Combination therapy with a raf inhibitor and a cdk4/6 inhibitor for use in the treatment of cancer

A technology for inhibitors and cancer, applied in the field of drug combinations, can solve problems such as off-target toxicity and unmet medical needs

Pending Publication Date: 2021-09-28
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, LY3009120 inhibits several other kinases, including those with important roles in cancer, such as the ephrin receptor, JNK, and SRC family members, thus potentially leading to off-target toxicity
[0010] Therefore, there is an unmet medical need for effective therapies targeting RAS-mutant cancers, including NRAS-mutant melanoma and KRAS pancreatic ductal adenocarcinoma (PDAC)

Method used

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  • Combination therapy with a raf inhibitor and a cdk4/6 inhibitor for use in the treatment of cancer
  • Combination therapy with a raf inhibitor and a cdk4/6 inhibitor for use in the treatment of cancer
  • Combination therapy with a raf inhibitor and a cdk4/6 inhibitor for use in the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0177] Example 1: Combination of RAF Inhibition and Enhancement of CDK4 / CDK6 Inhibition in NRAS Mutant Melanoma Cell Lines

[0178] method

[0179] A compound of formula (I) (NVP-LXH254) and ribociclib (NVP-ribociclib) were synthesized, and a compound stock solution of ribociclib was prepared in DMSO at a final concentration of 10 mM. For combination assays, the working stock was serially diluted in appropriate cell culture media in 3-fold increments (2-fold increments for ribociclib) to achieve final assay concentrations: NVP-LXH254 ranged from 10 μM to 1.5 nM, 10 μM to 39 nM (succinate form) for NVP-ribociclib.

[0180] SK-MEL-2 cells were purchased from American Type Culture Collection (ATCC), MEL-JUSO cells were purchased from German Microbiology and Cell Culture Series Co., Ltd. (DSMZ), MM415 cells were purchased from Australian Cell Bank, and IPC-298 and SK- MEL-30 cells were obtained from GNF. IPC-298, MEL-JUSO, MM415, and SK-MEL-30 cells were cultured in RPMI medium...

example 2

[0187] Example 2: Combination Efficacy of Compounds of Formula (I) and Ribociclib in Xenografts Derived from NRAS Mutant Melanoma Patients

[0188] The effect of selective dual RAF and CDK4 / 6 inhibition in vivo was investigated by combining a compound of formula (I) and ribociclib in nine xenografts derived from NRAS mutant melanoma patients.

[0189] method

[0190] Animal and Maintenance Conditions: At least 3 days prior to manipulation, outbred athymic (nu / nu) female mice (Athymic Nude-nu") (Charles River, Indianapolis, Indianapolis) were allowed ad libitum access to food and water. The Novartis NIBR animal facility was adapted to the new environment (Table 1).

[0191] Table 1 Animal characteristics

[0192]

[0193] Statement on animal welfare: Animals were handled in accordance with Novartis NIBR ACUC regulations and guidelines.

[0194] Test compounds and formulations: Compounds of formula (I) (free base form) in MEPC4 vehicle (45% Cremophor RH40+27% PEG400+18% co...

example 3

[0225] Example 3: Phase Ib, open-label, multicentre study of a compound of formula (I) in combination with ribociclib in patients with NRAS-mutant melanoma

[0226] The purpose of this study was to characterize the safety and tolerability of the dual combination of a compound of formula (I) and ribociclib in patients with NRAS-mutant melanoma and to determine the recommended dose.

[0227] The primary endpoint is

[0228] (1) Safety: Incidence and severity of adverse events (AEs) and serious AEs (SAEs), including changes in laboratory values, vital signs, and electrocardiogram (ECG), dose restrictions during cycle 1 (dose escalation only) The incidence and nature of toxicity (DLT),

[0229] (2) Tolerance: dose interruption, reduction and dose intensity.

[0230] Secondary objectives and endpoints are:

[0231] (a) Evaluation of the initial antitumor activity of a compound of formula (I) in combination with ribociclib. Overall response rate (ORR), disease control rate (DCR)...

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Abstract

The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor as defined herein, or a pharmaceutically acceptable salt thereof and (b) a CKD4 / 6 inhibitor, particularly ribociclib, particularly for use in the treatment of a proliferative disease, preferably melanoma or pancreatic ductal adenocarcinoma.

Description

technical field [0001] The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor (which is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof); and (b) a CDK4 / 6 inhibitor, In particular ribociclib or a pharmaceutically acceptable salt thereof. [0002] The invention also relates to such combinations for use in the treatment of cancer; the use of such combinations for the manufacture of a medicament for the treatment of cancer; a method of treating cancer in a subject in need thereof, the method comprising adding Administration of said subject in a combined therapeutically effective amount of said combination; use of such combination for treating cancer; and pharmaceutical compositions comprising such combination. [0003] The present invention also relates to a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for use in combination with a CDK4 / 6 inhibitor (especia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/519A61K31/5377A61K45/06A61P35/00
CPCA61K31/5377A61K31/519A61K31/00A61K45/06A61P35/00A61K2300/00
Inventor G·卡波尼格罗
Owner NOVARTIS AG
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