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Combination therapy for the treatment of cancer

a cancer and combination therapy technology, applied in the field of combination therapy, can solve the problems of abnormal cell metabolism, poor patient prognosis, and deregulation of cell proliferation, and achieve the effect of reducing the dose needed and increasing the maximum level of inhibition

Inactive Publication Date: 2019-02-14
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conversely over expression of cyclin E in solid tumours has been shown to correlate with poor patient prognosis.
gen. One or more of these signaling pathways may be abnormally activated in patients with many different types of cancer, resulting in deregulated cell proliferation, tumor angiogenesis, and abnormal cell metabo

Method used

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  • Combination therapy for the treatment of cancer
  • Combination therapy for the treatment of cancer
  • Combination therapy for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0235]The following experimental procedure is performed to demonstrate the efficacy and anti-proliferative activity of Compound A1 in double or triple combination in the treatment of breast cancer:

Preparation of Compounds / Reagent Solutions

[0236]Compound A1 (a CDK4 / 6 inhibitor, 10 mM), Compound B1 (Letrozole, Sigma, 10 mM), Compound B3 (Fulvestrant, Sigma, 10 mM), Compound B2 (Exemestane, Sigma, 10 mM), Compound C1 (a PI3K inhibitor, 10 mM), Compound C3 (an mTor inhibitor, 10 mM) and Compound C2 (a PI3K inhibitor, 10 mM) were dissolved in DMSO. Δ4A (the precursor androstenedione 10 mM) were dissolved in ethanol. All these reagents were stored in aliquots at −20° C.

Cell Culture

[0237]MCF7 human breast carcinoma cells were provided by Dr. Chen Shivan (City of Hope National Medical Center, CA, USA), which were stably transfected with the aromatase expression vector bearing the neomycin (G418) resistance gene (also named MCF7 / Aro). Aromatase converts the precursor androstenedione (Δ4A) in...

example 2

[0264]The following experimental procedure is performed to demonstrate the efficacy and anti-proliferative activity of Compound A2 or Compound A3 in double or triple combination in the treatment of breast cancer:

Preparation of Compounds / Reagent Solutions

[0265]Compound A2 (a CDK4 / 6 inhibitor, 10 mM), Compound A3 (a CDK4 / 6 inhibitor, 10 mM), Compound B1 (Letrozole, Sigma, 10 mM), Compound B3 (Fulvestrant, Sigma, 10 mM), Compound B2 (Exemestane, Sigma, 10 mM), Compound C1 (a PI3K inhibitor, 10 mM), and Compound C3 (an mTor inhibitor, 10 mM) were dissolved in DMSO. Δ4A (the precursor androstenedione, 10 mM) were dissolved in ethanol. All these reagents were stored in aliquots at −20° C.

Cell Culture

[0266]MCF7 human breast carcinoma cells were provided by Dr. Chen Shivan (City of Hope National Medical Center, CA, USA), which were stably transfected with the aromatase expression vector bearing the neomycin (G418) resistance gene (also named MCF7 / Aro). Aromatase converts the precursor andro...

example 3

[0300]A clinical trial is currently on going to further the clinical development of the two investigational agents in ER+ breast cancer, Compound A1 (CDK4 / 6 inhibitor) and Compound C1 (PI3K inhibitor). This is a multi-center, open-label, dose finding Phase Ib / II trial. The Phase Ib part is a three-part dose escalation study to estimate the MTD and / or RP2D for two double combinations: Compound A1 with letrozole and Compound C1 with letrozole followed by estimation of the MTD and / or RP2D of the triple combination of Compound A1+Compound C1 with letrozole.

[0301]The three-part Phase Ib will be followed by a randomized Phase II study to assess the preliminary anti-tumor activity of the two double combination regimens (Compound A1+letrozole and Compound C1+letrozole) versus the triple combination (Compound A1+Compound C1 with letrozole) and to further evaluate their safety in patients with ER+ / HER2− locally advanced or metastatic breast cancer.

[0302]Approximately 290 adult women with ER+ / ...

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Abstract

The present disclosure relates to a pharmaceutical combination comprising (1) a first agent which is a CDK inhibitor or a pharmaceutically acceptable salt thereof and (2) a second agent which is an anti-hormonal agent or a pharmaceutically acceptable salt thereof. The present disclosure also relates to a pharmaceutical combination comprising (1) a first agent which is a CDK inhibitor or a pharmaceutically acceptable salt thereof, (2) a second agent which is an anti-hormonal agent or a pharmaceutically acceptable salt thereof, and (3) a third agent which is an agent that regulates the PI3K / Akt / mTOR pathway or a pharmaceutically acceptable salt thereof.

Description

FIELD OF THE DISCLOSURE[0001]The present disclosure relates to a pharmaceutical combination comprising a CDK inhibitor and an anti-hormonal agent for the treatment of cancer; the uses of such combinations in the treatment of cancer; and to a method of treating warm-blooded animals including humans suffering cancer comprising administering to said animal in need of such treatment an effective dose of a CDK inhibitor and an anti-hormonal agent. In addition, the combination can optionally include an agent that regulates the PI3K / Akt / mTOR pathway.BACKGROUND OF THE DISCLOSURECDK Inhibitors[0002]Tumor development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for, e.g., cyclin D / CDK4 / 6 and that it may be possible to develop novel antineoplastic agents devoid of the general host t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519A61K31/5685A61K31/551A61K45/06A61K31/4439A61K31/5377A61K31/5513A61K31/436A61K31/4196A61K31/565A61K31/138
CPCA61K31/5685A61K31/551A61K45/06A61K31/4439A61K31/519A61K31/5377A61K31/436A61K31/4196A61K31/565A61K31/138A61K31/5513A61P35/00A61P35/02A61P43/00A61P5/00A61P5/32A61K2300/00A61K31/427A61K31/495A61K31/506A61K31/56
Inventor CHEN, YANHUANG, XIZHONGKIM, SUNKYU
Owner NOVARTIS AG
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