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Clinical Trial
. 2018 Oct 4;132(14):1486-1494.
doi: 10.1182/blood-2018-05-853499. Epub 2018 Aug 1.

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

Franck Morschhauser  1 , Gilles Salles  2 , Steven Le Gouill  3 , Herve Tilly  4 , Catherine Thieblemont  5 , Krimo Bouabdallah  6 , Bettina Fabiani  7 , Cédric Ménard  8   9 , Karin Tarte  8   9 , Guillaume Cartron  10 , Roch Houot  11
Affiliations
Clinical Trial

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

Franck Morschhauser et al. Blood. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: F.M. has received personal fees for consultancy, advisory boards, or scientific lectures from Gilead, Janssen, Celgene, Servier, Bristol-Myers Squibb, Roche, and Epizyme (outside the submitted work); S.L.G. received research grants, personal fees, and nonfinancial support from Celgene and Roche Genentech during the conduct of the study and has received grants, personal fees, and nonfinancial support from Celgene outside the submitted work; H.T. has received research grants and personal fees from Celgene, personal fees and nonfinancial support from Roche, and personal fees from Karyopharm, AstraZeneca, and Bristol-Myers Squibb outside the submitted work; C.T. has received consultancy fees or honoraria from Celgene, Bayer, AbbVie, and Janssen and research funding from Roche; C.M. has received research funding from Celgene and honoraria from Celgene and Bristol-Myers Squibb; K.T. has received research funding from Celgene and honoraria from Celgene and Roche; G.C. has received personal fees for consultancy and honoraria from Roche and Celgene and received personal fees for honoraria from Sanofi, Gilead, and Janssen during the conduct of the study; and R.H. has received consulting fees or honoraria from Bristol-Myers Squibb and Gilead. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
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.
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.
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.
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