Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727).

Philip A. Philip, Bryan Goldman, Ramesh K. Ramanathan, Heinz Josef Lenz, Andrew M. Lowy, Robert P. Whitehead, Takeru Wakatsuki, Syma Iqbal, Rakesh Gaur, Jacqueline K. Benedetti, Charles Blanke

Research output: Contribution to journalArticle

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Abstract

Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (<5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.

Original languageEnglish (US)
Pages (from-to)2980-2985
Number of pages6
JournalCancer
Volume120
Issue number19
DOIs
StatePublished - 2014
Externally publishedYes

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gemcitabine
Somatomedin Receptors
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Disease-Free Survival
Adenocarcinoma
Survival
Transaminases
Neutropenia
Natural History
Insulin-Like Growth Factor I
Drug Resistance
Hyperglycemia
Thrombocytopenia
Fatigue
Blood Glucose
anti-IGF-1R antibody A12
Erlotinib Hydrochloride
Fasting
Genotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer : phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). / Philip, Philip A.; Goldman, Bryan; Ramanathan, Ramesh K.; Lenz, Heinz Josef; Lowy, Andrew M.; Whitehead, Robert P.; Wakatsuki, Takeru; Iqbal, Syma; Gaur, Rakesh; Benedetti, Jacqueline K.; Blanke, Charles.

In: Cancer, Vol. 120, No. 19, 2014, p. 2980-2985.

Research output: Contribution to journalArticle

Philip, Philip A. ; Goldman, Bryan ; Ramanathan, Ramesh K. ; Lenz, Heinz Josef ; Lowy, Andrew M. ; Whitehead, Robert P. ; Wakatsuki, Takeru ; Iqbal, Syma ; Gaur, Rakesh ; Benedetti, Jacqueline K. ; Blanke, Charles. / Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer : phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). In: Cancer. 2014 ; Vol. 120, No. 19. pp. 2980-2985.
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abstract = "Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12{\%} and 6{\%}, respectively; fatigue, 16{\%} and 12{\%}, respectively; gastrointestinal, 35{\%} and 28{\%}, respectively; neutropenia, 21{\%} and 10{\%}, respectively; and thrombocytopenia, 16{\%} and 7{\%}, respecively. Grade 3/4 hyperglycemia was seen in 16{\%} of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (<5{\%}). No significant differences in PFS by genotype were seen for any of the polymorphisms. Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.",
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