Combination therapy with Notch and PI3K/mTOR inhibitors for use in treating cancer

Abstract

Medicaments for use in treating T-cell acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, breast cancer, ovarian cancer, melanoma, lung cancer, pancreatic cancer, glioblastoma, sarcoma, desmoid tumors, adenoid cystic carcinoma, colorectal cancer, head and neck cancer, cervical cancer, prostate cancer, liver cancer, or skin cancer in a patient comprising combination therapy with 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxoethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, and 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof.

Claims

1. A method of treating a cancer, comprising administering to a patient in need of treatment an effective amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, and an effective amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of T-cell acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, breast cancer, ovarian cancer, melanoma, lung cancer, pancreatic cancer, glioblastoma, sarcoma, desmoid tumors, adenoid cystic carcinoma, colorectal cancer, head and neck cancer, cervical cancer, prostate cancer, liver cancer, and skin cancer.

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

3. The method of claim 1, wherein the administering is by simultaneous administration of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof and 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the administering is by separate administration of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof and 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the administering is by sequential administration of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof and 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is between 2.5 mg and 75 mg.

7. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is between 5 mg and 50 mg.

8. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is 25 mg or 50 mg.

9. The method of claim 1, wherein the 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is administered once per day every other day over a five day period followed by two days without dosing (T.I.W.).

10. The method of claim 1, wherein the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is between 75 mg and 250 mg.

11. The method of claim 1, wherein the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is between 100 mg and 200 mg.

12. The method of claim 1, wherein the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is 150 mg or 200 mg.

13. The method of claim 1, wherein the 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is administered twice per day (B.I.D.).

14. The method of claim 1, wherein the 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof and the 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof are formulated for oral administration.

15. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is between 2.5 mg and 75 mg, and the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is between 75 mg and 250 mg.

16. The method of claim 2, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is between 2.5 mg and 75 mg, and the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is between 75 mg and 250 mg.

17. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is between 5 mg and 50 mg, and the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is between 100 mg and 200 mg.

18. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is 25 mg, and the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is 150 mg.

19. The method of claim 1, wherein the amount of 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is 50 mg, and the amount of 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is 150 mg or 200 mg.

20. The method of claim 15, wherein the 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof is for use T.I.W., and the 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof is administered B.I.D.

Description

BIOLOGICAL EXAMPLE 1

(1) A2780 is a human ovarian cell line (Sigma-Aldrich). The cells are grown in culture media at 37° C. in 5% CO.sub.2 with humidity in the atmosphere. Cell culture media for A2780 human ovarian carcinoma is RPMI-1640 (without phenol red) with 2.05 mM L-glutamine, 0.01 mg/ml insulin and 10% fetal bovine serum (EBS) added.

(2) To evaluate in viva efficacy and effect A2780 (2×10.sup.6) cells in a 1:1 Matrigel® mix (0.2 mL volume) are implanted by subcutaneous injection in the hind leg of 6-8 weeks of age athymic nude female mice (Harlan Laboratories). A total of 7 to 10 mice are used for each group. Just before implantation, animals are irradiated (450 Total Body Irradiation). Mice are fed ad libitum on normal chow. Treatment is initiated with oral administration (gavage) of Compound A or vehicle (1% sodium carboxymethylcellulose (Na-CMC) in 0.25% Tween®-80) or Compound B in 1% hydroxyethyl cellulose (HEC)/0.25% Tween® 80/0.05% Antifoam or their vehicle in 0.2 mL volume when tumor size reached to 150±50 mm.sup.3, in this case after the tumor measurements were taken on study day 9. Compound A was administered at 4 or 8 mg/kg on a Monday, Wednesday and Friday schedule for 4 weeks and Compound B was administered at 15 or 30 mg/kg daily for 28 days. Tumor growth and body weight are monitored over time to evaluate efficacy and signs of toxicity. Bidimensional measurements of tumors are performed twice a week and tumor volumes are calculated based on the following formula: (Tumor Volume)=[(L)×(W2)×(II/6)] where L is mid-axis length and W is mid-axis width. Tumor volume data are transformed to a long scale to equalize variance across time and treatment groups. The log volume data are analyzed with a two-way repeated measures analysis of variance by time and treatment using the MIXED™ procedure in SAS™ software (version 8.2). The correlation model for the repeated measures is spatial power. Least squares means from the repeated measures analysis, anti-logged to the tumor volume scale, are shown in Table 1. P-values for comparing each pair of groups on study day 36 are shown in Table 2. Test Groups are: 01: Control: 1% HEC/0.25% Tween 80/0.05% Antifoam; 1% CMC/0.25% Tween 80/0.05% Antifoam; 02: Compound A 8 mg/kg; 03: Compound B 30 mg/kg; 04: rapamycin 4 mg/kg; 05: Compound A 8 mg/kg and Compound B 30 mg/kg; 06: Compound A 4 mg/kg and Compound B 30 mg/kg; 07: Compound B 15 mg/kg and Compound A 8 mg/kg; 08: Compound B 15 mg/kg and Compound A 4 mg/kg; 09: Compound A 8 mg/kg and rapamycin 4 mg/kg.

