Combinations comprising a PARP-1 selective inhibitor and Anti-neoplastic agents for the treatment of cancer

Abstract

The present invention relates to the therapeutic combinations comprising (a) the PARP-1 selective non-trapper inhibitor Compound 1 and (b) an alkylating agent or (c) a topoisomerase inhibitor and the use of said combinations in the treatment of cancer, in particular lung tumors or ovarian and gastric tumors.

Description

[0001] NMS 136 COMBINATIONS COMPRISING A PARP-1 SELECTIVE INHIBITOR AND ANTI-NEOPLASTIC AGENTS FOR THE TREATMENT OF CANCER

[0002] The present invention relates to the therapeutic combinations comprising a PARP-1 selective non-trapper inhibitor and alkylating agents, and to the use of said combinations in the treatment of cancer, in particular lung tumors. Furthermore, the present invention refers to the therapeutic combinations comprising a PARP-1 selective non-trapper inhibitor and topoisomerase inhibitors, preferably topotecan and trastuzumab deruxtecan and to the use of said combinations in the treatment of cancer, in particular ovarian and gastric tumors.

[0003] BACKGROUND ART PARP-1 is a member of the poly (ADP-ribose) polymerase family of enzymes and, together with PARP-2, binds to sites of DNA damage and contributes to their repair by attaching multiple ADP-ribose units to proteins such as histones and various DNA repair enzymes. PARP-1 has the prominent role in this process. Upon PARP-1 inhibition, normal cells effectively repair the DNA double strand breaks, while in cancer cells with DNA repair defects, in particular in the homologous recombination repair (HRR) pathway, accumulation of DNA breaks leads to genomic instability and ultimately to cell death. PARP inhibitors have in fact demonstrated efficacy as single agent in tumors with deficiency in homologous recombination repair (HRR), including BRCA-mutant (BRCAm) tumors, resulting in the approval of olaparib (Drugs 2015, 75, 231-240), rucaparib (Drugs 2017, 77, 585-592), niraparib (Drugs 2017, 77, 1029-1034) and talazoparib (Drugs 2018, 78, 1939-1946) and, limited to China only, of fuzuloparib (Drugs 2021, 81, 1221-1226) and pamiparib (Drugs 2021 , 81 , 1343-1348) for the treatment of breast, ovarian, pancreatic and prostate cancer as single agent. All these approved PARP inhibitors have limited selectivity for PARP-1 versus PARP-2 (Ying-Qing Wang, Ping-Yuan Wang, Yu-Ting Wang, Guang-Fu Yang, Ao Zhang, and Ze-Hong Miao. An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy. J. Med. Chem. 2016, 59 (21), 9575-9598). These PARP-1 / -2 non-selective inhibitors have poor safety profiles with labeled warnings including drug-related leukemia, pneumonitis (sometimes fatal), and serious / fatal thrombotic events as well as common adverse events including gastrointestinal intolerance and bone marrow suppression. Thus, despite their potential unlimited application in all tumors in combination with agents that damage the DNA such as alkylating agents, topoisomerase inhibitors (including Antibody Drug Conjugates with topoisomerase inhibitor payloads - ADC-Topo I) and platinum derivatives, their lack of combinability with such drugs has been the major limitation of moving PARP inhibitors outside of BRCA mutation tumors. It has been demonstrated that PARP-2 inhibition is dispensable for antitumor activity and that it has instead a critical role in erythropoiesis and lifespan of circulating erythrocytes (a) Cell Death Differ. 2015, 22, 1144-1157; b) The EMBO journal, 2006, 25, 4350-4360, c) Mol. Cell 2024, 84, 3916-3931 ,e7) suggesting that a PARP-2 inhibition might drive the anemia observed with the approved unselective PARP inhibitors. Moreover, the approved PARP inhibitors display trapping activity, a feature of PARP inhibitors linked to higher efficacy associated with lower tolerability that limited their development in combination with chemotherapy (a) Mol. Cancer Res.

[0004] 2015, 13, 1465-1477; b) Mol. Cancer Res. 2019, 17, 409-419; c) Annu. Rev. Cancer Biol. 2019, 3, 131-150; d) Sci. Transl. Med. 2016, 8, 362ps17; e) Cancer Res. 2012, 72, 5588-5599).According to the National Comprehensive Cancer Network (NCCN), neuroendocrine tumors account for 20% of lung cancers of which 14% are SCLC. SCLC is characterized by rapid growth and high metastases, including brain. Extensive-stage disease is managed by systemic therapies in the front line with platinum-based immunotherapy combination. Paraneoplastic syndromes can occur including central and peripheral neuropathies as well as vasopressin and ACTH-related syndromes. For small cell lung cancer (SCLC) patients who were platinum-resistant in the first line, chemotherapy-free interval (CTFI) less than 6 months, subsequent treatment options have very poor outcomes and are considered to be a palliative setting. Concerning the use of TMZ, those SCLC with unmethylated methylguanine DNA-methyltransferase (MGMT) promoter have very low sensitivity to this drug. SCLC has a dismal prognosis in the relapse setting. Given the NCCN listing of TMZ, a DNA alkylating agent, in late lines, this drug could potentially be combined with PARP inhibitors with the potentiality of being active in both methylated and unmethylated MGMT promoter (TMZ-resistant) patients. This combination is, however, precluded by the impeding toxicities (e.g., anemia and neutropenia) associated with the use of currently approved PARP unselective trapper inhibitors. Therefore, in SCLC patients, combination of alkylating agents such as TMZ with highly selective non trapper PARP-1 inhibitors if demonstrated to be efficacious and synergistic, could have an improved safety profile.

