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

Abstract

Background: CC-90011 is a selective, reversible inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-tumor activity against neuroendocrine cells in vitro and in xenograft models. Methods: This is a phase I, first-in-human clinical study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/week in 28-day cycles. Primary objectives were to determine safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 15 Jan 2018, 35 pts were enrolled; 34 with advanced solid tumors, including 17 with neuroendocrine tumors (NETs) and 1 with R/R NHL. They received escalating doses of CC-90011 at 1.25 mg (n = 4), 2.5 mg (n = 5), 5 mg (n = 6), 10 mg (n = 4), 20 mg (n = 4), 40 mg (n = 6), or 80 mg (n = 4). The MTD and RP2D have not yet been established. The median age was 61 y (range, 22-75), 19 (54%) were male, with 2 (range, 1-4) median number of prior systemic anticancer therapies. No dose-limiting toxicities were reported. The only treatment-related grade 3/4 adverse event (AE) was thrombocytopenia (9%). Serious AEs occurred in 24% of pts; none were treatment-related. Peak plasma concentrations were 2-4 hours post-dose and terminal elimination half-life was approximately 64 hours; increase in plasma exposures was dose proportional. Blood biomarker analyses showed increasing suppression of MMD and MYL9 expression with higher CC-90011 doses suggesting target engagement at doses ≥ 40 mg. Overall, 13 (39%) pts had stable disease (SD). Prolonged SD (≥4 mo) was observed in 5 pts with solid tumors; notably, 3 of those pts had bronchial NETs [5 mg (n = 1), 20 mg (n = 1) and 40 mg (n = 1)]. Preliminary PD results from NETs showed CC-90011 decreased chromogranin A levels, correlating with clinical benefit. Conclusions: CC-90011 has dose-proportional PK with target engagement at tolerable doses with preliminary evidence of antitumor activity in advanced solid tumors and R/R NHL, including prolonged SD particularly in pts with NETs. Clinical trial identification: NCT02875223. Editorial acknowledgement: Editorial assistance was provided by BioConnections, LLC. Legal entity responsible for the study: Celgene Corporation. Funding: Celgene Corporation. Disclosure: A. Hollebecque: Honoraria: Merck Serono; Consulting or advisory role: Gritstone Oncology; Travel, accommodations: Amgen. J. de Bono: Consulting or advisory role: AstraZeneca, GlaxoSmithKline, Genentech, Pfizer, Merck, Sharp & Dhome, Bayer, Merck Serone, Janssen, Astellas, Seattle Genetics; Research funding: AstraZeneca, Sanofi, Genentech, GlaxoSmithKline, Daiichi, Taiho, Merck Serone, Merck Sharp & Dhome, Sierra; Speaker's bureau: AstraZeneca. R. Plummer: Honoraria: Novartis, Bristol-Myers Squibb, AstraZeneca; Consulting or advisory role: Clovis Oncology, Bayer, Novartis, Pierre Faber, Karus Therapeutics, Genmab, Octimet; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents, royalties, other intellectual property: Clovis Oncology; Travel, accommodations: Merck Sharpe & Dhome, Bristol-Myers Squibb. S. Mora, A. Harding, Z. Nikolova: Employment, equity ownership, travel, accommodations: Celgene, Inc. A. Nguyen: Employment, equity ownership, patents, royalties, other intellectual property: Celgene Corporation. E. Filvaroff: Employment: Celgene; Equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents, royalties, other intellectual property: Celgene, Genentech. M. Lamba: Employment, equity ownership, research funding: Pfizer Inc., Celgene Corporation; Patents, royalties, other intellectual property: Pfizer, Inc. K. Liu, M. Zuraek: Employment, equity ownership: Celgene Corporation. J. DiMartino: Employment, leadership, equity ownership: Celgene Corporation. All other authors have declared no conflicts of interest.