title: 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 μg/m²) 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 μg/m² 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.
  
  
  CONCLUSIONS
  This combination of 37.5 mg of temsirolimus with 20 μg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA;
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.forename: Tingting
authors.initials: T
authors.lastname: Tan
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Wong
authors.forename: Margaret M
authors.initials: MM
authors.lastname: von Mehren
authors.forename: Lois
authors.initials: L
authors.lastname: Malizzia
authors.forename: Susan K
authors.initials: SK
authors.lastname: Roethke
authors.forename: Samuel
authors.initials: S
authors.lastname: Litwin
authors.forename: Tianyu
authors.initials: T
authors.lastname: Li
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hudes
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Haas
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D054713:Bryostatins / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality; D004334:Drug Administration Schedule; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C046785:bryostatin 1; C401859:temsirolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D020123:Sirolimus