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A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma.

AbstractPURPOSE:
Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies.
EXPERIMENTAL DESIGN:
Carfilzomib (doses ranging from 1.2-27 mg/m(2)) was administered i.v. on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n = 37) was followed by a dose-expansion phase (n = 11) that comprised 2 cohorts (carfilzomib or carfilzomib + dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m(2) during the first week (days 1, 2) and then escalated to 27 mg/m(2) thereafter.
RESULTS:
A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of ≥ grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m(2), there was evidence of activity among patients with multiple myeloma and with non-Hodgkin lymphoma.
CONCLUSIONS:
Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE.
AuthorsMelissa Alsina, Suzanne Trudel, Richard R Furman, Peter J Rosen, Owen A O'Connor, Raymond L Comenzo, Alvin Wong, Lori A Kunkel, Christopher J Molineaux, Andre Goy
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 17 Pg. 4830-40 (Sep 01 2012) ISSN: 1557-3265 [Electronic] United States
PMID22761464 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2012 AACR.
Chemical References
  • Oligopeptides
  • Proteasome Inhibitors
  • carfilzomib
Topics
  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug-Related Side Effects and Adverse Reactions (chemically induced)
  • Female
  • Humans
  • Lymphoma (drug therapy, pathology)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Multiple Myeloma (drug therapy, pathology)
  • Oligopeptides (administration & dosage, adverse effects, pharmacokinetics)
  • Proteasome Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
  • Recurrence

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