Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma.
OBJECTIVE
Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC.


METHODS
Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information.


RESULTS
Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months.


CONCLUSIONS
The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.
Motzer
Robert J
RJ
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. motzerr@mskcc.org
Hudes
Gary R
GR
Curti
Brendan D
BD
McDermott
David F
DF
Escudier
Bernard J
BJ
Negrier
Sylvie
S
Duclos
Brigitte
B
Moore
Laurence
L
O'Toole
Timothy
T
Boni
Joseph P
JP
Dutcher
Janice P
JP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004066:Digestive System Diseases / Q000139:chemically induced; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000209:etiology; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012140:Respiratory Tract Diseases / Q000139:chemically induced; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D016898:Interferon-alpha; C401859:temsirolimus; D020123:Sirolimus