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

• Published in: Blood 2015-12, Vol.126 (23), p.2942-2942
• Main Authors: Mahadevan, Daruka, Pauli, Emily K., Cutter, Kathy, Dietz, Lee Ann, Sportelli, Peter, Miskin, Hari P., Schreeder, Marshall T.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.2942.2942

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 previou