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Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome

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Summary

Background The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation. Methods The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1 = 40 mg/m2; DL2 = 65 mg/m2; DL3 = 90 mg/m2). Results Thirteen patients were treated (DL1, n = 6; DL2, n = 4; DL3, n = 3) according to a traditional “3 + 3” design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3–4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1–2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m2 with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients’ mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study. Conclusion UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo.

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Acknowledgments

This work was supported in part by National Cancer Institute Cooperative Agreement UO-1 CA062487 (I.G. and E.A.S.), and the National Center for Research Resources grant M01 RR 16500 to the University of Maryland General Clinical Research Center. Keryx/AOI Pharmaceuticals, Inc. provided support for pharmacokinetic and pharmacodynamics studies (M.C and K.S.B.). The results of this study were in part presented at the American Society of Hematology meeting 2011 (abstract #1557).

Conflict of interest

The authors declare that they do not have further conflict of interest.

Ethical standards

All patients provided written, informed consent. The final study protocol, amendments, and informed consent were approved by the Institutional Review Board of the each participating center. The study was conducted in accordance with the Declaration of Helsinki and in compliance with International Conference on Harmonization Good Clinical Practice Guidelines.

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Authors and Affiliations

  1. University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA

    Ivana Gojo, Maria R. Baer, Kelly J. Norsworthy, Kenneth S. Bauer, Michael Tidwell, Stephanie Fleckinger & Edward A. Sausville

  2. University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA

    Alexander Perl, Selina Luger & Martin Carroll

  3. University of Maryland School of Pharmacy, Baltimore, MD, USA

    Kenneth S. Bauer

  4. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    Ivana Gojo

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Gojo, I., Perl, A., Luger, S. et al. Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. Invest New Drugs 31, 1217–1227 (2013). https://doi.org/10.1007/s10637-013-9937-8

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