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 node pain (grade 3, 5%), and pneumonitis (grade 3, 5%). Two grade 5 events were observed; 1 was attributed to disease progression and not related to study treatment; 1 was attributed to pneumonia possibly related to treatment. Common grade 2 AEs possibly, probably or definitely related to treatment in ≥ 15% of patients included anemia (25%), diarrhea (15%), fatigue (20%), hyperglycemia (15%), hypokalemia (15%), nausea (15%), neutropenia (15%), thrombocytopenia (20%), and vomiting (15%).
There were 2 DLTs at dose level 1, grade 3 pneumonitis and febrile neutropenia, and there were no DLTs at dose level -1 (carfilzomib 20/20 mg/m2 and vorinostat 100 mg twice daily). Two intermediate dose levels (-1a and -1b) were added between dose-levels 1 and -1. No DLTs or significant differences in toxicities were observed at dose levels -1a and -1b. Consequently, two MTD/RP2D levels have been identified: carfilzomib 20/20 mg/m2 and vorinostat 200 mg twice daily (level -1a) and carfilzomib 20/27 mg/m2 and vorinostat 100 mg twice daily (level -1b).
All 20 patients treated were evaluable for response. The best response on this phase 1 study was 1 partial response; 2 patients had stable disease.
Correlative studies evaluating pre- and post-treatment plasma levels of IL-10 and TNF are currently undergoing analysis.
Collectively, these findings indicate that the combination of carfilzomib and vorinostat is reasonably tolerable in this patient population. Two dose levels have been identified for the MTD/RP2D. The regimen appears to have modest activity in heavily pre-treated patients with relapsed and/or refractory B-cell lymphomas.
Friedberg:Merck & Co.: Research Funding.
Asterisk with author names denotes non-ASH members.