Investigational New Drugs

, Volume 32, Issue 2, pp 330–339 | Cite as

Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

  • John H. Strickler
  • Shannon McCall
  • Andrew B. Nixon
  • John C. Brady
  • Herbert Pang
  • Christel Rushing
  • Allen Cohn
  • Alexander Starodub
  • Christy Arrowood
  • Sherri Haley
  • Kellen L. Meadows
  • Michael A. Morse
  • Hope E. Uronis
  • Gerard C. Blobe
  • S. David Hsu
  • S. Yousuf Zafar
  • Herbert I. Hurwitz
PHASE I STUDIES

Summary

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a “3 + 3” design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1–14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high srcact expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Keywords

Dasatinib Bevacizumab Metastatic colorectal cancer Src 

Notes

Acknowledgments

We gratefully acknowledge the invaluable contributions of the patients and their families. We would also like to acknowledge the Duke University GI Oncology clinical trials team.

Conflict of interest

A.B.. Nixon, H.E. Uronis, M.A. Morse and H. I. Hurwitz currently have research funding with Bristol-Myers Squibb (BMS). M.A. Morse has received honoraria for speaking from Bristol-Myers Squibb. All other authors have declared no conflict of interest with BMS.

Role of the funding source

This was an investigator initiated study supported by Bristol-Myers Squibb, New Jersey, USA. The study was independently managed and analyzed. The final responsibility for the manuscript and the decision to submit for publication was made by the investigators. This work was also supported by National Institute of Health Grant 5K24-CA113755-05 (H Hurwitz).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • John H. Strickler
    • 1
  • Shannon McCall
    • 1
  • Andrew B. Nixon
    • 1
  • John C. Brady
    • 1
  • Herbert Pang
    • 1
  • Christel Rushing
    • 1
  • Allen Cohn
    • 2
  • Alexander Starodub
    • 1
    • 3
  • Christy Arrowood
    • 1
  • Sherri Haley
    • 1
  • Kellen L. Meadows
    • 1
  • Michael A. Morse
    • 1
  • Hope E. Uronis
    • 1
  • Gerard C. Blobe
    • 1
  • S. David Hsu
    • 1
  • S. Yousuf Zafar
    • 1
  • Herbert I. Hurwitz
    • 1
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Rocky Mountain Cancer CentersDenverUSA
  3. 3.Indiana University Health Goshen Cancer CenterGoshenUSA

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