Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma

Journal of Hematology & Oncology
Reham Abdel-WahabMilind Javle

Abstract

Binding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer. Our study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646. MK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was ...Continue Reading

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Citations

Aug 4, 2018·Der Nervenarzt·S KnaussM Endres
Nov 23, 2019·Current Drug Metabolism·Henu K VermaSmaranika Pattnaik
Aug 28, 2020·Signal Transduction and Targeted Therapy·Qing WangHsin-Sheng Yang
May 13, 2020·Nature Reviews. Gastroenterology & Hepatology·Abdel N HoseinAnirban Maitra
May 14, 2020·Signal Transduction and Targeted Therapy·Yan ZhengQiongzhu Dong
Oct 4, 2020·Journal of Hematology & Oncology·Yunzhen QianChen Liu
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Methods Mentioned

BETA
PCA
xenografts
xenograft
biopsies
enzyme-linked immunosorbent assay

Clinical Trials Mentioned

NCT00769483

Software Mentioned

SAS
S plus
LightCycler ® 480

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