Background: 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.
Methods: 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.
Results: 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 not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P = 0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3-4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B).
Conclusions: MK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome.
Trial registration: This trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008.
Keywords: Advanced pancreatic adenocarcinoma; Erlotinib; Gemcitabine; MK-0646.