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01-10-2013 | PHASE I STUDIES

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

Authors: Ivana Gojo, Alexander Perl, Selina Luger, Maria R. Baer, Kelly J. Norsworthy, Kenneth S. Bauer, Michael Tidwell, Stephanie Fleckinger, Martin Carroll, Edward A. Sausville

Published in: Investigational New Drugs | Issue 5/2013

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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Title: Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome
Authors: Ivana Gojo
Alexander Perl
Selina Luger
Maria R. Baer
Kelly J. Norsworthy
Kenneth S. Bauer
Michael Tidwell
Stephanie Fleckinger
Martin Carroll
Edward A. Sausville
Publication date: 01-10-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 5/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-013-9937-8

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