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 CLINICAL CANCER RESEARCH Holkova, B., Kmieciak, M., Perkins, E. B., Bose, P., Baz, R. C., Roodman, G. D., Stuart, R. K., Ramakrishnan, V., Wan, W., Peer, C. J., Dawson, J., Kang, L., Honeycutt, C., Tombes, M. B., Shrader, E., Weir-Wiggins, C., Wellons, M., Sankala, H., Hogan, K. T., Colevas, A. D., Doyle, L. A., Figg, W. D., Coppola, D., Roberts, J. D., Sullivan, D., Grant, S. 2014; 20 (22): 5652-5662


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).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.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.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.

View details for DOI 10.1158/1078-0432.CCR-14-0805

View details for Web of Science ID 000345130800011

View details for PubMedID 25248382