Combination of ATR kinase inhibitors and PD-1/PD-L1 inhibitors

Abstract

The present invention covers combinations of at least two components, component A and component B, comprising component A being an inhibitor of ATR kinase, particularly an inhibitor of ATR kinase selected from VX-803, VX-970, AZD-6738, a compound of general formula (I) described herein, a compound of general formula (Ib) described herein and Compound A described infra, and component B being a PD-1/PD-L1 inhibitor described herein. Another aspect of the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particularly for the treatment of a hyper-proliferative disease.

Claims

1. A method for treatment of a hyper-proliferative disease that is a cancer, comprising administering to a patient in need thereof, an effective amount of a combination-comprising at least two components, component A and component B, wherein component A is an inhibitor of ATR kinase having the structure: ##STR00017## or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof; and wherein component B is a PD-1 inhibitor or a PD-L1 inhibitor, and wherein component B is administered to the patient prior to the first administration of component A.

2. The method according to claim 1, wherein component B is a PD-1 inhibitor.

3. The method according to claim 2, wherein the PD-1 inhibitor of component B is selected from the group consisting of nivolumab, pembrolizumab, PDR-001, JS001, STI-A1110, atezolizumab, durvalumab, avelumab, BMS-936559 and LY3300054.

4. The method according to claim 3, wherein the PD-1 inhibitor of component B is pembrolizumab.

5. The method according to claim 1, wherein component B is a PD-L1 inhibitor.

6. The method combination according to claim 5, wherein the PD-L1 inhibitor of component B is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab.

7. The method according to claim 6, wherein the PD-L1 inhibitor of component B is atezolizumab.

8. The method according to claim 1, wherein the hyper-proliferative disease is lymphoma, lung carcinoma or colon carcinoma.

9. The method according to claim 1, wherein the hyper-proliferative disease is lung carcinoma.

10. The method according to claim 1, wherein the hyper-proliferative disease is colon carcinoma.

11. The method according to claim 1, wherein the hyper-proliferative disease is lymphoma.

12. The method according to claim 1, wherein either or both of said components A and B are in the form of a pharmaceutical composition.

13. The method according to claim 12, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.

14. The method according to claim 1, wherein the components A and B are present in separate formulations.

15. The method according to claim 1 wherein the combination further comprises a component C, wherein component C is one or more further pharmaceutical agents.

Description

DESCRIPTION OF FIGURES

(1) FIG. 1A shows tumor growth of the murine syngeneic lymphoma model A20 in female BALB/c mice after treatment with Compound A in combination with Compound B (=PD-1 antibody RMP1-14=“anti-PD-1”) (Schedule (2)) in comparison to the respective monotherapies and Control.

(2) Legend for FIG. 1A:

(3) Tumor growth murine B cell lymphoma A20 in BALB/c mice; *P<0.05, combination treatment compared to Control, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

(4) FIG. 1B shows tumor growth of the murine syngeneic lymphoma model A20 in female BALB/c mice after treatment with Compound A in combination with Compound B (=PD-1 antibody RMP1-14=“anti-PD-1”) upon different schedules in comparison to the respective monotherapies and Control.

(5) Legend for FIG. 1B:

(6) Tumor growth murine B cell lymphoma A20 in BALB/c mice; *P<0.05, combination treatment compared to Control, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

(7) FIG. 2 shows tumor growth of the murine syngeneic lung carcinoma model KLN205 in male DBA/2 mice after treatment with Compound A in combination with Compound B (=PD-1 antibody RMP1-14=“anti-PD-1”) upon different schedules in comparison to the respective monotherapies and Control.

(8) Legend for FIG. 2:

(9) Tumor growth murine lung carcinoma model KLN205 in male DBA/2 mice; *P<0.05, treatment compared to Control, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

(10) FIG. 3 shows tumor growth of the murine syngeneic colon carcinoma model MC38 in female C57BL/6N mice after treatment with Compound A in combination with Compound B (=PD-L1 antibody PPB-6721=“anti-PD-L1”) upon different schedules in comparison to the respective monotherapies and Control (study 1).

