SU5416 plus interferon alpha in advanced renal cell carcinoma: a phase II California Cancer Consortium Study with biological and imaging correlates of angiogenesis inhibition.
OBJECTIVE
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-alpha 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-alpha 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.


METHODS
Thirty patients were treated with SU5416 145 mg/m(2) 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 posttherapy 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.
Lara
Primo N
PN
University of California Davis Cancer Center, Sacramento, California 95817, USA. primo.lara@ucdmc.ucdavis.com
Quinn
David I
DI
Margolin
Kim
K
Meyers
Frederick J
FJ
Longmate
Jeff
J
Frankel
Paul
P
Mack
Philip C
PC
Turrell
Corinne
C
Valk
Peter
P
Rao
Jyotsna
J
Buckley
Penelope
P
Wun
Ted
T
Gosselin
Robert
R
Galvin
Irina
I
Gumerlock
Paul H
PH
Lenz
Heinz Josef
HJ
Doroshow
James H
JH
Gandara
David R
DR
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002140:California; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007211:Indoles / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011758:Pyrroles / Q000627:therapeutic use*; D011994:Recombinant Proteins; D013997:Time Factors; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D007211:Indoles; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011758:Pyrroles; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib