Recruiting
Phase 1

ZEN003694 with Cetuximab, Encorafenib

Sponsor:

National Cancer Institute (NCI)

Code:

NCT06102902

Conditions

Metastatic Colorectal Adenocarcinoma

Recurrent Colorectal Adenocarcinoma

Refractory Colorectal Adenocarcinoma

Stage IV Colorectal Cancer AJCC v8

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

BET Bromodomain Inhibitor ZEN-3694

Biopsy Procedure

Biospecimen Collection

Cetuximab

Computed Tomography

Study Details

Brief summary:

This phase I trial tests the safety, best dose, and effectiveness of ZEN003694 in combination with cetuximab and encorafenib in treating patients with colorectal cancer that has not responded to previous treatment (refractory), that has come back after a period of improvement (relapsed), and that has spread from where it first started (primary site) to other places in the body (metastatic). ZEN003694 is a protein inhibitor that binds to BET proteins. When ZEN003694 binds to BET proteins, it disrupts gene expression. Preventing the expression of certain growth-promoting genes may inhibit proliferation of tumor cells that over-express BET proteins. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Encorafenib is an enzyme inhibitor. It inhibits pathways that are responsible for controlling cell proliferation and survival, which may lead to a decrease in tumor cell proliferation. Both cetuximab and encorafenib have been approved to treat cancer. Adding ZEN003694 to cetuximab and encorafenib may be more effective at treating patients with refractory metastatic colorectal cancer than giving the usual treatment (cetuximab and encorafenib) alone.

Conditions

Metastatic Colorectal Adenocarcinoma

Recurrent Colorectal Adenocarcinoma

Refractory Colorectal Adenocarcinoma

Stage IV Colorectal Cancer AJCC v8

Study ID

NCT06102902

Start date

Jun 5, 2024

Status verified date

Aug, 2026

Completion date

Jan 30, 2027

Anticipated

Primary completion date

Jan 30, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Patients must have histologically confirmed and radiographically measurable metastatic colorectal adenocarcinoma with known BRAF V600E mutation, confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory with at least one tumor measurable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and for which standard curative or palliative measures do not exist or are no longer effective
  • Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ZEN003694 in combination with cetuximab and encorafenib in patients < 18 years of age, children are excluded from this study
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin (Hb) ≥ 9 mg/dl
  • Total bilirubin ≤ 1.5 mg/dl (excluding Gilbert's disease)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 x institutional upper limit of normal (ULN)
  • Creatinine clearance (CrCL) glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m\^2
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
  • Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. Patients should be New York Heart Association Functional Classification of class II or better
  • Patients must have progressed after at least 1 prior systemic treatment for incurable advanced or metastatic disease
  • Patients must have received prior treatment with the combination of encorafenib and cetuximab. They must have tolerated the combination at doses planned for the study
  • For the dose expansion phase, patients must have discontinued encorafenib at least 2 weeks prior to starting study treatment
  • The effects of ZEN003694 on the developing human fetus are unknown. For this reason and because BRD and BET inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 4 months following the last dose of study drug. Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 72 hours prior to the start of investigational product. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

  • Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
  • Patients who are receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or other agents used in study
  • Patients with uncontrolled intercurrent illness including, but not limited to, active bleeding diatheses, poorly controlled infection/disorders, or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy
  • Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694. As proton pump inhibitors (PPIs), H2 receptor antagonists, and antacids may alter the pharmacokinetics of ZEN003694 by reducing ZEN003694 exposure, patients receiving proton pump inhibitors are ineligible. If H2 blockers or other acid reducing agents are used concomitantly with ZEN003694, a staggered dosing schedule should be used, either dose ZEN003694 2 hours before the H2 blocker or 10-12 hours after an H2 blocker. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Pregnant women are excluded from this study because ZEN003694 is BRD and BET inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ZEN003694, breastfeeding should be discontinued if the mother is treated with ZEN003694. These potential risks may also apply to other agents used in this study

Study Design

Enrollment

30 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (ZEN003694, cetuximab, encorafenib)

Patients receive ZEN003694 PO QD on days 1-28 of each cycle, cetuximab 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 ECHO or MUGA, CT or MRI, and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study.

Interventions

BET Bromodomain Inhibitor ZEN-3694

Given PO

Biopsy Procedure

Undergo biopsy

Biospecimen Collection

Undergo collection of blood samples

Cetuximab

Given IV

Computed Tomography

Undergo CT

Echocardiography Test

Undergo ECHO

Encorafenib

Given PO

Magnetic Resonance Imaging

Undergo MRI

Multigated Acquisition Scan

Undergo MUGA

Primary outcome measure

  • Maximum tolerated dose (dose escalation cohort) [ Time Frame: Up to completion of dose escalation phase ]
  • Recommended phase 2 dose (dose escalation cohort) [ Time Frame: Up to completion of dose escalation phase ]

Central Contacts and Locations

Locations

UC Irvine Health Cancer Center-Newport

Recruiting

Costa Mesa, California, United States, 92627

Contacts

Site Public Contact

877-827-8839

Principal Investigator:

Farshid Dayyani

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Recruiting

Irvine, California, United States, 92612

Contacts

Site Public Contact

877-827-8839ucstudy@uci.edu

Principal Investigator:

Farshid Dayyani

USC / Norris Comprehensive Cancer Center

Recruiting

Los Angeles, California, United States, 90033

Contacts

Site Public Contact

323-865-0451

Principal Investigator:

Heinz-Josef Lenz

UC Irvine Health/Chao Family Comprehensive Cancer Center

Recruiting

Orange, California, United States, 92868

Contacts

Site Public Contact

877-827-8839ucstudy@uci.edu

Principal Investigator:

Farshid Dayyani

UCHealth University of Colorado Hospital

Recruiting

Aurora, Colorado, United States, 80045

Contacts

Site Public Contact

720-848-0650

Principal Investigator:

Alexis D. Leal

Ohio State University Comprehensive Cancer Center

Recruiting

Columbus, Ohio, United States, 43210

Contacts

Site Public Contact

800-293-5066Jamesline@osumc.edu

Principal Investigator:

Shafia Rahman

University of Oklahoma Health Sciences Center

Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contacts

Site Public Contact

405-271-8777ou-clinical-trials@ouhsc.edu

Principal Investigator:

Susanna V. Ulahannan

UT MD Anderson Cancer Center

Recruiting

Houston, Texas, United States, 77030

Contacts

Site Public Contact

866-632-6789askmdanderson@mdanderson.org

Principal Investigator:

Salvador Alonso Martinez

University of Virginia Cancer Center

Recruiting

Charlottesville, Virginia, United States, 22908

Contacts

Site Public Contact

434-243-6303uvacancertrials@hscmail.mcc.virginia.edu

Principal Investigator:

Paul Kunk

VCU Massey Comprehensive Cancer Center

Recruiting

Richmond, Virginia, United States, 23298

Contacts

Site Public Contact

804-628-6430CTOclinops@vcu.edu

Principal Investigator:

Khalid Matin

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Sep 10, 2026

Last verified

Aug, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-11. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-09-10.