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

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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

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lara, P. N., Quinn, D. I., Margolin, K., Meyers, F. J., Longmate, J., Frankel, P., Mack, P., Turrell, C., Valk, P., Rao, J., Buckley, P., Wun, T., Gosselin, R., Galvin, I., Gumerlock, P. H., Lenz, H. J., Doroshow, J. H., & Gandara, D. R. (2003). SU5416 Plus Interferon α in Advanced Renal Cell Carcinoma: A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition. Clinical Cancer Research, 9(13), 4772-4781.