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Combination therapy for treating malignancies

A technology for malignant, hematological oncology, in the field of combination therapy for the treatment of malignancies

Active Publication Date: 2018-10-23
LES LAB SERVIER +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, even with a good overall response, there is a genetic burden in patients

Method used

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  • Combination therapy for treating malignancies
  • Combination therapy for treating malignancies
  • Combination therapy for treating malignancies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0300] Example 1. Effect of the combination of compound 2 and azacitidine on EPO-differentiation in AML cells

[0301] TF1-IDH1 R132H EPO differentiation assay in cells. in TF1-IDH1 R132H Measures of cell differentiation, growth and death were assessed in cells using the in vitro EPO differentiation assay and the dose-schedule paradigm shown in Figure 1 . Cells were treated with vehicle, AZA alone, Compound 2 alone or the combination of AZA+Compound 2. In a sequential schedule, cells were pretreated with AZA for three days before compound 2 was added. In a concurrent schedule, cells were co-treated with AZA and compound 2 throughout the test. Endpoint assessment assays were: assessment of cell pellet color (hemoglobinization test); HBG and RKLF1 RNA by RT-qPCR; assessment of CD235a-positive cell population (differentiation marker) by flow cytometry; and assessment of growth and apoptosis.

[0302] Compounds: Compound 2 was used as a 10 mM stock solution in DMSO. This st...

Embodiment 2

[0320] Example 2. Phase 1b / 2 open-label randomized study of 2 combinations of isocitrate dehydrogenase (IDH) mutant-targeted therapy plus azacitidine: newly diagnosed acute Subjects with myeloid leukemia, oral compound 2 plus subcutaneous azacitidine and oral compound 1 plus subcutaneous azacitidine, where the subject is not a candidate for intensive induction chemotherapy.

[0321] Indications: Treatment of newly diagnosed acute myeloid leukemia (AML) subjects over 18 years of age who carry IDH1 or IDH2 mutations, respectively, and who are not candidates for intensive induction chemotherapy (IC).

[0322] Key Target - Phase 1b (Dose Escalation Phase)

[0323] main target

[0324] To evaluate oral compound 2 plus subcutaneous (SC) azacitidine and oral 2-methyl-1-[(4-[6-(tri Fluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2 - Safety and tolerability of alcohol (hereinafter referred to as compound 1) + SC azacitidine, ...

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Abstract

Provided are methods and compositions for treating cancers in patients carrying an IDHl mutation using a combination of an inhibitor of a mutant IDHl enzyme and a DNA demethylating agent.

Description

[0001] priority claim [0002] This application claims priority to U.S.S.N. 62 / 242,282, filed October 15, 2015, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention provides combination therapies for the treatment of hematologic malignancies and solid tumors. In one embodiment, the therapy involves treatment with an IDH1 inhibitor and a DNA demethylating agent. Background technique [0004] Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (ie, alpha-ketoglutarate). These enzymes belong to two different subclasses, one of which utilizes NAD(+) as an electron acceptor and the other utilizes NADP(+) as an electron acceptor. Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases localized to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which One is mitochondrial and the other is predomi...

Claims

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Application Information

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IPC IPC(8): A61K31/4439C07H19/12A61P35/00
CPCA61K45/06A61K31/444A61K31/706A61P35/02A61K2300/00A61K31/4439
Inventor S.V.阿格雷斯塔K.维斯瓦纳丹J.迪马蒂诺V.S.K.乔普拉K.J.麦克贝思R.D.奈特L.肯文Q.徐
Owner LES LAB SERVIER
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