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The study tested whether autophagy blockade with hydroxychloroquine (HCQ) could overcome resistance to MEK inhibition with binimetinib (BINI) and produce clinical benefit in previously treated KRAS-mutated metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: Single-arm, open-label phase I dose escalation/expansion evaluated safety and tolerability of BINI + HCQ (NCT04132505). Results: Among 31 response-evaluable patients, ORR was 6.5% and DCR 35.5%; median PFS was 1.9 months and median OS 5.3 months. Conclusion: Toxicity was challenging with limited clinical activity.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/phase-i-trial-of-binimetinib-plus-hydroxychloroquine-in-patients-with-previously-treated-metastatic-pancreatic-cancer/352591/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/phase-i-trial-of-binimetinib-plus-hydroxychloroquine-in-patients-with-previously-treated-metastatic-pancreatic-cancer/352591.png","ImageObject",300,407,{"name":92,"@type":93},"\tJames","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What was the main hypothesis of this phase I trial?","Question",{"text":112,"@type":113},"The trial hypothesized that blocking autophagy with hydroxychloroquine could overcome resistance to MEK inhibition caused by binimetinib and provide clinical benefit in previously treated KRAS-mutated metastatic PDAC.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was the study designed and what was the primary endpoint?",{"text":117,"@type":113},"This investigator-led, single-arm, open-label phase I study used dose escalation/expansion to evaluate safety and tolerability. The primary endpoint was the maximum-tolerated dose (MTD).",{"name":119,"@type":110,"acceptedAnswer":120},"What were the key efficacy and survival outcomes reported?",{"text":121,"@type":113},"Among response-evaluable patients, ORR was 6.5% and DCR was 35.5%. Median progression-free survival was 1.9 months and median overall survival was 5.3 months.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},352591,1790381039,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":39,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":46},2336474466412,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","The Oncologist, 2026, 31, oyag071  \n[https://doi.org/10.1093/oncolo/oyag071](https://doi.org/10.1093/oncolo/oyag071)  \n[Published: 27 February 2026](Published: 27 February 2026)  \nClinical Trial Results  \nPhase I trial of binimetinib plus hydroxychloroquine inpatients with previously treated metastatic pancreatic cancer  \nS. Daniel Haldar1,*,\\#, , Fen Saj1,\\#, So Jung Hong1, Rishi Surana2, Lianchun Xiao3, J. Jack Lee3, Brandon Smaglo1, Dan Zhao1, , Huili Zhu1, Ryan Huey1, Jason Willis1, , M. Pia Morelli1, Michael Overman1, Florencia McAllister1, Robert Wolff1, , Anirban Maitra4, David Fogelman5, Channing Der6, Shubham Pant1,‡  \n1 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, United States  \n3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States 4 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States 5 Merck & Co., Inc, North Wales, PA, 19454, United States  \n6 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States  \n*Corresponding author: S. Daniel Haldar, MD, Department of Gastrointestinal Medical Oncology, 1515 Holcombe Blvd, Unit 0426, Houston, TX 77030-4009, USA ([sdhaldar@mdanderson.org](sdhaldar@mdanderson.org)) .  \n‡ Principal Investigator: Shubham Pant, MD, MBBS  \n\\#S. Daniel Haldar and Fen Saj contributed equally to this work.  \nAbstract  \nBackground: Dual mitogen-activated protein kinase (MAPK) pathway and autophagy inhibition show synergistic antitumor activity in preclinical models of RAS-mutant cancers. We hypothesized that autophagy blockade with hydroxychloroquine (HCQ) could overcome resistance to MEK inhibition with binimetinib (BINI) and provide clinical benefit in previously treated, KRAS-mutated, metastatic pancreatic ductal adenocarcinoma (PDAC).  \nMethods: This investigator-led, single-arm, open-label, phase I dose escalation/expansion trial evaluated the safety and tolerability of BINI + HCQ in patients with previously treated, metastatic PDAC (NCT04132505). Key eligibility criteria: ECOG 0-1, adequate organ function, ≥1 prior line of therapy for metastatic disease, and presence of KRAS mutation. Dose escalation followed a Bayesian optimal interval design. The primary endpoint was the maximum-tolerated dose (MTD). Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR), progression-free survival, and overall survival (OS).  \nResults: From December 2019 to August 2024, 34 patients were enrolled in dose escalation (n = 17) and dose expansion (n = 17). Two dose-limiting toxicities occurred among the first 3 patients treated at dose level 1 (BINI 45 mg + HCQ 600 mg): grade 3 creatine phosphokinase elevation with renal impairment (BINI) and grade 3 QT prolongation (HCQ). Following dose de-escalation due to poor tolerance, the MTD was determined to be BINI 30 mg + HCQ 600 mg twice daily and used in the expansion. Out of 31 response-evaluable patients, 2 patients achieved a partial response and 9 patients achieved stable disease, yielding ORR 6.5% and DCR 35.5%, respectively. Median progression-free survival was 1.9 months, and median OS was 5.3 months.  \nConclusion: The combination of BINI + HCQ demonstrated a challenging toxicity profile and limited clinical activity inpatients with chemorefractory metastatic PDAC.  \nKey words: pancreatic cancer; KRAS; autophagy; MEK inhibition; hydroxychloroquine  \nReceived: July 24, 2025. Accepted: February 23, 2026 © The Author(s) 2026. Published by Oxford University Press.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)), which p","cbCaistjmltYP7qj","https://ap.wps.com/l/cbCaistjmltYP7qj","pdf",831685,"English","# Background\n# Methods\n# Results\n# Conclusion\n# Key words\n# Introduction\n# Lessons learned","[{\"question\":\"What was the main hypothesis of this phase I trial?\",\"answer\":\"The trial hypothesized that blocking autophagy with hydroxychloroquine could overcome resistance to MEK inhibition caused by binimetinib and provide clinical benefit in previously treated KRAS-mutated metastatic PDAC.\"},{\"question\":\"How was the study designed and what was the primary endpoint?\",\"answer\":\"This investigator-led, single-arm, open-label phase I study used dose escalation/expansion to evaluate safety and tolerability. The primary endpoint was the maximum-tolerated dose (MTD).\"},{\"question\":\"What were the key efficacy and survival outcomes reported?\",\"answer\":\"Among response-evaluable patients, ORR was 6.5% and DCR was 35.5%. Median progression-free survival was 1.9 months and median overall survival was 5.3 months.\"}]","Phase I trial of binimetinib plus hydroxychloroquine in patients with previously treated metastatic pancreatic cancer | PDF",1790100388]