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

Publication ,  Journal Article
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA ...
Published in: Invest New Drugs
April 2014

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/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) 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 (src(act)) 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 src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) 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.

Duke Scholars

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

April 2014

Volume

32

Issue

2

Start / End Page

330 / 339

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Vascular Endothelial Growth Factor A
  • Thiazoles
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Oxaliplatin
  • Organoplatinum Compounds
  • Oncology & Carcinogenesis
  • Middle Aged
  • Maximum Tolerated Dose
 

Citation

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Strickler, J. H., McCall, S., Nixon, A. B., Brady, J. C., Pang, H., Rushing, C., … Hurwitz, H. I. (2014). Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer. Invest New Drugs, 32(2), 330–339. https://doi.org/10.1007/s10637-013-0042-9
Strickler, John H., Shannon McCall, Andrew B. Nixon, John C. Brady, Herbert Pang, Christel Rushing, Allen Cohn, et al. “Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.Invest New Drugs 32, no. 2 (April 2014): 330–39. https://doi.org/10.1007/s10637-013-0042-9.
Strickler, John H., et al. “Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.Invest New Drugs, vol. 32, no. 2, Apr. 2014, pp. 330–39. Pubmed, doi:10.1007/s10637-013-0042-9.
Strickler JH, McCall S, Nixon AB, Brady JC, Pang H, Rushing C, Cohn A, Starodub A, Arrowood C, Haley S, Meadows KL, Morse MA, Uronis HE, Blobe GC, Hsu SD, Zafar SY, Hurwitz HI. Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer. Invest New Drugs. 2014 Apr;32(2):330–339.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

April 2014

Volume

32

Issue

2

Start / End Page

330 / 339

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Vascular Endothelial Growth Factor A
  • Thiazoles
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Oxaliplatin
  • Organoplatinum Compounds
  • Oncology & Carcinogenesis
  • Middle Aged
  • Maximum Tolerated Dose