A Phase 1 interventional study of BET Bromodomain Inhibitor ZEN-3694 and Biopsy Procedure in Metastatic Colorectal Carcinoma, Metastatic Malignant Solid Neoplasm and Stage IV Colorectal Cancer AJCC v8, sponsored by National Cancer Institute (NCI). Recruiting at 22 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-29.
Sponsored by National Cancer Institute (NCI) · Phase 1, Interventional, and Treatment
This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with the usual treatment with capecitabine in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable) and that it has progressed on previous standard treatment. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. Capecitabine is in a class of medications called antimetabolites. It is taken up by cancer cells and breaks down into fluorouracil, a substance that kills cancer cells. Giving ZEN003694 in combination with capecitabine may be safe in treating patients with metastatic or unresectable solid tumors.
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 [ZEN-3694]) in combination with capecitabine in patients with solid tumors.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine.
II. To determine the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine.
III. To determine the pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine (death receptor 5 [DR5] dynamics and apoptosis).
IV. To identify molecular subpopulations particularly sensitized to bromodomain and extra-terminal motif inhibitor (BETi) and capecitabine.
OUTLINE: This is a dose-escalation study of ZEN003694 and capecitabine, followed by a dose-expansion study.
Patients receive ZEN003694 orally (PO) once daily (QD) and capecitabine PO twice daily (BID) 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: Patients do not receive ZEN003694 on day 1 of cycle 1. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
After completion of study treatment, patients are followed up for safety 30 days after the last dose, and then every 3 months for 12 months.
Exclusion Criteria:
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: Patients do not receive ZEN003694 on day 1 of cycle 1. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
Drug: BET Bromodomain Inhibitor ZEN-3694 · Procedure: Biopsy Procedure · Procedure: Biospecimen Collection · Drug: Capecitabine · Procedure: Computed Tomography · Procedure: Magnetic Resonance Imaging · Procedure: Positron Emission Tomography
Given PO
Also known as: BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694
Undergo biopsy
Also known as: Biopsy, BIOPSY_TYPE, Bx
Undergo collection of blood samples
Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Given PO
Also known as: Ro 09-1978/000, Xeloda
Undergo CT and PET/CT
Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography
Undergo MRI
Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI
Undergo PET/CT
Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT
Incidence of adverse events
Adverse events and serious adverse events will be tabulated for each dose levels. As per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Time frame: Up to 30 days after last dose
Maximum tolerated dose (MTD)
Defined as the highest dose level with no more than 1/6 dose-limiting toxicity. Dose level 4 was selected as the MTD.
Time frame: During the first cycle of therapy (Cycles = 21 days)
Recommended phase 2 dose (RP2D)
Dose level 4 was selected as the RP2D.
Time frame: Up to 30 days after last dose
Anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine
Treatment response will be assessed for all patients based on Response Evaluation Criteria in Solid Tumors version 1.1: complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD). Clinical benefit rate is defined as the addition of CR, PR and SD.
Time frame: Up to 12 months
Progression free survival (PFS)
PFS will be estimated by the Kaplan-Meier method, along with 95% confidence regions.
Time frame: Up to 12 months
Objective response rate (ORR)
Defined as the addition of CR and PR. The probability of ORR and clinical benefit rate will be estimated with exact 95% binomial confidence intervals.
Time frame: Up to 12 months
Pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine
Will determine the PK of ZEN003694 (ZEN-3694) in combination with capecitabine. Capecitabine PK will be evaluated in the absence and presence of ZEN003694 (ZEN-3694) and Cmax and area under curve (AUC) will be compared with a paired test. ZEN003694 (ZEN-3694) PK will be evaluated in the presence of capecitabine and Cmax and AUC will be compared descriptively with historical data.
Time frame: Up to 12 months
Pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine
Will determine PD of ZEN003694 (ZEN-3694) in combination with capecitabine. Ribonucleic acid sequencing of death receptor 5 (DR5). DR5 is expected to be increased by the combination ZEN003694 (ZEN-3694) in combination with capecitabine. Pre-post comparisons will be made within patients enrolled on the expansion cohort using a non-parametric paired test, at a significance level (alpha) of 0.05. Apoptosis by Pharmacodynamic Assay Development and Implementation Section (PADIS) lab. Panel 3 is priority, but other panels will be evaluated with remaining lysate. Apoptosis is expected to be increased by the combination ZEN003694 (ZEN-3694) in combination with capecitabine. Pre-post comparisons will be made within patients enrolled on the expansion cohort using a non-parametric paired test, at a significance level (alpha) of 0.05.
Time frame: Up to 12 months
Molecular subpopulations particularly sensitized to BETi and capecitabine
Will identify molecular subpopulations particularly sensitized to BETi and capecitabine. Based on WES of archival tissue, we will evaluate descriptively any mutations in genes relevant to DNA damage repair, signaling and (fluoropyrimidine) metabolism, any relations with peculiar response and/or toxicity.
Time frame: Up to 12 months
Plan to share: Yes — "NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."
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