Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial

Autophagy, a regulated metabolic process that enables energy conservation in adverse environmental circumstances, has been shown in animal models to confer resistance to chemotherapy, which can be reversed by hydroxychloroquine (HCQ). After establishing safety in a Phase I run-in, 112 patients were randomized to receive standard gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) weekly x 3 every 4 weeks, with (n=55 evaluable) or without (n=55 evaluable) HCQ 600mg bid. Median age was 65 (range 43-86) of whom 47% were aged u003e 65, 40% were female, 93% Caucasian, ECOG PS 0/1 51%/49%, and did not differ between the arms. Treatment-related side-effects were consistent with prior studies, and were balanced by arm, except for Grade 3/4 neutropenia (42 vs 23%), nausea (9 vs 0%), and fatigue (7 vs 0%), all higher with HCQ. Partial responses were observed in 21/46 (46%) with HCQ, and 8/48 (17%) without HCQ. The primary endpoint, overall survival at 12 months, was 41% (95% CI 27-53%) in the HCQ arm and 51% (95% CI 36-63%) in the non-HCQ arm. Median progression-free survival was 5.7 months (95% CI 4.0-9.3) in the HCQ arm and 6.4 months in the non-HCQ arm (95% CI 4.5-7.6). Median overall survival was 11.1 months (95% CI 9.0-14.2) in the HCQ arm and 14.4 months (95% CI 9.5-15.6) in the non-HCQ arm. Genomic testing was performed on a subset of the patients (41%), in whom outcomes did not differ by p53 mutational status. We conclude that based on the primary endpoint, the addition of the autophagy reversal agent HCQ did not improve the survival of patients with metastatic pancreatic cancer. Response rates in patients who received HCQ were higher, and toxicity was tolerable. Autophagy reversal might be explored in the management of locally-advanced disease. Citation Format: Thomas B. Karasic, Mark H. O9Hara, Arturo Loaiza-Bonilla, Kim A. Reiss-Binder, Ursina R. Teitelbaum, Erkut Borazanci, Ana M. De Jesus-Acosta, Colleen Redlinger, Jessica A. Burrell, Daniel D. Von Hoff, Daniel A. Laheru, Ravi K. Amaravadi, Jeffrey A. Drebin, Peter J. O9Dwyer. Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT085.