Pulse High-Dose Vorinostat Can Be Delivered with Rituximab, Ifosphamide, Carboplatin, and Etoposide In Patients with Relapsed Lymphoma: Final Results of a Phase I Trial.
Authors: Budde Lihua E , Shustov Andrei , Pagel John M. , Gooley Ted , Oliviera George , Chen Tara , Zhang Michelle , Warr Thomas A. , Boyd Thomas , Press Oliver W. , Gopal Ajay K 
Published: October 2019

Abstract 2790

Background:

The development of more effective front-line regimens for lymphoma (e.g. R-CHOP, BEACOPP) has resulted in lower response rates to salvage regimens such as Ifosphamide, Carboplatin, Etoposide +/− Rituximab (RICE/ICE) and improved strategies are needed. Vorinostat (V) is a well-tolerated, oral pan-HDAC inhibitor approved for the treatment of cutaneous T cell lymphoma. In vitro data indicate that combinations of V at >2-5μM plus etoposide or platinum analogs yield synergistic anti-tumor activity, but these concentrations are not typically attained with standard dose regimens. We hypothesized that pulse high-dose V could safely augment the anti-tumor activity of ICE/RICE for patients with relapsed lymphoma. Here we present the final results of a multi-center Phase I trial defining the maximally tolerated dose (MTD) and pharmacokinetics of V that can be given with RICE or ICE.

Methods:

Eligibility included: relapsed/refractory lymphoma (untreated T-NHL or mantle cell lymphoma [MCL] allowed), age ≥18 years, performance status of 0–2, measurable disease, no active CNS involvement, ANC ≥ 1,500/μL, plts ≥ 100,000/μL, adequate hepatic/renal function, no known HIV. The primary objective was to define a maximally tolerated dose associated with a dose limiting toxicity (DLT) rate of ≤ 25%. DLT = gastrointestinal grade 3 NCI-CTCAE adverse event (AE) >7 days, any related non-hematologic grade ≥4 AE, inability to complete one full cycle of therapy due to toxicity, or any significant medical event at the discretion of the PI. Interpatient dose escalation was implemented using a “two stage” design (Storer et al) with single patient cohorts until a DLT was observed, followed by cohorts of 4 patients. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard ICE or RICE (CD20+ only) delivered on days 3 to 5 every 21 days for up to 2 cycles using G-CSF support.

Results:

Twenty-nine patients were treated, 9 in stage 1, 20 in stage 2. Baseline features: median age = 56 (range 23 to 69), median prior therapies 2 (range 0 – 7), refractory to last regimen = 14 (of 27 evaluable, 52%), and prior transplant 2 (7%). Histologies: Hodgkin Lymphoma (8), Diffuse large B-cell (7), MCL (5), T-NHL (4), Follicular (3), Marginal Zone (1), and Small Lymphocytic lymphoma (1). Fifteen patients received 2 cycles and 14 received 1 cycle due to a DLT (8), patient/MD choice (4), insurance denial (1), or progressive disease (1). Non-hematologic AEs ≥ grade 3 were observed in 25 patients with 14 experiencing grade 3 nausea, vomiting, diarrhea, and/or anorexia. The most common DLTs were infection (n=2), hypokalemia (n=2), transaminitis (n=2) (Table). The MTD was estimated to be 500mg BID × 5 days with full dose ICE/RICE. Responses were observed in 19 of 27 evaluable patients (70%) including 8 CR/CRU and 11 PR. Mobilization of peripheral blood stem cells was successful in 4 of 9 patients immediately following VICE/VRICE (median 5.52×106 CD34/kg), in all 4 attempting after prior unsuccessful VICE/VRICE mobilization (median 4.4 × 106 CD34/kg), and in all 12 others attempting after a subsequent regimen (median 7.5 × 106 CD34/kg). 25 (86%) patients are alive and 15 (52%) are progression-free with a median follow up of 5 months (range 1 – 23 months). Pharmacokinetic data indicated that the median peak V concentration day 3 was 4.5μM (range 4.2–6.0μM). Studies are underway evaluating the impact of high-dose V on histone acetylation patterns, BCL-2 family proteins, and gene expression profiles of patient-derived normal and tumor cells and will be reported.

Conclusions:

High-dose V can safely be delivered with ICE/RICE, achieves potentially synergistic drug levels, and responses are encouraging, though adequate prophylaxis and treatment of GI toxicity is required. The Phase II dose of V with ICE/RICE is defined as 500mg BID × 5 days and warrants further study.

Disclosures:

Budde: Merck: Research Funding. Off Label Use: Off label use of vorinostat. Shustov:Merck: Research Funding. Pagel:Merck: Research Funding. Gopal:Merck: Research Funding.