Combinations of a tubulin polymerization inhibitor and a poly (ADP-ribose) polymerase (PARP) inhibitor for use in the treatment of cancer

Abstract

Methods and combination therapies for treating, preventing, and/or delaying the onset and/or development of cancer using a tubulin polymerization inhibitor such as a compound of formula I, or a pharmaceutically acceptable salt thereof, and a poly (ADP-ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt thereof, are provided.

Claims

1. A method of treating, or alleviating ovarian cancer, pancreatic cancer, or prostate cancer, comprising administering to a human in need thereof: (i) N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine (NOV202), or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, wherein the amount of (i) administered to the human is a dose of in the range of 2.5-5 mg/kg, and (ii) olaparib, or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, wherein the amount of (ii) administered to the human is a dose of in the range of 400 mg/day-1200 mg/day.

2. The method of claim 1, wherein said cancer is a primary tumor.

3. The method of claim 1, wherein said cancer is a metastasis.

4. The method of claim 1, wherein said cancer is a solid tumor.

5. The method of claim 1, wherein said cancer is a BRCA mutated tumor.

6. The method of claim 1, wherein said cancer is a p53 suppressor gene mutated tumor.

7. The method of claim 1, wherein said cancer is a homologous recombination repair defect tumor with mutations in repair genes other than BRCA1/BRCA2.

8. The method of claim 1, wherein the cancer is ovarian cancer.

9. The method of claim 1, wherein the cancer is pancreatic cancer.

10. The method of claim 1, wherein the cancer is prostate cancer.

11. The method of claim 1, wherein the dose of (i) is 2.5 mg/kg.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 sets out results of study of an in vivo anti-tumor efficacy of NOV202 alone and in combination with olaparib in a patient-derived xenograft of ovarian cancer. Details are provided in Example 1.

(2) FIG. 2 sets out the mean body weight changes of an in vivo anti-tumor efficacy of NOV202 alone and in combination with olaparib in a patient-derived xenograft of ovarian cancer. Details are provided in Example 1.

(3) FIG. 3 sets out results of study of an in vivo anti-tumor efficacy of NOV202, olaparib and plinabulin alone, and combination of NOV202 and olaparib, and combination of plinabulin and olaparib, in a patient-derived xenograft of ovarian cancer. Details are provided in Example 2. A represents vehicle, B represents NOV202, C represents olaparib, D represents plinabulin, E represents combination of NOV202 and olaparib, and F represents combination of plinabulin and olaparib. Start of treatments were at day 6 and end of treatment were at day 19 (NOV202 and olaparib) and at day 20 (plinabulin).

(4) FIG. 4 sets out the mean body weight changes of an in vivo anti-tumor efficacy of NOV202, olaparib and plinabulin alone, and combination of NOV202 and olaparib, and combination of plinabulin and olaparib, in a patient-derived xenograft of ovarian cancer Details are provided in Example 2. A represents vehicle, B represents NOV202, C represents olaparib, D represents plinabulin, E represents combination of NOV202 and olaparib, and F represents combination of plinabulin and olaparib.

(5) The invention will be described in the following, non-limiting examples.

EXAMPLE 1

(6) A Study of Anti-Tumor Efficacy of NOV202 Alone and in Combination with Olaparib in a Patient-Derived Xenograft of Ovarian Cancer (Ov10584)

(7) NMRI:nu/nu female (Janvier) mice (8 weeks old) were used as follows: 4 animals in the vehicle group, 4 animals in NOV202 group, Olaparib group and in the combination group of NOV202 and olaparib, respectively. NOV202 was synthesized as described in WO 2012/127032. Olaparib was purchased from LC Laboratories. The patient-derived xenograft Ov10584 was used at passage number 7. All mice received tissue fragments of 2×2 mm subcutaneously at day 0, and tumors were allowed to reach palpable sizes of 118 mm.sup.3 (mean) (the study day 8) prior to start the treatments. NOV202 group was administered PO at a dose 30 mg/kg and olaparib group was administered PO at a dose 100 mg/kg. The combination of NOV202 and olaparib group had the same dosage and schedule as in monotherapy. NOV202 was given in the morning (5 ml/kg) and olaparib in the afternoon (10 ml/kg). All three groups were administered 14 days once a day (days 8-22). The tumor volumes and body weights of animals were measured at regular intervals (day 7, 9, 13, 15, 19, 22, 27, all groups, and continued to measure the combination group day 29, 33, 36, 40, 43, 47, 50, 54, 57).

