Phase I Trial Of Carfilzomib In Combination With Vorinostat (SAHA) In Patients With Relapsed/Refractory B-Cell Lymphomas

• Published in: Blood 2013-11, Vol.122 (21), p.4375-4375
• Main Authors: Holkova, Beata, Kmieciak, Maciej, Bose, Prithviraj, Barr, Paul M., Tombes, Mary Beth, Shrader, Ellen, Cebula, Erin, Pierce, Emily, Herr, Megan M., Sankala, Heidi, Feng, Changyong, Fisher, Richard I, Grant, Steven, Friedberg, Jonathan W.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.4375.4375

Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to promote cell death in various cancer cells, including malignant human hematopoietic cells. The novel, proteasome inhibitor carfilzomib is an attractive candidate for combination regimens due to diminished neurotoxicity, irreversible proteasome inhibition, favorable tolerability profile relative to bortezomib, and preclinical and clinical evidence of activity in bortezomib-resistant cells and patients. Preclinical studies demonstrated synergistic interactions between carfilzomib and vorinostat in human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells both in vitro and in vivo as well as in bortezomib-resistant cells (Dasmahapatra et al., Blood 115:4478; 2010; Mol Cancer Ther 10:1686, 2001). These preclinical findings prompted a phase 1 trial, using a 3+3 design, with the goal of determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the combination of carfilzomib and vorinostat in patients with recurrent or refractory B-cell lymphomas. Eligible patients included those with recurrent or refractory non-Hodgkin's lymphoma. The schedule of administration was vorinostat orally twice-daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Initial dose levels were 20/27 mg/m2 (carfilzomib) and 200 mg (vorinostat). To date, 20 patients have been treated at 4 dose levels. Patient characteristics included the following disease types: DLBCL, n = 6; follicular lymphoma, n = 2; MCL, n = 10; and transformed lymphoma, n = 2. The male to female ratio was 14:6, the median age was 67 years (range: 36-79), ECOG performance scores ranged from 0 to 2, and the median number of prior therapies was 3.5 (range: 1-13). Dose-limiting toxicities (DLTs) and adverse events were determined using CTCAE version 4. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment occurring in ≥ 5% of patients included anemia (grade 3, 15%), leukopenia (grade 4, 10%; grade 3, 15%), lymphopenia (grade 3, 10%), neutropenia (grade 4, 5%; grade 3, 25%), thrombocytopenia (grade 3, 10%), catheter-related infection (grade 3, 5%), dyspnea (grade 3, 5%), fatigue (grade 3, 5%), febrile neutropenia (grade 3, 5%), hypokalemia (grade 3, 5%), hyponatremia (grade 3, 5%), lymph nod