[0005] For ovarian cancer patients, the National Comprehensive Cancer Network (NCCN) states that platinum resistant or refractory ovarian patients have the highest unmet medical need and that such patients are essentially viewed as palliative in nature since options and outcomes are dismal. Such patients are strongly recommended for clinical trials. In the next lines, topotecan is an acceptable treatment option according to NCCN. However, outcomes are poor. Inhibitors of topoisomerase such as irinotecan and topotecan are known DNA damaging agents. Particularly, topoisomerase I inhibition induces covalent binding of this protein to DNA leading to stalled replication forks, formation of double strand DNA breaks and cell death {Eur. J. Med. Chem.2022, 236, 114304). Combinations of PARP inhibitors with topoisomerase I inhibitors have been limited by overlapping hematologic toxicities {Clin. Cancer Res. 2023, 14:29(6), 991-993). Several combinations in clinical trials have been performed with PARP inhibitors, however dosing has been limited by toxicities, particularly myelosuppression {Gynecol. Oncol. 2020, 156(2), 488-497). These data can be rationalized since all currently approved PARP inhibitors are not selective versus PARP-2 and have trapping activity. Therefore, in ovarian cancer patients, combination of topoisomerase inhibitors such as irinotecan and topotecan or ADCs comprising a topoisomerase inhibitor payload with highly selective non trapper PARP-1 inhibitors if demonstrated to be efficacious and synergistic could potentially have an improved safety profile, thus expanding the therapeutic options for these patients which are in high unmet medical need.

[0006] Patent application WO2014064149 in the name of the present Applicant, describes certain 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors.

[0007] Nevertheless, significant challenges remain, including the emergence of resistance mechanisms, variable responses across tumor types and treatment histories, and the need to improve pharmacokinetic, biodistribution, and safety profiles, particularly in combination regimens.

[0008] Therefore, there is a long existing need for development of additional safe proven combinational therapies to treat cancer.

[0009] SUMMARY OF THE INVENTIONThe present invention provides a combination comprising two or more anticancer drugs to achieve a synergistic effect. Specific combinations of the PARP-1 inhibitor, more particularly Compound 1 and an alkylating agent, or Compound 1 and a topoisomerase inhibitor have now been found to efficiently convey tumor regression.

[0010] In a first aspect, the present invention refers to a therapeutic combination comprising:

[0011] (a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):

[0012]

[0013] (Compound 1)

[0014] and

[0015] (b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1 for use in the treatment of lung cancer for use in the treatment of lung cancer; or

[0016] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer.

[0017] In a second aspect, the invention relates to the use of the therapeutic combination comprising (a) the Compound 1 and (b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1, in the preparation of a medicament for treating lung cancer; or

[0018] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) in the preparation of a medicament for treating ovarian or gastric cancer; wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0019] In a further aspect, the invention relates to a method of treating lung cancer or ovarian and gastric cancer to a patient in need thereof, comprising the administration to a patient of a therapeutically effective amount of (a) the Compound 1 in combination with respectively (b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1 for use in the treatment of lung cancer, or (c) a topoisomerase inhibitor (Tl) selected from topoisomerase I inhibitors and topoisomerase II inhibitors, or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I); wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0020] In a still further aspect, the invention provides a pharmaceutical composition according to the invention, admixed optionally together with a pharmaceutically acceptable carrier, diluent or excipient; wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0021] In a still further aspect, the invention provides a pharmaceutical composition comprising the therapeutic combination comprising: (a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide), and (b) an alkylating agent (AA) for use in the treatment of lung cancer; or (c) a topoisomerase I inhibitor(Tl) selected from topoisomerase I inhibitors and topoisomerase II inhibitors or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The invention is also illustrated by reference to the accompanying drawings described below.

[0024] Figure 1 shows the tumor volume traces after administering Compound 1, temozolomide, and their combination to female BALB / c nude mice bearing lung cancer xenografts. Data points represent group mean tumor volume. Error bars represent standard error of the mean (SEM).

[0025] Figure 2 shows the time to reach tumor size of 1000mm3from the same experiment represented in Figure 1.

[0026] DESCRIPTION OF THE INVENTION

[0027] The terms “poly (ADP-ribose) polymerase” or “PARP” are used herein interchangeably.

[0028] The term “topoisomerase inhibitor” as used herein refers to a substance that blocks the activity of topoisomerase enzymes, preventing the proper re-ligation of DNA strands required for DNA replication, transcription, and cell division. The term “topoisomerase I inhibitor" as used herein refers to a substance that blocks the activity of topoisomerase I, preventing the re-ligation of single-stranded DNA cleaved by the enzyme. This leads to the accumulation of DNA breaks, disrupts DNA replication and transcription, and induces cell cycle arrest and cell death, particularly in rapidly dividing cells.

[0029] The term “topoisomerase II inhibitor” as used herein refers to a substance that blocks the activity of topoisomerase II, preventing the re-ligation of double-stranded DNA cleaved by the enzyme. This results in the accumulation of doublestrand DNA breaks, disrupts DNA replication and transcription, and induces cell cycle arrest and cell death, particularly in rapidly dividing cells.

