Abstract | PURPOSE: 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.
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Authors | Melissa 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 |
Journal | Clinical 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 |
PMID | 22761464
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2012 AACR. |
Chemical References |
- Oligopeptides
- Proteasome Inhibitors
- carfilzomib
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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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