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 (CARRIE).
Ann Oncol
; 31(1): 79-87, 2020 01.
Article
en En
| MEDLINE
| ID: mdl-31912800
ABSTRACT
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 ANDMETHODS:
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.Palabras clave
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Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Protocolos de Quimioterapia Combinada Antineoplásica
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article