Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma

J Clin Oncol. 2015 Mar 1;33(7):732-9. doi: 10.1200/JCO.2013.52.3522. Epub 2014 Sep 15.

Abstract

Purpose: Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed.

Patients and methods: Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m(2), followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m(2). Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk).

Results: Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m(2) were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m(2). Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m(2) cohort). Increasing carfilzomib dosing from 20 to 56 mg/m(2) resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m(2) of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib.

Conclusion: Carfilzomib administered as a 30-minute IV infusion at 56 mg/m(2) (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

Trial registration: ClinicalTrials.gov NCT00531284.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Dexamethasone / administration & dosage
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Dyspnea / chemically induced
  • Fatigue / chemically induced
  • Female
  • Fever / chemically induced
  • Half-Life
  • Humans
  • Infusions, Intravenous
  • Kidney Cortex Necrosis / chemically induced
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Nausea / chemically induced
  • Oligopeptides / administration & dosage*
  • Oligopeptides / adverse effects*
  • Oligopeptides / pharmacokinetics
  • Proteasome Inhibitors / administration & dosage
  • Proteasome Inhibitors / adverse effects
  • Proteinuria / chemically induced
  • Recurrence
  • Thrombocytopenia / chemically induced

Substances

  • Antineoplastic Agents
  • Oligopeptides
  • Proteasome Inhibitors
  • carfilzomib
  • Dexamethasone

Associated data

  • ClinicalTrials.gov/NCT00531284