title: Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179).
abstract: BACKGROUND
  The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus.
  
  
  METHODS
  Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration.
  
  
  RESULTS
  Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n=2) and grade 3 fatigue (n=1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs.
  
  
  CONCLUSIONS
  Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m2, both given on day 1 with temsirolimus 25 mg on days 1 and 8.
authors: Division of Medical Oncology, BC Cancer Agency, Vancouver Cancer Centre, Vancouver.
authors: C
authors: C
authors: Kollmannsberger
authors: Division of Medical Oncology, Juravinski Cancer Centre, Hamilton.
authors: H
authors: H
authors: Hirte
authors: Princess Margaret Hospital, University Health Network, Drug Development Program, University of Toronto, Toronto.
authors: L L
authors: LL
authors: Siu
authors: Division of Gynecologic Oncology, Juravinski Cancer Centre, Hamilton.
authors: J
authors: J
authors: Mazurka
authors: Division of Medical Oncology, BC Cancer Agency, Vancouver Cancer Centre, Vancouver.
authors: K
authors: K
authors: Chi
authors: Division of Gynecologic Oncology, Juravinski Cancer Centre, Hamilton.
authors: L
authors: L
authors: Elit
authors: National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Canada.
authors: W
authors: W
authors: Walsh
authors: National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Canada.
authors: J
authors: J
authors: Sederias
authors: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA.
authors: A
authors: A
authors: Doyle
authors: National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Canada.
authors: E A
authors: EA
authors: Eisenhauer
authors: Princess Margaret Hospital, University Health Network, Drug Development Program, University of Toronto, Toronto. Electronic address: amit.oza@uhn.on.ca.
authors: A M
authors: AM
authors: Oza
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: C401859:temsirolimus; D016190:Carboplatin; D017239:Paclitaxel; D020123:Sirolimus