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4118 A Novel Gene Expression Classifier Enriches for Single Agent Clinical Activity of CC-122, a Cereblon Modulator, Administered Orally to Relapsed or Refractory Diffuse Large B-Cell Lymphoma Subjects: Results from the Phase I CC-122-ST-001 Study

Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials
Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster III
Monday, December 11, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Cecilia Carpio, MD1*, Reda Bouabdallah, MD2*, Loic Ysebaert, MD, PhD3*, Juan-Manuel Sancho, MD, PhD4*, Gilles Andre Salles, MD, PhD5, Raul Cordoba, MD, PhD6*, Antonio Pinto, MD7*, Mecide Gharibo, MD8*, Drew W. Rasco, MD9*, Carlos Panizo, MD, PhD10*, Jose A. Lopez-Martin, MD, PhD11*, Armando Santoro, MD12*, Antonio Salar, MD, PhD13*, Silvia Damian, MD14*, Alejandro Martín, MD, PhD15*, Gregor Verhoef, MD, PhD16*, Xin Wei17*, Patrick R. Hagner, PhD18*, Kristen Hege, MD19, Alberto Risueño, PhD20*, Anita K. Gandhi, PhD18, Tonia J. Buchholz, PhD19*, Michael Pourdehnad, MD19 and Vincent Ribrag, MD21

1Hospital Universitario Vall d´Hebron, Barcelona, Spain
2Institut Paoli-Calmettes, Marseille, France
3Centre Hospitalier Universitaire de Toulouse, Toulouse, France
4Hospital Universitari Germans Trias i Pujol, Badalona, Spain
5Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
6Hosp. Fundación Jimenez Díaz, Madrid, Spain
7Istituto Nazionale Tumori, Fondazione Pascale, Napoli, Italy
8The Cancer Institute of New Jersey, New Brunswick, NJ
9South Texas Accelerated Research Therapeutics LLC, San Antonio, TX
10Clínica Universidad de Navarra, Pamplona, Spain
1112 de Octubre University Hospital & Research Institute; GETICA, Madrid, Spain
12Instituto Clinico Humanitas, Milano, Italy
13Hospital del Mar, Barcelona, Spain
14Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
15Hospital Universitario de Salamanca and IBSAL, Salamanca, Spain
16UZ Gasthuisberg Leuven, Leuven, Belgium
17Celgene Corporation, Berkeley Heights, NJ
18Celgene Corporation, Summit, NJ
19Celgene Corporation, San Francisco, CA
20Celgene Institute for Translational Research Europe, Seville, Spain
21Institut Gustave Roussy, Villejuif, France

Introduction: Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) who receive standard therapy relapse or develop refractory disease, have poor clinical outcomes (median overall survival of 6 months) with subsequent salvage therapies (Sehn LH. Hematology Am Soc Hematol Educ Program. 2012; Crump, et al. ASCO 2016). The novel cereblon modulating agent CC-122 promotes ubiquitination and degradation of hematopoietic transcription factors Ikaros and Aiolos in a cereblon-dependent manner, resulting in both DLBCL cell autonomous activity as well as immunostimulatory effects. CC-122 induced Aiolos and Ikaros degradation leads to increased apoptosis in both activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines, in contrast to the ABC subtype selectivity of lenalidomide (Hagner P et al. Blood. 2015).

The maximum tolerated dose of CC‑122, active ingredient in capsule (AIC) was established for continuous oral dosing at 3 mg AIC daily (QD) in multi-tumor cohorts (Gandhi A, et al. Blood. 2013). Subsequently, intermittent dosing schedules were evaluated in lymphoma; 4 mg AIC taken 5 out of 7 days (5/7) was chosen for further expansion (Carpio C, et al. Blood 2015 126:1494). Finally, a formulated capsule was introduced, CC-122 (F6); the recommended phase II dose was chosen based on pharmacokinetics and tolerability (3 mg, 5/7).

Methods: Subjects received oral doses of CC-122 AIC on continuous (28/28) or intermittent (21/28 or 5/7) schedules, or CC-122 F6 on the 5/7 schedule. Key inclusion criteria include age ≥18 years, and relapsed or refractory disease, defined as progression following (or unable to tolerate) ≥1 prior anthracycline or alkylating agent containing regimen (with or without anti-CD20). Adverse events (AE) were evaluated per NCI CTCAE v4.03 and efficacy by 2007 IWG Criteria. 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.

