Novel Drug Combination Showed Antitumor Activity in Patients With Incurable BRCA-deficient Cancers
April 7, 2013
- Patients received sapacitabine and seliciclib as sequential treatments.
- Several patients with BRCA mutations achieved disease response or experienced prolonged stable disease.
- BRCA mutation carrier status may be a potential biomarker for response.
WASHINGTON, D.C. — When given sequentially, two orally available experimental drugs — sapacitabine and seliciclib — worked together to elicit antitumor effects in patients with incurable BRCA-deficient cancers, according to phase I data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. There are no drugs yet approved specifically for this patient population.
“Since we began to enroll predominantly patients who carried a BRCA mutation in the study, we have seen several responses among those patients, as well as instances of prolonged stable disease lasting more than a year,” said Geoffrey Shapiro, M.D., Ph.D., associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Mass.
Shapiro and colleagues initially designed the phase I study to exploit preclinical results that suggested that sapacitabine and seliciclib worked together synergistically. Sapacitabine is an oral nucleoside analogue that induces single-strand damage to DNA. If the damaged DNA is not repaired, it ultimately results in cell death. Repair of sapacitabine-induced DNA damage requires BRCA proteins, suggesting that BRCA-deficient cancers may be particularly sensitive.
Seliciclib inhibits cyclin-dependent kinases (CDKs); CDK inhibition has been shown to augment cancer cell death induced by drugs like sapacitabine by multiple mechanisms, in part by suppressing DNA repair pathways.
Researchers enrolled 38 patients with incurable solid tumors and adequate organ function. They assigned patients to treatment with sapacitabine twice daily for seven days followed by seliciclib twice daily for three days.
Four patients with BRCA-deficient pancreatic, breast or ovarian cancers had confirmed ongoing partial responses to the drug combination. Three patients are experiencing partial responses, with the longest lasting more than 78 weeks.
Furthermore, researchers observed stable disease of 12 weeks or more in eight additional patients, including two patients with ovarian and breast cancers who carried the BRCA mutation and whose stable disease lasted 64 weeks and 21 weeks, respectively.
The maximum tolerated doses were 50 mg sapacitabine twice daily and 1,200 mg seliciclib twice daily. Dose-limiting toxicities included reversible transaminase elevations and neutropenia. Adverse events were mild to moderate in intensity.
Results of skin biopsies after treatment showed a 2.3-fold increase in DNA damage induced by sapacitabine, as measured by gamma-H2AX immunohistochemistry. Additional DNA damage occurred after treatment with seliciclib with a 0.58-fold further increase in gamma-H2AX staining.
“Initially in the dose-escalation phase of the trial, this combination produced stable disease of modest duration in some patients, which has been the experience with sapacitabine and CDK inhibitors in solid tumors,” Shapiro said. “However, other published research during the course of the study indicated the role of the homologous recombination pathway, dependent on BRCA proteins, for repair of sapacitabine-induced DNA damage. Additionally, the CDK proteins were implicated in DNA repair pathways. These findings prompted us to enroll patients with advanced cancer who had the BRCA mutation and led to the first partial responses and instances of durable stable disease.”
Based on these emerging results, Shapiro and colleagues continue to enroll appropriate patients in the trial, where the combination has been most efficacious. Additional schedules of the combination therapy are under evaluation. According to Shapiro, if further work continues to confirm BRCA mutation status as a potential biomarker for response, these drugs, both individually and in combination, should ultimately be evaluated in larger groups of patients who carry BRCA mutation. If successful, these drugs may provide an important treatment alternative for patients with BRCA-deficient cancers.
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Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit www.AACR.org
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