(8) NOV202 inhibited the growth of Ov10584 significantly, resulting in a T/C (tumor/control) value of 37% (stable disease). The combination of NOV202 with olaparib had a distinct synergistic effect. The T/C value was improved to 3% in the combination group, compared to 37% for NOV202 and 20% for olaparib after monotherapy. Tumor remission was almost complete at the end of therapy (mean RTV=0.4, day 22), and continued until day 40 (mean RTV=0.8).

(9) Daily treatment with 30 mg/kg NOV202 for 14 days was well tolerated. One day after treatment stop, mice showed 6% body weight loss but they recovered soon. The combination of NOV202 and olaparib was also well tolerated. Results are set out in FIG. 1. The mean body weight changes of the animals are set out in FIG. 2.

EXAMPLE 2

(10) A Study of Anti-Tumor Efficacy of Combination of NOV202 with Olaparib Vs. Combination Plinabulin with Olaparib in a Patient-Derived Xenograft of Ovarian Cancer (Ov0584)

(11) NMRI:nu/nu female (Janvier) mice (8 weeks old) were used as follows: 4 animals in the vehicle group, 4 animals in NOV202 group, olaparib group, plinabulin group, in the combination group of NOV202 and Olaparib, and in the combination group of plinabulin and olaparib, respectively. NOV202 was synthesized as described in WO 2012/127032. Olaparib was purchased from LC Laboratories, and plinabulin was purchased from Sellechem. The patient-derived xenograft Ov10584 was used at passage number 4. All mice received tissue fragments of 2×2 mm subcutaneously into the left flank at day 0, and tumors were allowed to reach palpable sizes of 108 mm.sup.3 (mean) (the study day 6) prior to start the treatments. NOV202 group was administered PO at a dose 30 mg/kg and olaparib group was administered PO at a dose 100 mg/kg, and plinabulin was administered i.p. at a dose 7.5 mg/kg. The combination of NOV202 and olaparib group had the same dosage and schedule as in monotherapy, NOV202 was given in the morning (5 ml/kg) and olaparib in the afternoon (10 ml/kg). The combination of plinabulin and olaparib group had also the same dosage and schedule as in monotherapy. NOV202 and olaparib was administered 14 days once a day (days 6-19), and plinabulin was administered days 1, 4, 8, 11, 15 once a day. The tumor volumes and body weights of animals were measured at regular intervals (day 6, 7, 9, 12, 14, 16, 19, 23, 26 and 29), all groups.

(12) NOV202 inhibited the growth of Ov10584 significantly, resulting in a T/C (tumor/control) value of 32% (stable disease). The combination of NOV202 with olaparib had a distinct synergistic effect. The T/C value was improved to 6% in the combination group, compared to 32% for NOV202, 45% for olaparib and 58% for plinabulin after monotherapy. The combination of plinabulin with olaparib had also a synergistic effect. T/C value was improved to 14% in the combination group.

(13) Daily treatment for 14 days was well tolerated in all groups. Results are set out in FIG. 3. The mean body weight changes of the animals are set out in FIG. 4. A represents vehicle, B represents NOV202, C represents olaparib, D represents plinabulin, E represents combination of NOV202 and olaparib, and F represents combination of plinabulin and olaparib.

(14) Items of the Invention 1. A method of treating, preventing or alleviating cancer, comprising administering to a subject in need thereof (i) a therapeutically effective amount of a tubulin polymerization inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, and (ii) a therapeutically effective amount of a poly (ADP-ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof. 2. The method of item 1, wherein the tubulin polymerization inhibitor is a compound of formula I, or a pharmaceutically acceptable solvate or salt thereof; wherein said formula I is represented by:

