Tolerability and activity of chemo-free triplet combination of TGR-1202, ublituximab, and ibrutinib in patients with advanced CLL and NHL.

Abstract

7511 Background: Novel targeted agents are emerging for B-cell malignancies, but few studies have safely combined these agents. 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, demonstrating a favorable safety profile compared to prior inhibitors, including in long-term follow up (Burris, 2016). This Ph 1 trial evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb + PI3Kδ + BTK inhibitor (ibrutinib) in pts with B-cell malignancies. Methods: Eligible pts had CLL or rel/ref NHL w/o limit to prior therapies, including those ref to prior PI3Kδ or BTK inhibitors. UTX dosed on D1, 8, 15 of C1; D1 of C2-6, and C9 & 12. TGR-1202 dose escalated (400/600/800mg QD), ibrutinib dosed at 420mg (CLL) or 560mg (NHL), both on C1D1. Results: 38 pts were enrolled: 20 CLL/SLL and 18 NHL, including 6 follicular (FL), 6 DLBCL, 4 mantle cell (MCL) and 2 marginal zone (MZL). Med age 65 yrs (range 32-85); 29 M/9 F; med prior tx = 3 (range 0-6). 2 pts were ref to prior PI3Kδ and 2 were prev treated with ibrutinib (1 ref/1 rel). MTD was not reached. Most common ( > 20%) all causality AE’s were fatigue (42%), diarrhea (39%), dizziness (34%), nausea (32%), neutropenia, pyrexia, rash, infusion reaction, insomnia (each at 29%), thrombocytopenia, cough (each at 26%), anemia (24%) and sinusitis (21%). GR 3/4 AE’s were minimal, the only event > 10% was neutropenia (16%). ORR amongst 36 evaluable pts is shown in the table below. 53% of evaluable CLL pts had high-risk cytogenetics and 4/6 DLBCL pts were non-GCB. One CLL pt (17p/11q del) ref to both PI3Kδ and ibrutinib achieved a CR. Med time on study is 10 mos (range 1 – 27+ mos). Med DOR not reached (range 3 – 24+ mos). Conclusions: This is the first known triple combination of an anti-CD20 mAb + PI3Kδ + BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies. Expansion cohorts at the highest dose (800mg TGR-1202 + full dose ibrutinib) are underway. Future trials for the triplet are warranted. Clinical trial information: NCT02006485. [Table: see text]