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

Owen A. O'Connor, Alexander Keith Stewart, Marcy Vallone, Christopher J. Molineaux, Lori A. Kunkel, John F. Gerecitano, Robert Z. Orlowski

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7085-7091
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number22
DOIs
StatePublished - Nov 15 2009

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Proteasome Inhibitors
Hematologic Neoplasms
Pharmacokinetics
Safety
Proteasome Endopeptidase Complex
Multiple Myeloma
Waldenstrom Macroglobulinemia
Febrile Neutropenia
Maximum Tolerated Dose
Peripheral Nervous System Diseases
Nausea
Fatigue
PR-171
carfilzomib
Diarrhea
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. / O'Connor, Owen A.; Stewart, Alexander Keith; Vallone, Marcy; Molineaux, Christopher J.; Kunkel, Lori A.; Gerecitano, John F.; Orlowski, Robert Z.

In: Clinical Cancer Research, Vol. 15, No. 22, 15.11.2009, p. 7085-7091.

Research output: Contribution to journalArticle

O'Connor, Owen A. ; Stewart, Alexander Keith ; Vallone, Marcy ; Molineaux, Christopher J. ; Kunkel, Lori A. ; Gerecitano, John F. ; Orlowski, Robert Z. / A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 22. pp. 7085-7091.
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