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Войти в исследования The oncologist · 2026
Phase I trial of binimetinib plus hydroxychloroquine in patients with previously treated metastatic pancreatic cancer.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Haldar S Daniel, Saj Fen, Hong So Jung, Surana Rishi, Xiao Lianchun, Lee J Jack, Smaglo Brandon, Zhao Dan, Zhu Huili, Huey Ryan, Willis Jason, Morelli M Pia, Overman Michael, McAllister Florencia, Wolff Robert, Maitra Anirban, Fogelman David, Der Channing, Pant Shubham
Аннотация
BACKGROUND: 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).
METHODS: 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).
RESULTS: 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.
CONCLUSION: The combination of BINI + HCQ demonstrated a challenging toxicity profile and limited clinical activity in patients with chemorefractory metastatic PDAC.
METHODS: 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).
RESULTS: 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.
CONCLUSION: The combination of BINI + HCQ demonstrated a challenging toxicity profile and limited clinical activity in patients with chemorefractory metastatic PDAC.