A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma
Authors: Holkova Beata , Perkins Edward B. , Sokol Lubomir , Richards Kristy L. , Parekh Samir , Elstrom Rebecca , Badros Ashraf Z. , Espinoza-Delgado Igor , Schell Michael J. , Kimball Amy , Tombes Mary Beth , Shrader Ellen , Sankala Heidi , Coppola Domenico , Kmieciak Maciej , Sullivan Daniel , Roberts John D. , Grant Steven 
Published: October 2019

Abstract 779FN2

Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors which interact to induce cell death in various human tumors, particularly indolent B-cell malignancies such as multiple myeloma. Furthermore, recent phase I studies have shown promising results for proteasome/HDAC inhibitor regimens in myeloma. The primary objective of this phase II study was to estimate the response rates of patients with mantle cell lymphoma (MCL), or relapsed or refractory diffuse large B-cell lymphoma (DLBCL) to the proteasome inhibitor bortezomib administered in conjunction with the pan-HDAC inhibitor vorinostat.

Patients were assigned to 1 of 3 cohorts: (A) bortezomib - naïve MCL; (B) bortezomib - exposed MCL; and (C) relapsed or refractory DLBCL. The schedule of administration was vorinostat 400 mg administered orally on days 1–5 and 8–12, and bortezomib 1.3 mg/m2 administered intravenously on days 1, 4, 8, and 11; on a 21 day cycle.

Fifty-one patients have been enrolled and 47 treated, 17 in cohort A, 4 in cohort B, and 26 in cohort C. Cohort B was closed due to inadequate accrual. Patient characteristics included male/female n = 33 (70%)/14 (30%), median age = 62 years [range 33–83]. ECOG performance scores ranged from 0–2. The median number of prior therapies was 2 [range 0–8].

Common treatment-related adverse events included fatigue, dizziness, leukopenia, neutropenia, lymphopenia, peripheral sensory neuropathy, nausea, vomiting, anorexia, elevated creatinine, thrombocytopenia, diarrhea, and chills. Common grade 3 and 4 toxicities (CTCAE v4) included anemia, diarrhea, fatigue, thrombocytopenia, lymphopenia, dehydration, hyponatremia, and hypotension. Two deaths have occurred: 1 associated with neutropenic sepsis and felt possibly related to study treatment, and 1 due to disease progression after discontinuation of study treatment.

Patients were accrued according to a 2-stage Simon minimax design. Investigator-reported responses (CR + PR) have been achieved in cohort A (8 out of 17, 47%) and cohort C (3 out of 26, 12%). Both of these response rates met the thresholds to proceed from the 1st to the 2nd stage of enrollment.CohortTotalABCResponseComplete Response (CR)2–13Partial Response (PR)6–28Stable Disease (SD)32510Progressive Disease (PD)521522Too Early To Evaluate1––1Not Assessed––33Total1742647

Correlative studies are ongoing and are designed to determine whether the combination of bortezomib and vorinostat is more active in lymphomas in which baseline activation of NF-kappa B can be detected. Sample analysis and results are pending.

These findings indicate that combined treatment with vorinostat and bortezomib is active in patients with MCL, or relapsed or refractory DLBCL, particularly for MCL where the 47% response rate greatly exceeds the 29% (8 of 28) needed to proceed to stage 2.

Disclosures:

Sokol: Medimmune: Honoraria; Celgene: Consultancy, Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Allos: Consultancy. Richards:Celgene: Research Funding; Merck: Consultancy; Millennium: Consultancy.