(15) ##STR00010## wherein R.sup.1, R.sup.3, R.sup.8, R.sup.12, R.sup.13, and R.sup.14 represent hydrogen; R.sup.2 represents hydrogen or methyl; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are independently selected from hydrogen, halogen, hydroxy, (C.sub.1-C.sub.4)alkyl, O(C.sub.1-C.sub.4)alkyl, O(C.sub.1-C.sub.4)alkyl(C.sub.2-C.sub.5)heterocyclyl, and OCF.sub.3; R.sup.10 is selected from hydrogen, (C.sub.1-C.sub.4)alkyl and NH.sub.2; R.sup.11 is selected from hydrogen, (C.sub.1-C.sub.4)alkyl, (CO)NH.sub.2, and (C.sub.2-C.sub.5)heterocyclyl(C.sub.1-C.sub.4)alkyl; R.sup.9 is selected from

(16) ##STR00011## R.sup.15 is selected from hydrogen and methyl; and R.sup.16 and R.sup.17 are independently selected from hydrogen, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl-OH, and (CO)OH. 3. The method of item 2, wherein the tubulin polymerization inhibitor is a compound of formula I which is is selected from: N.sup.4-(1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(2-methyl-1H-indol-5-yl)-N.sup.2-{2-[5-(trifluoromethoxy)-1H-indol-3-yl]ethyl}pyrimidine-2,4-diamine; N.sup.2-[2-(5-methyl-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(6-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(7-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethyl-1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.4-(2,3-dimethyl-1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; (5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indol-2-yl)methanol; methyl 5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indole-2-carboxylate; N.sup.4-(1H-benzo[d]imidazol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1H-indol-6-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.4-(1H-indol-4-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; 2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-6-(2-methyl-1H-indol-5-ylamino)pyrimidine-4-carboxamide; and N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-5-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(4-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(2-methyl-1H-indol-5-yl)-N.sup.2-[2-(5-propoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-isopropoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5,6-dimethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-2-methyl-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; [5-(2-{[2-(5-methoxy-1H-indol-3-yl)ethyl][methyl]amino}pyrimidin-4-ylamino)-1H-indol-2-yl]methanol; (5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1-methyl-1H-benzo[d]imidazol-2-yl)methanol; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethyl-1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-methylpyrimidine-2,4-diamine; [5-({2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-yl}amino)-1H-indol-2-yl]methanol; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine; 3-[2-({4-[(1-methylindol-4-yl)amino]pyrimidin-2-yl}amino)ethyl]-1H-indol-5-ol; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-4-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethylindol-4-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine; 2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]-6-[(2-methyl-1H-indol-5-yl)amino]pyrimidine-4-carboxamide; 6-[(1,2-dimethylbenzimidazol-5-yl)amino]-2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidine-4-carboxamide; 2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-6-[(1-methylindol-4-yl)amino]pyrimidine-4-carboxamide; 2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]-6-[(1-methylindol-4-yl)amino]pyrimidine-4-carboxamide; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine; and N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4,5-triamine. 4. The method of item 1, wherein the tubulin polymerization inhibitor is a I compound of formula I which is N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine (NOV202). 5. The method of item 1, wherein the tubulin polymerization inhibitor is selected from combretastatin CA-4P (zybrestat), AVE-8062 (ombrabulin), BNC105P, MPC-6827 (azixa), ZD6126 (ANG453), Oxi-4503, BPI-2358 (plinabulin), MN029 (denibulin), EPC-2407 (crinobulin), ZIO-301 (indibulin), T115, BPROL075 and ABT-751. 6. The method of item 1, wherein the tubulin polymerization inhibitor is the compound (plinabulin):

