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Investigational New Drugs

, Volume 33, Issue 4, pp 890–894 | Cite as

A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer

  • Zahi Mitri
  • Cansu Karakas
  • Caimiao Wei
  • Brian Briones
  • Holly Simmons
  • Nuhad Ibrahim
  • Ricardo Alvarez
  • James L. Murray
  • Khandan Keyomarsi
  • Stacy Moulder
PHASE I STUDIES

Summary

Purpose, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. Results, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n = 2), syncope (grade 3, n = 2) and vomiting (grade 3, n = 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3–12 weeks). Thus, accrual was stopped rather than explore the −1 dose level. Conclusion, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

Keywords

Dinaciclib Epirubicin Triple negative breast cancer Metastatic Systemic treatment Phase 1 study 

Notes

Acknowledgments

This study was supported by R01CA152228, Dr. Khandan Keyomarsi is the PI of the R01 CA15228 and Cancer Center Support Grant CA45809 from the National Cancer Institute

Financial Disclosures: none declared

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zahi Mitri
    • 1
  • Cansu Karakas
    • 2
  • Caimiao Wei
    • 3
  • Brian Briones
    • 4
  • Holly Simmons
    • 4
  • Nuhad Ibrahim
    • 4
  • Ricardo Alvarez
    • 4
  • James L. Murray
    • 4
  • Khandan Keyomarsi
    • 2
  • Stacy Moulder
    • 4
    • 5
  1. 1.Department of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Experimental Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of BiostatisticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  5. 5.HoustonUSA

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