Skip to main content

Advertisement

SpringerLink
Log in

Phase I trial of dasatinib and ixabepilone in patients with solid tumors

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose. Dasatinib is an oral tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family and ixabepilone is an epothilone B analog. Synergistic activity has been reported when combining dasatinib with chemotherapy. This study was conducted to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) for this combination. Patients and methods. Patients with metastatic solid tumors who progressed on standard therapy received dasatinib orally daily and ixabepilone IV every 3 weeks at escalating doses using 3 + 3 design. An expansion cohort was studied after reaching the MTD. Pharmacokinetic studies were performed. Results. Nineteen patients were enrolled. No DLTs were observed at dose level (DL) 1 (dasatinib 100 mg and ixabepilone 30 mg/m2). At DL 2 (dasatinib 100 mg and ixabepilone 40 mg/m2), one patient had multiple DLTs. At DL 3 (dasatinib 150 mg and ixabepilone 40 mg/m2), the first patient developed grade 3 AE during cycle 2, the second patient had a DLT and a grade 3 AE during cycle 2. The accrual to DL 3 was halted without reaching the maximally administered dose (MAD) and MTDs were determined to be dasatinib 100 mg and ixabepilone 40 mg/m2 (DL 2). One patient had a partial response and 12 patients stable disease as their best response. Fourteen patients came off study due to toxicities. Conclusion. The combination of dasatinib and ixabepilone showed modest clinical activity with doses 100 mg orally daily and 40 mg/m2 IV every 3 weeks, respectively. Treatment related toxicities were seen frequently.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Aleshin A, Finn RS (2010) SRC: A century of science brought to the clinic. Neoplasia 12(8):599–607

    PubMed  CAS  Google Scholar 

  2. Tal J, Fujita DJ, Kawai S, Varmus HE, Bishop JM (1977) Purification of DNA complementary to the env gene of avian sarcoma virus and analysis of relationships among the env genes of avian leukosis-sarcoma viruses. J Virol 21(2):497–505

    PubMed  CAS  Google Scholar 

  3. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  PubMed  CAS  Google Scholar 

  4. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682):399–401

    Article  PubMed  CAS  Google Scholar 

  5. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM (2004) Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47(27):6658–6661

    Article  PubMed  CAS  Google Scholar 

  6. Sprycel (dasatinib): package insert. Rev. ed. New York: Bristol-Myers Squibb, November 2007

  7. Montero JC, Seoane S, Ocana A, Pandiella A (2011) Inhibition of Src family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res 17(17):5546–5552

    Article  PubMed  CAS  Google Scholar 

  8. Nettles JH, Li H, Cornett B, Krahn JM, Snyder JP, Downing KH (2004) The binding mode of epothilone A on alpha, beta-tubulin by electron crystallography. Science 305(5685):866–869

    Article  PubMed  CAS  Google Scholar 

  9. Goodin S, Kane MP, Rubin EH (2004) Epothilones: Mechanism of action and biologic activity. J Clin Oncol 22(10):2015–2025

    Article  PubMed  CAS  Google Scholar 

  10. Ixempra (ixabepilone) kit for injection: package insert. Princeton, NJ: Bristol-Myers Squibb, 2009

  11. Suter DM, Schaefer AW, Forscher P (2004) Microtubule dynamics are necessary for SRC family kinase-dependent growth cone steering. Curr Biol 14(13):1194–1199

    Article  PubMed  CAS  Google Scholar 

  12. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE (2004) Inhibition of Src tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells. Clin Cancer Res 10(7):2307–2318

    Article  PubMed  CAS  Google Scholar 

  13. Chen T, Pengetnze Y, Taylor CC (2005) Src inhibition enhances paclitaxel cytotoxicity in ovarian cancer cells by caspase-9-independent activation of caspase-3. Mol Cancer Ther 4(2):217–224

    PubMed  CAS  Google Scholar 

  14. Park BJ, Whichard ZL, Corey SJ (2012) Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lilnes—lessons for design of combination targeted therapy. Cancer Lett Feb1. [Epub ahead of print]

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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):205–216

    Article  PubMed  CAS  Google Scholar 

  16. Xu XS, Zeng J, Mylott W, Arnold M, Waltrip J, Iacono L, Mariannino T, Stouffer B (2010) Liquid chromatography and tandem mass spectrometry for the quantitative determination of ixabepilone (BMS-247550, Ixempra) in human plasma: method validation, overcoming curve splitting issues and eliminating chromatographic interferences from degradants. J Chromatogr B Analyt Technol Biomed Life Sci 878(5–6):525–537