(17) ##STR00012## or a pharmaceutically acceptable solvate or salt thereof. 7. The method according to any one of items 1 to 6, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is selected from olaparib, niraparib, veliparib, talazoparib, rucaparib, iniparib, fluzoparib, AZD2461, UPF 1069, PJ34, A-966492, AG-14361, E7449 and NMS-P118. 8. The method according to any one of items 1 to 6, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is olaparib. 9. The method according to any one of items 1 to 8, wherein said subject is a human patient. 10. The method according to any one of items 1 to 9, wherein said subject is diagnosed with a cancer, in treatment for cancer, or in post-therapy recovery from cancer. 11. The method according to any one of items 1 to 10, wherein said cancer is a primary tumor. 12. The method according to any one of items 1 to 10, wherein said cancer is a metastasis. 13. The method according to any one of items 1 to 10, wherein said cancer is a solid tumor. 14. The method according to any one of items 1 to 10, wherein said cancer is a BRCA mutated tumor. 15. The method to any one of items 1 to 10, wherein said cancer is a BRCA mutated breast, ovarian, prostate or pancreas cancer. 16. The method to any one of items 1 to 10, wherein said cancer is a p53 suppressor gene mutated tumor. 17. The method to any one of items 1 to 10, wherein said cancer is a p53 mutated breast, ovarian, prostate, lung, brain or pancreas cancer. 18. The method to any one of items 1 to 10, wherein said cancer is a p53 missense mutated tumor with expression of the full-length mutant p53 protein. 19. The method to any one of items 1 to 10, wherein said cancer is a p53 missense mutated breast, ovarian, prostate, lung, brain or pancreas cancer with expression of the full-length mutant p53 protein. 20. The method to any one of items 1 to 10, wherein said cancer is a homologous recombination repair defect tumor with mutations in repair genes other than BRCA1/BRCA2. 21. The method to any one of items 1 to 10, wherein said cancer is a homologous recombination repair defect breast, ovarian, prostate, lung, brain or pancreas cancer with mutations in repair genes other than BRCA1/BRCA2. 22. The method to any one of items 1 to 10, wherein said cancer is a homologous recombination repair defect tumor with mutations in repair genes other than BRCA1/BRCA2, such as ATM, ATR, PALB2, RAD51, CHEK1 and CHEK2, as well as epigenetic loss of BRCA1 function through promoter methylation. 23. The method to any one of items 1 to 10, wherein said cancer is a homologous recombination repair defect breast, ovarian, prostate, lung, brain or pancreas cancer with mutations in repair genes other than BRCA1/BRCA2, such as ATM, ATR, PALB2, RAD51, CHEK1 and CHEK2, as well as epigenetic loss of BRCA1 function through promoter methylation. 24. The method according to any one of items 1 to 10, wherein said cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, pharyngeal cancer, esophageal cancer, glioblastoma, adrenal cancer, B-cell malignancies, biliary tract cancer, bladder cancer, bone cancer, brain cancer, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, connective tissue cancer, cancer of the digestive system, gallbladder cancer, gastric cancer, cancer of the head and neck, hepatocellular carcinoma, intra-epithelial neoplasm, kidney cancer, liver cancer, lymphoma, skin cancer, neuroblastoma, mesothelioma, neuroglioma, oral cavity cancer, pediatric cancer, pancreatic cancer, pancreatic endocrine tumors, pituitary adenoma, thymoma, renal cell carcinoma, cancer of the respiratory system, salivary gland cancer, sarcoma, small bowel cancer, testicular cancer, thyroid cancer, ureteral cancer, cancer of the urinary system, and hematological cancer. 25. The method according to item 24, wherein said cancer is ovarian cancer. 26. The method according to item 24, wherein said cancer is BRCA mutated ovarian cancer. 27. The method according to item 24, wherein said breast cancer is selected from estrogen receptor positive or negative, progesterone receptor positive or negative, HER-2 positive or negative, triple-negative breast cancer, or BRCA1 and/or BRCA2 positive or negative breast cancer. 28. The method according to item 24, wherein said lung cancer is selected from non-small cell lung cancer and small cell lung cancer. 29. The method according to item 24, wherein said skin cancer is selected from melanoma and basal cell carcinoma. 30. The method according to item 24, wherein said sarcoma is selected from Ewing's sarcoma, fibrosarcoma, and rhabdomyosarcoma. 31. The method according to item 24, wherein said hematological cancer is selected from leukemia, lymphoma and multiple myeloma. 32. The method according to any one of items 1 to 31, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is administered at a dose ranging from 0.5 to 100 mg/kg per day. 33. The method according to any one of items 1 to 32, wherein said tubulin polymerization inhibitor and/or said poly (ADP-ribose) polymerase (PARP) inhibitor is administered by intravenous infusion. 34. The method according to any one of items 1 to 32, wherein said tubulin polymerization inhibitor and/or said poly (ADP-ribose) polymerase (PARP) inhibitor is administered orally. 35. The method according to any one of items 1 to 34, wherein said tubulin polymerization inhibitor and said poly (ADP-ribose) polymerase (PARP) inhibitor is administered once daily, during a 14-day cycle. 36. The method according to any one of item 1 to 35, wherein said tubulin polymerization inhibitor is administered at a dose ranging from 0.5 to 50 mg/kg per day. 37. The method according to item 36, wherein said tubulin polymerization inhibitor is a compound of formula I. 38. The method according to any one of item 1 to 4 and 7 to 37, wherein the tubulin polymerization inhibitor is a compound of formula I which is N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine (NOV202); said poly (ADP-ribose) polymerase (PARP) inhibitor is olaparib; and said cancer is ovarian cancer. 39. The method of item 1, wherein the tubulin polymerization inhibitor is plinabulin or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, the PARP inhibitor is olaparib or a pharmaceutically acceptable solvate or salt thereof. 40. The method according to item 39, wherein said cancer is as defined in any one of items 11 to 31. 41. A compound of formula I, or a pharmaceutically acceptable solvate or salt thereof, and a poly (ADP-ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, in combination, for use in treatment of cancer; wherein said formula I is represented by:

