Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer

PRIMARY OBJECTIVES: I. To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) when used in combination with cetuximab and encorafenib. II. To define the safety profile of combination of ZEN003694, encorafenib, and cetuximab. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate clinical response signals of the combination. III. To assess the pharmacodynamic (PD) profile of the combination as defined by MAPK inhibition. IV. To assess the pharmacokinetics (PK) of ZEN003694 in combination with encorafenib. EXPLORATORY OBJECTIVE: I. To characterize pharmacodynamics and potential mechanisms of resistance to therapy via whole exome sequencing (WES), reverse phase protein array (RPPA), ribonucleic acid sequencing (RNAseq), and assay for transposase-accessible chromatin with sequencing (ATACseq)/HiSeq 4000 or NovaSeq following progression on treatment. OUTLINE: This is a dose-escalation study of ZEN003694 followed by a dose-expansion study. Patients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 of each cycle, cetuximab intravenously (IV) over 120 minutes on days 1 and 15 of each cycle, and encorafenib PO QD on days 1-28 of each cycle. NOTE: In the dose-expansion study, patients receive encorafenib on days 2-28 of cycle 1 and then on days 1-28 of cycles thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA), computed tomography (CT) or magnetic resonance imaging (MRI), and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study. After completion of study treatment, patients are followed up every 2 months.