Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

Patrick B Johnston,Stefan Klaus Barta,Changchun Deng,Anne W Beaven,Sven De Vos,Yasuhiro Oki,Francine M Foss,Gajanan Bhat,Petros G Nikolinakos,Steven J Hasal,Amanda F Cashen

doi:10.1186/s40164-021-00203-8

Abstract

BackgroundBelinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK).MethodsPatients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose.ResultsTwenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent.ConclusionsBel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing.Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Highlights

Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL)
Results from this study indicated a 69% overall response rate (ORR), median progression-free survival (PFS) of 21.3 months, overall survival (OS) of 71% at 30 months, and a toxicity profile that was largely reflective of the manageable hematological and gastrointestinal events associated with the individual drugs constituting the regimen
The maximum administered dose (MAD) (Cohort 5) was not to exceed the single-agent dosing schedule of belinostat (1000 mg/m2 of belinostat administered on Days 1–5)

Summary

Introduction

Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). First-line treatment of PTCL often comprises combination therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). No other single-agent or combination regimen has demonstrated superior efficacy to CHOP and it remains a primary choice for first-line therapy for PTCL. In an attempt to increase the response rate and improve the durability of responses, several modifications to the CHOP regimen have been investigated with no clear improvements in long-term group efficacy observed, including the addition of agents (e.g., bleomycin, gemcitabine, etoposide, vindesine, liposomal doxorubicin, and bevacizumab), administration of more intensive dosing, and the use of autologous stem cell rescue as consolidation therapy in patients who attain complete remissions from high-dose chemotherapy [12,13,14,15,16]. Allogeneic stem cell transplantation has been found to be feasible in the subset of patients with PTCL who are candidates for the procedure, but it has been associated with significant treatment-related toxicity [17, 18]

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Discussion

Conclusion