Safety and Efficacy Of Obinutuzumab (GA101) With Fludarabine/Cyclophosphamide (G-FC) Or Bendamustine (G-B) In The Initial Therapy Of Patients With Chronic Lymphocytic Leukemia (CLL): Results From The Phase 1b Galton Trial (GAO4779g)

Chemoimmunotherapy (CIT) is the standard of care to treat fit patients (pts) with CLL. These CIT regimens include the use of rituximab, an anti-CD20 monoclonal antibody (mAb), with standard chemotherapy such as fludarabine/cyclophosphamide (FC) or bendamustine (B). GA101 is a novel, glycoengineered, type II CD20 mAb designed to increase direct and antibody-dependent cellular cytotoxicity. Early phase 1/2 GA101 studies in pts with CLL demonstrated single-agent activity with treatment-related neutropenia. GALTON (NCT01300247) is a non-randomized, parallel group, phase 1b study of the safety and preliminary efficacy of GA101 plus FC or B in the initial therapy of pts with CLL.

Untreated CLL pts requiring therapy who had a performance status ≤2 were treated with GA101 1000 mg (100 mg IV d1, 900 mg d2, 1000 mg d8 and d15 of cycle 1; 1000 mg d1 in cycles 2–8) with either FC (25/250 mg/m² IV on d2–4 of cycle 1, then d1–3 of cycles 2–6; G-FC) or B (70 mg/m² IV on d2–3 of cycle 1, then d1–2 of cycles 2–6; G-B). Each cycle was 28 days. Pts received acetaminophen and an antihistamine before each infusion of GA101. Pts also received methylprednisolone or dexamethasone prior to the 1^st and 2^nd GA101 infusions. Each center chose to participate in either the G-FC or G-B arm, and physicians could reduce the dose of FC or B after the 1^st cycle if there was concern about tolerance to chemotherapy. The primary endpoint was to evaluate safety and tolerability of GA101 with chemotherapy. Secondary endpoints included response rates per iwCLL criteria, including required CT scans to confirm response. Complete response (CR) required resolution of all disease, and single lymph nodes (LNs) needed to be ≤ 1.5 cm in long axis by CT. Partial response (PR) required a ≥ 50% decrease in lymphocyte count, ≥ 50% reduction in sum of product diameter (SPD) of LNs, ≥ 50% reduction of liver and/or spleen, and either neutrophil, platelet or hemoglobin recovery.

We enrolled 41 pts (Table 1) with a median follow-up time of 11.9 months. The most common adverse events (AEs) (any grade) occurring in ≥ 9 pts in the G-FC arm were GA101 infusion–related reactions (IRRs) (91%), nausea (76%), fatigue (57%), constipation (48%), and neutropenia (43%); in the G-B arm, they were GA101 IRRs (90%), nausea (65%), neutropenia (55%), diarrhea (50%), and pyrexia (45%). The most common Grade (Gr) 3/4 AEs are in Table 1. In both cohorts, Gr 3/4 GA101 IRRs only occurred with the 1^st dose. Fourteen pts experienced serious AEs (6 pts in G-FC, 8 pts in G-B), with events including febrile neutropenia (n=5 events); infections (n=4); IRRs (n=3); nausea, vomiting, pyrexia (n=2 each); and diarrhea, fatigue, tachycardia, tumor lysis syndrome, syncope, mental status changes, neutropenia, face swelling, and hypertension (n=1 each). Nine pts (7 in G-FC, 2 in G-B) had AEs leading to treatment discontinuation, including Gr 3/4 neutropenia (3 in G-FC [1 of 3 pts also had Gr 4 cellulitis], 2 in G-B), Gr 3 thrombocytopenia (2 in G-FC), Gr 4 pancytopenia (1 in G-FC), and Gr 4 AST/Gr 3 ALT elevation (1 in G-FC).

Table 1

Patient characteristics and response

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The overall response rate was 62% (2 CR, 3 CRi, 8 PR) in the G-FC arm, and 90% (4 CR, 5 CRi, 9 PR) in the G-B arm, including 6 pts (4 in G-FC, 2 in G-B) not evaluable due to inadequate response evaluation. Four pts in the G-FC arm (0 in G-B) had stable disease during and after therapy. No pt progressed during the study.

GA101 plus chemotherapy can be administered safely to pts requiring initial therapy for CLL. IRRs were the most common AE, but typically occurred during the initial infusions of GA101 and were not dose-limiting. The AE rates observed in pts treated with G-FC or G-B did not appear to be greater than those in pts treated with standard CIT. Our data show GA101 plus FC or B has clinical activity in the initial therapy of pts with CLL, warranting further clinical study.

Brown:Pharmacyclics, Genentech, Celgene, Emergent, Onyx, Sanofi Aventis, Vertex, Avila, Novartis: Consultancy; Genzyme, Celgene: Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. O'Brien:CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, Talon: Research Funding; Teva/Cephalon, Celgene, Emergent, Genentech, Gilead Sciences, Infinity, Pharmacyclics, Talon: Consultancy. Eradat:Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Lymp:Roche: Stock options, Stock options Other; Genentech: Employment. Hirata:Roche: Stock options, Stock options Other; Genentech: Employment. Kipps:Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding.