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

Research output: Contribution to journalArticle

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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
Externally publishedYes

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. / Holkova, Beata; Perkins, E. Brent; Ramakrishnan, Viswanathan; Tombes, Mary Beth; Shrader, Ellen; Talreja, Neha; Wellons, Martha D.; Hogan, Kevin T.; Roodman, G. David; Coppola, Domenico; Kang, Loveleen; Dawson, Jana; Stuart, Robert K.; Peer, Cody; Figg, William D.; Kolla, Sarah; Doyle, Austin; Wright, John; Sullivan, Daniel M.; Roberts, John D.; Grant, Steven.

In: Clinical Cancer Research, Vol. 17, No. 10, 15.05.2011, p. 3388-3397.

Research output: Contribution to journalArticle

Holkova, B, Perkins, EB, Ramakrishnan, V, Tombes, MB, Shrader, E, Talreja, N, Wellons, MD, Hogan, KT, Roodman, GD, Coppola, D, Kang, L, Dawson, J, Stuart, RK, Peer, C, Figg, WD, Kolla, S, Doyle, A, Wright, J, Sullivan, DM, Roberts, JD & 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, vol. 17, no. 10, pp. 3388-3397. https://doi.org/10.1158/1078-0432.CCR-10-2876
Holkova, Beata ; Perkins, E. Brent ; Ramakrishnan, Viswanathan ; Tombes, Mary Beth ; Shrader, Ellen ; Talreja, Neha ; Wellons, Martha D. ; Hogan, Kevin T. ; Roodman, G. David ; Coppola, Domenico ; Kang, Loveleen ; Dawson, Jana ; Stuart, Robert K. ; Peer, Cody ; Figg, William D. ; Kolla, Sarah ; Doyle, Austin ; Wright, John ; Sullivan, Daniel M. ; Roberts, John D. ; Grant, Steven. / Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 10. pp. 3388-3397.
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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.",
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T1 - Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms

AU - Holkova, Beata

AU - Perkins, E. Brent

AU - Ramakrishnan, Viswanathan

AU - Tombes, Mary Beth

AU - Shrader, Ellen

AU - Talreja, Neha

AU - Wellons, Martha D.

AU - Hogan, Kevin T.

AU - Roodman, G. David

AU - Coppola, Domenico

AU - Kang, Loveleen

AU - Dawson, Jana

AU - Stuart, Robert K.

AU - Peer, Cody

AU - Figg, William D.

AU - Kolla, Sarah

AU - Doyle, Austin

AU - Wright, John

AU - Sullivan, Daniel M.

AU - Roberts, John D.

AU - Grant, Steven

PY - 2011/5/15

Y1 - 2011/5/15

N2 - 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.

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