Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms

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BlankPhase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib

(Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell

Neoplasms

1.. Beata Holkova1,2,

2.. E. Brent Perkins1,2,

3.. Viswanathan Ramakrishnan1,3,

4.. Beth Tombes1,

5.. Ellen Shrader1,

6.. Neha Talreja7,

7.. Martha D. Wellons1,

8.. T. Hogan1,

9.. G. Roodman8,

10.. Domenico Coppola9,

11.. Loveleen Kang9,

12.. Jana Dawson9,

13.. K. Stuart10,

14.. Cody Peer11,

15.. D. Figg Sr.11,

16.. Kolla1,

17.. Austin Doyle12,

18.. 12,

19.. M. Sullivan9,

20.. D. 1,2, and

21.. Grant1,2,4,6

+ Author Affiliations

1.. Authors' Affiliations:1Massey Cancer Center and the Departments of

2Internal Medicine, 3Biostatistics, 4Microbiolog and Immunology, 5Biochemistry

and Molecular Biology, and 6The Institute for Molecular Medicine, 7Virginia

Commonwealth University, Richmond, Virginia; 8Department of Medicine, University

of Pittsburgh, Pittsburgh, Pennsylvania; 9H. Lee Moffitt Cancer Center &

Research Institute, University of South Florida, Tampa, Florida; 10Department of

Medicine, Medical University of South Carolina, ton, South Carolina; and

11Medical Oncology Branch and 12Cancer Therapy Evaluation Program, National

Cancer Institute, NIH, Bethesda, land

1.. Corresponding Author:

Grant, Virginia Commonwealth University, PO Box 980230, Richmond, VA

23298. Phone: 804-828-5211; Fax: 804-828-2174; E-mail: stgrant@...

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. Clin Cancer Res; 17(10); 3388–97. ©2011 AACR.

Footnotes

a.. Note: Supplementary data for this article are available at Clinical Cancer

Research Online (http://clincancerres.aacrjournals.org/ ).