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Plimack ER , Tan T , Wong YN , von Mehren MM , Malizzia L , Roethke SK , Litwin S , Li T , Hudes GR , Haas NB
A phase I study of temsirolimus and bryostatin-1 in patients with metastatic renal cell carcinoma and soft tissue sarcoma
Oncologist. 2014 Apr;19(4) :354-5
PMID: 24674872   
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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.
1549-490x Plimack, Elizabeth R Tan, Tingting Wong, Yu-Ning von Mehren, Margaret M Malizzia, Lois Roethke, Susan K Litwin, Samuel Li, Tianyu Hudes, Gary R Haas, Naomi B Clinical Trial, Phase I Journal Article United States Oncologist. 2014 Apr;19(4):354-5. doi: 10.1634/theoncologist.2014-0020. Epub 2014 Mar 27.