5796 - Phase I Study of CC-90011 in Patients With Advanced Solid Tumors (STs) and Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL)

Background

CC-90011, a potent, selective, and reversible oral inhibitor of lysine-specific demethylase 1A, has shown antiproliferative activity against cancer cells in vitro and in patient (pt)-derived xenografts.

Methods

CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in ptswith advanced unresectable STs and R/R NHL. Pts received oral CC-90011 once a week (QW) in 28-d cycles. Primary endpoints included safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy, pharmacokinetics, and pharmacodynamics (PD).

Results

As of 24 Apr2019, 64 pts with advanced STs and 1 with R/R NHL were enrolled; 25 pts had neuroendocrine neoplasms (NENs) (majority grade 3). Data presented are as of 18 Jan 2019 (n = 50). 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 nontolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. Median age was 61 y (range, 22–75), 52% were men, and pts received a median of 3 (range, 1–9) prior anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. Grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (20%), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). Serious AEs occurred in 21 pts (42%); 4 (8%) were treatment-related. Peak plasma concentrations occurred 2-4 h postdose and average terminal half-life was ∼71 h; exposure was dose proportional and with repeated QW dosing, limited accumulation of plasma exposures was observed. PD analysis showed decreased CgA and MMD in response to CC-90011. One pt with R/R NHL had a complete response (CR) (currently in cycle 19); 7 pts had stable disease (SD) ≥6 mo (1 pt with bronchial NEN is currently in cycle 29).

Conclusions

CC-90011 is well tolerated with promising antitumor activity in pts with advanced malignancies, including a durable CR in R/R NHL and prolonged SD in NENs. PD data showed significant target engagement. Further evaluation of CC-90011 in combination with other agents in advanced malignancies is warranted.

Clinical trial identification

NCT02875223; CC-90011-ST-001.

Editorial acknowledgement

Tisheeka Graham-Steed, PhD BioConnections, LLC.

Legal entity responsible for the study

Celgene Corporation.

Funding

Celgene Corporation.

Disclosure

A. Hollebecque: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Servier; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Incyte; Advisory / Consultancy: Debiopharm; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: MedImmune. J.S. de Bono: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sierra Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genmab; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: GSK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Research grant / Funding (institution), Travel / Accommodation / Expenses: Menarini Silicon Biosystems; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Orion; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Taiho; Research grant / Funding (institution): Cellcentric; Research grant / Funding (institution): Celgene. R. Plummer: Honoraria (self): Ellipses; Advisory / Consultancy: Pierre Faber; Advisory / Consultancy: Genmab; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy: Octimet; Advisory / Consultancy, Licensing / Royalties: Clovis Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Karus Therapeutics; Advisory / Consultancy: Biosceptre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Cybrexa; Advisory / Consultancy: Sanofi Aventis; Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Speaker Bureau / Expert testimony: Tesaro; Travel / Accommodation / Expenses: MSD. J. Capdevila: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Advanced Accelerator Applications; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (institution): Celgene. G. Curigliano: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self): Novartis; Honoraria (self): SEAGEN; Advisory / Consultancy: BMS. 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. F.G.M. De Braud: Advisory / Consultancy: TizianaLife Sciences; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Octimet Oncology; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Loxo Oncology; Research grant / Funding (institution): Tesaro; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Noema S.r.l.; Speaker Bureau / Expert testimony: ACCMED; Speaker Bureau / Expert testimony: Dephaforum S.r.l.; Speaker Bureau / Expert testimony: Nadirex; Speaker Bureau / Expert testimony: Biotechspert Ltd; Speaker Bureau / Expert testimony: Prime Oncology. P. Martin-Romano: Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (institution), Non-remunerated activity/ies: BMS; Research grant / Funding (institution), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution), Non-remunerated activity/ies: Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer; Research grant / Funding (institution), Non-remunerated activity/ies: Roche; Research grant / Funding (institution): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: NH TherAGuiX. J. Parra-Palau: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene, Inc. T. Sánchez Pérez: Full / Part-time employment: Celgene Corp. E. Filvaroff: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Celgene; Shareholder / Stockholder / Stock options: Amgen; Shareholder / Stockholder / Stock options: Gilead; Shareholder / Stockholder / Stock options: Genentech/Roche. M. Lamba: Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp.; Licensing / Royalties: Pfizer. Z. Nikolova: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Celgene Corp. All other authors have declared no conflicts of interest.