Detailed results from the Phase III SUCCEED trial show that oral ridaforolimus (Merck/MSD, Ariad Pharmaceuticals), also known as AP23573 and MK-8669 and formerly known as Deforolimus, an investigational drug candidate, achieved primary endpoint of improved progression-free survival in patients with metastatic soft-tissue or bone sarcomas.

The SUCCEED trial evaluated oral ridaforolimus, an investigational mTOR inhibitor, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN known to be important to malignancy. In this trial, patients with metastatic soft-tissue or bone sarcomas previously had a avorable response to chemotherapy. In this patient population, ridaforolimus improved progression-free survival (PFS) compared to placebo, the primary endpoint of the study. The complete study results were presented by Sant P. Chawla, M.D., director, Sarcoma Oncology Center, Santa Monica, CA, during the 47th American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

Sarcomas are a group of cancers of connective tissue of the body for which there are currently limited treatment options. Sarcomas can arise anywhere in the body and are divided into two main groups ? bone tumors and soft-tissue sarcomas.

New Drug Application
Based on these results, Merck plans to submit a New Drug Application (NDA) for ridaforolimus to the U.S. Food and Drug Administration (FDA) and a marketing application in the European Union this year. “These data bring us one step closer to making ridaforolimus available to patients with metastatic sarcoma who need it and reinforces our ongoing commitment to developing innovative therapies to treat cancer,” said Eric Rubin, M.D., vice president of clinical oncology research at Merck.

Trial Results
The SUCCEED (Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus) trial was a randomized (1:1), placebo-controlled, double-blind study of oral ridaforolimus administered at 40 mg/day (five of seven days per week) in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy. Oral ridaforolimus was granted a Special Protocol Assessment (SPA) by the FDA for the SUCCEED trial.

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Based on 552 progression-free survival (PFS) events in 711 patients, (ridaforolimus (N=347), placebo (N=364)) determined by an independent radiological review committee, the study achieved its primary endpoint of improvement in PFS, with a statistically significant (p=0.0001) 28% reduction in the risk of progression or death observed in those treated with ridaforolimus compared to placebo (hazard ratio=0.72). Median PFS was 17.7 weeks for those treated with ridaforolimus compared to 14.6 weeks in the placebo group. Furthermore, based on the full analysis of PFS determined by investigator assessment, there was a statistically significant (p<0.0001) 31% reduction by ridaforolimus in the risk of progression or death compared to placebo (hazard ratio=0.69). In the investigator assessment analysis, median PFS was 22.4 weeks for those treated with ridaforolimus compared to 14.7 weeks in the placebo group.

The independent radiological committee review analysis showed that the proportion of patients alive and free from disease progression in the ridaforolimus group compared to placebo was greater after three months (70% vs. 54%), and six months (34% vs 23%).

Secondary endpoints were trends in overall survival (OS), best target lesion response, assessment of cancer-related symptoms, and safety and tolerability. Follow-up for OS is ongoing, and the current trend favors ridaforolimus: results at the most recent data cut-off (386 OS events) showed a median OS of 21.4 months for the oral ridaforolimus group compared to 19.2 months for the placebo arm (hazard ratio=0.88, p=0.2256). For the best target lesion response, the oral ridaforolimus group showed an average target tumor lesion size reduction of 1.3 percent; whereas the placebo group showed an average target tumor lesion size increase of 10.3 percent (p<0.0001). No conclusions could be drawn from the exploratory analysis of cancer-related symptoms based on patient questionnaires about pain, cough and shortness of breath due to incomplete questionnaire data.

Adverse events
The most common severe (Grade > 3) adverse events occurring at an incidence > 7% in the ridaforolimus group compared to placebo were thrombocytopenia (10% vs. 1%), stomatitis (9% vs. < 1%), anemia (7% vs. 3%), and hyperglycemia (7% vs. < 1%). The most common side effects observed in the study were consistent with the known safety profile of ridaforolimus. The most common adverse events (all Grades) occurring at an incidence > 30% in the ridaforolimus group compared to placebo were stomatitis (e.g. mouth sores) (61% vs. 18%), infections (all sites included) (52% vs. 26%), fatigue (36% vs. 22%), thrombocytopenia (34% vs. 4%), diarrhea (32% vs. 18%) and cough (31% vs. 16%). For adverse events that led to death, there were 6 deaths (1.8%) due to pulmonary disorders in the ridaforolimus treatment group and no deaths (0%) due to pulmonary disorders in the placebo group.

“Patients with metastatic soft-tissue and bone sarcomas have limited treatment options available to them. Data from the SUCCEED trial show that ridaforolimus maintained the benefit of prior conventional chemotherapy,” said Chawla. “The study met the primary endpoint of progression-free survival, showing a clinically meaningful and statistically significant improvement in PFS in those patients treated with oral ridaforolimus.”

“These updated data illustrate how challenging metastatic sarcomas can be, even in patients who have responded favorably to chemotherapy,” said Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD. “We are pleased with the results of the SUCCEED trial and look forward to Merck filing for marketing approval of ridaforolimus.”

For more information:
– Ridaforolimus in Treatment of Sarcoma-SUCCEED (Sarcoma Multi-Center Clinical Eval. of the Efficacy of Ridaforolimus)(8669-011) [NCT00538239]

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