CC-122, a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed and Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL) (2017)

Introduction: Patients (pts) with R/R NHL, including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) have a poor prognosis with limited 2L and 3L treatment options (MacDonald et al. Curr Oncol 2016). Early relapse (ER) pts with FL experiencing progression within 2 years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al. J Clin Oncol 2015; Gopal et al. N Eng J Med 2014). CC-122 is a novel oral agent that binds the cereblon ubiquitin ligase complex, resulting in degradation of the hematopoietic transcription factors Aiolos and Ikaros. Preliminary results from CC-122-NHL-001, a phase Ib study of CC-122 in combination with obinutuzumab, have shown promising response rates in pts with R/R B-cell NHL (Michot et al. ASH 2016). Herein, we report updated results for safety and efficacy from CC-122-NHL-001 (NCT02417285) with further 12 months follow up. Methods: Eligible pts age ≥18 years had histologically or cytologically confirmed CD20+ B-cell R/R NHL after ≥1 prior regimen for FL/marginal zone lymphoma (MZL) or after ≥2 regimens and/or autologous stem cell transplant (ASCT) for DLBCL. CC-122 was given orally (5 of 7 d) for 28-d cycles in escalating doses plus a fixed dose of intravenous obinutuzumab 1000 mg on d2, 8, 15 of cycle 1 (c1), and d1 of c2-8, upon informed consent. CC-122 active ingredient in capsule formulation (AIC) 1, 2, 3, and 4 mg and CC-122 formulated capsules (F6) 3 and 4 mg were evaluated in separate cohorts. Primary endpoints included safety and tolerability, non-tolerated dose (NTD), and maximum-tolerated dose (MTD). Response was assessed using the Cheson 2007 criteria every 2 cycles to c6, every 3 cycles to c12, and every 6 cycles thereafter. Results: As of May 1, 2017, 38 pts with R/R B-cell NHL were enrolled in the dose-escalation phase of the study. Tumor types included 19 pts with DLBCL, 18 with FL, and 1 with MZL. Of the 18 pts with FL, 10 (5 DR+ER and 5 ER) were difficult to treat, high-risk pts. Median age was 60 years (range, 26-81), 26 (68%) were male, and 29 (76%) had stage III/IV disease. Of the 19 pts with DLBCL, 8 (42%) had transformed DLBCL, and of the 19 pts with FL/MZL, 8 (42%) relapsed in 1 pt. Three deaths occurred during the study (2 PD; 1 AE-related, tumor flare). Median duration of CC-122 treatment was 23.6 weeks (range, 3.4-87.0), equivalent to 7 cycles (range, 1-22). CC-122 dose reduction or temporary interruption occurred in 12 (32%, all due to AEs) or 32 (84%, 26 due to AEs) pts, respectively. Fifty-five percent of pts had Conclusions: The novel, chemotherapy-free combination of CC-122 and obinutuzumab was well tolerated with promising response rates, and durable remissions in R/R B-cell NHL. The safety profile was consistent with other studies of CC-122, with AEs being mainly hematological and manageable. Notably, subgroup analysis showed that the combination has similar efficacy in the high-risk ER and DR subgroups of RR FL compared with the overall FL population. A CC-122 dose of ≥3 mg with obinutuzumab shows the best response rates to date, with deep response upon prolonged treatment. Expansion part B is currently on-going in both lenalidomide naive and lenalidomide refractory FL pts. Disclosures Doorduijn: Celgene: Honoraria; Roche: Honoraria. Vitolo: Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria. Kersten: Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Milennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; Kite Pharma: Honoraria; Amgen: Honoraria; MSD: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chiappella: Teva: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Nanostring: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani: Celgene, Janssen, Gilead, Roche, Takeda, BMS, MSD, Sandoz, Servier, Mundipharma: Speakers Bureau; Merck: Consultancy, Other: Advisory board; ​Celgene, Roche, Janssen, Gilead, Takeda, BMS, MSD, Servier, Sandoz, Mundipharma: Honoraria. Sarmiento: Celgene Research S.L.: Employment, Equity Ownership. Mosulen: Celgene Institute for Translational Research Europe: Employment. Mendez: Celgene Institute for Translational Research Europe: Employment. Petrarca: Celgene Corporation: Employment, Equity Ownership. Pourdehnad: Celgene Corporation: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Li: Celgene Corp.: Employment. Nikolova: Celgene International Sarl: Employment, Equity Ownership. Ribrag: Epizyme: Honoraria; BMS: Honoraria; MSD: Honoraria; Infinity: Honoraria; Gilead: Honoraria; Nanostring: Honoraria; Roche: Honoraria; ArgenX: Research Funding; Servier: Consultancy, Honoraria.