7O - 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 potent, selective, reversible oral inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-proliferative activity against cancer cells in vitro and in patient-derived xenograft models. Methods: CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints included 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 September 4, 2018, 50 pts were enrolled. All had advanced solid tumors except 1 pt with R/R NHL; 26 pts had neuroendocrine neoplasms (NENs). Pts received escalating doses of CC-90011 at 1.25 (n = 4), 2.5 (n = 5), 5 (n = 6), 10 (n = 4), 20 (n = 5), 40 (n = 6), 60 (n = 6), 80 (n = 10), or 120 mg (n = 4). The non-tolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. The median age was 61 y (range, 22–75), 52% were male, and pts had received a median of 3 (range, 1–4) prior systemic anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. The most common grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (16%) and neutropenia (8%; occurring in the context of thrombocytopenia at the highest doses). Serious AEs occurred in 40% of pts; 6% were treatment-related. Peak plasma concentrations occurred 2-4 h post-dose and average terminal half-life was ∼60 h; exposure was dose proportional. PD analysis showed decreased CgA and MMD in response to CC-90011, correlating with clinical benefit. One pt achieved a complete response (CR) and 22 had stable disease (SD). Prolonged SD ≥ 4 months occurred in 7 pts, 5 with bronchial NEN and 2 with prostate NEN. Conclusions: CC-90011 is well-tolerated with promising antitumor activity in solid tumors and R/R NHL, including a CR and prolonged SD in pts with NENs. PD and PK data showed sufficient target engagement. Taken together, the preliminary clinical data provides the rationale for dose expansion of CC-90011 in pts with NENs. Editorial acknowledgement: Editorial assistance was provided by Johna Van Stelten, Ph.D., of BioConnections LLC, funded by Celgene Corp. Clinical trial identification: NCT02875223 and EUDRACT 2015-005243-13. Legal entity responsible for the study: Celgene Corp. Funding: Celgene Corp. Disclosure: A. Hollebecque: Honoraria: Merck Serono; Consultant or advisor: Gritstone Oncology; Travel funding: Amgen. J.S. de Bono: Advisor: AstraZeneca, Genentech, Pfizer, Merck Sharp & Dohme, Bayer, Merck Serono, Janssen, Astellas, Seattle Genetics; Research funds: AZ, Sanofi, Genentech, GSK, Daiichi Sankyo, Taiho Oncology, Merck Serono, Merck Sharp & Dohme, Sierra Oncology; Speaker bureau: AZ. R. Plummer: Honoraria: Novartis, BristolMyers Squibb; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents: with Clovis Oncology; Travel funding: Merck Sharp & Dohme, Bristol Myers Squibb. S. Mora: Travel funding: Celgene; Employment and equity ownership: Celgene. E. Filvaroff: Employee: Celgene; Stock or equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents/royalties: Celgene and Genentech. M. Lamba: Employee, equity ownership, research funding: Pfizer, Celgene; Patents/royalties: Pfizer. Z. Nikolova: Employee, equity ownership, travel funding: Celgene. All other authors have declared no conflicts of interest.