Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.
Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.
Dr. Jean-Marie Michot
CC-122 is a thalidomide analog that shares a molecular target with its cousin lenalidomide (Revlimid). Both molecules bind to the protein cereblon to cause degradation of the lymphoid transcription factors Aiolos and Ikaros.
As a single agent, CC-122 has been shown to have immunomodulatory effects on T-cell and natural killer (NK)–cell functions and has shown clinical activity in heavily pretreated patients with relapsed refractory NHL, including various cell-of-origin–based DLBCL subtypes, Dr, Michot said.
In preclinical studies, the combination of CC-122 and obinutuzumab, an anti-CD20 monoclonal antibody, has shown synergistic effects against FL and greater antilymphoma effects against DLBCL than either agent alone, he added.
In a multicenter, open-label, phase 1b dose-escalation and expansion study, investigators enrolled 19 patients with FL or MZL for whom at least one prior regimen had failed and 19 patients with relapsed/refractory DLBCL following at least two prior regimens and failed autologous stem cell transplant.
The patients received oral CC-122 at different dose levels for 5 of 7 days in each 28 day treatment cycle, plus intravenous obinutuzumab 1000 mg on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2 through 8.
Responses were assessed according to International Working Group 2007 revised response criteria for malignant lymphoma.
Among all 38 patients, 25 (66%) had a response. Responses consisted of 12 CR (3 in patients with DLBCL, and 9 in patients with FL/MZL) and 13 partial responses (six and seven patients, respectively),
The median time to best response was 57 days. Responses were seen in 23 of the 30 patients who received CC-122 at dose level of 3 mg or higher.
“To date, patients receiving CC-122 at a dose of 3 mg and higher have the best and more durable responses to CC-122 plus obinutuzumab,” Dr. Michot said.
Patients generally tolerated the combination well. The most common grade 3 or 4 adverse events were hematologic and included grade 4 febrile neutropenia in two patients. Two patients discontinued treatment because of adverse events.
There was a dose-limiting toxicity, grade 4 neutropenia in one patient who received CC-122 at the 3 mg dose level, and one death from a tumor flare reaction in a patient treated at the 4 mg dose level.
The dose-escalation arm of the study has completed, and investigators are enrolling patients in a dose expansion phase at the 3 mg level.
The study was sponsored by Celgene. Hoffman La-Roche contributed obinutuzumab for the study. Dr. Michot reported serving as an advisor to Bristol-Myers Squibb and receiving travel grants from BMS, Pfizer, and Roche. Seven coauthors are Celgene employees and stockholders.