(11) Legend for FIG. 3:

(12) Tumor growth MC38 murine CRC model in C57BL/6N mice; *P<0.05, treatment compared to Control, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

(13) FIG. 4 shows tumor growth of the murine syngeneic colon carcinoma model MC38 in female C57BL/6N mice after treatment with Compound A in combination with Compound B (=PD-L1 antibody PPB-6721=“anti-PD-L1”) upon different schedules in comparison to the respective monotherapies and Control (study 2).

(14) Legend for FIG. 4:

(15) Tumor growth MC38 murine CRC model in C57BL/6N mice; *P<0.05, treatment compared to Control, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

(16) FIG. 5A shows tumor growth of the murine syngeneic colon carcinoma model CT26 in female BALB/c mice after treatment with Compound A in combination with Compound B (=PD-L1 antibody PPB-6721=“anti-PD-L1”) (Schedule (2)) in comparison to the respective monotherapies and Control.

(17) Legend for FIG. 5A:

(18) Tumor growth CT26 murine CRC model in BALB/c mice; *P<0.05, treatment compared to Control, #P<0.05, combination treatment compared to Compound B, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

(19) FIG. 5B shows tumor growth of the murine syngeneic colon carcinoma model CT26 in female BALB/c mice after treatment with Compound A in combination with Compound B (=PD-L1 antibody PPB-6721=“anti-PD-L1”) upon different schedules in comparison to the respective monotherapies and control.

(20) Legend for FIG. 5B:

(21) Tumor growth CT26 murine CRC model in BALB/c mice; *P<0.05, treatment compared to Control, #P<0.05, combination treatment compared to Compound B, one way ANOVA (analysis of variance), Dunn's method, on tumor volumes.

Experimental Section

(22) Component A:

(23) In this Experimental Section, the term “Compound A” is an example of component A.

(24) Compound A is described in Example 111 of International Patent Application WO2016020320 (A1). As shown herein Compound A is 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine, of structure:

(25) ##STR00016##

(26) Component B:

(27) Compound B used in the Examples below is either anti-mouse PD-1 antibody (RMP1-14; BioXcell, USA; Yamazaki et al., J Immunol, (2005) 175(3), 1586-1592) or anti-mouse PD-L1 antibody (PPB-6721, Bayer AG).

(28) Anti-mouse PD-L1 antibody PPB-6721 was prepared as follows:

(29) HEK293-6E cells were maintained in F17 medium (Invitrogen) supplemented with 4 mM GlutaMAX (Invitrogen), 0.1% Pluronic F-68 (Sigma) and 25 μg/ml G418 (Invitrogen). Genes encoding the antibody heavy and light chains were subcloned separately in expression vector pTT5 and co-transfected into HEK293-6E cells (Dyson and Durocher 2007). After 5-8 days of transient expression, the cleared supernatant was used to affinity purify the antibody on an Äkta System (Amersham Pharmacia Biotech) using a 10-ml HiTrap MabSelect Sure protein A column (GE Healthcare). Antibodies were eluted in two steps with 50 mM sodium acetate and 500 mM NaCl at pH 3.5 and pH 3.0. Combined elution fractions were neutralized using appropriate volumes of 2.5 M Tris base (pH>11). Aggregation products were removed by preparative size exclusion chromatography (SEC) on an Äkta Purifier System (GE Healthcare) using a custom-made Superdex™ 200 50/600 column (GE Healthcare), with a mobile phase of PBS (pH 7.4) at a flow rate of 6.0 ml/min.

(30) Further information concerning methods for cloning, expression, and purification of anti-mouse PD-L1 antibody PPB-6721 are described in Hristodorov et al., Molecular biotechnology 53(3), (2013), 326-335.

(31) TABLE-US-00001 TABLE 1 Test systems Cell line Tumor entity Mutation Source A20 Lymphoma MSH2A733S Crown Bioscience (mouse) Inc., USA KLN205 Lung Carcinoma MSH2G247fs, Crown Bioscience (mouse) MSH6T1100fs Inc., USA CT26 Colon Carcinoma BRCA2R2066K, ATCC CRL-2638 (mouse) KRASG12D MC38 Colon Carcinoma ATMA2346S, Bayer AG (mouse) MSH6T1100fs, (Westhaven) BRAFW487C, CDKN2Adel, TRP53G242V, S258I ATCC = American Type Culture Collection

