Investigational New Drugs

, Volume 26, Issue 1, pp 59–65 | Cite as

A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors

  • Elisabeth I. HeathEmail author
  • Keith Bible
  • Robert E. Martell
  • Daniel C. Adelman
  • Patricia M. LoRusso


Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean C max and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 μg/ml and 0.103 to 0.553 μg h/ml, respectively. The CL and V ss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4–33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4–33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.


Phase I Cyclin-dependent kinase inhibitor Metastatic refractory solid tumors 


  1. 1.
    Santamaria D, Ortega S (2006) Cyclins and CDKS in development and cancer: lessons from genetically modified mice. Front Biosci 11:1164–1188PubMedCrossRefGoogle Scholar
  2. 2.
    Nuwayhid SJ, Hyde J, Aleshin A, Walker DH, Arkin MR (2006) SNS-032 is a potent and selective inhibitor of CDK2,7, and 9 and induces cell death by inhibiting cell cycle progression and the expression of antiapoptotic proteins, 491.Google Scholar
  3. 3.
    Muller-Tidow C, Metzger R, Kugler K, Diederichs S, Idos G, Thomas M, et al (2001) Cyclin E is the only cyclin-dependent kinase 2-associated cyclin that predicts metastasis and survival in early stage non-small cell lung cancer. Cancer Res 61(2):647–653PubMedGoogle Scholar
  4. 4.
    Hunt KK, Keyomarsi K (2005) Cyclin E as a prognostic and predictive marker in breast cancer. Semin Cancer Biol 15(4):319–326PubMedCrossRefGoogle Scholar
  5. 5.
    Kawana H, Tamaru J, Tanaka T, Hirai A, Saito Y, Kitagawa M, et al (1998) Role of p27Kip1 and cyclin-dependent kinase 2 in the proliferation of non-small cell lung cancer. Am J Pathol 153(2):505–513PubMedGoogle Scholar
  6. 6.
    Lee FYF (2001) In vivo antitumor efficacy of BMS-387032, a CDK inhibitor: Bristol Myers Squibb Pharmaceutical Research Institute, May 8Google Scholar
  7. 7.
    Iciek L. BMS-387032 Toxicology Integrated Summary (2001) Bristol Myers Squibb Pharmaceutical Research Institute, May 8Google Scholar
  8. 8.
    Iciek L (2001) BMS-387032 Single dose intravenous investigative toxicity study in dogs (Study Number DS0116): Bristol Myers Squibb Pharmaceutical Research InstituteGoogle Scholar
  9. 9.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 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
  10. 10.
    Grendys EC, Jr., Blessing JA, Burger R, Hoffman J (2005) A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 98(2):249–253PubMedCrossRefGoogle Scholar
  11. 11.
    Burdette-Radoux S, Tozer RG, Lohmann RC, Quirt I, Ernst DS, Walsh W, et al (2004) Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs 22(3):315–322PubMedCrossRefGoogle Scholar
  12. 12.
    Liu G, Gandara DR, Lara PN, Jr., Raghavan D, Doroshow JH, Twardowski P, et al (2004) A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res 10(3):924–928PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Elisabeth I. Heath
    • 1
    Email author
  • Keith Bible
    • 2
  • Robert E. Martell
    • 3
  • Daniel C. Adelman
    • 4
  • Patricia M. LoRusso
    • 1
  1. 1.Wayne State University/Karmanos Cancer InstituteDetroitUSA
  2. 2.Mayo ClinicRochesterUSA
  3. 3.MethylgeneMontrealCanada
  4. 4.Sunesis Pharmaceuticals, Inc.San FranciscoUSA

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