Nick Mulcahy

April 19, 2013

WASHINGTON, DC — The combination of 2 experimental agents may uniquely address the underlying biology of patients with treatment-refractory BRCA-deficient solid tumors, according to a presentation here.

The results are early but are especially of interest because no drugs are approved for this patient population.

The oral agents, sapacitabine and seliciclib (both under development by Cyclacel), were given sequentially in a phase 1 clinical trial that included heavily pretreated patients whose tumors lack BRCA function because of an inherited mutation.

Some of the responses among the BRCA mutation carriers have been long lasting, said lead author Geoffrey Shapiro, MD, PhD, of the Dana-Farber Cancer Institute's Early Drug Development Center in Boston, Massachusetts.

He spoke about the 38-patient trial at a press briefing at the American Association of Cancer Research (AACR) 104th Annual Meeting.

In the trial, 16 participants had an inherited BRCA mutation; 4 of them have had partial responses, including 1 with pancreatic, 2 with breast, and 1 with ovarian cancer. The longest of the responses is 78 weeks and counting.

Also, 2 other BRCA mutation carriers, with breast and ovarian cancer, experienced stable disease for 21 and 64 weeks, respectively.

Of the remaining 22 patients (all with normal BRCA genes) enrolled in the trial, 6 experienced stable disease for 12 weeks or longer.

These early results suggest that a BRCA mutation may be a biomarker that identifies patients who are more likely to respond to the drug combination, said Dr. Shapiro.

The study results may also indicate that the agents, which were given sequentially in the trial, may be effective alone.

Results of skin biopsies after treatment with sapacitabine for 7 consecutive days showed a 2.3-fold increase in cancer cell DNA damage induced by the single agent, as measured by immunohistochemistry. After subsequent treatment with seliciclib for 3 days, additional DNA damage occurred of a 0.58-fold magnitude.

Killer Combo

At the same time, there appears to be a synergy with the 2 agents, suggested Dr. Shapiro. "The pair itself may be best in patients with BRCA-deficient cancers," he said and explained how they may work in concert with each other.

Sapacitabine is an oral nucleoside analogue that is toxic to cancer cells by causing damage to their DNA, which, if not repaired, causes the tumor cells to self-destruct. Because the BRCA protein is essential for repair of the DNA damage caused by sapacitabine, patients with mutations that inactivate BRCA may be especially sensitive to the agent.

The second drug, seliciclib, is an inhibitor of cyclin-dependent kinases (CDKs), which are enzymes that have a role in DNA repair. This inhibition of the DNA repair further augments the cancer cell debilitation by sapacitabine.

The team at Dana Farber has some molecular proof of this augmentation. "We have done some assays that actually show that the CDK inhibition will increase the damage that is induced by sapacitabine," Dr. Shapiro told reporters.

The most frequent adverse events in the study included fatigue, abdominal pain, diarrhea, constipation, decreased appetite, nausea, vomiting, anemia, neutropenia, pyrexia, aspartate aminotransferase elevation, alkaline phosphatase elevation, creatinine elevation, hyperglycemia, hypophosphatemia, cough, and alopecia. The majority of the adverse effects were mild to moderate in intensity. Dr. Shapiro said that the phase 1 data have established that the combination is safe.

The 2 products are also being investigated as separate agents in more advanced clinical trials in a variety of cancers.

"The Wave of the Future"

Drug combinations, such as sapacitabine and seliciclib, are "the wave of the future" in cancer treatment, said Levi Garraway, MD, PhD, also of Dana-Farber. He was not involved in the study but moderated the press briefing.

Combinations are a "major thrust" in cancer drug development because of the complexity of the disease, which is borne out in multiple ways, such as the now well-established issue of treatment-induced resistance to targeted therapies, he said.

The study was supported by Cyclacel Ltd and the National Institutes of Health. The study authors included employees of the sponsoring company. Dr. Garraway reports financial relationships with Foundation Medicine, Millenium/Takeda, Novartis, Daichii Sankyo, Inc, and Boehringer Ingelheim.

American Association for Cancer Research (AACR) 104th Annual Meeting. Abstract LB-202. Presented April 9, 2013.

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