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Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias

  • PHASE I STUDIES
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Abstract

Purpose

Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial.

Patients and methods

Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days.

Results

Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression.

Conclusion

Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.

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Acknowledgments

We would like to thank all patients and their families as well as the staff at TCRS and the Virginia Piper Cancer Center.

Funding

This work was supported by funding the clinical trial at the institutions of RT, KTD, LL, DVH, TCS. The correlative research was partially funded by Erimos Pharmaceuticals to RT.

Disclosure of conflicts of interest

RT obtained a research grant funding from Erimos Pharmaceuticlas for co-funding the correlative research studies. All remaining authors have declared no conflicts of interest except their institutions received funding to support the clinical trial.

Author information

Authors and Affiliations

  1. Division of Hematology & Medical Oncology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ, 85259, USA

    R. Tibes & J. M. Bogenberger

  2. Division of Hematology & BMT, University of Kentucky, Lexington, USA

    K. T. McDonagh

  3. Sylvester Comprehensive Cancer, University of Miami, Miami, USA

    L. Lekakis

  4. Erimos Pharmaceuticals, Raleigh, USA

    N. Frazer & S. Mohrland

  5. Division of Hematology-Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, USA

    R. Garcia & T. C. Shea

  6. Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, USA

    S. Kim, V. Shanmugam & J. Carpten

  7. Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, USA

    R. T. Hagelstrom & C. Beaudry

  8. Virginia Piper Cancer Center, Scottsdale, USA

    D. Bassett, K. Schroeder & D. Von Hoff

Authors
  1. R. Tibes
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  2. K. T. McDonagh
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  4. J. M. Bogenberger
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  8. D. Bassett
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  9. R. Garcia
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  11. V. Shanmugam
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  12. J. Carpten
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  13. R. T. Hagelstrom
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  14. C. Beaudry
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  15. D. Von Hoff
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  16. T. C. Shea
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Corresponding author

Correspondence to R. Tibes.

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Tibes, R., McDonagh, K.T., Lekakis, L. et al. Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias. Invest New Drugs 33, 389–396 (2015). https://doi.org/10.1007/s10637-014-0198-y

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  • DOI: https://doi.org/10.1007/s10637-014-0198-y

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