Results: As of May 1, 2017, 97 R/R DLBCL subjects from 18 institutions were enrolled/treated; 81 were enrolled at doses/schedules selected for expansion (3 mg QD AIC n=24, 4 mg 5/7 AIC n=39, and 3 mg F6 5/7 n=18), and 16 were enrolled at other dose levels. Eight subjects were ongoing as of the data cutoff date. Twelve subjects had transformed lymphoma (12.4%) and 85 DLBCL, not otherwise specified (NOS) (87.6%). The median age was 62 (36% were >65) and 57% were male, 98% had ECOG 0-1 at screening, 62% were refractory to their last prior therapy (SD/PD), 30% had CR to prior R-CHOP, and 44% had <CR to prior R-CHOP. Median prior lines was 3 (range 1-13), 86% were treated with ≥2 prior lines of therapy.

Of the 57 R/R DLBCL subjects enrolled in the 5/7 schedule at doses chosen for expansion, a total of 46 subjects (81%) experienced ≥1 Grade 3-4 treatment emergent adverse event (TEAE), of which 34 (60%) was suspected to be related to CC-122, and serious adverse events (SAE) suspected to be related to CC-122 were reported in 25% of subjects. The most common grade 3-4 TEAEs were neutropenia (39%) and infections (combined term, 17.5%). There was 1 grade 5 event of pneumonia suspected to be related to CC-122. Dose reduction due to AEs (most commonly due to neutropenia) occurred in 12 subjects (21.1%); 40.4% of subjects received at least one dose of G‑CSF. Fifty-one subjects (89%) had discontinued treatment as of the data cutoff; the most common reasons for study discontinuation were disease progression (60%), adverse event (16%), death (5%), and candidate for transplant (4%).

Pooled efficacy is shown for DLBCL NOS subjects with at least 2 prior lines of therapy treated at doses/schedules of CC-122 selected for expansion. As observed in Table 1, gene classifier positive patients had a better outcome than gene classifier negative patients

Conclusions: CC-122 appears well tolerated with encouraging activity in patients with R/R DLBCL. CC‑122 has broad activity across cell of origin including in ABC, GCB, and unclassified subsets. Preliminary efficacy data demonstrated differential effects of CC-122 between gene classifier positive and negative subjects. A novel gene expression signature is being established to enrich for responders to CC-122. The observed signals of efficacy are encouraging in this R/R DLBCL subset. CC-122 studies are ongoing both as a single agent and in combination with other anti-lymphoma agents.

Disclosures: Ysebaert: Janssen: Consultancy, Research Funding, Speakers Bureau. Sancho: Janssen: Honoraria; Gilead: Honoraria; Laboratorios Servier: Consultancy; Celgene: Honoraria; Kern Pharma: Honoraria; Roche: Honoraria; Mundipharma: Honoraria. Salles: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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, Research Funding; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cordoba: Foundation Jimenez Diaz University Hospital: Employment; Roche: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Servier: Consultancy; Pfizer: Consultancy. Pinto: Merck Sharp Dome: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Millenium Takeda: Research Funding; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Gharibo: Bayer: Employment. Rasco: Celgene: Research Funding. Lopez-Martin: MSD: Consultancy; BMS: Consultancy; Novartis: Consultancy; Roche: Consultancy; Astra Zeneca: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Pharma Mar Sau: Equity Ownership, Patents & Royalties: WO2008135793; Pfizer: Research Funding. 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. Salar: Janssen: Speakers Bureau; Roche: Speakers Bureau; Servier: Speakers Bureau. Damian: Fondazione IRCCS Istituto Nazionale dei Tumor: Consultancy. Martín: Janssen: Honoraria; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy. Wei: Celgene Corporation: Employment, Equity Ownership. Hagner: Celgene: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Risueño: Celgene: Employment, Patents & Royalties: US15273205. Gandhi: Celgene Corporation: Employment, Equity Ownership. Buchholz: Celgene Corporation: Employment. Pourdehnad: Celgene Corporation: Employment, Equity Ownership. Ribrag: MSD: Honoraria; BMS: Honoraria; Gilead: Honoraria; Nanostring: Honoraria; Infinity: Honoraria; Roche: Honoraria; ArgenX: Research Funding; Servier: Consultancy, Honoraria; Epizyme: Honoraria.

*signifies non-member of ASH