CARRIE: A randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer

Abstract

Background: High serum IGF‐1 levels have been associated with more aggressive pancreatic cancer (PDAC). Pre‐clinical data suggest that dual blockade of the IGF‐1 and HER3 pathways has superior activity to IGF‐1 blockade alone in PDCA. We tested whether istiratumab, an IGF‐1R and ErbB3 bi‐specific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with high serum IGF‐1 levels. Methods: CARRIE was a randomized, double‐blind, placebo‐controlled, international Phase 2 study of nab‐paclitaxel/gemcitabine alone or in combination with istiratumab in front‐line metastatic PDAC. In Part 1, 10 patients were evaluated for PK and safety. In Part 2, patients with high free serum IGF‐1 levels were randomized 1:1 to receive either istiratumab (2.8 g. IV Q2W) or placebo plus nab‐paclitaxel/gemcitabine at the approved dose schedule. Heregulin (HRG) was tested in pre‐treatment tumor samples. The co‐primary endpoints were Progression Free Survival (PFS) in patients with high IGF‐1 levels and in patients with both high IGF‐1 levels and HRG+ tumors. Key secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) by RECIST v1.1, and adverse events (AEs) rate. Results: A total of 317 patients were screened to enroll 88 patients (experimental arm n=43; control n=45) in Part 2. In the high IGF‐1 cohort, median PFS was 3.6 and 7.3 months in the experimental vs. control arms, respectively (HR=1.88, p=0.027). In the combined high IGF‐1/HRG+ subgroup (n=44), median PFS was 4.1 and 7.3 months, respectively (HR=1.39, p=0.42). Median OS and ORR for the overall population were similar between two arms (8.9 and 11.7 months, HR=1.36, p=0.22 and 39.5 vs. 51.2%, p=0.33, respectively). No significant difference in serious or Grade > 3 AEs was observed, although low‐grade AEs leading to early discontinuation were higher in the experimental (39.5%) vs. control arm (24.4%). Conclusions: Istiratumab failed to improve the efficacy of SOC chemotherapy in the front‐line treatment of patients with metastatic PDAC and high IGF‐1. High serum IGF‐1 levels did not appear to be an adverse prognostic factor in this setting.