Drug Combination Potentially Effective in BRCA-Deficient Solid Tumors

Two orally available experimental drugs achieved response in patients with BRCA-deficient solid tumors in a phase 1 study of 38 patients. Responders were patients with BRCA mutations and incurable pancreatic, breast, and ovarian tumors.
“There is definitely a group of responders who appear to benefit from this drug combination. This should be studied in a new, much larger prospective trial,” said lead author Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, at the American Association for Cancer Research Annual Meeting.

Among the 38 patients, 16 had BRCA-deficient cancers. Patients received treatment with sapacitabine and seliciclib—2 drugs developed by Cyclacel Pharmaceuticals, Inc. Sapacitabine causes single-strand DNA breaks that are converted to double-strand DNA breaks during replication. The investigators in the phase 1 trial hypothesized that seliciclib would interfere with the repair of damaged DNA and enhance the cytotoxicity of sapacitabine, Shapiro explained.

Patients were treated with sequential administration of both drugs for 10 days, followed by an 11-day rest period. During the dose-escalation phase of the study, patients without BRCA mutations had stable disease. Two observations during the dose-escalation phase had researchers focusing on the patients with BRCA mutations: one, it was reported that the repair of DNA breaks caused by sapacitabine is dependent on the homologous repair pathway, which includes BRCA proteins and is downregulated in their absence; the second was a partial response (PR) observed in a patient with pancreatic cancer who was found to be a BRCA-mutation carrier.

The trial was then limited to patients with BRCA-deficient cancers. Three additional PRs were observed (2 with breast cancer and 1 with ovarian cancer). The PRs have been durable in 3 patients (from 9 to 21 months). These 3 patients are continuing on study.

In total, 6 of the 16 BRCA-mutation carriers benefited from the drug combination (4 with PRs and 2 with stable disease).
Shapiro said that nonresponders were heavily pretreated and too compromised to tolerate a cycle of the combination therapy, and were therefore not evaluable.

"Among the BRCA-proficient group, several patients had prolonged stable disease, but the response was not as dramatic as in the BRCA-deficient group,” he said. “Going forward, the combination therapy has the most chance of efficacy in BRCA-deficient patients.”

Sequential administration of the 2 experimental agents was used in the trial. Concurrent administration of sapacitabine and seliciclib will be studied, as will different dosing schedules.

PARP (poly ADP-ribose polymerase) inhibitors are effective in BRCA-deficient patients. Shapiro said the responders in the trial had not been pretreated with a PARP inhibitor. “We need to determine if the combination works in patients pretreated with PARP. Finally, we have some drug classes that address inherited cancers,” Shapiro stated.

Reference
Shapiro GI, Hilton J, Cleary JM, et al. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC. Abstract LB-202.