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Metastatic Colorectal AdenocarcinomaPhase 1NCT06102902

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

A Phase 1 study testing BET Bromodomain Inhibitor ZEN-3694, Biopsy Procedure and Biospecimen Collection in people with Metastatic Colorectal Adenocarcinoma and Recurrent Colorectal Adenocarcinoma, run by National Cancer Institute (NCI) at 16 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
BET Bromodomain Inhibitor ZEN-3694, Biopsy Procedure and Biospecimen Collection
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
16 sitesUnited States
Study dates
5 Jun 2024to 30 Jan 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 21Show fewer
  • 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

Who cannot join

  • 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

Trial locations and contacts

16 sites in 1 country. Contact the study team or a site near you to ask about taking part.

16 sites in 1 country

United States16 sites, 10 recruiting

  • UCHealth University of Colorado Hospital

    Aurora, Colorado, 80045

    Site Public Contact, 720-848-0650

    Alexis D. Leal

    Recruiting

  • University of Virginia Cancer Center

    Charlottesville, Virginia, 22908

    Site Public Contact, 434-243-6303, uvacancertrials@hscmail.mcc.virginia.edu

    Paul Kunk

    Recruiting

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

    Site Public Contact, 800-293-5066, Jamesline@osumc.edu

    Shafia Rahman

    Recruiting

  • UC Irvine Health Cancer Center-Newport

    Costa Mesa, California, 92627

    Site Public Contact, 877-827-8839

    Farshid Dayyani

    Recruiting

  • University of Kansas Clinical Research Center

    Fairway, Kansas, 66205

    Active, not recruiting

  • UT MD Anderson Cancer Center

    Houston, Texas, 77030

    Site Public Contact, 866-632-6789, askmdanderson@mdanderson.org

    Salvador Alonso Martinez

    Recruiting

  • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

    Irvine, California, 92612

    Site Public Contact, 877-827-8839, ucstudy@uci.edu

    Farshid Dayyani

    Recruiting

  • University of Kansas Cancer Center

    Kansas City, Kansas, 66160

    Active, not recruiting

  • Los Angeles General Medical Center

    Los Angeles, California, 90033

    Suspended

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

    Site Public Contact, 323-865-0451

    Heinz-Josef Lenz

    Recruiting

  • Ochsner Medical Center Jefferson

    New Orleans, Louisiana, 70121

    Active, not recruiting

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

    Site Public Contact, 405-271-8777, ou-clinical-trials@ouhsc.edu

    Susanna V. Ulahannan

    Recruiting

  • UC Irvine Health/Chao Family Comprehensive Cancer Center

    Orange, California, 92868

    Site Public Contact, 877-827-8839, ucstudy@uci.edu

    Farshid Dayyani

    Recruiting

  • University of Kansas Hospital-Indian Creek Campus

    Overland Park, Kansas, 66211

    Active, not recruiting

  • VCU Massey Comprehensive Cancer Center

    Richmond, Virginia, 23298

    Site Public Contact, 804-628-6430, CTOclinops@vcu.edu

    Khalid Matin

    Recruiting

  • University of Kansas Hospital-Westwood Cancer Center

    Westwood, Kansas, 66205

    Active, not recruiting

Other trials in United States

About this study

Official title: A Phase 1 Study of ZEN003694 (ZEN-3694) in Combination With Cetuximab and Encorafenib in Patients With Refractory BRAF V600E Metastatic Colorectal Cancer

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. To characterize pharmacodynamics and potential mechanisms of resistance to therapy via whole exome sequencing (WES), 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.

Being tested
BET Bromodomain Inhibitor ZEN-3694, Biopsy Procedure, Biospecimen Collection, Cetuximab, Computed Tomography
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BET Bromodomain Inhibitor ZEN-3694Drug

    Also called BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694

    Given PO

  • Biopsy ProcedureProcedure or surgery

    Also called Biopsy, BIOPSY_TYPE, Bx

    Undergo biopsy

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo collection of blood samples