[0030] The term “alkylating agent” as used herein refers to a chemical substance that covalently transfers alkyl groups to DNA, leading to DNA cross-linking, mispairing, or strand breaks, which interfere with DNA replication and transcription and ultimately cause cell death.

[0031] The Term “ADC“ or “antibody-drug conjugate” as used herein refers to a biologic drug composed of a monoclonal antibody covalently linked to a cytotoxic payload via a chemical linker, designed to selectively deliver the cytotoxic agent to target cells that express the antigen recognized by the antibody.

[0032] The terms 'co-administration' or 'combined administration' or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient) and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0033] The term “a synergic antineoplastic effect” as used herein is meant the inhibition of the growth tumor, or the delaying of its progression, by administering an effective amount of the combination of Compound 1 as defined above and the alkylating agent (AA), in particular TMZ or the topoisomerase I inhibitor, in particular topotecan or the ADC comprising topoisomerase I inhibitor payload (ADC-Topo I), in particular trastuzumab deruxtecan to mammals, including human. The terms “treating” or “treatment of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, or ameliorating abrogating,substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating or alleviating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms. Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) in patients that have previously had the disorder(s); and / or (e) limiting recurrence of symptoms in patients that were previously asymptomatic for the disorder(s). The term “treating” with respect to cancer should be understood to e.g. encompass treatment resulting in a decrease in tumor size; a decrease in rate of tumor growth; stasis of tumor size; a decrease in the number of metastasis; a decrease in the number of additional metastasis; a decrease in invasiveness of the cancer; a decrease in the rate of progression of the tumor from one stage to the next; inhibition of tumor growth in a tissue of a mammal having a malignant cancer; control of establishment of metastases; inhibition of tumor metastases formation; regression of established tumors as well as decrease in the angiogenesis induced by the cancer, inhibition of growth and proliferation of cancer cells and so forth. The term “treating cancer as used herein should also be understood to encompass prophylaxis such as prevention as cancer reoccurs after previous treatment (including surgical removal) and prevention of cancer in an individual prone (genetically, due to lifestyle, chronic inflammation and so forth) to develop cancer. As used herein, “prevention of cancer” is thus to be understood to include prevention of metastases, for example after surgical procedures or after chemotherapy.

[0034] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, diluent, adjuvant, vehicle or excipient that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use. Pharmaceutically acceptable carriers that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose and sodium carboxymethylcellulose), lactose monohydrate, sodium lauryl sulfate, polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, pregelatinized starch, and wool fat.

[0035] As used herein, a subject is “in need of a treatment” if such subject would benefit biologically, medically or in quality of life from such treatment.

[0036] As used herein, “safe and effective amount” means an amount of the compound sufficient to treat the patient’s condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan. By the term “administered" or “administering” as used herein is meant parenteral and / or oral administration. By “parenteral” is meant intravenous, subcutaneous and intramuscular administration.

[0037] The present invention provides a combination comprising two anticancer drugs to achieve a synergistic effect. In one aspect, the present invention provides combinations comprising a PARP-1 selective non trapper inhibitor (Proceedings of the American Association for Cancer Research Annual Meeting; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res. 2018, 78(13 Suppl): Abstract nr 4843), more particularly Compound 1 in freeform or in the form of a pharmaceutically acceptable salt or any hydrate thereof, and an alkylating agents; or Compound 1 and a topoisomerase inhibitors; or Compound 1 and an ADC comprising topoisomerase I inhibitor payload have now been found to efficiently convey tumor regression and anti-tumor activity against lung cancer or ovarian cancer or gastric cancer, respectively.

[0038] In a first aspect, the present invention refers to a therapeutic combination comprising:

[0039] (a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):

[0040]

[0041] (Compound 1)

[0042] and

[0043] (b) an alkylating agent (AA) for use in the treatment of lung cancer; or

[0044] (c) a topoisomerase inhibitor (Tl) selected from topoisomerase I inhibitors and topoisomerase II inhibitors or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer. Compound 1 and its method of preparation have been described in WO2014064149 in the name of Nerviano Medical Sciences. Pharmaceutically acceptable salts of Compound 1 include the acid addition salts with inorganic or organic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic, salicylic acid and the like.

[0045] Advantageously and surprisingly, the administration of a PARP-1 inhibitor, in particular the Compound 1 or a pharmaceutically acceptable salt thereof, or any hydrate form thereof, and an antineoplastics agent, as above defined, provides a synergistic anti-cancer effect, inducing a strong tumor growth delay and prolonged tumor regressions when compared to single agent.

[0046] In particular, as shown in the experimental part, the administration of the above-mentioned combinations of the invention provides a synergic effect in lung, ovarian and gastric tumor-derived cell lines in vitro (Table 2) and also in vivo lung cancer (Figure 1 and 2).

[0047] In one embodiment, the present invention provides a therapeutic combination comprising:

[0048] (a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):

[0049]

[0050] (Compound 1)

[0051] and

[0052] (b) an alkylating agent (AA) for use in the treatment of lung cancer; or

[0053] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in thetreatment of ovarian cancer or gastric cancer.

[0054] In one embodiment, the alkylating agent (AA) is selected from nitrogen mustards such as, for instance: cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine and the like; alkyl sulfonates such as, for instance: busulfan and the like; nitrosoureas such as, for instance: carmustine, lomustine and the like; platinum derivatives such as, for instance, cisplatin, carboplatin, oxalilplatin and the like; and other alkylating agents such as, for instance: procarbazine, dacarbazine, temozolomide (TMZ), mitozolomide, KL-50 {Science 2022, 377, 502-511), 1-1 (WO 2023 / 049806).

