QUINOLINE DERIVATIVE AND ANTIBODY SOFT TISSUE SARCOMA COMBINATION THERAPY

Abstract

The present invention belongs to the pharmaceutical field, and provides a quinoline derivative and antibody soft tissue sarcoma combination therapy, specifically relating to a use of a therapeutically effective amount of a quinoline derivative compound I or a pharmaceutically acceptable salt thereof in combination with at least one antibody drug in preparing a drug used for treating soft tissue sarcoma. The chemical name of the quinoline derivative compound I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine.

Claims

1. A pharmaceutical combination for use in treating a soft tissue sarcoma, comprising (i) a compound of formula I or a pharmaceutically acceptable salt thereof, and (ii) at least one antibody drug: ##STR00004##

2. The pharmaceutical combination according to claim 1, wherein the soft tissue sarcoma comprises a soft tissue sarcoma that has not previously been treated with a tyrosine kinase inhibitor, an inhibitor for interaction between PD-1 receptor and its ligand PD-L1, and/or a cytotoxic T-lymphocyte antigen 4 inhibitor.

3. The pharmaceutical combination according to claim, wherein the antibody drug is one or more of an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

4-5. cancelled

6. The pharmaceutical combination according to claim 1, wherein the antibody drug is selected from any one or more of the group consisting of nivolumab, pembrolizumab, durvalumab, toripalimab, sintilimab, camrelizumab, tislelizumab, AK105, genolimzumab, lizumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F520, SG001, GLS-010, atezolizumab, avelumab, durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014, KN035, MSB2311, HLX-20, CS-1001, ipilimumab, tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI310, olaratumab, bevacizumab, ramucirumab, pertuzumab, trastuzmab, cotuximab, nimotuzumab, panitumumab, necitumumab, dinutuximab, rituximab, ibritumomab, ofatumumab, obinutuzumab, alemtuzumab, daratumumab, gemtuzumab, elotuzumab, brentuximab, inotuzumab ozogamicin and blinatumomab.

7. The pharmaceutical combination according to claim 4, wherein the anti-PD-1 antibody or the anti-PD-L1 antibody is administered once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks, preferably once every 3 weeks; the compound of formula I or the pharmaceutically acceptable salt thereof is administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg once daily.

8. The pharmaceutical combination according to claim 4, wherein the anti-PD-1 antibody is AK105 or toripalimab.

9. The pharmaceutical combination according to claim 8, comprising: (i) a pharmaceutical composition of the compound of formula I or the pharmaceutically acceptable salt thereof in a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg, and (ii) a pharmaceutical composition of toripalimab in a single dose of 120-600 mg, and wherein, toripalimab is formulated into a pharmaceutical composition suitable for administration to a patient 240 mg in a single dose or multiple doses at first administration, and the compound of formula I or the pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition suitable for administration to a patient a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg daily for 14 consecutive days.

10. canceled

11. A kit comprising the pharmaceutical combination according to claim 1, wherein the kit comprises (a) a first pharmaceutical composition comprising the anti-PD-1 antibody or the anti-PD-L1 antibody as an active ingredient, and (b) a second pharmaceutical composition comprising the compound of formula I or the pharmaceutically acceptable salt thereof as an active ingredient.

12. canceled

13. A method for treating a soft tissue sarcoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of at least one antibody drug: ##STR00005##

14. The pharmaceutical combination according to claim 1, wherein the soft tissue sarcoma is selected from undifferentiated pleomorphic sarcoma, angiosarcoma, desmoid tumor, fibrosarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberan, nerve sheath tumor, malignant peripheral nerve sheath tumor, alveolar soft-part sarcoma, clear cell sarcoma, malignant mesenchymoma, epithelioid sarcoma, pulmonary alveolar soft-part sarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, mixed-type liposarcoma, adult fibrosarcoma, low grade fibromyxoid sarcoma, hyalinizing spindle cell tumor, sclerosing epithelioid fibrosarcoma, pericytic tumor, glomus tumor and variants, glomangiomatosis, malignant glomus tumor, myopericytoma, myofibroma, angioleiomyoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, epithelioid haemangioendothelioma, angiosarcoma of soft tissue, epithelioid malignant peripheral nerve sheath tumor, malignant triton tumor, malignant granular cell tumor, synovial sarcoma NOS, synovial sarcoma, synovial sarcoma, clear cell sarcoma of soft tissue, desmoplastic small round cell tumor, extra-renal rhabdoid tumor, neoplasms with perivascular epithelioid cell differentiation, intimal sarcoma, undifferentiated/unclassified sarcomas, undifferentiated spindle cell sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid cell sarcoma, desmoplastic small round cell tumor, low grade fibromyxoid sarcoma and borderline soft tissue tumor.

15. The method according to claim 13, wherein the soft tissue sarcoma is selected from undifferentiated pleomorphic sarcoma, angiosarcoma, desmoid tumor, fibrosarcoma, gastrointestinal stromal tumor, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberan, nerve sheath tumor, malignant peripheral nerve sheath tumor, alveolar soft-part sarcoma, clear cell sarcoma, malignant mesenchymoma, epithelioid sarcoma, pulmonary alveolar soft-part sarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, mixed-type liposarcoma, adult fibrosarcoma, low grade fibromyxoid sarcoma, hyalinizing spindle cell tumor, sclerosing epithelioid fibrosarcoma, pericytic tumor, glomus tumor and variants, glomangiomatosis, malignant glomus tumor, myopericytoma, myofibroma, angioleiomyoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, epithelioid haemangioendothelioma, angiosarcoma of soft tissue, epithelioid malignant peripheral nerve sheath tumor, malignant triton tumor, malignant granular cell tumor, synovial sarcoma NOS, synovial sarcoma, synovial sarcoma, clear cell sarcoma of soft tissue, desmoplastic small round cell tumor, extra-renal rhabdoid tumor, neoplasms with perivascular epithelioid cell differentiation, intimal sarcoma, undifferentiated/unclassified sarcomas, undifferentiated spindle cell sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid cell sarcoma, desmoplastic small round cell tumor, low grade fibromyxoid sarcoma and borderline soft tissue tumor.

16. The method according to claim 13, wherein the soft tissue sarcoma is selected from a recurrent soft tissue sarcoma, and/or a metastatic soft tissue sarcoma, and/or a refractory soft tissue sarcoma, and/or an unresectable soft tissue sarcoma, locally advanced soft tissue sarcoma, and/or advanced soft tissue sarcoma.

17. The method according to claim 13, wherein the soft tissue sarcoma is selected from a primary soft tissue sarcoma or secondary soft tissue sarcoma, and/or the soft tissue sarcoma that has progressed or recurred after being treated with at least one chemotherapy, and/or the soft tissue sarcoma that is intolerant to chemotherapy, and/or the soft tissue sarcoma that has not previously been systemically treated, and/or a soft tissue sarcoma that has not previously been treated with a tyrosine kinase inhibitor, an inhibitor for interaction between PD-1 receptor and its ligand PD-L1, and/or a cytotoxic T-lymphocyte antigen 4 inhibitor.

18. The method according to claim 13, wherein the subject has not previously been treated with systemic chemotherapy, and/or the subject has previously been treated with surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy, and/or the subject has not previously been treated with systemic chemotherapy but has been treated with surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy, and/or the subject has recurrence of disease progression after achieving complete response following surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy, and/or the subject has failed to achieve complete response or partial response following surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy, and/or the subject with the cancer metastasizes after the entity has been treated with surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy.

19. The method according to claim 13, wherein the antibody drug is one or more of an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

20. The method according to claim 13, wherein the antibody drug is selected from any one or more of the group consisting of nivolumab, pembrolizumab, durvalumab, toripalimab, sintilimab, camrelizumab, tislelizumab, AK105, genolimzumab, lizumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F520, SG001, GLS-010, atezolizumab, avelumab, durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014, KN035, MSB2311, HLX-20, CS-1001, ipilimumab, tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI310, olaratumab, bevacizumab, ramucirumab, pertuzumab, trastuzmab, cotuximab, nimotuzumab, panitumumab, necitumumab, dinutuximab, rituximab, ibritumomab, ofatumumab, obinutuzumab, alemtuzumab, daratumumab, gemtuzumab, elotuzumab, brentuximab, inotuzumab ozogamicin and blinatumomab.

21. The method according to claim 19, wherein the anti-PD-1 antibody or the anti-PD-L1 antibody is administered once a week, once every 2 weeks, once every 3 weeks or once every 4 weeks; the compound of formula I or the pharmaceutically acceptable salt thereof is administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg once daily.

22. The method according to claim 19, wherein the anti-PD-1 antibody is AK105 or toripalimab.

23. The method according to claim 22, comprising administering: (i) a pharmaceutical composition of the compound of formula I or the pharmaceutically acceptable salt thereof in a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg, and (ii) a pharmaceutical composition of toripalimab in a single dose of 120-600 mg.

24. The method according to claim 13, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is administered in an intermittent regimen of alternate treatment and interruption periods; wherein the ratio of the treatment period to the interruption period in days is 2:0.5-2:5, 2:0.5-2:3, 2:0.5-2:2, or 2:0.5-2:1; and wherein the intermittent regimen is in one of the following cycles: consecutively 2-week treatment and then 2-week interruption, consecutively 2-week treatment and then 1-week interruption, and consecutively 5-day treatment and then 2-day interruption.

