Phase I trial of sunitinib and temsirolimus in metastatic renal cell carcinoma - Abstract

BACKGROUND: Preclinical data suggest that anti-vascular endothelial growth factor agents combined with mammalian target of rapamycin inhibitors yield synergistic antitumor effects.

A phase I trial with a 3+3 dose escalation design of S with T was stopped after the first dose pair led to 2 of 3 patients experiencing dose-limiting toxicity (DLT).

PATIENTS AND METHODS: To explore multiple potential dosing pairs of S and T, a 2-stage outcome-adaptive Bayesian dose-finding method was designed. The primary objective was to find the MTD of S and T in patients with advanced renal cell carcinoma. A 3-week treatment cycle consisted of daily S, 2 weeks of treatment, 1 week without treatment, and weekly T.

RESULTS: Twenty patients received study drugs; the median number of previous therapies was 1. The number of patients (S and T doses in mg) was: 2 (S, 12.5; T, 6), 1 (S, 25; T, 12.5), 1 (S, 12.5; T, 8), 8 (S, 12.5 alternate 25; T, 9), 2 (S, 25; T, 6), 2 (S, 25 alternate 37.5; T, 6), 2 (S, 37.5; T, 6), and 2 (S, 37.5; T, 8). Six patients required dose reduction, 3 because of Grade 3 stomatitis, 2 because of Grade 3 thrombocytopenia; the mean number of cycles was 6.6 ± 5.3, the mean time during study was 159 ± 120 days. One patient experienced a DLT in cycle 1 and was nonevaluable, 1 had a partial response, 16 had stable disease, and 2 had progressive disease as best response. There were 21 Grade 3/4 adverse events but no treatment-related deaths.

CONCLUSION: The MTD of S and T were not determined because of premature trial closure. S 37.5 mg/d, 2 weeks of treatment, 1 week with no treatment, and T 8 mg to 10 mg weekly are close to the MTD.

Written by:
Campbell MT, Millikan RE, Altinmakas E, Xiao L, Wen SJ, Siefker-Radtke AO, Aparicio A, Corn PG, Tannir NM.   Are you the author?
Division of Cancer Medicine Fellowship Program, University of Texas M.D. Anderson Cancer Center, Houston, TX; Essential Health, Essentia Health Duluth Cancer Center, Duluth, MN; Diagnostic Radiology Department, University of Texas M.D. Anderson Cancer Center, Houston, TX; Biostatistics Department, University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Biostatistics, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV; Genitourinary Medical Oncology Department, University of Texas M.D. Anderson Cancer Center, Houston, TX.  

Reference: Clin Genitourin Cancer. 2014 Oct 24. pii: S1558-7673(14)00234-1.
doi: 10.1016/j.clgc.2014.10.004


PubMed Abstract
PMID: 25465491

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