[0055] In a preferred embodiment, the alkylating agent (AA) is selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1.

[0056] In a more preferred embodiment, the alkylating agent (AA) is selected from the group consisting of procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1.

[0057] In a further preferred embodiment, the alkylating agent (AA) is temozolomide (TMZ).

[0058] Temozolomide can be administered, e.g., in the form as it is marketed, e.g. under the trademark TEMODAR®. In another embodiment, the (c) a topoisomerase inhibitor (Tl) is a topoisomerase I inhibitor selected from the group consisting of topotecan, irinotecan, and SN-38 (metabolite of irinotecan).

[0059] In an equal preferred embodiment, the (c) a topoisomerase inhibitor (Tl) is a topoisomerase II inhibitor selected form the group consisting of mitoxantrone, etoposide, doxorubicin and epirubicin.

[0060] In another equal preferred embodiment, (c) a topoisomerase inhibitor (Tl) is an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) selected from the group consisting of trastuzumab deruxtecan (enhertu), sacituzumab govitecan (trodelvy), datopamab deruxtecan (dato-DXd) patritumab deruxtecan, CDH6-Dxd, and GPR20-Dxd.

[0061] According to a preferred embodiment of the invention, lung cancer is small cell lung cancer.

[0062] In one embodiment, the present invention refers to a therapeutic combination comprising:

[0063] (a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):

[0064]

[0065] (Compound 1)

[0066] and

[0067] (b) an alkylating agent (AA) for use in the treatment of lung cancer; or

[0068] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer, wherein the alkylating agent (AA) is temozolomide, the topoisomerase I inhibitor is topotecan, irinotecan, SN-38 or the ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) is trastuzumab deruxtecan.

[0069] In a second aspect, the invention relates to the use of the therapeutic combination comprising:

[0070] (a) the Compound 1 and (b) an alkylating agent (AA), in the preparation of a medicament for treating lung cancer; (c) a topoisomerase inhibitor (Tl) selected from topoisomerase I inhibitors and topoisomerase II inhibitors or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) in the preparation of a medicament for treating ovarian orgastric cancer; wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0071] In one embodiment, the invention relates to the use of the therapeutic combination comprising:

[0072] (a) the Compound 1 and

[0073] (b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1, in the preparation of a medicament for treating lung cancer; or

[0074] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I), in the preparation of a medicament for treating ovarian or gastric cancer; wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0075] In a further aspect, the invention relates to a method of treating lung cancer or ovarian and gastric cancer to a patient in need thereof, comprising the administration to a patient of a therapeutically effective amount of (a) the Compound 1 in combination with respectively (b) an alkylating agent (AA) or (c) a topoisomerase inhibitor (Tl) selected from topoisomerase I inhibitors and topoisomerase II inhibitors or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I), wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0076] In one embodiment, the invention relates to a method of treating lung cancer or ovarian and gastric cancer to a patient in need thereof, comprising the administration to a patient of a therapeutically effective amount of (a) the Compound 1 and

[0077] (b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1, in the preparation of a medicament for treating lung cancer; or

[0078] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I); wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

[0079] All the above combinations, uses and methods, can be performed indifferently by simultaneous, separate or sequential administration of the Compound 1 and an alkylating agent (AA), or a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I); said combinations, uses and methods can be performed by administering the Compound 1 and an alkylating agent (AA) or a topoisomerase I inhibitor as compounds as such, or as pharmaceutical compositions (where the Compound 1 and an alkylating agent (AA) or a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) can be formulated jointly or separated). When the administration is not simultaneous, the compound and the agents can be administered in any order.

[0080] In a still further aspect, the invention provides a pharmaceutical composition comprising the therapeutic combination according to the invention, admixed optionally together with a pharmaceutically acceptable carrier, diluent or excipient; wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.In one embodiment, the present invention refers to a pharmaceutical composition comprising the combination of the invention as abode defined, in admixture with one or more pharmaceutically acceptable carrier or excipients, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.. In one embodiment, the compounds of the combination of the invention, as above defined, can be administered in the form of separate pharmaceutical compositions for oral administration, each containing one of the active ingredients, or in the form of a single pharmaceutical composition for oral administration, in which the active ingredients are in admixture.

[0081] In another embodiment, the compounds of the combination of the invention as above defined can be administered in a variety of dosage forms, e.g., orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g., intramuscularly, or through intravenous and / or intrathecal and / or intraspinal injection or infusion.

[0082] In one embodiment, the pharmaceutical composition for oral administration comprising the compounds of the combination of the invention, as above defined, can be a solid oral dosage form such as a tablet, a gelcap, a capsule, a caplet, a granule, a lozenge and bulk powders. Such solid oral dosage form can also contain suitable pharmaceutically acceptable carriers, diluents, such as sucrose, mannitol, lactose, starches, and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.

[0083] In a further embodiment, the pharmaceutical composition comprising the combination of the invention is a liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups. Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and / or suspending the compounds of the invention.

[0084] In a preferred embodiment the Compound 1 is administered orally.

