Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 \[ZEN-3694\]) and binimetinib when given in combination in patients with advanced or metastatic solid tumors with rat sarcoma virus oncogene homolog (RAS) pathway alterations. (Part 1 \[Dose Escalation\]) II. To evaluate the safety and toxicity of ZEN003694 (ZEN-3694) and binimetinib when given in combination. (Part 2 \[Dose Expansion\]) SECONDARY OBJECTIVES: I. To determine the safety and tolerability of ZEN003694 (ZEN-3694) and binimetinib when given in combination in patients with advanced or metastatic solid tumors with RAS pathway alterations. (Part 1 \[Dose Escalation\]) II. To characterize the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) when given in combination with binimetinib. (Part 1 \[Dose Escalation\]) III. To observe and record the preliminary antitumor activity of ZEN003694 (ZEN-3694) and binimetinib when given in combination. (Part 1 \[Dose Escalation\]) IV. To determine the effects of ZEN003694 (ZEN-3694) and binimetinib when given in combination on patient survival and other metrics of clinical activity. (Part 2 \[Dose Expansion\]) IVa. To evaluate objective response rate (ORR); IVb. To evaluate progression-free survival (PFS); IVc. To evaluate duration of response (DOR); IVd. To evaluate disease control rate (DCR) at 4 months. EXPLORATORY OBJECTIVES: I. To characterize the PK of the ZEN003694 (ZEN-3694) and binimetinib combination. (Part 2 \[Dose Expansion\]) II. To identify biomarkers of sensitivity and response to the ZEN003694 (ZEN-3694) and binimetinib combination. (Part 2 \[Dose Expansion\]) III. To determine histone H3 acetylated at lysine 27 (H3K27ac) levels via chromatin immunoprecipitation sequencing (ChIPseq) on tumor biopsy specimen. (Part 2 \[Dose Expansion\]) IV. To determine the open chromatin regions in response to the ZEN003694 (ZEN-3694) and binimetinib combination using assay for transposase-accessible chromatin sequencing (ATACseq). (Part 2 \[Dose Expansion\]) OUTLINE: This is a dose-escalation study of ZEN-3694 with fixed dose binimetinib followed by a dose expansion. Patients receive ZEN-3694 orally (PO) either once daily (QD) on days 1-28 of each cycle or for 5 days on followed by 2 days off during each week of each cycle and binimetinib PO twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. During the dose expansion phase, patients will have two mandatory biopsies - one before beginning the study and the second at day 15 of cycle 1. The study biopsy takes small pieces of cancer tissue from patient's body to look for markers (substances made by, on, or in tumor cells) related to how the study treatment works. Patients also undergo collection of blood samples at screening and on study and undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. After completion of study treatment, patients are followed up every 3 months for up to 2 years.