A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies Journal Article
| Authors: | O'Connor, O. A.; Stewart, A. K.; Vallone, M.; Molineaux, C. J.; Kunkel, L. A.; Gerecitano, J. F.; Orlowski, R. Z. |
| Article Title: | A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies |
| 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/m<sup>2</sup> 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/m<sup>2</sup>, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m<sup>2</sup> as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses ≥11 mg/m<sup>2</sup>: 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. © 2009 American Association for Cancer Research. |
| Keywords: | adult; clinical article; controlled study; treatment outcome; treatment response; aged; aged, 80 and over; middle aged; human cell; clinical trial; constipation; fatigue; neutropenia; paresthesia; diarrhea; drug efficacy; drug safety; drug withdrawal; gastrointestinal hemorrhage; side effect; treatment duration; antineoplastic agents; antineoplastic agent; bortezomib; mantle cell lymphoma; multiple cycle treatment; multiple myeloma; pain; protease inhibitors; proteasome endopeptidase complex; anemia; nausea; thrombocytopenia; peripheral neuropathy; creatinine blood level; waldenstroem macroglobulinemia; antineoplastic activity; dose-response relationship, drug; hodgkin disease; abdominal pain; chill; coughing; drug dose escalation; dyspnea; febrile neutropenia; hyperglycemia; syncope; drug induced headache; t cell lymphoma; disease severity; hematologic malignancy; nonhodgkin lymphoma; hematologic neoplasms; peripheral edema; large cell lymphoma; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; chronic lymphatic leukemia; oligopeptides; skin infection; lymphocytoma; bronchitis; carfilzomib; colon biopsy; hematemesis; hypesthesia |
| Journal Title: | Clinical Cancer Research |
| Volume: | 15 |
| Issue: | 22 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2009-11-15 |
| Start Page: | 7085 |
| End Page: | 7091 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-09-0822 |
| PUBMED: | 19903785 |
| PROVIDER: | scopus |
| PMCID: | PMC4019989 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 11" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus" |
