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

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 & 6 others L. Austin Doyle, William D. Figg, Domenico Coppola, John D. Roberts, Daniel Sullivan, Steven Grant

Research output: Contribution to journalArticle

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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/m2 for bortezomib and 40 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)5652-5662
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number22
DOIs
StatePublished - Nov 15 2014

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alvocidib
Appointments and Schedules
B-Lymphocytes
Maximum Tolerated Dose
Neoplasms
Multiple Myeloma
Pharmacokinetics
Mantle-Cell Lymphoma
Waldenstrom Macroglobulinemia
Lymphopenia
Leukopenia
Neutropenia
Thrombocytopenia
Non-Hodgkin's Lymphoma
Fatigue
Bortezomib
Diarrhea
Lymphoma
Research Design
Research Personnel

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Holkova, Beata; Kmieciak, Maciej; Perkins, E. Brent; Bose, Prithviraj; Baz, Rachid C.; Roodman, G. David; Stuart, Robert K.; Ramakrishnan, Viswanathan; Wan, Wen; Peer, Cody J.; Dawson, Jana; Kang, Loveleen; Honeycutt, Connie; Tombes, Mary Beth; Shrader, Ellen; Weir-Wiggins, Caryn; Wellons, Martha; Sankala, Heidi; Hogan, Kevin T.; Colevas, A. Dimitrios; Doyle, L. Austin; Figg, William D.; Coppola, Domenico; Roberts, John D.; Sullivan, Daniel; Grant, Steven.

In: Clinical Cancer Research, Vol. 20, No. 22, 15.11.2014, p. 5652-5662.

Research output: Contribution to journalArticle

Holkova, B, Kmieciak, M, Perkins, EB, Bose, P, Baz, RC, Roodman, GD, Stuart, RK, Ramakrishnan, V, Wan, W, Peer, CJ, Dawson, J, Kang, L, Honeycutt, C, Tombes, MB, Shrader, E, Weir-Wiggins, C, Wellons, M, Sankala, H, Hogan, KT, Colevas, AD, Doyle, LA, Figg, WD, Coppola, D, Roberts, JD, Sullivan, D & Grant, S 2014, '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, vol. 20, no. 22, pp. 5652-5662. https://doi.org/10.1158/1078-0432.CCR-14-0805
Holkova, Beata ; Kmieciak, Maciej ; Perkins, E. Brent ; Bose, Prithviraj ; Baz, Rachid C. ; Roodman, G. David ; Stuart, Robert K. ; Ramakrishnan, Viswanathan ; Wan, Wen ; Peer, Cody J. ; Dawson, Jana ; Kang, Loveleen ; Honeycutt, Connie ; Tombes, Mary Beth ; Shrader, Ellen ; Weir-Wiggins, Caryn ; Wellons, Martha ; Sankala, Heidi ; Hogan, Kevin T. ; Colevas, A. Dimitrios ; Doyle, L. Austin ; Figg, William D. ; Coppola, Domenico ; Roberts, John D. ; Sullivan, Daniel ; Grant, Steven. / 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. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 22. pp. 5652-5662.
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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/m2 for bortezomib and 40 mg/m2 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.",
author = "Beata Holkova and Maciej Kmieciak and Perkins, {E. Brent} and Prithviraj Bose and Baz, {Rachid C.} and Roodman, {G. David} and Stuart, {Robert K.} and Viswanathan Ramakrishnan and Wen Wan and Peer, {Cody J.} and Jana Dawson and Loveleen Kang and Connie Honeycutt and Tombes, {Mary Beth} and Ellen Shrader and Caryn Weir-Wiggins and Martha Wellons and Heidi Sankala and Hogan, {Kevin T.} and Colevas, {A. Dimitrios} and Doyle, {L. Austin} and Figg, {William D.} and Domenico Coppola and Roberts, {John D.} and Daniel Sullivan and Steven Grant",
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T1 - 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

AU - Holkova, Beata

AU - Kmieciak, Maciej

AU - Perkins, E. Brent

AU - Bose, Prithviraj

AU - Baz, Rachid C.

AU - Roodman, G. David

AU - Stuart, Robert K.

AU - Ramakrishnan, Viswanathan

AU - Wan, Wen

AU - Peer, Cody J.

AU - Dawson, Jana

AU - Kang, Loveleen

AU - Honeycutt, Connie

AU - Tombes, Mary Beth

AU - Shrader, Ellen

AU - Weir-Wiggins, Caryn

AU - Wellons, Martha

AU - Sankala, Heidi

AU - Hogan, Kevin T.

AU - Colevas, A. Dimitrios

AU - Doyle, L. Austin

AU - Figg, William D.

AU - Coppola, Domenico

AU - Roberts, John D.

AU - Sullivan, Daniel

AU - Grant, Steven

PY - 2014/11/15

Y1 - 2014/11/15

N2 - 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/m2 for bortezomib and 40 mg/m2 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.

AB - 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/m2 for bortezomib and 40 mg/m2 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.

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