527O - CC-90010, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients (Pts) with advanced solid tumours (STs) and relapsed/refractory (R/R) non-Hodgkin lymphoma: Updated results of a phase I study

Background

BET proteins are epigenetic readers implicated in cancer pathogenesis. CC-90010 is a potent BET inhibitor that showed promising clinical activity in pts with advanced malignancies.

Methods

CC-90010-ST-001 is a phase I dose-escalation (part A) and -expansion (part B) study of CC-90010 in pts with advanced STs and R/R diffuse large B-cell lymphoma (DLBCL). Eleven dose levels (DLs) and 4 dosing schedules (2 weekly [2 d on/5 d off; 3 d on/4 d off], 1 biweekly [3 d on/11 d off], and 1 monthly [4 d on/24 d off]) were evaluated. Primary objectives were to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Secondary and exploratory objectives were to assess antitumor activity, pharmacokinetics, and pharmacodynamics (PD).

Results

As of 7 Feb 2020, 84 pts were enrolled. In part A, 67 pts had advanced STs and 2 had R/R DLBCL. In part B, 13 pts had R/R DLBCL (1 pt was not treated until after the data cutoff), and 2 had advanced STs. MTDs were identified for 3 of the 4 dosing schedules. The RP2Ds were 30 mg 3 d on/11 d off and 45 mg 4 d on/24 d off. Six pts from part A had dose-limiting toxicities, in all dosing schedules. The most common grade 3/4 treatment-related adverse event (TRAE) was thrombocytopenia (part A=16%, part B=64%). Eight pts (12%) in part A and 4 pts (29%) in part B had serious TRAEs. In part A, 1 pt with progressive grade 2 astrocytoma had a complete response (CR; ongoing in cycle 19), and 1 pt with advanced endometrial carcinoma had a partial response (PR); 10 pts had stable disease (SD) ≥4 cycles, 3 had prolonged SD (19, 20, and 24 mo). In part B, 2 pts with R/R DLBCL had responses (CR and PR). Plasma exposures increased in an ∼ dose-proportional manner across DLs. The terminal half-life (t_1/2) of CC-90010 was ∼60 h. CC-90010 induced ≥50% decrease of the PD biomarker CCR1 at doses ≥25 mg 4 h post last dose.

Conclusions

CC-90010 was well tolerated and showed antitumor activity in heavily pretreated pts with advanced malignancies. The long t_1/2 and favorable PD profile improved tolerability and enabled less frequent dosing. These results support further evaluation of CC-90010 in STs and R/R DLBCL.

Clinical trial identification

Study ID: CC-90010-ST-001 NCT03220347; 2015-004371-79 (EudraCT Number).

Editorial acknowledgement

Tisheeka Graham-Steed, PhD BioConnections, LLC.

Legal entity responsible for the study

Celgene Corporation.

Funding

Celgene Corporation.

Disclosure

V. Moreno: Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Bayer; Advisory/Consultancy: Pieris; Advisory/Consultancy: Janssen. I. Braña: Research grant/Funding (self): Celgene, A Bristol-Myers Squibb Company. J.M. Sepulveda Sanchez: Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: AbbVie; Advisory/Consultancy: Celgene, A Bristol-Myers Squibb Company; Advisory/Consultancy: GW Pharma; Speaker Bureau/Expert testimony: Astellas; Travel/Accommodation/Expenses: Ipsen. M. Vieito: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Debio; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Merck-Serono. O. Saavedra: Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Kyowakirin. C. Carlo-Stella: Honoraria (self): Bristol Myers Squibb; Honoraria (self), Speaker Bureau/Expert testimony: MSD; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): ADCT; Honoraria (self), Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy: Sanofi; Research grant/Funding (self): Novartis; Speaker Bureau/Expert testimony: AstraZeneca; Travel/Accommodation/Expenses: Takeda. J-M. Michot: Honoraria (self): Celgene, A Bristol-Myers Squibb Company; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): AstraZeneca; Honoraria (self): Janssen. A. Italiano: Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: Springworks; Advisory/Consultancy: Epizyme; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Merck; Research grant/Funding (self): MSD; Research grant/Funding (self): Pharmamar. G. Musuraca: Advisory/Consultancy: Servier. R. Sarmiento: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. B. Amoroso: Advisory/Consultancy, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company; Advisory/Consultancy: NordicNanovector; Advisory/Consultancy: ArgenX. T. Sánchez-Pérez: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. I. Aronchik: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. E. Filvaroff: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Bristol-Myers Squibb; 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: Bristol-Myers Squibb. Z. Nikolova: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Celgene, A Bristol-Myers Squibb Company. A. Pinto: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self): Celgene, A Bristol Myers Squibb Company; Honoraria (self): Servier; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Takeda. All other authors have declared no conflicts of interest.