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 language | English (US) |
|---|---|
| Pages (from-to) | 4772-4781 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 9 |
| Issue number | 13 |
| State | Published - Oct 15 2003 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
SU5416 Plus Interferon α in Advanced Renal Cell Carcinoma : A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition. / Lara, Primo N; Quinn, David I.; Margolin, Kim; Meyers, Frederick J; Longmate, Jeff; Frankel, Paul; Mack, Philip; Turrell, Corinne; Valk, Peter; Rao, Jyotsna; Buckley, Penelope; Wun, Theodore; Gosselin, Robert; Galvin, Irina; Gumerlock, Paul H.; Lenz, Heinz Josef; Doroshow, James H.; Gandara, David R.
In: Clinical Cancer Research, Vol. 9, No. 13, 15.10.2003, p. 4772-4781.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - SU5416 Plus Interferon α in Advanced Renal Cell Carcinoma
T2 - A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition
AU - Lara, Primo N
AU - Quinn, David I.
AU - Margolin, Kim
AU - Meyers, Frederick J
AU - Longmate, Jeff
AU - Frankel, Paul
AU - Mack, Philip
AU - Turrell, Corinne
AU - Valk, Peter
AU - Rao, Jyotsna
AU - Buckley, Penelope
AU - Wun, Theodore
AU - Gosselin, Robert
AU - Galvin, Irina
AU - Gumerlock, Paul H.
AU - Lenz, Heinz Josef
AU - Doroshow, James H.
AU - Gandara, David R
PY - 2003/10/15
Y1 - 2003/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=10744225601&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=10744225601&partnerID=8YFLogxK
M3 - Article
C2 - 14581348
AN - SCOPUS:10744225601
VL - 9
SP - 4772
EP - 4781
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 13
ER -