  • CetuximabBiological

    Also called C 225, C-225, C225, Cetuxa

    Given IV

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT

  • Echocardiography TestProcedure or surgery

    Also called EC, Echocardiography

    Undergo ECHO

  • EncorafenibDrug

    Also called Braftovi, LGX 818, LGX-818, LGX818

    Given PO

  • Magnetic Resonance ImagingProcedure or surgery

    Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan

    Undergo MRI

  • Multigated Acquisition ScanProcedure or surgery

    Also called Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan

    Undergo MUGA

Study groups in NCT06102902
Study groupRoleWhat they receive
Treatment (ZEN003694, cetuximab, encorafenib)ExperimentalPatients 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.
Receives: Drug: BET Bromodomain Inhibitor ZEN-3694; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Biological: Cetuximab; Procedure: Computed Tomography; Procedure: Echocardiography Test; Drug: Encorafenib; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose (dose escalation cohort)

    Will be determined based on the number of grade 3 or 4 adverse events in patients who participate on the study. Toxicities will be graded according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0).

    Measured: Up to completion of dose escalation phase

  2. Recommended phase 2 dose (dose escalation cohort)

    Will be determined based on the number of grade 3 or 4 adverse events in patients who participate on the study. Toxicities will be graded according to CTCAE v 5.0.

    Measured: Up to completion of dose escalation phase

Secondary outcomes (6)

  1. Time to progression

    Will be estimated according to Kaplan-Meier analysis.

    Measured: Time between consent onto study and progression, withdraw, or death, assessed up to 3 years

  2. Time to death

    Will be estimated according to Kaplan-Meier analysis.

    Measured: Time between consent onto study and death, assessed up to 3 years

  3. Overall survival (OS)

    Median OS will be estimated according to Kaplan-Meier analysis.

    Measured: Up to 3 years

  4. Progression-free survival (PFS)

    Median PFS will be estimated according to Kaplan-Meier analysis.

    Measured: From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

  5. MAPK inhibition

    MAPK inhibition, measured by phosphorylated ERK pharmacodynamic profiling, will be evaluated to determine efficacy of the combination.

    Measured: Baseline and cycle 1 day 14 (C1D14)

  6. Pharmacokinetic profile of ZEN003694 when combined with encorafenib

    Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied.

    Measured: Prior to ZEN003694 administration on C1D1, C1D2 and C1D15, as well as 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours post ZEN003694 administration on C1D1 and C1D15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Oct 2023
  2. Study start5 Jun 2024
  3. Primary completion30 Jan 2027 (estimated)
  4. Study completion30 Jan 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06102902
Sponsor's protocol ID
NCI-2023-08787
Other IDs
NCI-2023-08787, 2024-0120, 10605, 10605, UM1CA186688
Status last verified
Sep 2026
First submitted
25 Oct 2023
Last updated
30 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
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.

Publications

  • Lee HM, Zheng Z, Sorokin A, Wong CW, Napolitano S, Chowdhury S, Kanikarla Marie P, Singh AK, Kochat V, Bristow CA, Srinivasan S, Peoples M, Arslan E, Alshenaifi JY, Villarreal OE, Morris VK, Shen JP, Meric-Bernstam F, Jain AK, Fowlkes NW, Anderson A, Menter DG, Saw AK, Rai K, Kopetz S. Reprogramming of Cellular Plasticity via ETS and MYC Core-Regulatory Circuits during Response to MAPK Inhibition in BRAF-Mutant Colorectal Cancer. Clin Cancer Res. 2026 Aug 3;32(15):3309-3324. doi: 10.1158/1078-0432.CCR-25-4370.

    PubMed 42101296

  • Lee HM, Zheng Z, Sorokin A, Wong CW, Napolitano S, Chowdhury S, Kanikarla PM, Singh AK, Kochat V, Bristow CA, Srinivasan S, Peoples M, Arslan E, Alshenaifi JY, Villarreal OE, Morris VK, Shen JP, Meric-Bernstam F, Jain AK, Fowlkes NW, Anderson A, Menter DG, Saw AK, Rai K, Kopetz S. Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer. bioRxiv [Preprint]. 2025 Jun 20:2025.06.15.659716. doi: 10.1101/2025.06.15.659716.

    PubMed 40611889

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing BET Bromodomain Inhibitor ZEN-3694, Biopsy Procedure and Biospecimen Collection in people with Metastatic Colorectal Adenocarcinoma and Recurrent Colorectal Adenocarcinoma, run by National Cancer Institute (NCI) at 16 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 30 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 16 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (dose escalation cohort) (time frame: Up to completion of dose escalation phase). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06102902, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2026.

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