(3) TABLE-US-00001 TABLE 1 Human A2780 Xenograft Geometric Mean Study Days Group 7 9 12 15 19 22 26 29 33 36 01 137.56 92.02 134.29 217.68 453.38 928.72 1775.80 2652.22 3475.10 3710.66 02 121.62 109.98 131.53 194.78 408.55 639.48 1140.46 1384.21 1631.82 1616.05 03 149.36 118.70 138.06 201.95 326.33 488.21 776.88 1135.14 1527.41 1664.20 04 130.45 100.08 130.81 215.88 428.88 786.46 1291.64 1664.57 2136.31 2461.81 05 138.91 119.86 129.42 199.60 283.38 357.34 434.30 474.43 453.05 358.07 06 130.01 118.32 135.10 206.49 388.24 412.30 553.37 645.74 851.05 659.56 07 135.16 117.22 130.76 201.63 344.19 502.40 595.27 677.03 716.51 609.44 08 133.14 113.25 126.46 207.38 398.80 588.69 834.86 976.89 1128.71 1061.94 09 131.74 105.06 125.28 200.25 363.74 565.04 833.21 929.53 1209.81 1358.23

(4) TABLE-US-00002 TABLE 2 Between Group P-Values (Repeated Measures ANOVA) Cmpd. Cmpd. Cmpd. Cmpd. A 8 A4 B 15 B 15 Rapamycin 4 mg/kg mg/kg mg/kg mg/kg mg/kg and and and and and Cmpd. Cmpd. Cmpd. Cmpd. Cmpd. Cmpd. Cmpd. A 8 B 30 Rapamycin 4 B 30 B 30 A 8 A 4 A 8 Study mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg Day Group 2 3 4 5 6 7 8 9 Day Control HEC/CMC 1 <0.001 <0.001 0.030 <0.001 <0.001 <0.001 <0.001 <0.001 36 Cmpd. A 8 mg/kg 2 0.874 0.027 <0.001 <0.001 <0.001 0.028 0.361 36 Cmpd. B 30 mg/kg 3 0.038 <0.001 <0.001 <0.001 0.018 0.281 36 Rapamycin 4 mg/kg 4 <0.001 <0.001 <0.001 <0.001 0.002 36 Cmpd. A 8 mg/kg and 5 0.010 0.026 <0.001 <0.001 36 Cmpd. B 30 mg/kg Cmpd. A 4 mg/kg and 6 0.617 0.022 <0.001 36 Cmpd. B 30 mg/kg Cmpd. B 15 mg/kg and 7 0.004 <0.001 36 Cmpd. A 8 mg/kg Cmpd. B 15 mg/kg and 8 0.192 36 Cmpd. A 4 mg/kg

(5) Table 2 shows combinations of Compound A and Compound B, in this test, demonstrated statistically significant tumor growth inhibition results over each of Compound A and Compound B alone (Group 5 vs. either Group 2 or Group 3).

Combination Analysis Method

(6) Using the repeated measures analysis previously described, a contrast statement is used to test for an interaction effect on study day 36, using the two specific treatments that were combined. This test is statistically significant with p=0.022, demonstrating better than additive, or synergistic, activity, since the estimated mean tumor volume in the combination group (358 mm.sup.3) is less than the expected additive tumor volume per the Bliss Independence method (1616×1664/3711=725 mm.sup.3).

Clinical Evaluation

(7) A study of 4,4,4-Trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide hydrate, Compound A in combination with 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one Compound B in patients with advanced or metastatic solid tumors.

(8) Study Design

(9) This study is a multicenter, nonrandomized, open-label study consisting of a dose escalation phase in patients with advanced/metastatic cancer from a variety of solid tumors followed by a dose confirmation phase in specific tumor types. In the dose escalation phase, eligible patients will receive Compound A given orally, TIW in combination with a class I phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) (PI3K/mTOR) inhibitor Compound B given orally, every 12 hours, on a 28-day cycle. A single dose of Compound B will also be raven on Day 1 during a 3-day lead-in period (dose-escalation phase only) for PK evaluation. In the dose-confirmation phase, approximately 10 patients each with advanced or metastatic colon cancer or soft tissue sarcoma will be treated. Colon cancer patients are required to have mutations, amplification, or gene expression alterations related to Notch pathway signaling.

