121] 13. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 12 wherein the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease. 14. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 12 wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0122] 15. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 11 to 14, wherein the cancer is a solid tumour.

[0123] 16. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 11 to 15, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX- 317, Val-Arg-Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0124] 17. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 11 to 16, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0125] 18. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 11 to 16, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and 1 g per day.

[0126] 19. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 11 to 17, wherein the MALT1-GLS pathway inhibitor is safimaltib, or a pharmaceutically acceptable salt thereof.

[0127] 20. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 11 to 17, wherein the MALT1-GLS pathway inhibitor is telagelnastat.

[0128] 21. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, to said subject.

[0129] 22. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 21, wherein the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway.

[0130] 23. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 22 wherein the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease.

[0131] 24. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 22 wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0132] 25. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 22 wherein the cancer is a solid tumour

[0133] 26. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 21 to 24, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, MPT-0118, MALT-IN- 6, MALT-IN-7, MLT-231, MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat. 27. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 21 to 26, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0134] 28. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 21 to 27, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and

[0135] 1 g per day.

[0136] 29. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 21 to 27, wherein the MALT1-GLS pathway inhibitor is safimaltib, or a pharmaceutically acceptable salt thereof.

[0137] 30. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 21 to 27, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

[0138] 31. The use of a compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a cancer, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, to said subject.

[0139] 32. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 31, wherein the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway. 33. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 32, wherein the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease.

[0140] 34. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 32, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

[0141] 35. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to statement 32, wherein the cancer is a solid tumour.

[0142] 36. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to according to any one of statements 31 to 35, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, M PT-0118, MALT-IN-6, MALT-IN-7, MLT-231, MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

[0143] 37. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to according to any one of statements 31 to 36, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0144] 38. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to according to any one of statements 31 to 37, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and 1 g per day.

[0145] 39. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to according to any one of statements 31 to 38, wherein the MALT1-GLS pathway inhibitor is safimaltib, or a pharmaceutically acceptable salt thereof.

[0146] 40. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 31 to 37, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

[0147] 41. A pharmaceutical product comprising i) a compound of Formula I:

[0148] Formula I, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof. 42. A kit comprising: a first pharmaceutical composition comprising a compound of

[0149] Formula I: Formula I, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

Claims

Claimsor a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, to said subject.

2. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 1 , wherein the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway.

3. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 2, wherein the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease.

4. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 2, wherein the cancer is cutaneous T-cell leukemia, cutaneous T-cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

5. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 4, wherein the cancer is a solid tumour.

6. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 5, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, M PT-0118, MALT-IN-6, MALT-IN-7, M LT-231 ,MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val- Arg-Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

7. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 6, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

8. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 6, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and 1 g per day.

9. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 7, wherein the MALT1-GLS pathway inhibitor is safimaltib, or a pharmaceutically acceptable salt thereof.

10. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 7, wherein the MALT1-GLS pathway inhibitor is telagelnastat.

11. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, to said subject.

12. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 11 , wherein the cancer is a cancer ameliorated by inhibition of the MALT1-GLS pathway.

13. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 12, wherein the cancer is a haematological malignancy, wherein said haematological malignancy may be lymphoma, leukaemia, myeloma, myelodysplastic syndrome and myeloproliferative disease.

14. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 12, wherein the cancer is cutaneous T-cell leukemia, cutaneous T- cell lymphoma, peripheral T-cell lymphoma or mantle cell lymphoma.

15. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to claim 12, wherein the cancer is a solid tumour16. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 11 to 14, wherein the MALT1-GLS pathway inhibitor is selected from safimaltib, ABBV-525, ONO-7018, SGR-1505, XL114, M PT-0118, MALT-IN-6, MALT-IN-7, MLT-231 , MLT-748, MLT-943, mepazine, RGT-068A, EXS-73565, AIC-110, PSII-115, RHX-317, Val-Arg-Pro-DL-Arg-Fluoromethylketone, IPN60090, JHU-083, OP-329, RP-10107, and telaglenastat.

17. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 11 to 16, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

18. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 11 to 17, wherein the MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose between 10 mg and 1 g per day.

19. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 11 to 17, wherein the MALT1-GLS pathway inhibitor is safimaltib, or a pharmaceutically acceptable salt thereof.

20. A MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 11 to 17, wherein the MALT1-GLS pathway inhibitor is telaglenastat.

21. A pharmaceutical product comprising i) a compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, and ii) a MALT1-GLS pathway inhibitor or a pharmaceutically acceptable salt thereof.

22. A kit comprising: a first pharmaceutical composition comprising a compound ofFormula I:Formula I, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a MALT1-GLS pathway inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

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