EXAMPLE 1

In Vivo Transplantation of Tumor

(32) The anti-tumor activity of combination treatment of Compound A and Compound B (=anti-mouse PD-1 antibody or anti-mouse PD-L1 antibody) was evaluated in the murine syngeneic tumor models A20 (lymphoma), KLN205 (lung carcinoma), CT26 and MC38 (both colon carcinoma). For this purpose, female BALB/c mice from Shanghai Lingchang Bio-Technology Co. Ltd., China (A20) or from Charles River Sulzfeld, Germany (CT26) were implanted subcutaneously with A20 or CT26, male DBA/2 mice from Beijing Vital River Laboratory Animal Technology Co., Ltd. with KLN205 and female C57BL/6N mice from Charles River Sulzfeld, Germany with MC38 murine tumor cells, At a mean tumor volume of 100 mm.sup.3 (A20), 117 mm.sup.3 (KLN205), 70 mm.sup.3 (CT26 and MC38 study 1) or 150 mm.sup.3 (MC38 study 2) animals were randomized into treatment and control groups (n=8-10 animals/group) and treatment started with Compound A monotherapy (formulation: 60% PEG400, 10% Ethanol, 30% Water; application route: p.o./peroral; dose/schedule: 50 mg/kg twice daily for 3 days on/4 days off each week), Compound B monotherapy (formulation: PBS; application route: i.v./intravenous; dose/schedule: 10 mg/kg once per day twice weekly), and combination of Compound A and Compound B at the same doses/schedules as in the respective monotherapies. Two (A20 and

(33) KLN205) or three (CT26 and MC38 study 1) or only one (MC38 study 2) different combination schedules were tested:

(34) Schedule (1): Compound A applied on days 1, 2 and 3 each week, Compound B applied on days 4 and 7 each week;

(35) Schedule (2): Compound A applied on days 5, 6 and 7 each week, Compound B applied on days 1 and 4 each week;

(36) Schedule (3): Compound A applied on days 1, 2 and 3 each week, Compound B applied on days 1 and 4 each week.

(37) The oral application volume was 10 ml/kg and the intravenous application volume 5 ml/kg. The time interval between two applications per day was 6-7 h. The tumor size and the body weight were determined three times weekly. Changes in the body weight were a measure of treatment-related toxicity (>10%=critical, stop of treatment until recovery, >20%=toxic, termination). The tumor volume was detected by means of an electronic caliper gauge [0.5×length in mm×(width in mm).sup.2]. Animals for which the tumor volume exceeded 2000 mm.sup.3 (or for which the mean tumor volume of the group exceeds 2000 mm.sup.3) were euthanized. In vivo anti-tumor efficacy is presented as T/C ratio (Treatment/Control) calculated with tumor volumes at day of control group termination by the formula [(tumor volume of treatment group at day x)−(tumor volume of treatment group at day before first treatment)]/[(tumor volume control group at day x)−(tumor volume of control group at day before first treatment)]. Compounds having a T/C ratio below 0.5 are defined as active (effective). Statistical analysis was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control were compared by a pair-wise comparison procedure (Dunn's method). To evaluate the cooperativity of the combination of Compound A with Compound B expected additivity was calculated according to the Bliss model (C=A+B−A*B; wherein C is the expected T/C of the combination of drug A and drug B if they act additive, A is T/C of drug A, B is T/C of drug B). Excess>10% over the expected additive effect is assumed to indicate synergism of the two drugs, less than 10% of the expected additive effect is assumed to indicate antagonism (Bliss, C. I., The toxicity of poisons applied jointly. Ann. Appl. Biol. 26, 585-615, 1939).

(38) Results:

(39) In the murine syngeneic lymphoma model A20 treatment started at day 11 after tumor inoculation. Monotherapy of Compound A showed moderate anti-tumor efficacy determined at day 26 after tumor inoculation when control group was terminated due to maximal tumor size. Monotherapy of Compound B (anti-PD-1=RMP1-14) showed no anti-tumor efficacy. Combination of Compound A with Compound B in schedule (1), when Compound A was applied before Compound B, showed no effect of tumor growth inhibition. Combination treatment in schedule (2), when Compound B was applied before Compound A, showed synergistic anti-tumor efficacy at day 26 and statistically significant improvement of tumor growth inhibition in comparison to control. Treatments with Compound A alone and the two combination groups (schedules (1) and (2), respectively) of Compound A with Compound B were continued after day 26. Compound A monotherapy group as well as combination treatment group in schedule (1) were terminated on day 33 after tumor inoculation because tumors reached maximal size. Combination treatment with Compound A and Compound B in schedule (2) was further continued until day 42 after tumor inoculation, demonstrating clear tumor growth delay in comparison to respective monotherapies and control (Table 2, FIGS. 1A and 1B). Treatments were well tolerated.