[0085] In a still further aspect, the invention provides a pharmaceutical composition comprising the therapeutic combination comprising:

[0086] (a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):

[0087]

[0088] (Compound 1)

[0089] and

[0090] (b) an alkylating agent (AA) for use in the treatment of lung cancer; or

[0091] (c) a topoisomerase inhibitor (Tl) selected from topoisomerase I inhibitors and topoisomerase II inhibitors or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer. In one embodiment, the invention provides a pharmaceutical composition comprising the therapeutic combination comprising:(a) the Compound 1 (2-(1 -cyclohexylpiperidin-4-yl)-6- fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):

[0092]

[0093] (Compound 1)

[0094] and

[0095] (b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1. for use in the treatment of lung cancer

[0096] for use in the treatment of lung cancer; or

[0097] (c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer.

[0098] In the present invention, each of the active ingredients of the combination is in amount effective to produce a synergic antineoplastic effect.

[0099] The term “therapeutic combination” as used herein also includes preparation in the form of “kit of parts” wherein the combination partners (a) the Compound 1 and (b) the alkylating agent (AA) or (c) the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I), as defined above, can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (Compound 1 and the alkylating agent (AA) or the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I), i.e. simultaneously or at different time points. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Very preferably, the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners Compound 1 and the alkylating agent (AA) or the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I). The ratio of the total amounts of the combination partner Compound 1 and the alkylating agent (AA) or the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, age, sex, body weight, etc. of the patients. There is at least one beneficial effect, e.g., a mutual enhancing of the effect of the combination partners Compound 1 and the alkylating agent (AA) or the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I), in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutic effect in a non-effective dosage of one or both of the combination partners Compound 1 and the alkylating agent (AA) or the topoisomerase I inhibitor, and very preferably a strong synergism of the combination partners Compound 1 and either the alkylating agent (AA) or the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I).

[0100] The effect of the combination of the invention is significantly increased without a parallel increased toxicity. In other words, the combined therapy of the present invention enhances the antitumoral effects of Compound 1 and either thealkylating agent (AA) or the topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) partners of the combination of the invention and thus yields the most effective and less toxic treatment for tumors.

[0101] The amount of Compound 1 generally employed is in the range from 1 mg / day to 1 g / day as free base. More preferably, the course of therapy employed is from about 40 mg / day to about 260 mg / day as free base. Typical regimens comprises the following administration schedules: daily for up to 21 consecutive days; daily for 7 consecutive days, followed by a rest period of three weeks for a total of 28-day cycle (four-weeks cycle); daily for 14 days, followed by a rest period of one week (three-weeks cycle); daily on days 1 to 7 and 15 to 21 of a four-weeks cycle; continuous until disease progression, Compound 1 can be administered once or twice a day. In a preferred embodiment Compound 1 is administered twice a day.

[0102] For the administration of the alkylating agent TMZ, the course of therapy generally employed is from 15 mg / m2to 300 mg / m2daily. More preferably, the course of therapy generally employed is from about 50 mg / m2to 200 mg / m2daily. Most preferably, the course of therapy generally employed is from about 150 mg / m2to 200 mg / m2for up to 7 consecutive days each 28 days, wherein TMZ is administered preferably orally.

[0103] In the method of the subject invention, for the administration of the topoisomerase I inhibitor topotecan, the course of therapy generally employed is from 0.5 mg / m2to 20 mg / m2on days 1 , 8, 15 of 21 or 28 days cycle or on days 1 up to 7 of 21 or 28 days cycle. More preferably, the course of therapy generally employed is from about 1 mg / m2to 5 mg / m2on days 1, 8, 15 of 28 days cycle. Most preferably, the course of therapy generally employed is on days 1, 8 and 15 each 28 days, wherein topotecan is administered preferably intravenous.

[0104] For the administration of ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) trastuzumab deruxtecan, the course of therapy generally employed is from 1 mg / kg to 10 mg / kg, preferably from 2.5 mg / kg to 6 mg / kg, preferably once every three weeks. Preferably, trastuzumab deruxtecan is administered intravenous.

[0105] The present invention further provides a commercial package (kit of parts) comprising, in a suitable container mean, (a) the Compound 1 and (b) the alkylating agent (AA), or (c) the topoisomerase I inhibitor or the ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) as described above, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof, together with instructions for simultaneous, separate or sequential use thereof. In a package according to the invention Compound 1 and the partner (the alkylating agent (AA) or the topoisomerase I inhibitor or the ADC comprising topoisomerase I inhibitor payload (ADC-Topo I)) are present within a single container mean or within distinct container means.

[0106] Another embodiment of the present invention is a commercial package comprising a pharmaceutical composition or product as described above.

[0107] All preferred groups or embodiments described above for the combination of the invention may be combined among each other and apply as well mutatis mutandis.

[0108] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[0109] The activities of the combination of the present invention are shown for instance by the following in vitro tests and supported by the ongoing clinical phase I results, which are intended to illustrate but not to limit the present invention.EXPERIMENTAL PART

[0110] Evaluation of in vitro synergism: General procedure

[0111] The human ovarian cancer cell lines A2780 and A2780 / cis were purchased from ECACC; the cancer cell lines OVCAR-3, OVCAR-4, OVCAR-8 (all derived from platinum refractory patients - Cancer Res 1997; 57:850—856) and SK-OV-3 (platinum sensitive - Cancer Res 1997; 57:850— 856) were purchased from NCI-DTP; the SCLC cell lines NCI-H146, NCI-H209 and NCI-H526 were purchased from ATCCs; the gastric cell line NCI-N87 was also purchased from ATCC. The cisplatin-resistant A2780 / cis cell line has been developed by chronic exposure of the parent cisplatin-sensitive A2780 cell line (ECACC No. 93112519) to increasing concentrations of cisplatin. A2780 / cis is cross-resistant to melphalan, adriamycin and irradiation. In order to retain resistance, cisplatin is added to the medium every 2-3 passages. The growth media compositions of all cell lines are listed in Table 1.

