Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms

Beata Holkova, E. Brent Perkins, Viswanathan Ramakrishnan, Mary Beth Tombes, Ellen Shrader, Neha Talreja, Martha D. Wellons, Kevin T. Hogan, G. David Roodman, Domenico Coppola, Loveleen Kang, Jana Dawson, Robert K. Stuart, Cody Peer, William D. Figg, Sarah Kolla, Austin Doyle, John Wright, Daniel M. Sullivan, John D. RobertsSteven Grant

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37 Scopus citations

Abstract

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively.

Original languageEnglish (US)
Pages (from-to)3388-3397
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number10
DOIs
StatePublished - May 15 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Holkova, B., Perkins, E. B., Ramakrishnan, V., Tombes, M. B., Shrader, E., Talreja, N., Wellons, M. D., Hogan, K. T., Roodman, G. D., Coppola, D., Kang, L., Dawson, J., Stuart, R. K., Peer, C., Figg, W. D., Kolla, S., Doyle, A., Wright, J., Sullivan, D. M., ... Grant, S. (2011). Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clinical Cancer Research, 17(10), 3388-3397. https://doi.org/10.1158/1078-0432.CCR-10-2876