(10) Study Objectives

(11) The primary objective of this study is to determine the recommended Phase 2 dose of Compound A in individual combination with a PI3K/mTOR inhibitor Compound B anticancer agent.

(12) The secondary objectives of the study are to characterize the safety and toxicity profile of Compound A in combination with Compound B as assessed by National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0; to estimate the PK parameters of Compound B in combination with Compound A; to document any antitumor activity observed with Compound A in combination with Compound B; and to assess duration of response and progression free survival (PFS).

(13) Exploratory objectives are to explore pharmacodynamic (PD) effects of Compound A on biomarkers indicative of Notch activity or Compound B; to explore the utility of positron emission tomography (PET) scan to assess treatment effect with Compound A in combination with Compound B; to explore predictive biomarkers related to induction of cytochrome P450 (CYP) enzymes, such as cortisol and 6β-hydroxycortisol; and to evaluate tumor tissue and blood for biomarkers related to the Notch signaling pathway and drug target pathways, immune functioning, mechanism of action of study drug(s) or disease state, and their potential association with the objectives of the study.

(14) Trial Drug

(15) 4,4,4-Trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide hydrate (Compound A), as 25 and 50 mg capsules for oral administration once per day on days of administration, 3 times per week, during a 28-day cycle.

(16) 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (Compound B), as 100 or 200 mg capsules, or as 50, 100, 150, or 200 mg tablets for oral administration as a chronic/continuous treatment approximately every 12 hours during a 28-day cycle. For dose escalation, a single dose of Compound B is administered on Day 1 during a 3-day lead-in period and administered B.I.D. on Days 1 to 28 of a 28-day cycle.

(17) Planned Duration of Treatment/Dosing

(18) By nature of being a dose escalation study, data will be evaluated on an ongoing basis until the maximum tolerated dose (MTD) of the combination is determined. Dose escalation will be driven by the 3+3 method.

(19) Each new dose level will have a minimum of 3 patients enrolled to it. If 1 patient, at any dose level, experiences a dose-limiting toxicity (DLT) within the first cycle of Compound A, then up to 3 additional patients will be enrolled at that dose level. If a DLT is observed in 2 or more patients at any dose level, dose escalation will cease and either the previous dose level will be declared the MTD or, following discussions between the sponsor and investigators additional patients may be treated at intermediate doses between the previous and current dose levels.

(20) During dose escalation, the starting dose of Compound A will be 25 mg TIW and the starting dose of Compound B will be 150 mg BID. Dose escalation is scheduled to proceed according to Table 3.

(21) TABLE-US-00003 TABLE 3 Dose-Escalation Scheme Compound A Compound B Dose Level Dose (mg) Dose (mg) 1 25 150 BID 2 50 150 BID 3 50 200 BID Abbreviation: BID = twice daily.

(22) Criteria for Evaluation

(23) Safety: NCI CTCAE, version 4.0, dose-limiting toxicities (DLT).

(24) Efficacy: Each patient will be assessed by one or more of the following radiologic tests for tumor measurement: Computed tomography (CT) scan; Magnetic resonance imaging (MRI); and PET scan (pre- and postdose). Each patient's full extent of disease will also be assessed with:

(25) Tumor measurement by RECIST 1.1 (Eisenhauer et al., Eur. J. Cancer, 2009; 45(2): 228-247). For tumor measurement evaluations in patients with soft tissue sarcomas, Choi et al., J. Clin. Oncol., 2007; 25(13): 1753-1759 response criteria will be used in addition to RECIST 1.1. Response Assessment in Neuro-Oncology (RANO) criteria will be used for glioblastoma patients (Wen et al., J. Clin. Oncol., 2010; 28(11): 1963-1972);

(26) Evaluation of tumor markers, if indicated;

(27) Evaluation of performance status (Eastern Cooperative Oncology Group (ECOG); Oken et al., Am. J. Clin. Oncol., 1982; 5: 649-655).

(28) To confirm objective responses, all lesions should be radiologically assessed, and the same radiologic method used for the initial response determination should be repeated at least 4 weeks following the initial observation of an objective response, using the sample method that was used at baseline. If a patient is discontinued from the study, repeat radiology assessments may be omitted if clear clinical signs of progressive disease are present.