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)

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 <12 months after first-line treatment. The median number of prior anticancer therapies was 4 (range, 1-12), and 14 (37%) pts had 1 prior ASCT. Two pts experienced a dose-limiting toxicity, consisting of 1 grade 4 neutropenia (CC-122 AIC 3 mg) and 1 grade 5 tumor flare (CC-122 F6 4 mg). The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (55%) and thrombocytopenia (26%). Eight pts (21%) had ≥1 serious TEAE related to CC-122, with febrile neutropenia (n=2) being the only serious TEAE occurring 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 <1 week of interruption due to AEs. ORR in the overall population was 66%, with 11 pts (29%) achieving CR. ORR/CR rate in DLBCL and FL pts were 47%/11%; and 83%/50% respectively. Kaplan-Meier estimated median DOR was 294 days and median PFS was 336 days. Subgroup analysis was performed to further examine the high-risk ER and DR pts with FL. Response rates were comparable across the subgroups. In DR pts, ORR/CR rate was 80%/40%, compared with 85%/54% in non-DR pts. Similar analysis in ER pts showed an ORR/CR rate of 80%/50%, compared with 88%/50% in non-ER pts. PFS rates at 12 months for DR vs non-DR pts were 60% and 51%; and in the ER vs non-ER pts were 51% vs 58%.

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 naïve and lenalidomide refractory FL pts.