Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial

Vaibhav Sahai, Paul J. Catalano, Mark M. Zalupski, Sam Joseph Lubner, Mark R. Menge, Halla Sayed Nimeiri, Hidayatullah G Munshi, Al B Benson III, Peter J. O'Dwyer

Research output: Contribution to journalArticle

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Abstract

Importance: Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity. Objective: To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma. Design, Setting, and Participants: This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted. Interventions: Patients received intravenous nab-paclitaxel, 125 mg/m 2 , followed by gemcitabine, 1000 mg/m 2 , on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55% and 70%, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival. Results: Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60%), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61% (95% CI, 48%-73%) did not favor the alternative hypothesis. Median PFS was 7.7 (95% CI, 5.4-13.1) months, median OS was 12.4 (95% CI, 9.2-15.9) months, and median time to progression was 7.7 (95% CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30% and 66%, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95% CI, 0.86-4.75) (P =.10) and 1.54 (95% CI, 0.64-3.71) (P =.34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43%) and fatigue (14%), respectively. Conclusions and Relevance: Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma.

Original languageEnglish (US)
Pages (from-to)1707-1712
Number of pages6
JournalJAMA Oncology
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2018

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gemcitabine
Cholangiocarcinoma
Clinical Trials
Disease-Free Survival
Nanoparticles
Survival
Therapeutics
Survival Rate
Carbohydrates
Antigens
Poisons
Drug Combinations
Paclitaxel
130-nm albumin-bound paclitaxel
Neutropenia
Platinum
Fatigue
Disease Progression
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sahai, V., Catalano, P. J., Zalupski, M. M., Lubner, S. J., Menge, M. R., Nimeiri, H. S., ... O'Dwyer, P. J. (2018). Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncology, 4(12), 1707-1712. https://doi.org/10.1001/jamaoncol.2018.3277
Sahai, Vaibhav ; Catalano, Paul J. ; Zalupski, Mark M. ; Lubner, Sam Joseph ; Menge, Mark R. ; Nimeiri, Halla Sayed ; Munshi, Hidayatullah G ; Benson III, Al B ; O'Dwyer, Peter J. / Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma : A Phase 2 Clinical Trial. In: JAMA Oncology. 2018 ; Vol. 4, No. 12. pp. 1707-1712.
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abstract = "Importance: Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity. Objective: To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma. Design, Setting, and Participants: This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted. Interventions: Patients received intravenous nab-paclitaxel, 125 mg/m 2 , followed by gemcitabine, 1000 mg/m 2 , on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55{\%} and 70{\%}, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival. Results: Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60{\%}), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61{\%} (95{\%} CI, 48{\%}-73{\%}) did not favor the alternative hypothesis. Median PFS was 7.7 (95{\%} CI, 5.4-13.1) months, median OS was 12.4 (95{\%} CI, 9.2-15.9) months, and median time to progression was 7.7 (95{\%} CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30{\%} and 66{\%}, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95{\%} CI, 0.86-4.75) (P =.10) and 1.54 (95{\%} CI, 0.64-3.71) (P =.34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43{\%}) and fatigue (14{\%}), respectively. Conclusions and Relevance: Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma.",
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Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma : A Phase 2 Clinical Trial. / Sahai, Vaibhav; Catalano, Paul J.; Zalupski, Mark M.; Lubner, Sam Joseph; Menge, Mark R.; Nimeiri, Halla Sayed; Munshi, Hidayatullah G; Benson III, Al B; O'Dwyer, Peter J.

In: JAMA Oncology, Vol. 4, No. 12, 01.12.2018, p. 1707-1712.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma

T2 - A Phase 2 Clinical Trial

AU - Sahai, Vaibhav

AU - Catalano, Paul J.

AU - Zalupski, Mark M.

AU - Lubner, Sam Joseph

AU - Menge, Mark R.

AU - Nimeiri, Halla Sayed

AU - Munshi, Hidayatullah G

AU - Benson III, Al B

AU - O'Dwyer, Peter J.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Importance: Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity. Objective: To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma. Design, Setting, and Participants: This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted. Interventions: Patients received intravenous nab-paclitaxel, 125 mg/m 2 , followed by gemcitabine, 1000 mg/m 2 , on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55% and 70%, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival. Results: Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60%), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61% (95% CI, 48%-73%) did not favor the alternative hypothesis. Median PFS was 7.7 (95% CI, 5.4-13.1) months, median OS was 12.4 (95% CI, 9.2-15.9) months, and median time to progression was 7.7 (95% CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30% and 66%, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95% CI, 0.86-4.75) (P =.10) and 1.54 (95% CI, 0.64-3.71) (P =.34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43%) and fatigue (14%), respectively. Conclusions and Relevance: Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma.

AB - Importance: Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity. Objective: To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma. Design, Setting, and Participants: This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted. Interventions: Patients received intravenous nab-paclitaxel, 125 mg/m 2 , followed by gemcitabine, 1000 mg/m 2 , on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55% and 70%, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival. Results: Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60%), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61% (95% CI, 48%-73%) did not favor the alternative hypothesis. Median PFS was 7.7 (95% CI, 5.4-13.1) months, median OS was 12.4 (95% CI, 9.2-15.9) months, and median time to progression was 7.7 (95% CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30% and 66%, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95% CI, 0.86-4.75) (P =.10) and 1.54 (95% CI, 0.64-3.71) (P =.34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43%) and fatigue (14%), respectively. Conclusions and Relevance: Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma.

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