A Phase I Trial of CC-486, Lenalidomide, Obinutuzumab in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Background: Despite recent therapeutic advancements in the treatment of indolent non-Hodgkins Lymphoma (iNHL), most patients eventually relapse. Active agents that are utilized to treat relapse/refractory (R/R) iNHL include the combination of obinutuzumab and lenalidomide, which have demonstrated significant efficacy by enhancing host immune effector mechanisms and antibody-dependent cellular toxicity (ADCC), surpassing the efficacy of rituximab plus lenalidomide (Reddy 2008, Wu 2009, Gandhi 2009). Hypomethylating agents, such as azacitidine (CC-486), have been shown to mimic a viral infection by induction of dsRNA expression potentially leading to neo-antigen expression that mediates an enhanced adaptive immune response (Chiappinelli K, 2015). Consequently, CC-486 may make tumors more susceptible to cell-mediated immune responses and work synergistically with immunotherapy like lenalidomide. Thus, in this single-center phase I study, we evaluated the safety and efficacy of the triplet combination that includes CC-486, lenalidomide, and obituzumab in R/R iNHL.

Methods: Patients with R/R iNHL that had been previously treated with at least one prior therapy were eligible for enrollment. Patients previously treated with a lenalidomide-based regimen were eligible. Patients with active CNS disease were excluded. CC-486 was administered at 300mg/d (dose level 1) which was deescalated if ≥2 dose-limiting toxicities were observed. CC-486 was given on days 1-28 of cycle 1, and the same dose on days 1-21 of subsequent cycles. Lenalidomide was administered at 10 mg on days 8-28 of cycle 1, and on days 1-21 of subsequent cycles to facilitate correlative analysis. The total number of planned cycles was 12. Obinutuzumab 1000 mg IV was given on days 8,15, 22, and 29 of cycle 1, and only on day 1 of each subsequent cycle. Cycle 1 was 35 days and subsequent cycles were 28 days. The primary end point was assessing the safety and toxicity of CC-486 in combination with lenalidomide and obinutuzumab. Secondary endpoints included complete response rate (CRR), as determined by PET/CT based on Lugano 2014 criteria, overall response rate (ORR), time to response (TTR), duration of response (DoR), treatment-emergent adverse events (TEAEs), and determination of the recommended phase II dose (RP2D). DoR was defined as time from the first response, either partial (PR) or complete response, to progression, death, or date of the last follow-up.

Results: The study was terminated due to withdrawal of support from the sponsor. Eight patients were enrolled and 7 were evaluable for efficacy, and all 8 were evaluable for toxicity. Eligible candidates were diagnosed either with follicular lymphoma (n=5) or marginal zone lymphoma (n=3). The median age (range) was 68.5 years old (58-78) with a 50:50 male-to-female ration. All patients had an ECOG ≤1 and the median number of prior therapies was 2 (range,1-4). No DLTs were observed, and the RP2D of CC-486 with lenalidomide and obituzumab was 300mg daily. The CRR and ORR were 71% and 100%, respectively. This included one patient that had been previously treated with lenalidomide and rituximab and progressed on treatment that subsequently obtained a CR on study. The median TTR was 64 days. In total,2/7 patients achieved CR upon first response assessment after 3 cycles, 1 additional patient achieved CR upon first response assessment after 5 cycles, and 2 additional patients achieved CR at the end of treatment (EOT) after a median of 4 cycles. Two patients achieved a PR as their best response, one upon the third response assessment after 7 cycles and the other one at the first response assessment. The median DoR was 2 years, and the median number of cycles administered was 11 (range, 1-12)

The TEAEs observed were leukopenia [grade 4 (n=1), grade 1-2 (n=1)], neutropenia [grade 4 (n=1)], sepsis [grade 3 (n=1)], diarrhea [grade 3 (n=1), grade 1-2 (n=5)], nausea [grade 3 (n=1), grade 1-2 (n=7)], constipation [grade 3 (n=1), grade 1-2 (n=5)], and enterocolitis [grade 3 (n=1), grade 1-2 (n=1)].

Conclusion: The combination of CC-486, lenalidomide, and obinutuzumab was well tolerated, and all toxicities were manageable. The RP2D of CC-486 was 300mg/d. The early results reveal promising efficacy, which warrants further study with lenalidomide or a next generation cereblon-targeted CELMoD.

Esteghamat:Seagen: Ended employment in the past 24 months, Speakers Bureau. Abedi:AbbVie, BMS and Gilead Sciences: Speakers Bureau; Autolus, BMS and Gilead Sciences: Research Funding; CytoDyn: Current holder of stock options in a privately-held company; BMS, Autolus: Consultancy; Orca Bio: Research Funding.

CC-486 is not FAD approved for the treatment of lymphoma