Open-Label Phase 2 Study Of The Bispecific T-Cell Engager (BiTE®) Blinatumomab In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Viardot Andreas , Goebeler Mariele , Pfreundschuh Michael , Adrian Nicole , Libicher Martin , Degenhard Evelyn , Stieglmaier Julia , Zhang Alicia , Nagorsen Dirk , Bargou Ralf C. 
Published: October 2019

Abstract

Introduction
Blinatumomab, a bispecific T-cell engager (BiTE®) that redirects cytotoxic T cells to CD19+ B-lineage cells, has shown anticancer activity and acceptable toxicity in a phase 1 study in patients with relapsed/refractory non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Using a stepwise dose escalation treatment, the overall response rate (ORR) in patients with DLBCL was 55% (Goebeler et al. Hematol Oncol 2013;31[suppl 1]:197). This open-label phase 2 study has been initiated to investigate the efficacy and tolerability of blinatumomab in patients with relapsed/refractory DLBCL, comparing stepwise dose escalation with constant target dosing.

Methods
In this ongoing study, eligible patients must be ≥18 years of age, must have relapsed/refractory DLBCL and Eastern Cooperative Oncology Group performance status ≤2. Blinatumomab is administered by continuous intravenous infusion over 8 weeks. In part 1 of the study, two cohorts were evaluated using a double-step or flat dose escalation regimen, respectively, in order to achieve the target dose of 112 μg/d. Part 2 will investigate the selected treatment schedule from part 1. Data from part 1 (cohorts I and II) are presented herein. Patients in cohort I received stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, respectively; patients in cohort II received blinatumomab at 112 μg/d throughout. After a 4-week treatment-free period, patients achieving an objective response were permitted to receive a 4-week consolidation cycle. All patients received prophylactic dexamethasone. The primary endpoint is ORR by Cheson (2007) revised response criteria for malignant lymphomas.

Results
To date, 11 patients have been enrolled and treated in part 1 of the study: nine in cohort I and two in cohort II. The median age was 73 years (range, 55–85); 64% of patients were women. Six (55%) patients had received ≥3 lines of previous systemic antitumor therapy; study treatment was given as fourth-line (median) systemic treatment. Three patients had received autologous hematopoietic stem cell transplantation. At the time of this analysis, seven patients were evaluable for response (cohort I, n=6; cohort II, n=1). The ORR based on independent radiological assessment was 57% (cohort I: complete response, n=1; partial response, n=2; cohort II: partial response, n=1). Three patients had progressive disease (all in cohort I). Four patients were not evaluable for ORR per protocol definition: early treatment discontinuation after <1 week on target dose in absence of disease progression, n=3; transformed DLBCL, patient only pre-treated for follicular lymphoma (patient achieved a CR), n=1. The most common adverse events (AEs) regardless of causality were tremor (64%), diarrhea (46%), and fatigue (46%). Ten of 11 patients had at least one grade ≥3 AE regardless of causality, with two patients (both in cohort II) experiencing grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no grade 5 AEs. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor (64%), speech disorder (36%), and disorientation (27%). Five patients (cohort I, n=3; cohort II, n=2) had grade 3 CNS AEs (there were no grade 4 or 5 CNS events). The overall benefit/risk assessment revealed the dose administered in cohort I (stepwise dosing: 9, 28, 112 μg/d) to be the recommended dose for part 2 of the protocol.

Conclusions
In this ongoing phase 2 study, blinatumomab was tolerable and showed antitumor activity in adult, heavily pretreated patients with relapsed/refractory DLBCL. Part 1 of the study established a recommended blinatumomab dose for this patient population. The study continues to enroll patients in part 2 (cohort III).

Disclosures:
Libicher: Amgen Inc.: Consultancy. Degenhard:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Stieglmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhang:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Bargou:University of Würzburg: Consultancy; University of Würzburg: Honoraria; Amgen Inc.: patent, patent Other.