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 journalArticle

59 Citations (Scopus)

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

Fingerprint

Renal Cell Carcinoma
Interferons
Vascular Endothelial Growth Factor A
Neoplasms
Disease-Free Survival
Plasminogen Activator Inhibitor 1
Positron-Emission Tomography
Introns
Lymphopenia
Cell- and Tissue-Based Therapy
Semaxinib
Protein-Tyrosine Kinases
Immunotherapy
Fatigue
Appointments and Schedules
Research Design
Therapeutics
Perfusion
Confidence Intervals
Survival

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 journalArticle

Lara, PN, Quinn, DI, Margolin, K, Meyers, FJ, Longmate, J, Frankel, P, Mack, P, Turrell, C, Valk, P, Rao, J, Buckley, P, Wun, T, Gosselin, R, Galvin, I, Gumerlock, PH, Lenz, HJ, Doroshow, JH & Gandara, DR 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, vol. 9, no. 13, pp. 4772-4781.
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. / SU5416 Plus Interferon α in Advanced Renal Cell Carcinoma : A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 13. pp. 4772-4781.
@article{7bf703fa2d684a868ef70d593b5ef63a,
title = "SU5416 Plus Interferon α in Advanced Renal Cell Carcinoma: A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition",
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.",
author = "Lara, {Primo N} and Quinn, {David I.} and Kim Margolin and Meyers, {Frederick J} and Jeff Longmate and Paul Frankel and Philip Mack and Corinne Turrell and Peter Valk and Jyotsna Rao and Penelope Buckley and Theodore Wun and Robert Gosselin and Irina Galvin and Gumerlock, {Paul H.} and Lenz, {Heinz Josef} and Doroshow, {James H.} and Gandara, {David R}",
year = "2003",
month = "10",
day = "15",
language = "English (US)",
volume = "9",
pages = "4772--4781",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

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 -