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Treatment cancers using combination comprising parp inhibitors, temozolomide and/or radiation therapy

An inhibitor, cancer technology, applied in the directions of X-ray/γ-ray/particle irradiation therapy, drug combination, medical preparations containing active ingredients, etc., can solve the problem of insufficiently obtained, undisclosed clinical benefits, and aggravate the adverse effects of myelosuppression and other issues to achieve an effective anti-tumor response

Inactive Publication Date: 2020-03-17
百济神州(苏州)生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0034] Although various clinical trials have tried combining Parp inhibitors such as veliparib, olaparib, etc. with TMZ and / or radiation for the treatment of solid tumors, no significant clinical benefit has been disclosed, especially in patients such as GBM brain cancer treatment
The failure of those clinical trials may have been due to unexpected myelosuppressive adverse effects exacerbated by the combination therapy, thus patients were not fully able to obtain the benefits of the combination of Parp inhibitors, TMZ and / or radiation

Method used

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  • Treatment cancers using combination comprising parp inhibitors, temozolomide and/or radiation therapy
  • Treatment cancers using combination comprising parp inhibitors, temozolomide and/or radiation therapy
  • Treatment cancers using combination comprising parp inhibitors, temozolomide and/or radiation therapy

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] Embodiment 1. Preparation of compound A and compound B

[0175] Step 1: Synthesis of Compound-2

[0176]

[0177] Tert-butyl bromoacetate (51.7Kg) was dissolved in anhydrous acetonitrile (72Kg). The temperature was raised to 65°C-75°C, then methylpyrroline (22Kg) was added. After the reaction was complete, the reaction mixture was concentrated and residual acetonitrile was removed by adding THF and then concentrating. After GC showed complete removal of acetonitrile, more THF was added and stirred. The resulting solid was collected by filtration. 44.1 Kg of off-white solid Compound-2 was obtained. 1 H NMR (400MHz, DMSO-d6) δ4.91(s,2H),4.15(m,2H),3.29(m,2H),2.46(s,3H),),2.14(m,2H),1.46( s, 9H) ppm.

[0178] Step 2: Synthesis of Compound-3

[0179]

[0180] To a THF-cooled (-60°C) solution of trimethylsilylacetyne (12.4 Kg) was added n-butyllithium in hexane (43.4 Kg). After complete addition of n-BuLi solution, the resulting mixture was stirred for anot...

Embodiment 2

[0203] The effect of the combination of embodiment 2 PARP inhibitor and temozolomide (TMZ)

[0204] Compound B as a single agent has demonstrated excellent in vitro activity against tumor cell lines with defects in the HR pathway. In vivo, compound B showed potent antitumor activity against BRCA1 mutant mouse xenograft model (MDA-MB-436 breast cancer) and was 16-fold more potent than olaparib. In a pharmacokinetic (PK) / pharmacodynamic (PD) study, oral administration of Compound B produced a time- and dose-dependent inhibition of PARylation in MDA-MB-436 breast cancer xenografts in mice. Inhibition of PARylation in tumor tissue correlates with compound B tumor drug concentrations.

[0205] The antiproliferative effect of Compound B in combination with TMZ was evaluated in eight human GB cell lines resistant to single agent TMZ (EC50 of 32 μM or greater). Compound B exhibited synergy with TMZ in 7 of 8 cell lines, with 5-fold or greater changes in EC50 for TMZ. This synergy w...

Embodiment 3

[0207] Embodiment 3: clinical trial

[0208] An open-label, multicenter, multidose, dose-escalation phase 1b / 2 study of compound B in combination with radiation therapy (RT) and / or temozolomide (TMZ).

[0209] (1) In patients with first-line glioblastoma (GB) with unmethylated MGMT promoter ("unmethylated GB") Compound B in combination with RT in patients.

[0210] Compound B (60 mg BID) was administered to patients in combination with RT at increasing exposures of 2, 4 and 6 weeks for 6 to 7 weeks. After completion of RT, the patient received no further treatment.

[0211] (2) Compound B in combination with both TMZ and RT in subjects with first-line unmethylated GB.

[0212] Compound B (60 mg BID) was administered to patients in combination with RT for 6 to 7 weeks and increasing doses of TMZ. After completion of RT, the patient received no further treatment.

[0213] (3) In subjects with relapsed / refractory GB with methylated or unmethylated MGMT promoter Comp...

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Abstract

Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, incombination with temozolomide and / or radiation therapy. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with temozolomide and the use thereof.

Description

[0001] related application [0002] This application claims the benefit of International Patent Application No. PCT / CN2017 / 093192 filed on July 17, 2017, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. technical field [0003] Disclosed herein is a method for preventing cancer, delaying the progression of cancer, or treating cancer in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a PARP inhibitor and a therapeutically effective amount of temozolomide and / or A combination of radiation therapies. [0004] Background of the invention [0005] One of the hallmarks and driving forces of cancer is genetic instability [Hanahan D and Weinberg R A, Hallmarks of cancer: the next generation. Cell, 2011.144(5): pp. 646-74.]. Particularly in familial cancers, mutations in the breast cancer susceptibility BRCA1 and BRCA2 tumor suppressor genes, key players in homologous recombination ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/551A61K31/4188A61N5/10C07D487/06C07D487/22A61P35/00
CPCA61K31/551A61P35/00A61N2005/1098A61K31/495A61K2300/00A61P31/00A61K9/0053A61N5/10
Inventor 汪来汤志宇罗吕松魏旻A·彼得森王鹤翔任博周昌友
Owner 百济神州(苏州)生物科技有限公司
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