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A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors

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Summary

Purpose Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors. Experimental Design In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks). Dose escalation began with dasatinib 70 mg orally (PO) daily and gemcitabine 800 mg/m2 intravenously (IV) weekly. Results Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100 mg PO qd and gemcitabine 600 mg/m2 IV weekly. The most common grade 3–4 toxicities were anemia (21.5 %), thrombocytopenia (26.2 %), leukopenia (26.2 %), and pleural effusion (10.7 %). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed. Conclusions The combination was well tolerated at doses of dasatinib 100 mg PO daily and gemcitabine 600 mg/m2 IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.

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Acknowledgements

We would like to thank Joann Aaron, MA, Scientific Editor in the Department of Investigational Cancer Therapeutics at MD Anderson, for her editorial assistance.

Research Support

This study was funded in part by Bristol-Myers Squibb, Inc.

Conflict of interest statement

Dr. Lewis C. Strauss is employed with Bristol-Myers Squibb. Dr. Razelle Kurzrock has received a commercial research grant from Genentech and honoraria from Speakers Bureau of Genentech. The other authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    David S. Hong, Jennifer Hsing Choe, Aung Naing, Jennifer J. Wheler, Gerald S. Falchook, Sarina Piha-Paul, Stacy L. Moulder, Goldy C. George, Jonathan M. Choe & Razelle Kurzrock

  2. Bristol-Myers Squibb, New York, NY, USA

    Lewis C. Strauss

  3. Department of Genitourinary Medical Oncology—Research, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Gary E. Gallick

  4. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 455, Houston, TX, 77030, USA

    David S. Hong

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  1. David S. Hong
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Correspondence to David S. Hong.

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Hong, D.S., Choe, J.H., Naing, A. et al. A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors. Invest New Drugs 31, 918–926 (2013). https://doi.org/10.1007/s10637-012-9898-3

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