[0112] All cell lines were authenticated by DNA short tandem repeats fingerprinting and were regularly checked for the absence of mycoplasma.

[0113] Cells were seeded in 96-well black plates in 200 l / well of appropriate culture medium at different cell densities such that the cells were still actively proliferating at the end of the experiment. Cells were incubated at 37° C in a humidified 5% CO2 atmosphere for 24 hours, then treated with compounds alone or in combination matrices typically of 6 x 9 doses, using the digital dispenser D300e (Tecan) or a Biomek i5 robotic station (Beckman Coulter). After 144 hours of drug treatment, cells were lysed using 50 l / well of CellTiter Gio reagent solution (Promega) in the plates. After mixing for 10 minutes, the plates were analyzed with a luminescence plate reader (EnVision, PerkinElmer). Compound antiproliferative activity was measured using CellTiter Gio cell viability assay (Promega), a luciferase-based assay that evaluates the number of metabolical ly active cells by quantification of ATP.

[0114] The effect of compound combinations (antagonism, additivity, synergism) was calculated by comparing, for each combination of doses of the matrix, the observed effect, and the expected additive effect according to the Bliss independence model. Combination Indexes were calculated according to Demidenko E, Miller TW PLoS One; 2019 Nov 25;14(11):e0224137):

[0115] VAB = VA* VB

[0116] C.L = Observed viability (VObs) / Expected viability (VAB)

[0117] where:

[0118] V (Viability) = % viability as compared with DMSO treated controls (V = 0%: complete cytotoxicity, no cells left alive; V = 100%: no cytotoxicity, all cells are alive);

[0119] VA = Observed viability after treatment with compound A, single agent;

[0120] VB = Observed viability after treatment with compound B, single agent;

[0121] VAB = Predicted viability after simultaneous treatment with both drug A and drug B if the combination would be additive; C.L (Combination Index) = ratio between experimentally measured Viability (Vobs) and predicted viability (VAB);. C.L = 1 indicates perfect additivity.

[0122] Theoretically, C.L values just below 1 (e.g. 0.99) can be defined as synergistic and C.Ls just above 1 (e.g. 1.01) can be defined as antagonistic. However, to limit any effects due to experimental variability and to be more stringent in the definitions of antagonism and synergy, it was decided to set the following range of additivity: 0.8 C.L < 1.2. Therefore, C.L s 0.8 indicates synergism; 0.8 s C.L s 1.2 indicates additivity; C.L ^1.2 indicates antagonism.Unequivocal combination effects can usually be assessed when both substances are used in a concentration range such as to induce, as single agents, 15-90% cell viability as compared to untreated controls. Outside this range, the data can be affected by experimental variability. Thus, C.I.s of combinations in which the same doses of the two compounds as single agents killed >85% of cells (producing residual cell viability less than 15%), were considered as not evaluable (“N.E.”) for in vitro combination effect. Vice-versa, C.I.s of combinations in which the same doses of compounds as single agents showed null effect, resulting in a cell viability of more than 90%, were considered only in the case that they produced clear synergistic or antagonistic effect; if the effect resulted to be additive, they were considered not evaluable (“N.E.”). By convention, to be able to evaluate the effect of the combination of the two compounds, we assume in the matrix of combinations at least three points must be valid (i.e., combinations whose single agents have an effect that results between 15% and 90% of cell viability).

[0123] The Results of antiproliferative combination experiments are summarized in Table 2: for all combinations of compound 1 with topoisomerase I inhibitors (SN-38 and topotecan) in ovarian cell lines and with the ADC-topo I inhibitor (trastuzumab deruxtecan) in gastric cancer, the mean measured C.I.s resulted < 0.8 indicating synergistic effects; for all combinations of compound 1 with temozolomide the mean measured C.I.s resulted < 0.8 indicating synergistic effects.

[0124] Table 1 : Cell lines, sources and growth media compositions.

[0125]

[0126] Table 2: In vitro simultaneous combination effect of Compound 1 with topoisomerase I inhibitors or TMZ lung ovarian and gastric cancer cell lines @ 144h treatment

[0127]

[0128] % syn. comb. = percentage of synergistic combinations.

[0129] In vivo activity of the combinations: General procedure

[0130] Tumor inoculation and study design

[0131] Each mouse was inoculated subcutaneously at the right flank with the tumor cells (5 x 106) in 0.2 mL of PBS supplemented with Matrigel (1:1) for tumor development. The animals were randomized and treatments started when the average tumor volume reached approximately 139 mm3. The test articles, doses, schedules and the animal numbers in each group are shown Table 3.

[0132] Tumor measurements and the endpoints

[0133] Prior to the onset of drug treatment, mice were measured for tumor size in two dimensions using a caliper, and the tumor volume (mm3) was calculated using formula V = 0.5 a x b2where a and b are the long and short diameters of the tumor in mm, respectively. Mice were randomized into different treatment groups based on the tumor volume. During the study, individual animals were terminated when the tumor volume reached 2000 mm3(ethical endpoint) before PG-D46 and terminated when the tumor volume reached 1000 mm3(requested by the sponsor) after PG-D46. The major endpoint was to see if the tumor growth could be delayed or mice could be cured.