(40) TABLE-US-00002 TABLE 2 Anti-tumor activity of Compound A and Compound B (anti- PD-1) in monotherapy and in combination in the murine syngeneic lymphoma model A20 in female BALB/c mice. Excess over Bliss additivism Max. [%] based on weight Substance Dosage T/C.sup.a tumor size loss.sup.b (%) Control — 1.00 — — Compound A 50 mg/kg, p.o., 0.38 — −2 twice daily, 3 days on/4 days off, days 1,2, 3 each week Compound B 10 mg/kg, i.v., 1.23 — — (anti-PD-1) once daily, twice weekly, days 1,4 each week Schedule (1): 50 mg/kg, p.o., 0.52 — −4 Compound A + twice daily, Compound B 3 days on/4 days (anti-PD-1) off, days 1,2, 3 each week + 10 mg/kg, i.v., once daily, twice weekly, days 4,7 each week Schedule (2): 50 mg/kg, p.o., 0.15* 60 −4 Compound A + twice daily, Compound B 3 days on/4 days (anti-PD-1) off, days 5,6, 7 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week *P < 0.05 (compared to control at day 26 after tumor inoculation) .sup.aT/C = ratio of the tumor volume of treatment versus control at day of control termination [(tumor volume of treatment group at day x) − (tumor volume of treatment group at day before first treatment)]/[(tumor volume control group at day x) − (tumor volume of control group at day before first treatment)]. .sup.bLoss of body weight: Changes in body weight compared to the initial body weight at the start of treatment (>10% = critical, stoppage in treatment until recovery, >20% = toxic, termination). The abbreviation p.o. means peroral, i.v. means intravenous

(41) In the murine syngeneic lung carcinoma model KLN205 treatment started at day 4 after tumor inoculation. Monotherapy of Compound A showed moderate anti-tumor efficacy determined at day 30 after tumor inoculation when control group was terminated due to maximal tumor size. Monotherapy of Compound B (anti-PD-1=RMP1-14) showed no anti-tumor efficacy. Combination of Compound A with Compound B did not improve anti-tumor efficacy achieved by Compound A alone in the tested combination treatment schedules (1) and (2). Due to critical body weight loss in groups treated with Compound A alone or in combination with Compound B, Compound A has been applied upon reduced dose (40 mg/kg) from day 18 after tumor inoculation (Table 3, FIG. 2).

(42) TABLE-US-00003 TABLE 3 Anti-tumor activity of Compound A and Compound B (anti- PD-1) in monotherapy and in combination in the murine syngeneic lung carcinoma model KLN205 in male DBA/2 mice. Excess over Bliss additivism Max. [%] based on weight Substance Dosage T/C.sup.a tumor size loss.sup.b (%) Control — 1.00 — −7 Compound A 50/40(d 18) 0.36* — −19 (d9) mg/kg, p.o., twice daily, 3 days on/4 days off, days 1,2,3 each week Compound B 10 mg/kg, i.v., 1.18 — −5 (anti-PD-1) once daily, twice weekly, days 1,4 each week Schedule (1): 50/40(d 18) 0.42* — −20 (d9) Compound A + mg/kg, p.o., Compound B twice daily, (anti-PD-1) 3 days on/4 days off, days 1,2,3 each week + 10 mg/kg, i.v., once daily, twice weekly, days 4,7 each week Schedule (2): 50/40(d 18) 0.38* — −20 (d13) Compound A + mg/kg, p.o., Compound B twice daily, (anti-PD-1) 3 days on/4 days off, days 5,6,7 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week *P < 0.05 (compared to Control at day 30 after tumor inoculation) .sup.aT/C = ratio of the tumor volume of treatment versus control at day of control termination [(tumor volume of treatment group at day x) − (tumor volume of treatment group at day before first treatment)]/[(tumor volume control group at day x) − (tumor volume of control group at day before first treatment)]. .sup.bLoss of body weight: Changes in body weight compared to the initial body weight at the start of treatment (>10% = critical, stoppage in treatment until recovery, >20% = toxic, termination). The abbreviation d means day (after tumor inoculation), p.o. means peroral, i.v. means intravenous

