Investigational New Drugs

, Volume 30, Issue 3, pp 1211–1215 | Cite as

Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium

  • Manish R. Sharma
  • Kristen Wroblewski
  • Blase N. Polite
  • James A. Knost
  • James A. Wallace
  • Sanjiv Modi
  • Bethany G. Sleckman
  • David Taber
  • Everett E. Vokes
  • Walter M. Stadler
  • Hedy L. Kindler


Background Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimidine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. Patients and methods We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage. Results Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%. Conclusion Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.


Colorectal cancer Phase II trial Dasatinib 


Funding source

NCI Grant N01-CM-62201.


  1. 1.
    Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664PubMedCrossRefGoogle Scholar
  2. 2.
    Amado RG, Wolf M, Peeters M et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634PubMedCrossRefGoogle Scholar
  3. 3.
    Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA (2011) Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med 154(1):37–49PubMedGoogle Scholar
  4. 4.
    Mayer EL, Krop IE (2010) Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clin Cancer Res 16(14):3526–3532PubMedCrossRefGoogle Scholar
  5. 5.
    Windham TC, Parikh NU, Siwak DR et al (2002) Src activation regulates anoikis in human colon tumor cell lines. Oncogene 21(51):7797–7807PubMedCrossRefGoogle Scholar
  6. 6.
    Talamonti MS, Roh MS, Curley SA, Gallick GE (1993) Increase in activity and level of pp 60c-src in progressive stages of human colorectal cancer. J Clin Invest 91(1):53–60PubMedCrossRefGoogle Scholar
  7. 7.
    Aligayer H, Boyd DD, Heiss MM et al (2002) Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 94(2):344–351PubMedCrossRefGoogle Scholar
  8. 8.
    Staley CA, Parikh NU, Gallick GE (1997) Decreased tumorigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src. Cell Growth Differ 8(3):269–274PubMedGoogle Scholar
  9. 9.
    Ellis LM, Staley CA, Liu W et al (1998) Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J Biol Chem 273(2):1052–1057PubMedCrossRefGoogle Scholar
  10. 10.
    Golas JM, Lucas J, Etienne C et al (2005) SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Cancer Res 65(12):5358–5364PubMedCrossRefGoogle Scholar
  11. 11.
    Dasatinib Investigator’s Brochure (2006)Google Scholar
  12. 12.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRefGoogle Scholar
  13. 13.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10PubMedCrossRefGoogle Scholar
  14. 14.
    Kaplan E, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481Google Scholar
  15. 15.
    Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. Biometrics 38:29–41CrossRefGoogle Scholar
  16. 16.
    Miller AA, Pang H, Hodgson L et al (2010) A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602). J Thorac Oncol 5(3):380–384PubMedCrossRefGoogle Scholar
  17. 17.
    Brooks HD, Glisson BS, Bekele BN et al (2010) Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma. Cancer [Epub ahead of print]Google Scholar
  18. 18.
    Kopetz S, Lesslie DP, Dallas NA et al (2009) Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res 69(9):3842–3849PubMedCrossRefGoogle Scholar
  19. 19.
    Nautiyal J, Banerjee S, Kanwar SS et al (2011) Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells. Int J Cancer 128(4):951–961PubMedCrossRefGoogle Scholar
  20. 20.
    Lieu CH, Wolff RA, Eng C et al (2010) Phase IB study of the Src inhibitor dasatinib with FOLFOX and cetuximab in metastatic colorectal cancer. J Clin Oncol 28:3536Google Scholar
  21. 21.
  22. 22.
    Demetri GD, Lo Russo P, MacPherson IR et al (2009) Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 15(19):6232–6240PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson FM, Agrawal S, Burris H et al (2010) Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors. Cancer 116(6):1582–1591PubMedCrossRefGoogle Scholar
  24. 24.
    Shah NP, Kantarjian HM, Kim DW et al (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26(19):3204–3212PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Manish R. Sharma
    • 1
  • Kristen Wroblewski
    • 2
  • Blase N. Polite
    • 1
  • James A. Knost
    • 3
  • James A. Wallace
    • 1
  • Sanjiv Modi
    • 4
  • Bethany G. Sleckman
    • 5
  • David Taber
    • 6
  • Everett E. Vokes
    • 1
  • Walter M. Stadler
    • 1
  • Hedy L. Kindler
    • 1
  1. 1.Section of Hematology/OncologyUniversity of ChicagoChicagoUSA
  2. 2.Department of Health StudiesUniversity of ChicagoChicagoUSA
  3. 3.Illinois Cancer CarePeoriaUSA
  4. 4.Joliet Hematology/OncologyJolietUSA
  5. 5.St Johns Mercy Medical CenterSt LouisUSA
  6. 6.Michiana Hematology/OncologySouth BendUSA

Personalised recommendations