The combination of GDC-0575, a new checkpoint kinase 1 (CHK1) inhibitor, with gemcitabine, an antineoplastic agent used to treat sarcomas, killed cancer cells in laboratory tests, in mice, and in human patients, including to an unusually long-lasting period without disease progression, according to a presentation at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.1
Soft tissue sarcomas are rare cancers of the fat, muscle, blood vessels, nerves, ligaments, or tendons. They are difficult to treat, especially in cases of advanced disease or metastasis.
Forty percent of patients with soft tissue sarcomas develop recurrent disease with metastasis. Treatment options are few and median overall survival is poor (12-18 months). Therefore, researchers sought to assess the antitumor efficacy of combining a CHK1 inhibitor with gemcitabine.
The new drug, GDC-0575 inhibits CHK1, which prevents cancer cells from recovering from DNA damage leading to cell death. The combination of GDC-0575 and gemcitabine significantly reduced tumor growth compared with just one drug in laboratory tests and in mice.
In a phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT01564251), 2 patients had a meaningful response despite that the dose of gemcitabine used in the combination was significantly lower dose than when the drug is used alone. The patients were given gemcitabine 250 mg/m3 weekly intravenously and GDC-0575 orally with a range of different doses.
Both patients achieved rapid and substantial tumor shrinkage that was unusually long-lasting. One patient, who had a leiomyosarcoma with extensive metastases in the peritoneum, had a partial response that lasted for 1 year. The other patient, who had lung metastases, achieved a complete response that is ongoing 9 months after initiating treatment.
This trial is no longer accepting new patients; however, based on these results, the researchers are looking to set up a phase II clinical trial to assess safety and efficacy of a gemcitabine-CHKI inhibitor combination for soft-tissue sarcoma.