(43) In the murine syngeneic colorectal carcinoma model MC38 two studies have been performed. In MC38 study 1, treatment started at day 6 after tumor inoculation at a tumor size of 70 mm.sup.3. Monotherapy of Compound A showed good anti-tumor efficacy and statistically significant improvement of tumor growth inhibition compared to control at day 24 after tumor inoculation, when control treatment group was terminated due to maximal tumor size. Monotherapy of Compound B (anti-PD-L1=PPB-6721) showed moderate anti-tumor efficacy at day 24 with statistically significant improvement of tumor growth inhibition in comparison to control. Combination of Compound A with Compound B did not enhance anti-tumor efficacy achieved by Compound A monotherapy in all tested schedules (1), (2) and (3) in this study. Treatments were well tolerated (Table 4, FIG. 3).

(44) TABLE-US-00004 TABLE 4 Anti-tumor activity of Compound A and Compound B (anti-PD-L1) in monotherapy and in combination in the murine syngeneic colon carcinoma model MC38 in female C57BL/6N mice (MC38 study 1). Excess over Bliss additivism Max. [%] based on weight Substance Dosage T/C.sup.a tumor size loss.sup.b (%) Control — 1.00 — — Compound A 50 mg/kg, p.o., 0.10* — −3 twice daily, 3 days on/4 days off, days 1,2,3 each week Compound B 10 mg/kg, i.v., 0.41* — −4 (anti-PD-L1) once daily, twice weekly, days 1,4 each week Schedule (1) 50 mg/kg, p.o., 0.12* — −4 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 1,2,3 each week + 10 mg/kg, i.v., once daily, twice weekly, days 4,7 each week Schedule (2) 50 mg/kg, p.o., 0.09* — −6 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 5,6,7 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week Schedule (3) 50 mg/kg, p.o., 0.10* — −6 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 1,2,3 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week *P < 0.05 (compared to Control at day 24 after tumor inoculation) .sup.aT/C = ratio of the tumor volume of treatment versus control at day of control termination [(tumor volume of treatment group at day x) − (tumor volume of treatment group at day before first treatment)]/[(tumor volume control group at day x) − (tumor volume of control group at day before first treatment)]. .sup.bLoss of body weight: Changes in body weight compared to the initial body weight at the start of treatment (>10% = critical, stoppage in treatment until recovery, >20% = toxic, termination). The abbreviation p.o. means peroral, i.v. means intravenous.

(45) In MC38 study 2, treatment started also at day 6 after tumor inoculation but at a tumor size of 150 mm.sup.3. Monotherapy of Compound A showed moderate anti-tumor efficacy and statistically significant improvement of tumor growth inhibition compared to control at day 17 after tumor inoculation, when control treatment group was terminated due to maximal tumor size. Monotherapy of Compound B (anti-PD-L1=PPB-6721) showed moderate to weak anti-tumor efficacy at day 17 with statistically significant improvement of tumor growth inhibition in comparison to control. Remarkably, in contrast to MC38 study 1, in this study combination of Compound A with Compound B in schedule (2) did significantly enhance anti-tumor efficacy achieved by Compound A or Compound B monotherapy, which is probably due to treatment start at larger tumor size. Treatments were well tolerated (Table 5, FIG. 4).

