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

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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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Acknowledgments

The authors thank Bill Reisdorph for his excellent management of the study specific IND 114,716. Young Lee processed urinary samples for the correlative molecular biomarker analysis. Donald Bottaro of the Urologic Oncology Branch at the National Cancer Institute (NCI) provided access to the electrochemiluminescence instrument for the c-Met assay. Exelixis, Inc. provided cabozantinib for this study. Research reported in this publication was supported by the NCI of the National Institutes of Health under award number P30CA046592, Michigan Institute for Clinical and Health Research (MICHR) under award number UL1TR000433, and funded in part by the intramural program of the NCI.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, 3-219 CC, 1500 E Medical Center Dr., SPC 5934, Ann Arbor, MI, 48109-5934, USA

    David B. Zhen, Joshua M. Ruch, Edward J. Kim, Vaibhav Sahai & Mark M. Zalupski

  2. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Kent A. Griffith

  3. Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Kevin Camphausen & Jason E. Savage

  4. Department of Surgery, University of Michigan, Ann Arbor, MI, USA

    Diane M. Simeone

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Correspondence to Mark M. Zalupski.

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Zhen, D.B., Griffith, K.A., Ruch, J.M. et al. A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer. Invest New Drugs 34, 733–739 (2016). https://doi.org/10.1007/s10637-016-0376-1

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