[0134] The T / C value (in percent) is an indication of antitumor effectiveness; T and C are the mean volumes of the treated and control groups, respectively.

[0135] TGI was calculated for each group using the formula: TGI (i) (%) = (1 -(Ti-To) / (Vi-Vo)]*1OO and TGI (ii) (%)=((Vi- ) / Vi)*100; was the average tumor volume of a treatment group on a given day, Towas the average tumor volume of the treatment group on the day of treatment start, Vi was the average tumor volume of the vehicle control group on a given day, and Vowas the average tumor volume of the vehicle group on the day of treatment start, as reported in Table 4.Statistical Analysis

[0136] Summary statistics, including mean and the standard error of the mean (SEM), are provided for the tumor volume of each group at each time point.

[0137] Statistical analysis of difference in tumor volume among the groups was conducted on the data obtained on PG-D28. Time-to-event (time required for tumors to reach 1000 mm3) was performed at the end of the study. All data was analyzed using Graphpad Prism 10. A p<0.05 value is considered to be statistically significant.

[0138] Statistical analysis of the different median time for tumors to reach the predetermined size was performed by Log-Rank (Mantle-Cox) test. A p<0.05 value is considered to be statistically significant, as reported in Table 5.

[0139] Table 3: Groups and Treatments Information

[0140]

[0141] Notes:

[0142] a. N: animal number.

[0143] b. Compound 1 as was formulated in “0.5% methylcellulose 400 cP”. Temozolomide was diluted in 0.5% Hydroxypropyl Methyl Cellulose in PBS.

[0144] Table 4: Tumor Growth Inhibition Analysis (PG-D21)

[0145] Tumor Size (mm3)aTGI (I)bT / CcpdTGI (ii)bGroup Treatment

[0146] on PG-D21 (%) (%) value (%)

[0147] 1 Vehicle, QD x 28 days 1167 + 145 - . . .

[0148] Temozolomide, 5 mg / kg, QD x

[0149] 2 782 + 103 37.44 67.01 ns 32.99

[0150] 5 days

[0151] Compound 1, 25 mg / kg, QD x

[0152] 3 639 + 90 51.40 54.71 * 45.29

[0153] 28 days

[0154] Compound 1, 25 mg / kg, QD x

[0155] 4 7 days + temozolomide, 5 360 + 28 78.51 30.83 ** 69.17 mg / kg, QD x 5 days

[0156] Notes:

[0157] a. Data are shown as Mean ± SEM.

[0158] b. Tumor Growth Inhibition (TGI) was calculated using the formula: TGI (i) (%) = (1-(T-To) / (V-Vo))*1OO, TGI (ii) (%)=((Vi-Ti) / Vi)*100, where T21 = mean tumor size at day 21 of treatment group; To = mean tumor size at day 0 of treatment group; V21 = mean tumor size at day 21 of control group; and Vo= mean tumor size at day 0 of control group.

[0159] c. Antitumor activity (T / C) was determined by dividing the average tumor volume for treated group (T) by the average tumor volume for control group (C).

[0160] d. All data were analyzed using Graphpad Prism. A one-way ANOVA followed by Dunnett’s multiple comparison test was performed to compare tumor volume among vehicle group and treatment groups, **** indicates p<0.0001.Table 5: p Values for Pairwise Comparisons between single agent groups (temozolomide or Compound 1) and the Combination Group (PG-D28)

[0161] Tumor Size (mm3)a

[0162] Group Treatment pbvalue

[0163] on PG-D28

[0164] 3 Compound 1 , 25 mg / kg, QD x 28 days 639 ± 90

[0165] . Compound 1 , 25 mg / kg, QD x 7 days + „ TMZ, 5 mg / kg, QD x 5 days

[0166]

[0167] 2 TMZ, 5 mg / kg, QD x 5 days 782 + 103

[0168] . Compound 1 , 25 mg / kg, QD x 7 days + TMZ, 5 mg / kg, QD x 5 days

[0169]

[0170] Note:

[0171] a. Data are shown as Mean ± SEM.

[0172] b. Mann-Whitney test was performed to compare tumor volume between twogroups, ns indicates p>0.05, * indicates p<0.05, ** indicates p<0.01 , *** p<0.001.

[0173] The effect of Compound 1 , temozolomide, and their combination on delaying the growth of NCI-H209 xenografts was measured and shown in Table 6 and the statistical analysis is shown in Table 7.

[0174] Table 6: Tumor Growth Delay Analysis

[0175] _T_ . _ . Predetermined Days post the T-CUP size (mm3)arandomizationb(days)c1 Vehicle, QD x 28 days, 2 cycles 29.5

[0176] 2 TMZ, 5 mg / kg, QD x 5 days, 2 cycles 36.5 7 3 Compound 1 , 25 mg / kg, QD x 28 days, 2 cycles100035 5.5 . Compound 1 , 25 mg / kg, QD x 7 days, 2 cycles +

[0177]

[0178] TMZ, 5 mg / kg, QD x 5 days, 2 cycles

[0179] Note:

[0180] a. Data are shown as the specific tumor size.

[0181] b. The median time (in days) was evaluated according to the time needed for tumors to reach the specific size (1000 mm3). Forthat, the first measurement day in which each tumor was ^1000 mm3was used for the analysis. The median time for each group is reported.

