A Phase I Study of Temsirolimus and Bryostatin-1 in Patients With Metastatic Renal Cell Carcinoma and Soft Tissue Sarcoma

Abstract

BACKGROUND: Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 mug/m(2)) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles. RESULTS: Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 mug/m(2) every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and >/= 80 months, respectively. Partial responses were seen in both clear cell and papillary histology. CONCLUSION: This combination of 37.5 mg of temsirolimus with 20 mug/m(2) of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.