    PubMed  CAS  Google Scholar 

  17. Furlong MT, Agrawal S, Hawthorne D, Lago M, Unger S, Krueger L, Stouffer B (2012) A validated LC-MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma: application to a clinical pharmacokinetic study. J Pharm Biomed Anal 58:130–135

    Article  PubMed  CAS  Google Scholar 

  18. Low JA, Wedam SB, Lee JJ, Berman AW, Brufsky A, Yang SX, Poruchynsky MS, Steinberg SM, Mannan N, Fojo T, Swain SM (2005) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23(12):2726–2734

    Article  PubMed  CAS  Google Scholar 

  19. Denduluri N, Low JA, Lee JJ, Berman AW, Walshe JM, Vatas U, Chow CK, Steinberg SM, Yang SX, Swain SM (2007) Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol 25(23):3421–3427

    Article  PubMed  CAS  Google Scholar 

  20. Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN (2007) Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane and capecitabine. J Clin Oncol 25(23):3407–3414

    Article  PubMed  CAS  Google Scholar 

  21. Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, Vahdat LT, Bunnell CA, Burris HA, Viens P, Baselga J, Rivera E, Guarneri V, Poulart V, Klimovsky J, Lebwohl D, Martin M (2007) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 25(23):3399–3406

    Article  PubMed  CAS  Google Scholar 

  22. Shah NP, Kantarjian HM, Kim DW, Rea D, Dorlhiac-Llacer PE, Milone JH, Vela-Ojeda J, Silver RT, Khoury HJ, Charbonnier A, Khoroshko N, Paquette RL, Deininger M, Collins RH, Otero I, Hughes T, Bleickardt E, Strauss L, Francis S, Hochhaus A (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improved tolerability in imatinib-resistant and –intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26(19):3204–3212

    Article  PubMed  CAS  Google Scholar 

  23. Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, Hochhaus A, Guilhot F, Saglio G, Apperley J, Ottman O, Shah N, Erben P, Branford S, Agarwal P, Gollerkeri A, Baccarani M (2007) Dasatinib indoces complete hematologic and cytogenetic responses in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in blast crisis. Blood 109(8):3207–3213

    Article  PubMed  CAS  Google Scholar 

  24. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354(24):2531–2541

    Article  PubMed  CAS  Google Scholar 

  25. Evans TR, Morgan JA, van den Abbeele AD et al. Phase I dose-escalation study of the SRC and multi-kinase inhibitor BMS-354825 in patients (pts) with GIST and other solid tumors (2005) J Clin Oncol 23(16S). Abstract 3034.

  26. Fornier MN, Morris PG, Abbruzzi A, D’Andrea G, Gilewski T, Bromberg J, Dang C, Dickler M, Modi S, Seidman AD, Sklarin N, Chang J, Norton L, Hudis CA (2011) A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer. Ann Oncol 22(12):2575–2581

    Article  PubMed  CAS  Google Scholar 

  27. Araujo J, Gallick G, Trudel P, et al. Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: a phase I/II study (CA180-086) (2009) Genitourinary Cancers Symposium. Abstract 177

Download references

Acknowledgements

The contribution of Kristin Ferguson, a research nurse, is gratefully acknowledged.

Funding

This work was supported by Bristol-Myers Squibb.

Disclosures

Dr. Sandra M. Swain has received research funding from Bristol-Myers Squibb and travel support from Sanofi-Aventis. Dr. Swain is involved in the advisory boards (uncompensated) for Sanofi-Aventis and Roche (Genentech).

Author information

Authors and Affiliations

  1. Washington Cancer Institute (WCI)/ Medstar Washington Hospital Center (WHC), 110 Irving Street, NW, Washington, DC, 20010, USA

    P. Herbolsheimer, R. Kapoor, K. L. Smith, D. Perry, N. Verma, I. Veytsman, J. Jelinek & S. M. Swain

Authors
  1. P. Herbolsheimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Kapoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. L. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I. Veytsman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Jelinek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S. M. Swain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Herbolsheimer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herbolsheimer, P., Kapoor, R., Smith, K.L. et al. Phase I trial of dasatinib and ixabepilone in patients with solid tumors. Invest New Drugs 31, 92–98 (2013). https://doi.org/10.1007/s10637-012-9805-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-012-9805-y

Keywords

Search

Navigation