Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers

A Phase 2 Clinical Trial

Rachna T. Shroff, Milind M. Javle, Lianchun Xiao, Ahmed O. Kaseb, Gauri R. Varadhachary, Robert A. Wolff, Kanwal P.S. Raghav, Michiko Iwasaki, Peter Masci, Ramesk K Ramanathan, Daniel Ahn, Tanios Bekaii-Saab, Mitesh J Borad

Research output: Contribution to journalArticle

2 Citations (Scopus)

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/m 2 , cisplatin, 25 mg/m 2 , and nab-paclitaxel, 125 mg/m 2 , 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/m 2 , 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.

Original languageEnglish (US)
JournalJAMA Oncology
DOIs
StatePublished - Jan 1 2019

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gemcitabine
Biliary Tract Neoplasms
Nanoparticles
Cisplatin
Clinical Trials
Disease-Free Survival
Therapeutics
Survival
Cholangiocarcinoma
Albumin-Bound Paclitaxel
Gallbladder Neoplasms
Phase III Clinical Trials
Patient Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers : A Phase 2 Clinical Trial. / Shroff, Rachna T.; Javle, Milind M.; Xiao, Lianchun; Kaseb, Ahmed O.; Varadhachary, Gauri R.; Wolff, Robert A.; Raghav, Kanwal P.S.; Iwasaki, Michiko; Masci, Peter; Ramanathan, Ramesk K; Ahn, Daniel; Bekaii-Saab, Tanios; Borad, Mitesh J.

In: JAMA Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Shroff, Rachna T. ; Javle, Milind M. ; Xiao, Lianchun ; Kaseb, Ahmed O. ; Varadhachary, Gauri R. ; Wolff, Robert A. ; Raghav, Kanwal P.S. ; Iwasaki, Michiko ; Masci, Peter ; Ramanathan, Ramesk K ; Ahn, Daniel ; Bekaii-Saab, Tanios ; Borad, Mitesh J. / Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers : A Phase 2 Clinical Trial. In: JAMA Oncology. 2019.
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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/m 2 , cisplatin, 25 mg/m 2 , and nab-paclitaxel, 125 mg/m 2 , 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/m 2 , 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.",
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TY - JOUR

T1 - Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers

T2 - A Phase 2 Clinical Trial

AU - Shroff, Rachna T.

AU - Javle, Milind M.

AU - Xiao, Lianchun

AU - Kaseb, Ahmed O.

AU - Varadhachary, Gauri R.

AU - Wolff, Robert A.

AU - Raghav, Kanwal P.S.

AU - Iwasaki, Michiko

AU - Masci, Peter

AU - Ramanathan, Ramesk K

AU - Ahn, Daniel

AU - Bekaii-Saab, Tanios

AU - Borad, Mitesh J

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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/m 2 , cisplatin, 25 mg/m 2 , and nab-paclitaxel, 125 mg/m 2 , 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/m 2 , 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.

AB - 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/m 2 , cisplatin, 25 mg/m 2 , and nab-paclitaxel, 125 mg/m 2 , 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/m 2 , 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.

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