Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial

Abstract

Importance: Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed.

Objective: To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer.

Design, setting, and participants: This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017.

Interventions: Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients.

Main outcomes and measures: The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population.

Results: Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment.

Conclusions and relevance: Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial.

Trial registration: ClinicalTrials.gov identifier: NCT02392637.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shroff reported receiving grants, personal fees, and nonfinancial support from Celgene during the conduct of the study; grants and personal fees from Halozyme Therapeutics, and Agios Pharmaceuticals; grants from Eli Lilly; and personal fees from Seattle Genetics, Exelixis, Merck & Co, and Codiak Biosciences outside the submitted work. Dr Javle reported being a consultant for QED Therapeutics, Merck & Co, EDO Pharma, Merck Serono, Taiho Pharmaceutical, and Incyte Corp. Dr Varadhachary reported receiving personal fees and being a member of the advisory council of Celgene outside the submitted work. Dr Ahn reported receiving consultant fees from Eisai, Exelixis, Astellas Pharma, Paradigm Biopharma, and Heron Therapeutics outside the submitted work. Dr Ramanathan reported receiving grants from Celgene during the conduct of the study and being employed by Merck & Co after conduct of the study. Dr Bekaii-Saab reported receiving personal fees from Celgene outside the submitted work. Dr Borad reported receiving grants from Celgene during the conduct of the study; grants from Fujifilm, Agios Pharmaceuticals, Halozyme Therpaeutics, Incyte Corp, Basilea Pharmaceutica, Senhwa Biosciences, Toray Pharmaceuticals, EMD Serono, Pieris Pharmaceuticals, Sun Biopharma, Mirna Therapeutics, BiolineRx, ARIAD Pharmaceuticals, Puma Biotechnology, Novartis, and QED Therapeutics; and personal fees from G1 Therapeutics, Inspyr Pharmaceuticals, Exelixis, Immunovative Therapies, OncBioMune Pharmaceuticals Inc, ADC Therapeutics, Systems Oncology, Western Oncolytics, and Lynx Group, outside the submitted work. No other disclosures are reported.

Figures

Figure 1.. Patient Enrollment and Disposition

ITT represents intention-to-treat; OS, overall survival; PFS, progression-free survival.

Figure 2.. Survival Among All Patients in the Intention-to-Treat Population for Whom Data Were Available

A, Progression-free survival (PFS) among 58 patients. B, Overall survival (OS) among 57 patients. The shaded regions represent 95% CIs.

Figure 3.. Change in Tumor Size From Baseline to Best Response Among 50 Patients in the Intention-to-Treat Population for Whom Data Were Available