Phase I trial of bortezomib (PS-341; NSC 681239) and "nonhybrid" (bolus) infusion schedule of alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms.

Abstract

PURPOSE:

This 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, Waldenstrom macroglobulinemia, and mantle cell lymphoma).

EXPERIMENTAL DESIGN:

Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted.

RESULTS:

A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses.

CONCLUSIONS:

The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies.

• Authors: Beata Holkova, Maciej Kmieciak, E Brent Perkins, Prithviraj Bose, Rachid C Baz, G David Roodman, Robert K Stuart, Viswanathan Ramakrishnan, Wen Wan, Cody J Peer, Jana Dawson, Loveleen Kang, Connie Honeycutt, Mary Beth Tombes, Ellen Shrader, Caryn Weir-Wiggins, Martha Wellons, Heidi Sankala, Kevin T Hogan, A Dimitrios Colevas, L Austin Doyle, William D Figg, Domenico Coppola, John D Roberts, Daniel Sullivan, Steven Grant
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 22 Pg. 5652-62 (Nov 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25248382 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Boronic Acids
• Flavonoids
• Piperidines
• Pyrazines
• alvocidib
• Bortezomib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• B-Lymphocytes (pathology)
• Boronic Acids (administration & dosage, pharmacokinetics)
• Bortezomib
• Combined Modality Therapy
• Drug Administration Schedule
• Drug Monitoring
• Female
• Flavonoids (administration & dosage, pharmacokinetics)
• Humans
• Lymphoproliferative Disorders (diagnosis, drug therapy, pathology)
• Male
• Middle Aged
• Piperidines (administration & dosage, pharmacokinetics)
• Pyrazines (administration & dosage, pharmacokinetics)
• Recurrence
• Retreatment
• Treatment Outcome