An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma

Abstract

Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.

Graphical abstract

Figure 1.

Treatment schedule. Escalating doses of oral lenalidomide (10, 15, 20, or 25 mg) were administered to 4 patient cohorts (n = 3-6) from days 1 to 21 in cycle 1 and day 2 to 22 in cycles 2 through 6. Obinutuzumab (1000 mg) IV was administered on days 8, 15, and 22 of cycle 1 and day 1 of cycles 2 through 6 (total of 8 infusions). Cycles are 28 days in length.

Figure 2.

PFS, DOR, and OS in the treated set. (A) PFS; (B) DOR; and (C) OS. CL, confidence limit; NR, not reached.

Figure 3.

Lenalidomide activates T cells in vivo and does not alter CD20 expression. (A) HLA-DR expression was measured by flow cytometry in peripheral blood on CD4 and CD8 T cells at various time points. (B) CD20 expression was measured by flow cytometry on circulating normal and/or malignant B cells. End of induction was 28th day of sixth cycle of treatment. Median value is depicted as a black bar. *P ≤ .05, ***P ≤ .001. C1D1, first day of first treatment cycle (before lenalidomide intake); C1D8, eighth day of first cycle (before or after obinutuzumab [GA101] infusion); C2D1, first day of second cycle (before lenalidomide intake); MFI, mean fluorescence intensity; ns, not significant.