(18) ##STR00013## wherein R.sup.1, R.sup.3, R.sup.8, R.sup.12, R.sup.13, and R.sup.14 represent hydrogen; R.sup.2 represents hydrogen or methyl; R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are independently selected from hydrogen, halogen, hydroxy, (C.sub.1-C.sub.4)alkyl, O(C.sub.1-C.sub.4)alkyl, O(C.sub.1-C.sub.4)alkyl(C.sub.2-C.sub.5)heterocyclyl, and OCF.sub.3; R.sup.10 is selected from hydrogen, (C.sub.1-C.sub.4)alkyl and NH.sub.2; R.sup.11 is selected from hydrogen, (C.sub.1-C.sub.4)alkyl, (CO)NH.sub.2, and (C.sub.2-C.sub.5)heterocyclyl(C.sub.1-C.sub.4)alkyl; R.sup.9 is selected from

(19) ##STR00014## R.sup.15 is selected from hydrogen and methyl; and R.sup.16 and R.sup.17 are independently selected from hydrogen, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl-OH, and (CO)OH. 38. The combination for use according to item 37, wherein said compound of formula I is selected from: N.sup.4-(1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(2-methyl-1H-indol-5-yl)-N.sup.2-{2-[5-(trifluoromethoxy)-1H-indol-3-yl]ethyl}pyrimidine-2,4-diamine; N.sup.2-[2-(5-methyl-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(6-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(7-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethyl-1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.4-(2,3-dimethyl-1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; (5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indol-2-yl)methanol; methyl 5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1H-indole-2-carboxylate; N.sup.4-(1H-benzo[d]imidazol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1H-indol-6-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.4-(1H-indol-4-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; 2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-6-(2-methyl-1H-indol-5-ylamino)pyrimidine-4-carboxamide; and N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-5-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(4-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(2-methyl-1H-indol-5-yl)-N.sup.2-[2-(5-propoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-isopropoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5,6-dimethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-2-methyl-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-6-methyl-N.sup.4-(2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidine-2,4-diamine; [5-(2-{[2-(5-methoxy-1H-indol-3-yl)ethyl][methyl]amino}pyrimidin-4-ylamino)-1H-indol-2-yl]methanol; (5-{2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-ylamino}-1-methyl-1H-benzo[d]imidazol-2-yl)methanol; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-methyl-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethyl-1H-indol-5-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-methylpyrimidine-2,4-diamine; [5-({2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]pyrimidin-4-yl}amino)-1H-indol-2-yl]methanol; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-6-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine; 3-[2-({4-[(1-methylindol-4-yl)amino]pyrimidin-2-yl}amino)ethyl]-1H-indol-5-ol; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-4-yl)pyrimidine-2,4-diamine; N.sup.4-(1,2-dimethylindol-4-yl)-N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine; N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-benzimidazol-4-yl)pyrimidine-2,4-diamine; 2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]-6-[(2-methyl-1H-indol-5-yl)amino]pyrimidine-4-carboxamide; 6-[(1,2-dimethylbenzimidazol-5-yl)amino]-2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]pyrimidine-4-carboxamide; 2-[2-(5-methoxy-1H-indol-3-yl)ethylamino]-6-[(1-methylindol-4-yl)amino]pyrimidine-4-carboxamide; 2-[2-(5-ethoxy-1H-indol-3-yl)ethylamino]-6-[(1-methylindol-4-yl)amino]pyrimidine-4-carboxamide; N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methylindol-4-yl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine; and N.sup.2-[2-(5-ethoxy-1H-indol-3-yl)ethyl]-N.sup.4-(2-methyl-1H-indol-5-yl)pyrimidine-2,4,5-triamine. 42. The combination for use according to item 41, wherein said compound of formula I is N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine (NOV202). 