Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: A phase I/II trial

Daniel D. Von Hoff, Ramesk K Ramanathan, Mitesh J Borad, Daniel A. Laheru, Lon S. Smith, Tina E. Wood, Ronald L. Korn, Neil Desai, Vuong Trieu, Jose L. Iglesias, Hui Zhang, Patrick Soon-Shiong, Tao Shi, N. V. Rajeshkumar, Anirban Maitra, Manuel Hidalgo

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Abstract

Purpose: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2, respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. Conclusion: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

Original languageEnglish (US)
Pages (from-to)4548-4554
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number34
DOIs
StatePublished - Dec 1 2011

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gemcitabine
Pancreatic Neoplasms
Maximum Tolerated Dose
Survival
Positron-Emission Tomography
Cysteine
130-nm albumin-bound paclitaxel
Fluorodeoxyglucose F18
Neutropenia
Heterografts
Disease-Free Survival
Sepsis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer : A phase I/II trial. / Von Hoff, Daniel D.; Ramanathan, Ramesk K; Borad, Mitesh J; Laheru, Daniel A.; Smith, Lon S.; Wood, Tina E.; Korn, Ronald L.; Desai, Neil; Trieu, Vuong; Iglesias, Jose L.; Zhang, Hui; Soon-Shiong, Patrick; Shi, Tao; Rajeshkumar, N. V.; Maitra, Anirban; Hidalgo, Manuel.

In: Journal of Clinical Oncology, Vol. 29, No. 34, 01.12.2011, p. 4548-4554.

Research output: Contribution to journalArticle

Von Hoff, DD, Ramanathan, RK, Borad, MJ, Laheru, DA, Smith, LS, Wood, TE, Korn, RL, Desai, N, Trieu, V, Iglesias, JL, Zhang, H, Soon-Shiong, P, Shi, T, Rajeshkumar, NV, Maitra, A & Hidalgo, M 2011, 'Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: A phase I/II trial', Journal of Clinical Oncology, vol. 29, no. 34, pp. 4548-4554. https://doi.org/10.1200/JCO.2011.36.5742
Von Hoff, Daniel D. ; Ramanathan, Ramesk K ; Borad, Mitesh J ; Laheru, Daniel A. ; Smith, Lon S. ; Wood, Tina E. ; Korn, Ronald L. ; Desai, Neil ; Trieu, Vuong ; Iglesias, Jose L. ; Zhang, Hui ; Soon-Shiong, Patrick ; Shi, Tao ; Rajeshkumar, N. V. ; Maitra, Anirban ; Hidalgo, Manuel. / Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer : A phase I/II trial. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 34. pp. 4548-4554.
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abstract = "Purpose: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2, respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48{\%}, with 12.2 median months of overall survival (OS) and 48{\%} 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. Conclusion: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.",
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T1 - Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer

T2 - A phase I/II trial

AU - Von Hoff, Daniel D.

AU - Ramanathan, Ramesk K

AU - Borad, Mitesh J

AU - Laheru, Daniel A.

AU - Smith, Lon S.

AU - Wood, Tina E.

AU - Korn, Ronald L.

AU - Desai, Neil

AU - Trieu, Vuong

AU - Iglesias, Jose L.

AU - Zhang, Hui

AU - Soon-Shiong, Patrick

AU - Shi, Tao

AU - Rajeshkumar, N. V.

AU - Maitra, Anirban

AU - Hidalgo, Manuel

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Purpose: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2, respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. Conclusion: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

AB - Purpose: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2, respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. Conclusion: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

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