A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies.
OBJECTIVE
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.


METHODS
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 > or =11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenström's macroglobulinemia).


CONCLUSIONS
This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing.
O'Connor
Owen A
OA
NYU Cancer Institute, NYU Langone Medical Center, 522 First Ave., Smilow 1101, New York, NY, USA. owen.o'connor@nyumc.org
Stewart
A Keith
AK
Vallone
Marcy
M
Molineaux
Christopher J
CJ
Kunkel
Lori A
LA
Gerecitano
John F
JF
Orlowski
Robert Z
RZ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C524865:carfilzomib