A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2.

Abstract

PURPOSE:

This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination.

EXPERIMENTAL DESIGN:

Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design.

RESULTS:

Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m(2) (30-minute loading infusion) followed by 20 mg/m(2) (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent.

CONCLUSIONS:

Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules.

• Authors: Beata Holkova, Jeffrey G Supko, Matthew M Ames, Joel M Reid, Geoffrey I Shapiro, Edward Brent Perkins, Viswanathan Ramakrishnan, Mary Beth Tombes, Connie Honeycutt, Renee M McGovern, Maciej Kmieciak, Ellen Shrader, Martha D Wellons, Heidi Sankala, Austin Doyle, John Wright, John D Roberts, Steven Grant
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 7 Pg. 1873-83 (Apr 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23515411 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2013 AACR.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Flavonoids
• Hydroxamic Acids
• Myeloid Cell Leukemia Sequence 1 Protein
• Piperidines
• Proto-Oncogene Proteins c-bcl-2
• alvocidib
• Vorinostat
• RNA Polymerase II

Topics

• Acute Disease
• Adult
• Aged
• Anemia, Refractory, with Excess of Blasts (drug therapy)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Female
• Flavonoids (administration & dosage)
• Humans
• Hydroxamic Acids (administration & dosage)
• Leukemia (diagnosis, drug therapy, metabolism)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Myeloid Cell Leukemia Sequence 1 Protein
• Piperidines (administration & dosage)
• Prognosis
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA Polymerase II (metabolism)
• Recurrence
• Treatment Outcome
• Vorinostat
• Young Adult