TY - JOUR
T1 - A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies
AU - O'Connor, Owen A.
AU - Stewart, A. Keith
AU - Vallone, Marcy
AU - Molineaux, Christopher J.
AU - Kunkel, Lori A.
AU - Gerecitano, John F.
AU - Orlowski, Robert Z.
PY - 2009/11/15
Y1 - 2009/11/15
N2 - Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patients - mostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses ≥11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenström's macroglobulinemia). Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologicmalignancies using consecutive-day dosing.
AB - Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patients - mostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses ≥11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenström's macroglobulinemia). Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologicmalignancies using consecutive-day dosing.
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U2 - 10.1158/1078-0432.CCR-09-0822
DO - 10.1158/1078-0432.CCR-09-0822
M3 - Article
C2 - 19903785
AN - SCOPUS:72549116835
SN - 1078-0432
VL - 15
SP - 7085
EP - 7091
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -