A Phase I Study of Lenalidomide Plus a Next Generation Anti-CD20 Antibody, Obinutuzumab, in Relapsed Indolent Lymphoma

Background:  Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Lenalidomide activates NK cells ± T cells and leads to in vivoexpansion of immune effector cells in NHL models. In preclinical studies, we have shown the synergistic anti-tumor effect of combining lenalidomide with anti-CD20 molecules. (Wang 2007)  The combination of rituximab and lenalidomide (R2) in relapsed and untreated iNHL is highly active. (Fowler 2014) We hypothesize these responses are related to augmentation of immune response and ADCC through alteration of immune cell subsets in tumor and peripheral blood.  Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC.  The primary objective of this study was to determine the safety and maximum tolerated dose of lenalidomide and obinutuzumab in patients with relapsed/refractory iNHL.

 Methods:   Patients with relapsed SLL, marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle.  Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles.   All patients received prophylactic steroids prior to obinutuzumab. In the absence of toxicity or progression, the combination was continued for up to 12 cycles. The standard ‘3+3’ design was used with dose limiting toxicities (DLT) assessed during cycle 1.   Patients attaining ≥partial response continued obinutuzumab every 2 months for up to 24 months. Prophylactic growth factors were not used.  Adverse events were graded using CTCAE version 4.03.

 Results:  15 patients (9 during dose escalation, 6 during dose expansion at target dose) were enrolled; all were evaluated for safety  and efficacy (all having had at least 1 post-baseline response assessment).   The median age was 60 (36-82) years, and 7 (47%) were male.  21% of patients with follicular lymphoma had low, 29% intermediate, and 50% high FLIPI scores at study entry, 1 patient had SLL.  No DLTs were observed during dose escalation. The most common grade 1-2 non-hematologic toxicities were fatigue 12/15 (80%), constipation 9/15 (60%), diarrhea 7/15 (47%), dyspnea 7/15 (47%), and myalgia 7/15 (47%). Grade ≥ 3 events included neutropenia (n=3, 20%), infection (n=2, 13%),thrombocytopenia (n=1, 6%), and  two infusion related reactions (13%), both occurring during the first infusion of obinutuzumab. With a median follow up of 8.2 (4.1-14 mo), the overall response rate was 93% with 27% (4/15) achieving a complete response and 67% (10/15) with a partial response, all responding patients remain on active therapy. One patient progressed after 8 months and was withdrawn from study.

 Conclusion:  The combination of 20 mg of lenalidomide and 1000mg obinatuzumab is safe and effective in patients with relapsed iNHL.   Adverse events appeared similar to our prior experience with lenalidomide and rituximab.   Overall response rates were high, with complete responses increasing with prolonged duration of therapy.   Correlative efforts are ongoing to study the immunomodulatory potential of the combination and to identify biomarkers of response.   The phase II portion of this study is currently enrolling with dose expansions in relapsed iNHL.