[0182] c. T-C is calculated with T as the median time (in days) required for the treatment group tumors to reach a predetermined size (^1000 mm3), and C is the median time (in days) for the control group tumors to reach the same size.Table 7: Statistical Analysis of Differences in Median Time for Tumors to Reach the Predetermined Size (1000 mm3)

[0183] Curve Curve

[0184] Group Treatment comparison3comparisonavs

[0185] vs vehicle single agents

[0186] 1 Vehicle, QD x 28 days, 2 cycles

[0187] 2 Temozolomide, 5 mg / kg, QD x 5 days, 2 cycles 3 Compound 1 , 25 mg / kg, QD x 28 days, 2 cycles4Compound 1 , 25 mg / kg, QD x 7 days, 2 cycles + Temozolomide, 5 mg / kg, QD x 5 days, 2 cycles

[0188]

[0189] Note:

[0190] a. Statistical analysis of the different median time for tumors to reach the predetermined size (1000 mm3) was performed by Log-Rank (Mantle-Cox) test, **** indicates p<0.0001, *** indicates p<0.001, ** indicates p<0.01, * indicates p<0.05, ns indicates p>0.05.

[0191] In vivo efficacy of Compound 1, temozolomide and their combinations were investigated after treatment of BALB / c nude mice bearing the small cell lung cancer NCI-H209 xenografts (Figure 1 and 2).

[0192] Tumor growth inhibition of Compound 1, temozolomide or their combinations in female BALB / c nude mice bearing NCI-H209 tumors was calculated based on tumor volume measured at the end of treatment cycle 1 (PG-D28). The maximum TGI, tumor growth delay and the median time to tumor size of 1000mm3were also analyzed.

[0193] Compared with vehicle group, Compound 1 and its combination with temozolomide significantly reduced tumor growth (PG-D28), compared to vehicle, and importantly the combination group had a significant difference in tumor growth inhibition compared to the single agent groups. Additionally, all treatment groups delayed the growth of tumors (to 1000 mm3) compared to the control group and the combination of Compound 1 and temozolomide significantly delayed the tumor growth compared to the single agent arms. Overall, these data from the in vivo efficacy study, confirm the synergism observed between Compound 1 and temozolomide in cell proliferation assays.

Claims

CLAIMS1. A therapeutic combination comprising:(a) the Compound 1 1 (2-(1 -cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide): 1 (2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxamide):(Compound 1)and(b) an alkylating agent (AA) selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1, for use in the treatment of lung cancer; or(c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) for use in the treatment of ovarian cancer or gastric cancer, wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

2. The therapeutic combination for use according to claim 1 , wherein the lung cancer is small cell lung cancer.

3. The therapeutic combination for use according to claim 1 wherein the alkylating agent is temozolomide.

4. The therapeutic combination for use according to claim 1 wherein the topoisomerase I inhibitor is a topoisomerase I inhibitor selected from topotecan, irinotecan and SN-38.

5. The therapeutic combination for use according to claim 1, wherein the ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) is selected from trastuzumab deruxtecan (enhertu), sacituzumab govitecan (trodelvy), datopamab deruxtecan (dato-DXd) patritumab deruxtecan, CDH6-Dxd, and GPR20-Dxd.

6. The therapeutic combination for use according to claims 5 wherein the ADC comprising topoisomerase I inhibitor payload (ADC-Topo I) is trastuzumab deruxtecan.

7. The therapeutic combination for use according to claim 4 wherein the cancer is ovarian cancer.

8. The therapeutic combination for use according to claims 5 wherein the cancer is gastric cancer.

9. The therapeutic combination for use according to anyone of claims 1 to 8, for simultaneous, separate or sequential administration.

10. The therapeutic combination for use according to anyone of claims 1 to 9, wherein the combination is formulated as a pharmaceutical composition.

11. A pharmaceutical composition comprising the combination according to any of claims 1 to 9, admixed with a pharmaceutically acceptable carrier, diluent or excipient.

12. The therapeutic combination for use according to anyone of claims 1 to 10, in form of kit of parts comprising, in a suitable container, said agents (a) and (b) or (a) and (c), together with instructions for simultaneous, separate or sequential use thereof.

13. Use of a therapeutic combination comprising:(a) Compound 1 :(Compound 1)and(b) the alkylating agent selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1. for use in the treatment of lung cancer, in the preparation of a medicament for treating lung cancer, or(c) a topoisomerase I inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo) in the preparation of a medicament for treating ovarian and gastric cancer; wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

14. A method of treating lung cancer or ovarian and gastric cancer to a patient in need thereof, comprising the administration to a patient of a therapeutically effective amount of a combination of:(a) Compound 1 :(Compound 1)andb) the alkylating agent selected from the group consisting of carmustine, lomustine, cisplatin, carboplatin, oxalilplatin, procarbazine, dacarbazine, temozolomide, mitozolomide, KL-50 and 1-1. for use in the treatment of lung cancer, or c) a topoisomerase (I) inhibitor or an ADC comprising topoisomerase I inhibitor payload (ADC-Topo), wherein the active ingredients (a) and (b) or (c) are present independently in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof.

15. The therapeutic combination for use according to claim 1 , wherein the dose of Compound 1 is from 1 mg / day to 1 g / day.

16. The therapeutic combination for use according to claim 15 wherein the dose of Compound 1 is from 40 mg / day to 260 mg / day.

17. The therapeutic combination for use according to anyone of claims 1 to 11, wherein Compound 1 is administered orally.

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