PMID- 31912800 OWN - NLM STAT- MEDLINE DCOM- 20210106 LR - 20221207 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 31 IP - 1 DP - 2020 Jan TI - 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). PG - 79-87 LID - S0923-7534(19)35405-5 [pii] LID - 10.1016/j.annonc.2019.09.004 [doi] AB - 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. CI - Copyright (c) 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved. FAU - Kundranda, M AU - Kundranda M AD - Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, USA. FAU - Gracian, A C AU - Gracian AC AD - Medical Oncology, Centro Integral Oncologico Clara Campal, Madrid, Spain; Departamento de Ciencias Medicas Clinicas, Universidad CEU San Pablo, Madrid, Spain. FAU - Zafar, S F AU - Zafar SF AD - Hematology and Oncology, Florida Cancer Specialists, Fort Myers, USA. FAU - Meiri, E AU - Meiri E AD - Medical Oncology, Comprehensive Care and Research Center, Atlanta, USA. FAU - Bendell, J AU - Bendell J AD - GI Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA. FAU - Algul, H AU - Algul H AD - TUM School of Medicine, Klinikum rechts der Isar, Medizinische Klinik II, Technical University of Munich, Munich, Germany. FAU - Rivera, F AU - Rivera F AD - Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander, Spain. FAU - Ahn, E R AU - Ahn ER AD - Medical Oncology, Cancer Treatment Centers of America Chicago, Zion, USA. FAU - Watkins, D AU - Watkins D AD - Department of Medicine, Royal Marsden Hospital, Sutton, UK. FAU - Pelzer, U AU - Pelzer U AD - Charite - Universitatsmedizin Berlin, Germany. FAU - Charu, V AU - Charu V AD - Hematology/Oncology, Pacific Cancer Medical Center, Anaheim, USA. FAU - Zalutskaya, A AU - Zalutskaya A AD - Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge, USA. FAU - Kuesters, G AU - Kuesters G AD - Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge, USA. FAU - Pipas, J M AU - Pipas JM AD - Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge, USA. FAU - Santillana, S AU - Santillana S AD - Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge, USA. FAU - Askoxylakis, V AU - Askoxylakis V AD - Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge, USA. FAU - Ko, A H AU - Ko AH AD - Hematology/Oncology, University of California San Francisco Cancer Center, San Francisco, USA. Electronic address: andrew.ko@ucsf.edu. LA - eng SI - ClinicalTrials.gov/NCT02399137 SI - EudraCT/2014-004572-34 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (130-nm albumin-bound paclitaxel) RN - 0 (Albumins) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0W860991D6 (Deoxycytidine) RN - P88XT4IS4D (Paclitaxel) RN - XLR461MD3M (Istiratumab) RN - 0 (Gemcitabine) SB - IM EIN - Ann Oncol. 2020 Aug;31(8):1094. PMID: 32507672 MH - Albumins MH - Antibodies, Monoclonal, Humanized MH - *Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Deoxycytidine/analogs & derivatives MH - Humans MH - Paclitaxel/therapeutic use MH - *Pancreatic Neoplasms/drug therapy MH - Gemcitabine OTO - NOTNLM OT - CARRIE OT - MM-141 OT - heregulin OT - insulin-like growth factor 1 OT - istiratumab OT - metastatic pancreatic cancer EDAT- 2020/01/09 06:00 MHDA- 2021/01/07 06:00 CRDT- 2020/01/09 06:00 PHST- 2019/05/02 00:00 [received] PHST- 2019/07/25 00:00 [revised] PHST- 2019/09/24 00:00 [accepted] PHST- 2020/01/09 06:00 [entrez] PHST- 2020/01/09 06:00 [pubmed] PHST- 2021/01/07 06:00 [medline] AID - S0923-7534(19)35405-5 [pii] AID - 10.1016/j.annonc.2019.09.004 [doi] PST - ppublish SO - Ann Oncol. 2020 Jan;31(1):79-87. doi: 10.1016/j.annonc.2019.09.004.