A multicenter phase II study of istiratumab (MM-141) plus nab-paclitaxel (A) and gemcitabine (G) in metastatic pancreatic cancer (MPC).

Abstract

TPS481 Background: Despite recent advances in the treatment of MPC, overall prognosis for patients remains poor. This may be attributed in part to the ability of pancreatic tumors to co-opt growth factor signaling pathways to counteract the activity of chemotherapy. We previously demonstrated that IGF-1 and heregulin, the ligands for IGF-1R and ErbB3, respectively, can decrease the cytotoxic activity of A/G (JCO 33 2015 s3 a289). Additionally, co-expression of IGF-1R and ErbB3 is known to be associated with poor survival prognosis in MPC patients (JCO 33 2015 s3 a295). Istiratumab, a fully human bispecific antibody directed at IGF-1R and ErbB3, produced significant tumor regression, including durable complete responses, when combined with A/G in preclinical models of pancreatic cancer, and has been shown to be safe and tolerable in a Phase 1 study (JCO 33 2015 s3 a384). On these bases, the current Phase 2 study was developed to evaluate istiratumab plus A/G in pts with MPC. Methods: Eligible patients have biopsy-confirmed MPC, ECOG PS 0-1, no prior therapy for advanced disease, and elevated serum levels of free IGF-1 (estimated to be ~40% of all screened patients). The study design includes two parts: Part 1 (n = 12) is an open-label assessment of the safety, tolerability, and pharmacokinetics (PK) of a fixed dose of istiratumab (2.8 grams IV q 2 weeks) in combination with A/G; in Part 2 (n = 146), pts are randomized 1:1 to receive A/G plus either istiratumab or placebo. The primary objective of Part 2 is to compare progression free survival (PFS) between the two treatment arms in two distinct cohorts: a) patients with high free serum IGF-1 levels (i.e., the entire study cohort), and b) patients with both high free serum IGF-1 levels and positive expression of heregulin in tumor tissue. Additional objectives include safety, overall survival, PK and immunogenicity analyses of istiratumab, and correlative analyses of pre-defined biomarkers and their potential correlation with study outcomes. The study is designed with 80% power to detect a hazard ratio of 0.63 in favor of the experimental arm (8 vs 5 months) at a one-sided significance level of 0.05. The study has been open to enrollment as of September 2015. Clinical trial information: NCT02399137.