(46) TABLE-US-00005 TABLE 5 Anti-tumor activity of Compound A and Compound B (anti-PD-L1) in monotherapy and in combination in the murine syngeneic colon carcinoma model MC38 in female C57BL/6N mice (MC38 study 2). Excess over Bliss additivism Max. [%] based on weight Substance Dosage T/C.sup.a tumor size loss.sup.b (%) Control — 1.00 — −3 Compound A 50 mg/kg, p.o., 0.46* — −5 twice daily, 3 days on/4 days off, days 1,2,3 each week Compound B 10 mg/kg, i.v., 0.78* — −3 (anti-PD-L1) once daily, twice weekly, days 1,4 each week Schedule (2) 50 mg/kg, p.o., 0.33* 4 −4 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 5,6,7 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week *P < 0.05 (compared to Control at day 17 after tumor inoculation) .sup.aT/C = ratio of the tumor volume of treatment versus control at day of control termination [(tumor volume of treatment group at day x) − (tumor volume of treatment group at day before first treatment)]/[(tumor volume control group at day x) − (tumor volume of control group at day before first treatment)]. .sup.bLoss of body weight: Changes in body weight compared to the initial body weight at the start of treatment (>10% = critical, stoppage in treatment until recovery, >20% = toxic, termination). The abbreviation p.o. means peroral, i.v. means intravenous.

(47) In the murine syngeneic colorectal carcinoma model CT26 monotherapy of Compound A showed moderate anti-tumor efficacy but statistically significant improvement of tumor growth inhibition compared to control at day 21 after tumor inoculation, when control and Compound A treatment group were terminated due to maximal tumor size. Monotherapy of Compound B (anti-PD-L1=PPB-6721) showed good anti-tumor efficacy at day 21 with statistically significant improvement of tumor growth inhibition in comparison to control. Combination of Compound A with Compound B in schedule (2), when Compound B was applied before Compound A, enhanced anti-tumor efficacy of Compound B monotherapy at day 21, demonstrating synergistic anti-tumor activity of Compound A and Compound B in this combination schedule. Treatments of groups with Compound B alone and the combination of Compound A with Compound B in schedule (2) were continued until study termination at day 26 after tumor inoculation. Prolonged combination treatment of Compound A with Compound B in schedule (2) achieved strong and continuous tumor growth inhibition, as shown by statistically significant improvement of anti-tumor efficacy in comparison to Compound B alone, determined at day 26 after tumor inoculation (Table 6). In contrast, combination of Compound A with Compound B in schedules (1) and (3), when Compound A was applied before Compound B (schedule (1)) or when Compound A and Compound B were applied at the same time (schedule (3)), did not show any synergy, but rather a reduction of anti-tumor activity that is achieved by Compound B alone (FIGS. 5A and 5B).-Both groups (schedules (1) and (3), respectively) were terminated at day 21 after tumor inoculation, due to maximal tumor size. Treatments were well tolerated.

(48) TABLE-US-00006 TABLE 6 Anti-tumor activity of Compound A and Compound B (anti- PD-L1) in monotherapy and in combination in the murine syngeneic colon carcinoma model CT26 in female BALB/c mice. Excess over Bliss additivism Max. [%] based on weight Substance Dosage T/C.sup.a tumor size loss.sup.b (%) Control — 1.00 — — Compound A 50 mg/kg, p.o., 0.50* — −1 twice daily, 3 days on/4 days off, days 1,2,3 each week Compound B 10 mg/kg, i.v., 0.17* — — (anti-PD-L1) once daily, twice weekly, days 1,4 each week Schedule (1) 50 mg/kg, p.o., 0.49 — −1 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 1,2,3 each week + 10 mg/kg, i.v., once daily, twice weekly, days 4,7 each week Schedule (2) 50 mg/kg, p.o., 0.00*.sup.# 9 −1 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 5,6,7 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week Schedule (3) 50 mg/kg, p.o., 0.62 — −1 Compound A + twice daily, Compound B 3 days on/4 (anti-PD-L1) days off, days 1,2,3 each week + 10 mg/kg, i.v., once daily, twice weekly, days 1,4 each week *P < 0.05 (compared to Control at day 21 after tumor inoculation) .sup.#P < 0.05 (compared to Compound B monotherapy at termination day 26 after tumor inoculation) .sup.aT/C = ratio of the tumor volume of treatment versus control at day of control termination [(tumor volume of treatment group at day x) − (tumor volume of treatment group at day before first treatment)]/[(tumor volume control group at day x) − (tumor volume of control group at day before first treatment)]. .sup.bLoss of body weight: Changes in body weight compared to the initial body weight at the start of treatment (>10% = critical, stoppage in treatment until recovery, >20% = toxic, termination). The abbreviation p.o. means peroral, i.v. means intravenous.