Description

DETAILED DESCRIPTION

[0119] The present application is further described below with reference to specific examples. However, these examples are only illustrative and not intended to limit the scope of the present application. Likewise, the present application is not limited to any particular preferred embodiment described herein. It should be appreciated by those skilled in the art that equivalent substitutions or corresponding modifications for the technical features of the present application still fall with the scope of the present application. Unless otherwise specified, the reagents used in the following examples are commercially available products, and the solutions can be prepared by conventional techniques in the art.

EXAMPLE 1:

Combination Therapy with Anlotinib Hydrochloride for Treatment of Undifferentiated Pleomorphic Sarcoma

[0120] Research on the combination of anlotinib hydrochloride and toripalimab for use in treating undifferentiated pleomorphic sarcoma was carried out, and the main target group was patients with undifferentiated pleomorphic sarcoma that was unresectable by surgery or was metastatic.

[0121] The primary research endpoint: PFS [time limit: 3 months after implementation of therapeutic protocol]; secondary research endpoints: ORR [time limit: 3 months, 6 months and 12 months after the start of treatment], CBR [time limit: 3 months, 6 months and 12 months after start of treatment], OS [time limit: research ending, average of 12 months], and safety and toxicity [time limit: until 30 days after the end of treatment].

[0122] The key inclusion criteria are as follows: patients with histologically confirmed sarcoma, only histologically high-grade pleomorphic undifferentiated sarcoma that was untreated and for which first-line standard chemotherapy was rejected, the presence of measurable lesions that met RECIST 1.1 criteria, 0-1 points for ECOG physical condition, and no possibility of complete surgical resection of lesions.

[0123] Administration Dose of Drug: Anlotinib

[0124] Anlotinib hydrochloride capsule (anlotinib dihydrochloride as the active ingredient): for the first cycle of treatment (28 days), anlotinib hydrochloride was orally administered to a patient before breakfast at 12 mg/day (once daily, 1 capsule each time), and the administration was performed for 2 weeks consecutively and then interrupted for 2 weeks; subsequent cycles of treatment each consisted of 3 weeks (21 days), and the administration was performed for 2 weeks consecutively and then interrupted for 1 week.

[0125] Administration Dose of Antibody Drug: Toripalimab

[0126] Toripalimab was administered intravenously at a dose of 240 mg. For the first cycle of treatment (28 days), the administration time was on day 8; for each subsequent cycle of treatment (21 days), the administration time was on day 1, i.e., injection every 21 days.

[0127] After an initial safety assessment of the patient, self dose escalation research of anlotinib in combination with toripalimab would be performed.

[0128] Preliminary results show that the combination of anlotinib hydrochloride and toripalimab is effective in treating undifferentiated pleomorphic sarcoma.

[0129] Patient Case

[0130] A female, aged 72, with no smoking history, had left thigh lump resection in May 2018, pathologically diagnosed as malignant tumor of left thigh, had enlarged resection after soft tissue lump resection on Aug. 30, 2018; clinical diagnosis: left thigh undifferentiated sarcoma, and double lung metastatic tumor after the second surgery for the left thigh undifferentiated sarcoma.

[0131] Administration: anlotinib (12 mg, p.o., qd, two week treatment from d1-d14 and then one-week interruption) in combination with toripalimab (240 mg, once every 21 days).

[0132] Time of first administration was Nov. 22, 2019. The sum of diameters of measurable target lesions was 44.3 mm (32.3 mm for the inferior lobe of left lung and 12.0 mm for the middle lobe of right lung). The patient was evaluated as SD in all three efficacy evaluations. Progression-free survival PFS was approximately 5 months. The therapeutic protocol and efficacy evaluations are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Administration Efficacy Cycle regimen Target lesion evaluation Before the first — Sum: 44.3 mm (32.3 mm for the administration inferior lobe of left lung, and 12.0 mm for the middle lobe of right lung) Cycle 1 (28 days for one Anlotinib (d 1-d 14) + Sum: 40.4 mm (29.4 mm for the SD cycle) toripalimab (d 8) inferior lobe of left lung, and 11.0 mm for the middle lobe of right lung) Cycle 2 (21 days for one Anlotinib (d 1-d 14) + Sum: 40 mm (28.0 mm for the SD cycle) toripalimab (d 1) inferior lobe of left lung, and 12.0 mm for the middle lobe of right lung) Cycle 3 (21 days for one Anlotinib (d 1-d 14) + Sum: 33.3 mm (22.3 mm for the SD cycle) toripalimab (d 1) inferior lobe of left lung, and 11.0 mm for the middle lobe of right lung) Cycle 4 (21 days for one Anlotinib (d 1-d 14, cycle) dose reduced to 10 mg) + toripalimab (d 1)

[0133] According to the content disclosed herein, the compositions and methods of the present application have been described in terms of preferred embodiments. However, it will be apparent to those skilled in the art that variations may be applied to the compositions and/or methods and the steps or the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the present application.

[0134] The disclosed content of all documents cited herein are hereby incorporated by reference to the extent that they provide exemplary, procedural and other details supplementary to those described herein.