43. The combination for use according to any one of items 41 to 42, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is selected from olaparib, niraparib, veliparib, talazoparib, rucaparib, iniparib, fluzoparib, AZD2461, UPF 1069, PJ34, A-966492, AG-14361, E7449 and NMS-P118. 44. The combination for use according to any one of items 41 to 43, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is olaparib. 45. The combination for use according to any one of items 41 to 44, wherein said cancer is a primary tumor. 46. The combination for use according to any one of items 41 to 44, wherein said cancer is a metastasis. 47. The combination for use according to any one of items 41 to 44, wherein said cancer is a solid tumor. 48. The combination for use according to any one of items 41 to 44, wherein said cancer is a BRCA mutated tumor. 49. The combination for use according to any one of items 41 to 44, wherein said cancer is a BRCA mutated breast, ovarian, prostate or pancreas cancer. 50. The combination for use according to any one of items 41 to 44, wherein said cancer is a p53 suppressor gene mutated tumor. 51. The combination for use according to any one of items 41 to 44, wherein said cancer is a p53 mutated breast, ovarian, prostate, lung, brain or pancreas cancer. 52. The combination for use according to any one of items 41 to 44, wherein said cancer is a p53 missense mutated tumor with expression of the full-length mutant p53 protein. 53. The combination for use according to any one of items 41 to 44, wherein said cancer is a p53 missense mutated breast, ovarian, prostate, lung, brain or pancreas cancer with expression of the full-length mutant p53 protein. 54. The combination for use according to any one of items 41 to 44, wherein said cancer is a homologous recombination repair defect tumor with mutations in repair genes other than BRCA1/BRCA2. 55. The combination for use according to any one of items 41 to 44, wherein said cancer is a homologous recombination repair defect breast, ovarian, prostate, lung, brain or pancreas cancer with mutations in repair genes other than BRCA1/BRCA2. 56. The combination for use according to any one of items 41 to 44, wherein said cancer is a homologous recombination repair defect tumor with mutations in repair genes other than BRCA1/BRCA2, such as ATM, ATR, PALB2, RAD51, CHEK1 and CHEK2, as well as epigenetic loss of BRCA1 function through promoter methylation. 57. The combination for use according to any one of items 41 to 44, wherein said cancer is a homologous recombination repair defect breast, ovarian, prostate, lung, brain or pancreas cancer with mutations in repair genes other than BRCA1/BRCA2, such as ATM, ATR, PALB2, RAD51, CHEK1 and CHEK2, as well as epigenetic loss of BRCA1 function through promoter methylation. 58. The combination for use according to any one of items 41 to 44, wherein said cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, pharyngeal cancer, esophageal cancer, glioblastoma, adrenal cancer, B-cell malignancies, biliary tract cancer, bladder cancer, bone cancer, brain cancer, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, connective tissue cancer, cancer of the digestive system, gallbladder cancer, gastric cancer, cancer of the head and neck, hepatocellular carcinoma, intra-epithelial neoplasm, kidney cancer, liver cancer, lymphoma, skin cancer, neuroblastoma, mesothelioma, neuroglioma, oral cavity cancer, pediatric cancer, pancreatic cancer, pancreatic endocrine tumors, pituitary adenoma, thymoma, renal cell carcinoma, cancer of the respiratory system, salivary gland cancer, sarcoma, small bowel cancer, testicular cancer, thyroid cancer, ureteral cancer, cancer of the urinary system, and hematological cancer. 59. The combination for use according to item 58, wherein said cancer is ovarian cancer. 60. The combination for use according to item 59, wherein said ovarian cancer is BRCA mutated ovarian cancer. 61. The combination for use according to item 58, wherein said breast cancer is selected from estrogen receptor positive or negative, progesterone receptor positive or negative, HER-2 positive or negative, triple-negative breast cancer, or BRCA1 and/or BRCA2 positive or negative breast cancer. 