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Avadomide (CC-122), a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Jean-Marie Michot, Reda Bouabdallah, Jeanette K. Doorduijn, Umberto Vitolo, Marie José Kersten, Annalisa Chiappella, Pier Luigi Zinzani, Gilles Salles, Fontanet Bijou, Rafael Sarmiento, Silvia Mosulen, Cristina Mendez, Shailaja Uttamsingh, Michael Pourdehnad, Kristen Hege, Li Li, Zariana Nikolova and Vincent Ribrag

Abstract

Background: Relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL), remains a clinical challenge with limited second- and third-line treatment options. Patients (pts) with follicular lymphoma (FL) experiencing early relapse (ER) 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 Engl J Med 2014).Avadomide (CC-122) is a cereblon modulating agent that promotes degradation of transcription factors Aiolos and Ikaros, resulting in potent antilymphoma and immunomodulatory effects on T- and NK-cell function. Phase I clinical data from the CC-122-NHL-001 study (NCT02417285) revealed promising activity with avadomide plus obinutuzumab in pts with R/R B-cell NHL (Michot et al. Blood 2017). Herein, we report results from CC-122-NHL-001 in pts with R/R FL.

Methods: CC-122-NHL-001 is a phase Ib, open-label, dose escalation/expansion study of avadomide in combination with obinutuzumab. Eligible pts were aged ≥18 y with histologically or cytologically confirmed CD20+ B-cell NHL after ≥1 prior regimen for FL/marginal zone lymphoma (MZL). Upon informed consent, pts received escalating doses of avadomide for 5 out of 7 d/wk in 28-d cycles plus a fixed dose of intravenous obinutuzumab 1000 mg on d 2, 8, and 15 of cycle 1 (C1), and d 1 of C2-8. Avadomide active ingredient in capsule (AIC) formulation at doses of 1, 2, 3, and 4 mg and avadomide formulated capsules (F6) of 3 and 4 mg were evaluated in separate cohorts. Primary endpoints included safety and tolerability, non-tolerated dose, and maximum-tolerated dose. 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, 2018, 58 pts with R/R B-cell NHL were treated in the study, including 19 with R/R DLBCL,38 with R/R FL, and 1 with R/R MZL. Among the 38 pts with R/R FL, 18 were treated in the dose escalation phase (median of 16.5 cycles; 78% initiated ≥6 cycles) and 20 were treated in the expansion phase (median of 4 cycles; 40% initiated ≥6 cycles). Of the 38 pts, 36 pts received 3 mg of 4 mg of avadomide (F6 or AIC); 2 pts received 2 mg of avadomide (AIC). The median age among R/R FL pts was 60 y (range, 41-83), 22 pts (58%) were male, and 32 (84%) had stage III/IV disease. The median number of prior antilymphoma therapies was 3 (range, 1-8), and 12 (32%) pts had 1 prior autologous stem cell transplant. As of data cutoff, 19 pts (50%) were ongoing treatment. One pt experienced a dose-limiting toxicity, consisting of grade 4 neutropenia (avadomide 3 mg AIC). Among the 38 pts in the dose escalation/dose expansion phases, the most common (≥25%) any-grade treatment-emergent adverse events (TEAEs) were neutropenia (66%), thrombocytopenia (29%), and pyrexia (29%). The most common (≥10%) grade 3/4 TEAEs were neutropenia (58%) and thrombocytopenia (11%). Nine pts (24%) had ≥1 serious TEAE related to avadomide; only cytokine release syndrome (11%) and infusion related reactions (8%) occurred in >1 pt. Avadomide dose reduction and temporary interruption occurred in 10 pts (26%; all due to AEs), and 27 pts (71%; 25 pts due to AEs), respectively. Median duration of interruption due to AEs was 15 d (range, 2-48). The overall response rate (ORR) among all R/R FL pts (n=38) was 68%, with 16 pts (42%) achieving complete response (CR). Median duration of response was 19.4 mo (95% CI, 8.4-not reached). Median progression-free survival (mPFS) was 16.6 mo (95% CI, 11.4-24.9) with a median follow up time for PFS of 5.4 mo. Subgroup analysis examined activity of the combination in standard-risk and high-risk (ER and/or DR) FL pts (Table). Both response rates and mPFS were similar in standard-risk and high-risk FL pts (ORR: 70% vs 67%, P=0.83; CR: 40% vs 44%, P=0.78; mPFS: 16.6 mo [95% CI, 5.4-not reached] vs 21.2 mo [3.7-24.9], P=0.60). The median duration of PFS follow up in the expansion phase (n=20/38) is 3.5 mo. Updated data will be presented at ASH.

Conclusions: Avadomide given in combination with obinutuzumab was well-tolerated and demonstrated promising clinical activity, with encouraging response rates and mPFS observed in pts with R/R FL, irrespective of their disease risk status. Avadomide plus obinutuzumab may provide a new chemotherapy-free treatment option for pts with R/R FL failing standard therapies.

Disclosures Vitolo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kersten: Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite/Gilead: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chiappella: Roche: Other: lecture fees; Amgen: Other: lecture fees; Nanostring: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Teva: Other: lecture fees. Zinzani: Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles: ACERTA: Honoraria; SERVIER: Honoraria; TAKEDA: Honoraria; GILEAD: Honoraria; CELGENE: Honoraria, Research Funding; AMGEN: Honoraria; JANSSEN: Honoraria; MERCK: Honoraria; MORPHOSYS: Honoraria; PFIZER: Honoraria; ABBVIE: Honoraria; EPIZYME: Honoraria; NOVARTIS: Consultancy, Honoraria; ROCHE: Honoraria, Research Funding. Sarmiento: Celgene Institute for Translational Research Europe: Employment, Equity Ownership. Mosulen: Celgene Institute for Translational Research Europe: Employment, Equity Ownership. Mendez: Celgene Institute for Translational Research Europe: Employment, Equity Ownership. Uttamsingh: Celgene Corporation: Employment, Equity Ownership. Pourdehnad: Celgene Corporation: Employment, Equity Ownership. Hege: Arcus Biosicences: Membership on an entity's Board of Directors or advisory committees; SITC: Membership on an entity's Board of Directors or advisory committees; Mersana: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: multiple. Li: Celgene Corporation: Employment. Nikolova: Celgene International Sarl: Employment, Equity Ownership. Ribrag: argenX: Research Funding; Infinity: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; pharmamar: Other: travel; MSD: Honoraria; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Amgen: Research Funding; Incyte Corporation: Consultancy.

  • * Asterisk with author names denotes non-ASH members.