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Clinical Trial
. 2019 Jul 1;5(7):993-998.
doi: 10.1001/jamaoncol.2019.0684.

Effect of Gemcitabine and nab-Paclitaxel With or Without Hydroxychloroquine on Patients With Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial

Thomas B Karasic  1 , Mark H O'Hara  1 , Arturo Loaiza-Bonilla  1   2 , Kim A Reiss  1 , Ursina R Teitelbaum  1 , Erkut Borazanci  3 , Ana De Jesus-Acosta  4 , Colleen Redlinger  1 , Jessica A Burrell  1 , Daniel A Laheru  4 , Daniel D Von Hoff  3   5 , Ravi K Amaravadi  1 , Jeffrey A Drebin  1   6 , Peter J O'Dwyer  1
Affiliations
Clinical Trial

Effect of Gemcitabine and nab-Paclitaxel With or Without Hydroxychloroquine on Patients With Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial

Thomas B Karasic et al. JAMA Oncol. .

Abstract

Importance: Autophagy is a mechanism of treatment resistance to chemotherapy that has a role in the maintenance of pancreatic cancer. Hydroxychloroquine sulfate (HCQ) is an inhibitor of autophagy that inhibits the fusion of the autophagosome to the lysosome.

Objective: To determine whether HCQ improves overall survival at 1 year in combination with gemcitabine hydrochloride and nab-paclitaxel (GA) among patients with metastatic pancreatic cancer.

Design, setting, and participants: Open-label, phase 2 randomized clinical trial conducted between March 18, 2013, and November 16, 2017, at the University of Pennsylvania, HonorHealth, and The Johns Hopkins University among 112 patients with previously untreated metastatic or advanced pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate marrow and organ function. All efficacy analyses were performed for the intention-to-treat population.

Interventions: Patients were randomized in a 1:1 ratio to receive GA with or without HCQ. All patients received standard doses of GA, and those randomized to receive HCQ were treated continuously with 600 mg orally twice daily.

Main outcome and measure: Overall survival at 1 year.

Results: A total of 112 patients (45 women and 67 men; median age, 65 years; range, 43-86 years) were enrolled; 55 were randomized to receive GA plus HCQ, and 57 to receive GA. Overall survival at 12 months was 41% (95% CI, 27%-53%) in the HCQ group and 49% (95% CI, 35%-61%) in the non-HCQ group. Median progression-free survival was 5.7 months (95% CI, 4.0-9.3 months) in the HCQ group and 6.4 months (95% CI, 4.5-7.6 months) in the non-HCQ group. Median overall survival was 11.1 months (95% CI, 9.0-14.2 months) in the HCQ group and 12.1 months (95% CI, 9.3-15.5 months) in the non-HCQ group. Overall response rate was 38.2% (n = 21) in the HCQ group and 21.1% (n = 12) in the non-HCQ group (P = .047). Treatment-related grade 3 or 4 adverse events that differed between the HCQ and non-HCQ groups were neutropenia (23 of 54 [42.6%] vs 12 of 53 [22.6%]), anemia (2 of 54 [3.7%] vs 9 of 53 [17.0%]), fatigue (4 of 54 [7.4%] vs 0), nausea (5 of 54 [9.3%] vs 0), peripheral neuropathy (7 of 54 [13.0%] vs 3 of 53 [5.7%]), visual changes (3 of 54 [5.6%] vs 0), and neuropsychiatric symptoms (3 of 54 [5.6%] vs 0).

Conclusions and relevance: The addition of HCQ to block autophagy did not improve the primary end point of overall survival at 12 months. These data do not support the routine use of GA plus HCQ for metastatic pancreatic cancer in the absence of a biomarker. However, improvement seen in the overall response rate with HCQ may indicate a role for HCQ in the locally advanced setting, where tumor response may permit resection.

Trial registration: ClinicalTrials.gov identifier: NCT01506973.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Karasic reported receiving grants from Celgene, Stand Up To Cancer (SU2C), and Sirtex during the conduct of the study; nonfinancial support from Syndax Corporation; and grants and nonfinancial support from Eli Lilly, Bristol-Myers Squibb, Taiho, and H3Biomedicine outside the submitted work. Dr O’Hara reported receiving grants from Bristol-Myers Squibb, Parker Institute for Cancer Immunotherapy, and Eli Lilly and personal fees from Exelixis, Karyopharm, and AstraZeneca outside the submitted work. Dr Loaiza-Bonilla reported receiving personal fees from Massive Bio, Celgene, Eisai, Guardant Health, Caris, Bristol-Myers Squibb, Taiho, Pfizer, Blueprint, and PSI CRO outside the submitted work. Dr Reiss reported grants and nonfinancial support from Lilly Oncology, Bristol-Myers Squibb, Clovis Oncology, and Tesaro outside the submitted work. Dr Borazanci reported serving on the speakers bureau for Ipsen; serving on the advisory board for Ipsen, Fujifilm, and Corcept; and receiving research funding from Bristol-Myers Squibb, Pharmacyclics, Idera, Daiichi Sankyo, Minneamrita Therapeutics, Ambry Genetics, Mabvax, Eli Lilly, and Samumed. Dr Von Hoff reported receiving grants from Stand Up To Cancer during the conduct of the study and personal fees from Celgene and Eli Lilly outside the submitted work. Dr Amaravadi reported being a founder of and owning equity in Pinpoint Therapeutics, serving as a consultant for Sprint Biosciences Immunaccell outside the submitted work, and having a patent to Lys05 issued, a patent to assyemtric bisaminoquinolines issued, and a patent to Dimeric quinacrines pending. Dr Drebin reported receiving personal fees from Luitpold Pharmaceuticals outside the submitted work. Dr O’Dwyer reported receiving grants and personal fees from Celgene during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
HCQ indicates hydroxychloroquine; ITT, intention-to-treat; and XRT, external beam radiotherapy.
Figure 2.
Figure 2.. Best Objective Response
Waterfall plot of the best objective response according to treatment group, measured as the maximum change from baseline in the sum of the longest diameter of each target lesion. HCQ indicates hydroxychloroquine; GA, gemcitabine and nab-paclitaxel.
Figure 3.
Figure 3.. Kaplan-Meier Curves for Progression-Free Survival and Overall Survival in the Intention-to-Treat Population
HCQ indicates hydroxychloroquine; HR, hazard ratio.
See this image and copyright information in PMC

References

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