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Reporter: Prabodh Kandala PhD

Researchers at Moffitt Cancer Center and Duke University Medical Center have conducted a phase I trial of dasatinib, an oral SRC-family tyrosine kinase inhibitor, to determine the maximum tolerated dose when combined with paclitaxel and carboplatin to treat patients with advanced or recurrent ovarian cancer. They found that 150 mg daily in combination with the two other drugs was optimum.

The study appears in the October issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.

Dasatinib has promising potential in treating advanced ovarian cancer because the SRC pathways play a role in the increased activation of cell migration, proliferation, survival, invasion and angiogenesis (tumor blood vessel growth). The SRC pathways have been found to be frequently disregulated in solid tumors and can increase chemotherapy resistance.

Previous laboratory studies have shown that SRC inhibition enhanced the cytotoxic efficacy of both paclitaxel and cisplatin in ovarian cancer cell lines. In vivo studies found that SRC inhibition resulted in decreased tumor growth.

“This is the first study to define the proper dose of dasatinib that, in combination with paclitaxel and carboplatin, can be moved forward into phase II or III studies,” said study co-author Robert M. Wenham, M.D., M.S., F.A.C.O.G., F.A.C.S., member of the Center for Women’s Oncology and Experimental Therapeutics Program at Moffitt. “Those additional trials may better help us understand not only the tolerability of the combination, but the efficacy in treating cancers.”

The study found that administration of dasatinib with paclitaxel did not alter the effects of either drug and that dasatinib may be better used in combination with chemotherapy agents for a synergistic effect.

“It may also be better to combine dasatinib with only one cytotoxic therapy to improve tolerability,” Wenham added.

The researchers concluded that finding biomarkers to direct the use of targeted therapies is of the utmost importance. Although SRC gene expression was not correlated with response, the research team found several differentially regulated genes between responders and those with stable disease.

“Unfortunately, a biomarker was unable to be identified to demonstrate which women are most likely to benefit from dasatinib,” said study contributor Johnathan M. Lancaster, M.D., Ph.D., chair of Moffitt’s Department of Women’s Oncology, member of the Experimental Therapeutics Program and president of the Moffitt Medical Group. “Further study should explore relevant biomarkers and identify a patient population most likely to benefit from the addition of dasatinib.”

 Abstract:

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.

Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m²) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.

Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS_6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.

Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity

Ref:

1. Moffitt Cancer Center (2012, November 14). Researchers investigate dasatinib in combination with other drugs for advanced, recurrent ovarian cancer. ScienceDaily. Retrieved December 8, 2012, from http://www.sciencedaily.com­

2. http://clincancerres.aacrjournals.org/content/18/19/5489