Combination of Ublituximab, TGR-1202, and Bendamustine Demonstrates Significant Activity in Patients with Advanced DLBCL and Follicular Lymphoma

Introduction: Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. TGR-1202 is a next generation, once daily, PI3Kδ inhibitor, active in patients (pts) with rel/ref hematologic malignancies that has demonstrated a notably differentiated safety profile, including in long-term follow up (Burris, 2016). Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UTX + TGR-1202 has been previously explored in patients with rel/ref hematologic malignancies and is both well tolerated and highly active. This Phase 1 trial evaluates the safety and efficacy of UTX + TGR-1202 + Benda in pts with advanced diffuse large B-cell lymphoma (DLBCL) and Follicular Lymphoma (FL).

Methods: Eligible pts had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (safety evaluation period). Pts refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. The study was designed to evaluate the safety and efficacy of the triplet combination. UTX was dosed on Days 1, 8 & 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. TGR-1202 was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 pts. Benda was dosed at 90 mg/m²on Days 1 & 2 of Cycles 1-6 only. Efficacy was evaluated per Cheson 2007.

Results: Thirteen pts were evaluable for safety: 9 diffuse large B-cell (DLBCL) and 4 follicular (FL). Med age 65 yo (range 51-81); 7 M/6 F; median prior treatment regimens = 3 (range 1-6); 8 pts (62%) were refractory to prior treatment; 10 pts (77%) were rituximab refractory; ECOG PS 0/1 (1/12). Two of four pts at 800 mg TGR-1202 experienced AE's in Cycle 1 (rash, neutropenia) that led to treatment interruption thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded (n=9). The most common AE's regardless of causality included diarrhea (46%), nausea (38%), decreased appetite and neutropenia (31% each). Grade 3/4 AE's (all causality) reported in > 10% of pts were neutropenia (31%), followed by anemia and hypokalemia (15% each). Two pts had dose reductions (both benda and TGR-1202 reduced). Eight pts (6 DLBCL/2 FL) were evaluable for efficacy (4 too early, 1 withdrew due to non-related AE): ORR was 100% (8/8) with all pts achieving a response at the first efficacy assessment (8 weeks), and 50% (4/8) achieving a complete response (CR), of which 3 were DLBCL and 1 FL. Median follow-up time on study is 3 mos for all pts (range 1 - 9+ mos). No pts have progressed on study to date.

Conclusions: The combination of UTX, TGR-1202, and bendamustine has exhibited manageable toxicity with significant activity (100% ORR) including a 50% CR rate in pts with advanced DLBCL and FL. Enrollment continues at the 600 mg TGR-1202 dose level and the use of growth factor prophylaxis is now being explored at the TGR-1202 800 mg dose in consideration of the advanced patient population. Safety and efficacy data for all pts will be updated at the meeting. Based upon the early activity of the triplet, future registration directed studies are under consideration.