62. The combination for use according to item 58, wherein said lung cancer is selected from non-small cell lung cancer and small cell lung cancer. 63. The combination for use according to item 58, wherein said skin cancer is selected from melanoma and basal cell carcinoma. 64. The combination for use according to item 58, wherein said sarcoma is selected from Ewing's sarcoma, fibrosarcoma, and rhabdomyosarcoma. 65. The combination for use according to item 58, wherein said hematological cancer is selected from leukemia, lymphoma and multiple myeloma. 66. The combination for use according to any one of items 41 to 65, wherein said compound of formula I is N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine (NOV202); said poly (ADP-ribose) polymerase (PARP) inhibitor is olaparib; and said cancer is ovarian cancer. 67. The combination for use according to any one of items 41 to 66, wherein said compound of formula I is administered at a dose ranging from 0.5 to 50 mg/kg per day. 68. The combination for use according to any one of items 41 to 66, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is administered at a dose ranging from 0.5 to 100 mg/kg per day. 69. The combination for use according to any one of items 41 to 68, wherein said compound of formula I and/or said poly (ADP-ribose) polymerase (PARP) inhibitor is administered by intravenous infusion. 70. The combination for use according to any one of items 41 to 68, wherein said compound of formula I and/or said poly (ADP-ribose) polymerase (PARP) inhibitor is administered orally. 71. The combination for use according to any one of items 41 to 70, wherein said compound of formula I and said poly (ADP-ribose) polymerase (PARP) inhibitor is administered once daily, during a 14-day cycle. 72. A pharmaceutical composition for use in treatment of ovarian cancer, comprising NOV202 and/or a pharmaceutically acceptable salt thereof, and olaparib and/or a pharmaceutically acceptable salt thereof. 73. A kit for use in treating cancer or decreasing tumor size, said kit comprising (i) a compound of formula I or a pharmaceutically acceptable solvate or salt thereof, according to item 1 or item 36; and (ii) a poly (ADP-ribose) polymerase (PARP) inhibitor, or a and/or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof. 74. The kit for use, according to item 73, wherein said compound of formula I is N.sup.2-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N.sup.4-(1-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine (NOV202); said poly (ADP-ribose) polymerase (PARP) inhibitor is olaparib; and said cancer is ovarian cancer. 75. Olaparib, or a pharmaceutically acceptable solvate or salt thereof, and plinabulin, or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, in combination, for use in treatment of cancer. 76. The combination for use, according to item 72, wherein said cancer is as defined in any one of items 45 to 65. 77. A tubulin polymerization inhibitor, or a pharmaceutically acceptable solvate or salt thereof, and a poly (ADP-ribose) polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or amorphous solid thereof, in combination, for use in treatment of cancer. 78. The combination for use of item 77, wherein the tubulin polymerization inhibitor is combretastatin CA-4P (zybrestat), AVE-8062 (ombrabulin), BNC105P, MPC-6827 (azixa), ZD6126 (ANG453), Oxi-4503, BPI-2358 (plinabulin), MN029 (denibulin), EPC-2407 (crinobulin), ZIO-301 (indibulin), T115 or BPROL075, ABT-751. 79. The combination for use according to item 77 or 78, wherein the tubulin polymerization inhibitor is plinabulin. 80. The combination for use according to any one of items 77 to 79, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is selected from olaparib, niraparib, veliparib, talazoparib, rucaparib, iniparib, fluzoparib, AZD2461, UPF 1069, PJ34, A-966492, AG-14361, E7449 and NMS-P118. 81. The combination for use according to any one of items 77 to 80, wherein said poly (ADP-ribose) polymerase (PARP) inhibitor is olaparib. 82. The combination for use according to any one of items 77 to 81, wherein said cancer is as defined in any one of items 45 to 65.