Dataset Information

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.

ABSTRACT: A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3?+?3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20?mg/m2 carfilzomib and 100?mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-?B activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

SUBMITTER: Holkova B

PROVIDER: S-EPMC4798896 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.

Holkova Beata B Kmieciak Maciej M Bose Prithviraj P Yazbeck Victor Y VY Barr Paul M PM Tombes Mary Beth MB Shrader Ellen E Weir-Wiggins Caryn C Rollins April D AD Cebula Erin M EM Pierce Emily E Herr Megan M Sankala Heidi H Hogan Kevin T KT Wan Wen W Feng Changyong C Peterson Derick R DR Fisher Richard I RI Grant Steven S Friedberg Jonathan W JW

Leukemia & lymphoma 20151012 3

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat ...[more]

PMID: 26284612

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Project description:BackgroundIsatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM).MethodsThis phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m2 intravenously for cycle 1, days 1 and 2, and then 27 mg/m2 for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity.ResultsWith a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing.ConclusionsTreatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM.Lay summaryThis phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months.

Dataset Information

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.

Publications

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas.

Similar Datasets

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