Abstract
Introduction: Chemo-refractory patients with DLBCL have a particularly poor outcome with standard-of-care treatment (median overall survival of 6 months) and represent a population with a significant unmet medical need (Crump et al, ASCO 2016). CC-122 is a novel oral agent that binds cereblon ubiquitin ligase complex, resulting in degradation of the hematopoietic transcription factors Ikaros and Aiolos. CC-122 has shown promising phase I clinical activity as a single agent or in combination with obinutuzumab in DLBCL and follicular lymphoma (FL) (NCT01421524 Rasco et al, ASH 2013; NCT02417285 Michot et al, ASH 2016). Preliminary data from CC-122 DLBCL-001, a dose escalation study of CC-122 combined with CC-223, CC-292, or rituximab (R), has shown encouraging activity in relapsed/refractory DLBCL (Ribrag et al, ASH 2016). Herein we report updated results including the dose expansion phase and DLBCL subgroup analyses for the CC-122 plus R combination arm of the CC-122 DLBCL-001 study.
Methods: CC-122-DLBCL-001 is a phase Ib dose escalation/expansion study of the novel compounds CC-122, CC-223, and CC-292 administered as doublets and triplets in combination with R as well as a CC-122 plus R doublet (Arm D) (NCT02031419). Cohorts of DLBCL and FL patients in the dose expansion phase of R + CC-122 received 3 mg CC-122 as a formulated capsule. All DLBCL subjects in dose expansion were chemo-refractory by eligibility. Study endpoints were: safety, tolerability, pharmacokinetics, preliminary efficacy (overall response rate [ORR] and complete response [CR]), and blood pharmacodynamic markers of CC-122. DLBCL cell-of-origin and a novel gene expression classifier representing tumor microenvironment content were tested using Nanostring on tumor biopsies and correlated to efficacy (Gandhi et al, ASH Meeting on Lymphoma Biology 2016).
Results: As of May 1, 2017, a total of 40 subjects (DLBCL, n=26; FL, n=14) were enrolled in Arm D expansion. Only DLBCL data are described here while FL data are immature and will be reported at a later time. At enrollment, median age was 64 years (range, 33-84), 81% had stage III-IV disease, and 27% had transformed DLBCL. Median number of prior systemic anticancer regimens was 3 (range, 2-6). Eleven (42%) discontinued from the study either due to progressive disease (N=7) or death due to underlying disease (N=4). The most common adverse events (AEs) (grades 1-4) included neutropenia (50%), anemia 19%), peripheral edema (23%), cough, constipation, fatigue, and rash (19% each). Grade 3/4 AEs occurring in more than 1 subject were neutropenia (42%), increased lipase (12%), febrile neutropenia, abdominal pain, fatigue, and pain in extremity (8% each). Nine subjects experienced serious AEs (SAE); 1 SAE of asthenia was suspected to be related to study drugs. CC-122 dose reduction was required in 10 subjects (39%); the most common reason was neutropenia. Median relative dose intensity was 100% of intended dose. Thirteen patients (50%) received at least 1 dose of granulocyte colony-stimulating factor. ORR was 39% with a CR rate of 15% in the treated population (n=26). Efficacy results based on subgroup analysis of patients are shown in Table 1. Classifier positive patients had a CR rate of 50% with mPFS not reached compared with 0% CR rate in classifier negative patients and mPFS of 2.9 months.
Conclusions : Data from this ongoing study suggest that CC-122 is well-tolerated when combined with rituximab. Promising activity was observed accross DLBCL cell-of-origin in this chemo-refractory patient population at the recommended phase II dose of 3.0 mg/day using CC-122 formulated capsule. Gene expression classifier based on tumor microenvironment content shows a trend towards predicting deeper and durable responses.
Ribbag: Roche: Honoraria, Other: travel, accommodation, expenses; Pharmamar: Consultancy; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Esai: Honoraria, Research Funding; Servier: Consultancy, Honoraria; ArgenX: Research Funding; Epizyme: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria. Chavez: Kite: Speakers Bureau; Abbvie: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau. Vitolo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria. Kaplan: Janssen: Research Funding; Seattle Genetics: Research Funding; Millennium: Research Funding. Chandler: BMS: Consultancy; Janssen: Consultancy, Speakers Bureau; Vector Oncology: Consultancy. Santoro: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Corradini: Sanofi: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Roche: Honoraria; Gilead: Honoraria. Flinn: Takeda: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Curis: Research Funding; Calithera: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; Beigene: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Agios: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; KITE: Research Funding; Acerta: Research Funding; Pharmacyclics LLC: Research Funding; AbbVie Company: Research Funding; Trillium: Research Funding; TG Therapeutics: Research Funding. Nastoupil: TG Therapeutics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Karus Therapeutics: Research Funding. Cassier: Elsalys: Consultancy; Plexxikon: Research Funding; Roche: Research Funding; Astra-Zeneca: Honoraria, Research Funding; Novartis: Research Funding; Bayer: Research Funding; Blueprint: Research Funding; MSD: Research Funding; Merck Serono: Research Funding; BMS: Research Funding; Amgen: Honoraria. Sangha: BI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Lundbeck: Honoraria. Advani: Millennium: Research Funding; Cell Medica: Research Funding; FortySeven: Research Funding; Genentech: Research Funding; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kura: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Juno Therapeutics: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Sutro: Consultancy; Regeneron: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; Agensys: Research Funding; Infinity: Research Funding; Nanostring: Consultancy; Gilead: Consultancy. Isufi: Yale University: Employment. Witzig: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Acerta: Research Funding; Novartis: Research Funding. Petrarca: Celgene Corporation: Employment, Equity Ownership. Hagner: Celgene: Employment, Equity Ownership. Gandhi: Celgene Corporation: Employment, Equity Ownership. Wu: Celgene Corporation: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Pourdehnad: Celgene Corporation: Employment, Equity Ownership. Kuruvilla: Roche: Honoraria; Janssen: Honoraria; Janssen: Consultancy; Lundbeck: Honoraria; Amgen: Honoraria; Hoffman LaRoche: Consultancy; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding; Merck: Honoraria.
