Lenalidomide and Obinutuzumab with CHOP for Newly Diagnosed Diffuse Large B-Cell Lymphoma: Phase I Results
Authors: Westin Jason R. , Sathyanarayanan Vishwanath , Fayad Luis E. , Nastoupil Loretta J. , Turturro Francesco , Hagemeister Fredrick B. , Simar Kristin A. , Young Ken H. , McDonnell Timothy J. , Chuang Hubert H , Kamil Fazal , Feng Lei , Davis Eric Richard , Neelapu Sattva S. , Oki Yasuhiro 
Published: October 2019

Abstract
Introduction:
Diffuse large B-cell Lymphoma (DLBCL) is the most common lymphoid malignancy with ~30K diagnoses each year in the United States. The standard initial therapy for all patients is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) which cures ~65% of patients. Multiple novel agents have shown promising efficacy in the treatment of patients with DLBCL, including lenalidomide (L) and obinutuzumab (O). Obinutuzumab is a novel, humanized, glycoengineered CD20 monoclonal antibody with increased pre-clinical affinity to the FcGRIIIa receptor in comparison to rituximab, and thus may have increased antibody dependent cell-mediated cytotoxicity (ADCC). Lenalidomide is small molecule which is toxic to DLBCL via interferon signaling and immunomodulation. As single agents, L and O achieve overall response rates (ORR) of 28% and 32%, respectively, in patients with relapsed DLBCL (Hernandez-Ilizaliturri, 2011, Morschhauser, 2013). The addition of L to RCHOP may overcome the adverse features of the non-germinal center (non-GCB) subtype of DLBCL. Separate randomized clinical trials are evaluating RCHOP +/- Len in non-GCB DLBCL and RCHOP vs OCHOP in all patients with newly diagnosed DLBCL. We hypothesize the combination of OLCHOP will result in down-regulation of interferon regulatory factor 4, enhanced NK cell-mediated cytotoxicity, and a complete response (CR) rate ≥ to OCHOP (55% in Gather trial, Zelenetz et al, ASH 2013).
Methods: Patients with newly diagnosed, CD20+ DLBCL are eligible if they have measurable disease, age ≥18 years, and adequate organ function. In the Phase Ib trial, Obinutuzumab was dosed at 1000mg IV days 1, 8, and 15 during cycle 1, and day 1 on cycles 2-6, CHOP was dosed in standard fashion, and lenalidomide dose was 15mg po daily days 1 - 14 cycles 1 - 6 in the first cohort, and lower dose was to be considered only if we observed DLT in the initial cohort. The Phase Ib trial was designed with a 3+3 design, with dose de-escalation for toxicity. Once the maximum tolerated dose is identified, an additional 44 patients will be enrolled. The primary objectives of this investigator initiated phase Ib/II trial are to determine the maximum tolerated dose and efficacy of LOCHOP. Correlative studies, including minimal disease assessment, cell of origin determination, and immune profiling, are planned on blood and tumor samples.
Results: Six patients were enrolled on the Phase Ib trial, with all evaluable for safety and efficacy. The median age was 62.5 years (50-73), with 83% males and a median IPI of 2 (1-3). One patient had double hit DLBCL, and 5 patients were non-GCB DLBCL. No dose limiting toxicities were identified in the six patients treated at L 15mg daily. Toxicities encountered include neutropenia (Grade 3: 50%, Grade 4 33%), thrombocytopenia (grade 3: 17%), and rash (grade 2: 17%). All six patients achieved a complete response, and the Phase II trial has now enrolled 17 patients as of 8/2/16, with accrual projected to complete in December 2016. In patients treated on the Phase II trial, 8 patients have an interim disease assessment with a 100% overall response rate.
Conclusions: The combination of Obinutuzumab 1000mg, Lenalidomide 15mg day 1-14, and CHOP is well tolerated in the phase Ib trial, with no dose limiting toxicity encountered, and enrollment is continuing in the Phase II trial. Adverse events do not appear to be different than expected with standard RCHOP. In the patients with at least 1 disease assessment at data cutoff, the efficacy appears promising but additional patients are required. Results from additional patients will be presented at the ASH meeting.

Disclosures
Westin: ProNAi: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Fayad:Seattle Genetics: Consultancy, Research Funding. Oki:Novartis: Research Funding.