A Phase I Study of Vorinostat (V) in Combination with Rituximab (R), Ifosphamide, Carboplatin, and Etoposide (ICE) for Patients with Relapsed or Refractory Lymphoid Malignancies or Untreated T- or Mantle Cell Lymphoma.
Authors: Budde Lihua E. , Zhang Michelle M. , Shustov Andrei R. , Pagel John M. , Warr Thomas A. , Chen Tara L , Oliveira George R. , Gooley Ted , Gopal Ajay K. 
Published: October 2019

Abstract
Abstract 3696
Poster Board III-632
Platinum based regimens such as ICE with or without Rituximab (RICE) have been widely used to treat relapsed or refractory lymphoid malignancies prior to transplantation. However, a significant portion of patients do not respond to treatment, and improved therapies are needed. Vorinostat (V) is an oral HDAC inhibitor with moderate toxicity and has clinical activity against a variety of tumors including cutaneous T cell lymphoma. Preclinical data demonstrated marked anti-tumor synergism between V and platinum analogues as well as etoposide. We present data from a phase I, open-label, multicenter, dose escalation study estimating the maximally tolerated dose of V that can be combined with RICE or ICE (V-RICE or VICE) in patients with relapsed or refractory lymphoid malignancies or untreated T- or Mantle Cell Lymphoma. Other endpoints include tolerability, exploratory anti-tumor activity and impact of above regimen on stem cell reserve. Patients (aged ≥18 years, an ECOG performance status of 0-2, measurable disease, no active central nervous system involvement, adequate bone marrow, hepatic and renal function, no active arrhythmias on EKG) were sequentially enrolled on escalating doses of V combination therapy using the “two stage” design introduced by Storer with single patient cohorts until a dose limiting toxicity (DLT) is observed, followed by cohorts of 4 patients. A DLT was defined as any gastrointestinal grade 3 NCI-CTCAE adverse event (AE) lasting longer than 7 days, or any related non-hematologic grade 4 or 5 AE; any event that prevents the completion of one full cycle of therapy (5 days of V) due to toxicity from V; or any AE at the discretion of the principal investigator. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard RICE or ICE on days 3 to 5 every 21 days. A total of 18 patients have been enrolled on this study thus far (9 in stage 1, 9 in stage 2) and 14are fully evaluable to date, including: Hodgkin lymphoma (4), T-cell lymphoma (3); mantle cell lymphoma (2); diffuse large B cell lymphoma (2); follicular lymphoma (2), and chronic lymphocytic leukemia (1). Baseline characteristics (n=14) included: median age 55 (range: 33-67), male 10 (71%), stage III/IV 14 (100%), median number of prior therapies 2 (range: 0-6), elevated LDH 5 (35%), prior anthracycline 13 (93%), prior platinum 2 (14%), refractory diseases 5 (36%), relapsed diseases 8 (57%), untreated disease 1 (7%). A maximum V dose of 700 mg BID was attained in stage I (Table). The dose adjustment schema of stage II has ranged from 600 mg BID to 400 mg BID currently. Among the 14 evaluable patients, six received only1 cycle of treatment (3/5 patients declined the second cycle; 2/5 patients developed DLT), 8 completed 2 cycles. Eight of 14 (57%) patients experienced non-hematologic AEs≥ grade 3 with most common being nausea, vomiting, or diarrhea seen in 6 and grade 4 hypokalemia in 2. Twelve patients (86%) responded including 1 with complete remission (CR), 2 with unconfirmed CR, and 9 with partial responses. One patient had stable disease and one had disease progression. Nine of 12 patients (75%) who attempted peripheral blood stem cell collection following VICE/V-RICE were successful (>5×106 CD34+/kg) Collectively, these findings indicate that the combination of vorinostat with RICE or ICE, is feasible and active in patients with lymphoid malignancies. Special attention should be given to the management of the frequent gastrointestinal AEs. Pending identification of the MTD, phase II evaluation of VICE or V-RICE regimen will be designed to formally define its efficacy.
Table Summary of DLTs and responses at various dose levels Stage Dose level Dose n DLTs responses I 1 400 mg QD 2 0 PR(1); SD (1) 2 300 mg BID 1 0 PR (1) 3 400 mg BID 1 0 PD (1) 4 500 mg BID 2 0 PR (1); CR (1) 5 600 mg BID 1 0 PR (1) 6 700 mg BID 2 1 PR (2) II 5 600 mg BID 4 3 PR (1); CRu (3) 4 500 mg BID 1 1 PR (1) Total - - 14 5 12 (86%)

Disclosures:
No relevant conflicts of interest to declare.