SU5416 Plus Interferon α in Advanced Renal Cell Carcinoma: A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition

Primo N Lara, David I. Quinn, Kim Margolin, Frederick J Meyers, Jeff Longmate, Paul Frankel, Philip Mack, Corinne Turrell, Peter Valk, Jyotsna Rao, Penelope Buckley, Theodore Wun, Robert Gosselin, Irina Galvin, Paul H. Gumerlock, Heinz Josef Lenz, James H. Doroshow, David R Gandara

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Purpose: Vascular endothelial growth factor (VEGF) is expressed in up to 70% of renal cell carcinomas (RCCs) and is a rational therapeutic target. SU5416 is a small molecule inhibitor of VEGF-mediated signaling through Flk-1, a transmembrane tyrosine kinase. IFN-α also possesses dose-and schedule-dependent antiangiogenic effects at doses lower than those used for RCC therapy. We hypothesized that SU5416 plus low dose IFN-α 2B (Intron-A) would result in a 1-year event-free survival (EFS), exceeding 20% in patients with metastatic RCC using the results of a randomized immunotherapy trial as historical control. Efficacy was correlated with serial plasma VEGF and plasminogen activator inhibitor-1 levels and with positron emission tomography scans. Experimental Design: Thirty patients were treated with SU5416 145 mg/m2 i.v. twice weekly plus Intron-A 1 million units s.c. twice daily, cycled every 6 weeks. Results: Fifteen patients (50%) had stable disease (SD) at 12 weeks, including 1 minor response and 8 with progressive disease (27%). Median survival time was 10 months, and 1-year EFS was 6% (95% confidence interval, 1-35). The most common grade 3 or 4 toxicities included fatigue and lymphopenia, among others. There were 3 on-study deaths, 2 of which were infection-related. Significant declines in median plasma levels of VEGF pre- and post-therapy were observed. In 5 patients with paired FDG and O-15 positron emission tomography scans, tumor metabolism and perfusion were unchanged in 3 patients with SD, increased in 1 patient with progression, and decreased in 1 patient with SD. Conclusions: Although SU5146 plus low-dose IFN exhibits biological activity in RCC as evidenced by significant declines in serial VEGF and plasminogen activator inhibitor-1 plasma levels, the 1-year EFS of 6% and adverse toxicity profile diminishes enthusiasm for additional studies with this combination in advanced RCC.

Original languageEnglish (US)
Pages (from-to)4772-4781
Number of pages10
JournalClinical Cancer Research
Volume9
Issue number13
StatePublished - Oct 15 2003

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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