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Investigational New Drugs
Published in: Investigational New Drugs 2/2014

01-04-2014 | PHASE I STUDIES

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

Authors: 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

Published in: Investigational New Drugs | Issue 2/2014

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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.
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Metadata
Title
Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer
Authors
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
Publication date
01-04-2014
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2014
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-013-0042-9

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