A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer

David B. Zhen, Kent A. Griffith, Joshua M. Ruch, Kevin Camphausen, Jason E. Savage, Edward Kim, Vaibhav Sahai, Diane M. Simeone, Mark M. Zalupski

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Summary: Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (−)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4–9.7) and 10.1 months (95 % CI: 3.6–20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Jul 21 2016
Externally publishedYes

Fingerprint

gemcitabine
Pancreatic Neoplasms
Maximum Tolerated Dose
Adenocarcinoma
Disease-Free Survival
Biomarkers
Survival
Thrombocytopenia
Sample Size
Vascular Endothelial Growth Factor A
cabozantinib
Therapeutics

Keywords

  • Cabozantinib
  • Gemcitabine
  • Pancreatic cancer
  • XL-184

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Zhen, D. B., Griffith, K. A., Ruch, J. M., Camphausen, K., Savage, J. E., Kim, E., ... Zalupski, M. M. (Accepted/In press). A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. Investigational New Drugs, 1-7. https://doi.org/10.1007/s10637-016-0376-1

A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. / Zhen, David B.; Griffith, Kent A.; Ruch, Joshua M.; Camphausen, Kevin; Savage, Jason E.; Kim, Edward; Sahai, Vaibhav; Simeone, Diane M.; Zalupski, Mark M.

In: Investigational New Drugs, 21.07.2016, p. 1-7.

Research output: Contribution to journalArticle

Zhen, DB, Griffith, KA, Ruch, JM, Camphausen, K, Savage, JE, Kim, E, Sahai, V, Simeone, DM & Zalupski, MM 2016, 'A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer', Investigational New Drugs, pp. 1-7. https://doi.org/10.1007/s10637-016-0376-1
Zhen, David B. ; Griffith, Kent A. ; Ruch, Joshua M. ; Camphausen, Kevin ; Savage, Jason E. ; Kim, Edward ; Sahai, Vaibhav ; Simeone, Diane M. ; Zalupski, Mark M. / A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. In: Investigational New Drugs. 2016 ; pp. 1-7.
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abstract = "Summary: Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (−)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 {\%} of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 {\%} for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 {\%} CI: 1.4–9.7) and 10.1 months (95 {\%} CI: 3.6–20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.",
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AU - Griffith, Kent A.

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AU - Camphausen, Kevin

AU - Savage, Jason E.

AU - Kim, Edward

AU - Sahai, Vaibhav

AU - Simeone, Diane M.

AU - Zalupski, Mark M.

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N2 - Summary: Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (−)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4–9.7) and 10.1 months (95 % CI: 3.6–20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

AB - Summary: Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (−)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4–9.7) and 10.1 months (95 % CI: 3.6–20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

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