{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:00:42Z","timestamp":1790913642731,"version":"4.1.0"},"reference-count":14,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pancreatic Cancer Action Network-AACR Research Acceleration Network","award":["15-90-25-DER"],"award-info":[{"award-number":["15-90-25-DER"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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, \u22651 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>From December 2019 to August 2024, 34 patients were enrolled in dose escalation (n\u2009=\u200917) and dose expansion (n\u2009=\u200917). Two dose-limiting toxicities occurred among the first 3 patients treated at dose level 1 (BINI 45\u2009mg + HCQ 600\u2009mg): 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\u2009mg + HCQ 600\u2009mg 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\u2009months, and median OS was 5.3\u2009months.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The combination of BINI + HCQ demonstrated a challenging toxicity profile and limited clinical activity in patients with chemorefractory metastatic PDAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag071","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T12:42:34Z","timestamp":1772109754000},"source":"Crossref","is-referenced-by-count":5,"title":["Phase I trial of binimetinib plus hydroxychloroquine in patients with previously treated metastatic pancreatic cancer"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2346-0566","authenticated-orcid":false,"given":"S Daniel","family":"Haldar","sequence":"first","affiliation":[{"name":"Department of 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