BACKGROUND: Preclinical data suggest that dual blockade of the insulin-like 
growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to 
IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested 
whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the 
efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC 
selected for high IGF-1 serum levels.
PATIENTS AND METHODS: CARRIE was an international, randomized, double-blind, 
placebo-controlled phase II study for patients with previously untreated 
metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and 
safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 
: 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or 
placebo combined with gemcitabine/nab-paclitaxel at approved dose schedule. The 
co-primary endpoints were progression-free survival (PFS) in patients with high 
IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin 
(HRG)+ tumors. Key secondary endpoints were overall survival (OS), objective 
response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate.
RESULTS: A total of 317 patients were screened, with 88 patients randomized in 
part 2 (experimental arm n = 43; control n = 45). In the high IGF-1 cohort, 
median PFS was 3.6 and 7.3 months in the experimental versus control arms, 
respectively [hazard ratio (HR) = 1.88, P = 0.027]. In the 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. 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%) versus control arm (24.4%).
CONCLUSIONS: Istiratumab failed to improve the efficacy of SOC chemotherapy in 
this patient setting. High serum IGF-1 levels did not appear to be an adverse 
prognostic factor when compared with non-biomarker-selected historic controls.
CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02399137; EUDRA CT: 
2014-004572-34.