Chk1 Inhibition Plus Gemcitabine May Be Safe and Effective In Some Solid Tumors

Presented by Dr. Jeffrey R. Infante, MD 2015 American Association for Cancer Research Director of the Drug Development Program Sarah Cannon Research Institute in Nashville, Tennessee.MedicalResearch.com Interview with:
Presented by Dr. Jeffrey R. Infante, MD
2015 American Association for Cancer Research
Director of the Drug Development Program
Sarah Cannon Research Institute in Nashville, Tennessee.


Medical Research: What is the background for this study?

  • Inhibition of Checkpoint Kinase 1 (Chk1) may be effective at enhancing the effects of chemotherapeutic agents in tumor cells that lack other key cell cycle checkpoint regulators, such as the tumor suppressor protein p53 (p53 mutant tumors).
  • In a broad range of pre-clinical models, GDC-0425, an oral, selective Chk1 inhibitor, enhanced the efficacy of the chemotherapy drug gemcitabine. Greater efficacy was also observed in cancer cell lines lacking p53 activity.
  • Based on its proposed mechanism of action in enhancing the cytotoxicity of DNA damaging chemotherapy, GDC-0425 was evaluated in combination with a standard dose of gemcitabine.

Medical Research: What are the main findings?

  • Clinical data from a Phase I dose-escalation study evaluating GDC-0425 in combination with gemcitabine showed encouraging clinical activity and an acceptable safety profile in patients with refractory solid tumors.  The most common adverse events related to GDC-0425 and/or gemcitabine were nausea, vomiting, neutropenia, and anemia.
  • Among the 40 patients who were treated, three patients had a partial response based on RECIST criteria.
    • One patient with TP53 mutated triple-negative breast cancer (TNBC) who received 60 mg of GDC-0425 in combination with 1000 mg/m2 gemcitabine had a confirmed partial response. This patent showed the best tumor response on study: -53%.
  • Each of the three patients with a partial response continued study treatment for more than six months. There are no active, ongoing patients.
  • We are encouraged that one patient with a partial response also showed a TP53 mutation detected, but we cannot yet definitively conclude a correlation exists between p53 status and tumor responses to GDC-0425 and gemcitabine.

Medical Research: What should clinicians and patients take away from your report?

  • We believe Chk1 inhibition is a key strategy for enhancing the efficacy of chemotherapeutic and other agents in cancer patients.
  • This data highlights our long-term commitment to finding new treatment options for people with cancer.

Medical Research: What recommendations do you have for future research as a result of this study?

  • Another oral ChK1 inhibitor, GDC-0575, is continuing to be evaluated in combination with gemcitabine in patients with refractory solid tumors and builds on what we have learned with GDC-0425 from this study.
  • Although there is no current plan to continue to evaluate the combination of GDC-0425 and gemcitabine, we have learned much about the Chk1 target and safety with oral ChK1 inhibition.
    • The decision to halt further clinical development of GDC-0425 was not based on safety, pharmacokinetic (PK) properties, or lack of efficacy.
  • GDC-0425 and GDC-0574 are part of an oncology agreement between Genentech and Array BioPharma. Genentech is responsible for all clinical development and commercialization activities.

Citation:

Abstract presented at the April 2015 American Association for Cancer Research

CT139: Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors

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MedicalResearch.com Interview with: Presented by Dr. Jeffrey R. Infante, MD (2015). Chk1 Inhibition Plus Gemcitabine May Be Safe and Effective In Some Solid Tumors 

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