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Methods for cancer therapy

a cancer and cancer technology, applied in the field of cancer therapy, can solve the problems of inability of second-generation inhibitors to inhibit the most refractory bcr-abl, and the difficulty of overcoming acquired resistance to imatinib,

Pending Publication Date: 2022-06-23
ASCENTAGE PHARMA SUZHOU CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to methods for treating cancer, specifically hematological malignancy such as chronic myelogenous leukemia. The invention involves administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to patients in need of treatment. The compound can be administered orally and can be given once every other day during a treatment cycle. The compound has been found to inhibit BCR-ABL mutants, particularly T315I, which is associated with chronic myelogenous leukemia. The invention provides a new treatment option for patients who are resistant to current therapies.

Problems solved by technology

However, emerging acquired resistance to imatinib has become a major challenge for clinical management of CML.
Nonetheless, the second-generation inhibitors are not capable of inhibiting the most refractory BCR-ABLT315I mutant.
BCR-ABLT315I induced drug resistance remains an unmet clinical challenge for CML treatment.

Method used

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  • Methods for cancer therapy
  • Methods for cancer therapy
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Examples

Experimental program
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Effect test

example 1

[0097]A single-agent, open-label dose escalation and dose expansion Phase I study to assess the safety, preliminary efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) properties of orally administered the compound of formula (I-A) in the TKI-resistant patients with chronic phase (CP) or accelerated phase (AP) CML.

[0098]Methods: the compound of formula (I-A) was administered orally once every other day (QOD) in 28-days cycles at 11 dose cohorts ranging from 1 mg to 60 mg. The eligible patients received treatments until disease progression or intolerable toxicities. The primary efficacy endpoint in the CML AP and CP patients, was complete hematological response (CHR) and major cytogenetic response (MCyR) respectively, MCyR includes partial cytogenetic response (PCyR) and complete cytogenetic response (CCyR). Blood samples were collected at various time points on Day 1-2 and Day 27-28 during cycle 1 for PK analyses. BCR-ABL inhibition was evaluated using tyrosine phosphorylation o...

example 2

[0167]Further Efficacy and Safety Results of Phase 1 Study of the compound of formula (I-A) in Patients with Resistant Chronic Myeloid Leukemia

[0168]The compound of formula (I-A) is designed for treatment of patients with chronic myeloid leukemia (CML) resistant to current TKI-therapies including those with T315I mutation. This experiment is focus on the efficacy and safety assessment of the compound of formula (I-A) in a relatively long term.

[0169]Methods:

[0170]An open-label, 3+3 dose escalation, phase 1 trial of the compound of formula (I-A) design to determine maximum tolerated dose (MTD) and identify dose-limiting toxicities (DLTs) in patients with chronic phase (CP / CML-CP) or accelerated phase (AP / CML-AP) CML resistant to or intolerant of ≥2 prior TKIs or patients with BCR-ABL T315I M after ≥1 prior TKI is ongoing. The compound of formula (I-A) was administered once every other day (QOD) in 28-day cycles at 11 dose cohorts ranging from 1 mg to 60 mg. The eligible patients recei...

example 3

[0179]In this experiment, BCR-ABL complex mutation cells were used to determine the inhibitory effect of the compound of the formula (I-A) and Ponatinib on the proliferation of BCR-ABL complex mutation cells. The experiment proved that the compound of the formula (I-A) was a potential effective medicament capable of overcoming the drug resistance of the Ponatinib. Ba / F3 cells stably expressing BCR-ABL (F359V, H396R, E255K, Y253H, T315I, F317L) mutations were provided by the Institute of Life and Health, Guangzhou Academy of Sciences.

[0180]1. The mutated Ba / F3 cell line stably expressing BCR-ABL (E255V, T315M, Y253H / E255V, Y253H / T315I, Y253H / F359V, T315I / F317L, F317L / F359V) mutation was constructed by electro-transformation method, the Ba / F3 cell line stably expressing the BCR-ABL (E255V / T315I, T315I / F359V) mutation was constructed by lentivirus infection method. Cell gene sequencing results confirmed that the BCR-ABL mutant gene was integrated into the genome of Ba / F3 cells. Western...

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Abstract

The present invention relates to methods for treating patients with cancer, including patients with hematological malignancy, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined herein.

Description

FIELD OF THE INVENTION[0001]The present invention relates to methods for treating patients with cancer, including patients with hematological malignancy.BACKGROUND OF THE INVENTION[0002]Cancer has a major impact on society across the world. Cancer is the second most common cause after cardiovascular disease responsible for human death. The National Cancer Institute estimates that in 2015, approximately 1,658,370 new cases of cancer will be diagnosed in the United States and 589,430 people will die from the disease.[0003]Chronic myeloid leukemia (CML) is a type of cancer that starts in certain blood forming cells of the bone marrow. CML cells contain an abnormal gene, BCR-ABL, that isn't found in normal cells. This gene makes a protein, BCR-ABL, which causes CML cells to grow and reproduce out of control. BCR-ABL is a type of protein known as a tyrosine kinase. Drugs known as tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard treatment for CML.[0004]Imatinib (Glee...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496A61P35/00
CPCA61K31/496A61P35/00A61P35/02A61K31/437A61K9/0053
Inventor ZHAI, YIFANCHEN, ZIJIANG, QIANHUANG, XIAOJUNLIU, WEIYANG, DAJUN
Owner ASCENTAGE PHARMA SUZHOU CO LTD