A Phase I Trial of TGR-1202, a Next Generation Once Daily PI3K-Delta Inhibitor in Combination with Obinutuzumab Plus Chlorambucil, in Patients with Chronic Lymphocytic Leukemia
Authors: Mahadevan Daruka , Pauli Emily K. , Cutter Kathy , Dietz Lee Ann , Sportelli Peter , Miskin Hari P. , Schreeder Marshall T. 
Published: October 2019

Abstract
Introduction: TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor that displays promising clinical activity in patients with relapsed and refractory hematologic malignancies, with a differentiated safety and tolerability profile compared to other PI3Kδ inhibitors (Burris, ASCO 2015). Obinutuzumab is a glycoengineered Type II anti-CD20 monoclonal antibody approved for patients with chronic lymphocytic leukemia (CLL) in combination with chlorambucil. TGR-1202 has previously been combined with a similarly glycoengineered Type I anti-CD20 mAb, ublituximab, demonstrating clinical activity in patients with heavily pre-treated hematologic malignancies (Lunning, ASCO 2015). The purpose of this study is to explore the safety and efficacy of TGR-1202 + obinutuzumab + chlorambucil in patients with CLL, evaluating a novel treatment regimen of a glycoengineered anti-CD20 with a PI3Kδ inhibitor.
Methods: Eligible patients have a diagnosis of CLL/SLL with an ECOG PS ≤ 2. TGR-1202 is escalated in a 3 + 3 design. Cohort 1 was intiated at 800 mg of an initial formulation, with an improved micronized formulation introduced in Cohort 2 at 400 mg and increased in subsequent cohorts. Obinutuzumab is administered as a fixed IV infusion at 1000 mg on days 1, 8 and 15 of cycle 1, followed by day 1 of cycles 2 - 6. Chlorambucil is administered at 0.5 mg/kg on days 1 and 15 of cycle 1 and optional for cycles 2 - 6. After cycle 6, patients remain on TGR-1202 monotherapy until disease progression. Safety is the primary endpoint and is evaluated by CTCAE v. 4.0. Efficacy (ORR and duration of response) is a secondary endpoint, with responses evaluated according to IWCLL (Hallek, et. al. 2008).
Results: As of August 2015, 18 patients (15 naïve/3 rel/ref) have been enrolled: Median age is 66 years (range 51-85y); 12 female/6 male, median ECOG PS = 1. FISH from the 3 relapsed patients are del13q/del17p, del11q/del17p and del11q/+12/del13q and 4 treatment naïve patients with 11q del only. All patients are evaluable for safety: AE's have been manageable, with neutropenia (61% Gr3/4), thrombocytopenia (33% Gr3/4) and increases in ALT/AST (28% Gr3/4) being the most frequent Gr3/4 events reported. Chlorambucil was discontinued in 4 patients in cycle 2 due to adverse events. No patient discontinued TGR-1202 due to ALT/AST elevations or neutropenia. 17 patients are evaluable for efficacy of which 14 were treatment naïve and 3 were previously treated, notably all 3 of which had previously progressed on a BTK inhibitor. To date, 93% (13/14) of the treatment naïve patients have achieved an objective response, including 4/14 (28%) complete responses, while 2/3 previously treated patients have achieved a response. The remaining 2 patients not in response have stable disease with 48% and 42% nodal reductions, respectively, with both remaining on study. Notably 6 of the 14 treatment naïve patients (43%) are MRD negative by peripheral blood.
Conclusions: The combination of TGR-1202 + obinutuzumab + chlorambucil is well tolerated, with clinical activity observed in all patients, including patients with del17p, previously progressing on a BTK inhibitor. 7/14 (50%) of treatment naïve patients, including those with del11q, achieved either a CR or MRD negativity. Neutropenia, the highest reported AE, was manageable. Notably the ALT/AST increases observed with this combination have not been seen when TGR-1202 is administered as a single agent or in combination with another glycoengineered anti-CD20 mAb, ublituximab (<5% ALT/AST increase; N=137; O'Connor, ICML 2015).

Disclosures
Mahadevan: Pharmacyclics: Speakers Bureau; Alexion: Speakers Bureau. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Cutter:Clearview Cancer Center: Employment. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Schreeder:TG Therapeutics, Inc: Research Funding.