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Investigational New Drugs

, Volume 34, Issue 2, pp 176–183 | Cite as

Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers

  • Elizabeth R. Kessler
  • S. Gail Eckhardt
  • Todd M. Pitts
  • Erica L. Bradshaw-Pierce
  • Cindy L. O’byrant
  • Wells A. Messersmith
  • Sujatha Nallapreddy
  • Colin Weekes
  • Jennifer Spratlin
  • Christopher H. Lieu
  • Madeleine A. Kane
  • Sarah Eppers
  • Elizabeth Freas
  • Stephen Leong
PHASE I STUDIES

Summary

Background Vandetanib is a multitargeted tyrosine kinase inhibitor that affects vascular endothelial growth factor receptor (VEGF), epidermal growth factor (EGF), and rearranged during transfection (RET) mediated receptors which are important for growth and invasion of biliary and pancreatic cancers. This phase I study evaluated the safety profile of vandetanib in combination with standard doses of gemcitabine and capecitabine in order to determine the maximum tolerated dose (MTD). Methods In this single center phase I trial, patients received gemcitabine intravenously (IV) at 1000 mg/m2 days 1, 8, 15 in a 28 day cycle, capecitabine orally at 850 mg/m2 twice daily on days 1–21, and escalating doses of vandetanib (200 or 300 mg orally daily). Once the MTD was defined, an expansion cohort of patients with advanced biliary cancers and locally advanced or metastatic pancreatic cancer was enrolled. Blood samples were also collected at predetermined time points for biomarker analysis. Results Twenty-three patients were enrolled: 9 in the dose escalation and 14 in the dose expansion cohort. One dose limiting toxicity (DLT), of grade 4 neutropenia, occurred in the 200 mg vandetanib cohort. The most common adverse effects were diarrhea (39 %), nausea and vomiting (34 %), and rash (33 %). There were 3 partial responses and stable disease of >2 months (range 2–45, median 5) was observed in 15/23 patients. There was no association between changes in biomarker analytes and disease response. Conclusion The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1–21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096.

Keywords

Phase I Pancreatic cancer Cholangiocarcinoma VEGF EGF RET Vandetanib 

Notes

Acknowledgments

Funding provided by: This research was conducted with support from the Investigator-Sponsored Study Program of AstraZeneca and K12CA086913-10 (SL): K12 Institutional Training Award (Paul Calabresi Award for Clinical Oncology)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Elizabeth R. Kessler
    • 1
    • 2
  • S. Gail Eckhardt
    • 1
    • 2
  • Todd M. Pitts
    • 1
    • 2
  • Erica L. Bradshaw-Pierce
    • 2
    • 3
  • Cindy L. O’byrant
    • 4
  • Wells A. Messersmith
    • 1
    • 2
  • Sujatha Nallapreddy
    • 1
    • 2
  • Colin Weekes
    • 1
    • 2
  • Jennifer Spratlin
    • 5
  • Christopher H. Lieu
    • 1
    • 2
  • Madeleine A. Kane
    • 1
    • 2
  • Sarah Eppers
    • 2
  • Elizabeth Freas
    • 2
  • Stephen Leong
    • 1
    • 2
  1. 1.Division of Medical Oncology, Department of MedicineUniversity of Colorado School of MedicineAuroraUSA
  2. 2.University of Colorado Cancer CenterAuroraUSA
  3. 3.Department of Pharmaceutical Sciences, Skaggs School of PharmacyAuroraUSA
  4. 4.Department of Clinical PharmacySkaggs School of PharmacyAuroraUSA
  5. 5.Department of OncologyUniversity of AlbertaEdmontonCanada

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