1832PDPhase I study of CC-90011 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL)

Abstract Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate the expression of genes involved in cell growth and oncogenesis. CC-90010 is a potent, reversible oral BET inhibitor that reduces tumor growth in xenograft models. Methods CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Four dosing schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine maximum-tolerated dose, safety, and/or recommended phase II dose (RP2D). A Bayesian logistic regression model guided the dose escalation. Secondary objectives were to identify early activity signals, pharmacokinetics, and pharmacodynamics (PD). Results As of 4 Mar 2019, 69 pts were enrolled, 67 with solid tumors, including 10 with glioblastoma and 2 with R/R NHL. Median age was 57 y (range, 21–80), 38 (55%) were men, and median number of prior systemic anticancer regimens was 3 (range, 1–9). Two RP2Ds were identified (dose cohorts 3A and 4B); 4B was selected for expansion. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 21 pts (30%), most commonly (>2 pts) thrombocytopenia (16%), asthenia/fatigue (4%), and anemia (4%). Seven pts died, all from progressive disease.Eleven pts remained on treatment >6 mo with clinical benefit. Two pts (endometrial carcinoma and astrocytoma) had a partial response, and 6 had prolonged stable disease ≥9 mo. Plasma exposures and PD marker regulation increased with each dose level; terminal half-life was ∼73 h. Conclusions Most TRAEs were mild or moderate in severity and manageable with dose modifications. CC-90010 had a long terminal half-life that enabled less frequent dosing and promising anticancer activity. Dose escalation is complete, and expansion in select advanced malignancies is ongoing. Table: 1075P . Dose Level: 1 (n = 7) 2 (n = 7) 3A (n = 4) 3B (n = 6) 3C (n = 6) 4A (n = 7) 4B (n = 7) 4C (n = 7) 5A (n = 6) 5B (n = 6) 5C (n = 6) Dose, mg 15 15 25 30 15 40 45 25 30 55 35 Schedule, days on/off 3/4 3/11 3/11 4/24 2/5 3/11 4/24 2/5 3/11 4/24 2/5 Clinical trial identification NCT03220347; 2015-004371-79. Editorial acknowledgement Tisheeka Graham-Steed, PhD BioConnections, LLC. Legal entity responsible for the study Celgene Corporation. Funding Celgene Corporation. Disclosure V. Moreno: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Regeneron; Speaker Bureau / Expert testimony: Bayer/Loxo. I. Brana: Research grant / Funding (self): Celgene. J.M. Sepulveda Sanchez: Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: AbbVie; Advisory / Consultancy: Celgene; Advisory / Consultancy: GW Pharma; Speaker Bureau / Expert testimony: Astellas; Travel / Accommodation / Expenses: Ipsen. M. Vieito Villar: Travel / Accommodation / Expenses: Roche. O. Saavedra: Travel / Accommodation / Expenses: Mundipharma; Travel / Accommodation / Expenses: Teva; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Grunenthal; Travel / Accommodation / Expenses: Kyowakirin; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Debiopharm. G. Musuraca: Advisory / Consultancy: Servier. P.A. Asierto: Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Incyte; Advisory / Consultancy: Newlinks Genetics; Advisory / Consultancy: Genmab; Advisory / Consultancy: Medimmune; Advisory / Consultancy: Sindax; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): BMS; Research grant / Funding (institution): ROCHE Genentech; Research grant / Funding (institution): Array; Travel / Accommodation / Expenses: MSD. C. Carlo-Stella: Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: ADC Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Rhizen Pharma; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Takeda. R. Sarmiento: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene. J. Di Martino: Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Celgene Corp. M. Zuraek: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp. T. Sanchez Perez: Full / Part-time employment: Celgene Corp. E. Filvaroff: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Celgene Corp.; Shareholder / Stockholder / Stock options: Amgen; Shareholder / Stockholder / Stock options: Gilead; Shareholder / Stockholder / Stock options: Genentech/Roche. B. Hanna: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp. Z. Nikolova: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp. All other authors have declared no conflicts of interest.