Prueba de la adición del fármaco anticancerígeno ZEN003694 al tratamiento de quimioterapia habitual, cetuximab más encorafenib, para el cáncer colorrectal
29 de octubre de 2026 actualizado por: National Cancer Institute (NCI)
Un estudio de fase 1 de ZEN003694 (ZEN-3694) en combinación con cetuximab y encorafenib en pacientes con cáncer colorrectal metastásico BRAF V600E refractario
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.
Descripción general del estudio
Estado
Estado
Reclutamiento
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
- Procedimiento: Computed Tomography
- Procedimiento: Magnetic Resonance Imaging
- Procedimiento: Echocardiography Test
- Procedimiento: Multigated Acquisition Scan
- Procedimiento: Biopsy Procedure
- Procedimiento: Biospecimen Collection
- Biológico: Cetuximab
- Droga: BET Bromodomain Inhibitor ZEN-3694
- Droga: Encorafenib
Descripción detallada
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), 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.
Tipo de estudio
Tipo de estudio
Intervencionista
Inscripción (Estimado)
Inscripción
30
Fase
Fase
- Fase 1
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
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California
-
Costa Mesa, California, Estados Unidos, 92627
- Reclutamiento
- UC Irvine Health Cancer Center-Newport
-
Investigador principal:
- Farshid Dayyani
-
Contacto:
- Site Public Contact
- Número de teléfono: 877-827-8839
-
Irvine, California, Estados Unidos, 92612
- Reclutamiento
- UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
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Contacto:
- Site Public Contact
- Número de teléfono: 877-827-8839
- Correo electrónico: ucstudy@uci.edu
-
Investigador principal:
- Farshid Dayyani
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Los Angeles, California, Estados Unidos, 90033
- Reclutamiento
- USC / Norris Comprehensive Cancer Center
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Investigador principal:
- Heinz-Josef Lenz
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Contacto:
- Site Public Contact
- Número de teléfono: 323-865-0451
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Los Angeles, California, Estados Unidos, 90033
- Suspendido
- Los Angeles General Medical Center
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Orange, California, Estados Unidos, 92868
- Reclutamiento
- UC Irvine Health/Chao Family Comprehensive Cancer Center
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Contacto:
- Site Public Contact
- Número de teléfono: 877-827-8839
- Correo electrónico: ucstudy@uci.edu
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Investigador principal:
- Farshid Dayyani
-
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Colorado
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Aurora, Colorado, Estados Unidos, 80045
- Reclutamiento
- UCHealth University of Colorado Hospital
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Contacto:
- Site Public Contact
- Número de teléfono: 720-848-0650
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Investigador principal:
- Alexis D. Leal
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Kansas
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Fairway, Kansas, Estados Unidos, 66205
- Activo, no reclutando
- University of Kansas Clinical Research Center
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Kansas City, Kansas, Estados Unidos, 66160
- Activo, no reclutando
- University of Kansas Cancer Center
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Overland Park, Kansas, Estados Unidos, 66211
- Activo, no reclutando
- University of Kansas Hospital-Indian Creek Campus
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Westwood, Kansas, Estados Unidos, 66205
- Activo, no reclutando
- University of Kansas Hospital-Westwood Cancer Center
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Louisiana
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New Orleans, Louisiana, Estados Unidos, 70121
- Activo, no reclutando
- Ochsner Medical Center Jefferson
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Ohio
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Columbus, Ohio, Estados Unidos, 43210
- Reclutamiento
- Ohio State University Comprehensive Cancer Center
-
Investigador principal:
- Shafia Rahman
-
Contacto:
- Site Public Contact
- Número de teléfono: 800-293-5066
- Correo electrónico: Jamesline@osumc.edu
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Oklahoma
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Oklahoma City, Oklahoma, Estados Unidos, 73104
- Reclutamiento
- University of Oklahoma Health Sciences Center
-
Contacto:
- Site Public Contact
- Número de teléfono: 405-271-8777
- Correo electrónico: ou-clinical-trials@ouhsc.edu
-
Investigador principal:
- Susanna V. Ulahannan
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Texas
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Houston, Texas, Estados Unidos, 77030
- Reclutamiento
- UT MD Anderson Cancer Center
-
Contacto:
- Site Public Contact
- Número de teléfono: 866-632-6789
- Correo electrónico: askmdanderson@mdanderson.org
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Investigador principal:
- Salvador Alonso Martinez
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Virginia
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Charlottesville, Virginia, Estados Unidos, 22908
- Reclutamiento
- University of Virginia Cancer Center
-
Investigador principal:
- Paul Kunk
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Contacto:
- Site Public Contact
- Número de teléfono: 434-243-6303
- Correo electrónico: uvacancertrials@hscmail.mcc.virginia.edu
-
Richmond, Virginia, Estados Unidos, 23298
- Reclutamiento
- VCU Massey Comprehensive Cancer Center
-
Investigador principal:
- Khalid Matin
-
Contacto:
- Site Public Contact
- Número de teléfono: 804-628-6430
- Correo electrónico: CTOclinops@vcu.edu
-
-
Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
18 años y mayores (Adulto, Adulto Mayor)
Acepta Voluntarios Saludables
No
Géneros elegibles para el estudio
Todos
Descripción
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
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Número de brazos
1
Armas e Intervenciones
Grupo de participantes/brazoGrupo de participantes/brazo |
Intervención / TratamientoIntervención / Tratamiento |
|---|---|
|
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. |
Undergo CT
Otros nombres:
Undergo MRI
Otros nombres:
Undergo ECHO
Otros nombres:
Undergo MUGA
Otros nombres:
Undergo biopsy
Otros nombres:
Undergo collection of blood samples
Otros nombres:
Given IV
Otros nombres:
Given PO
Otros nombres:
Given PO
Otros nombres:
|
¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Maximum tolerated dose (dose escalation cohort)
Periodo de tiempo: Up to completion of dose escalation phase
|
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). |
Up to completion of dose escalation phase
|
|
Recommended phase 2 dose (dose escalation cohort)
Periodo de tiempo: Up to completion of dose escalation phase
|
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. |
Up to completion of dose escalation phase
|
Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Time to progression
Periodo de tiempo: Time between consent onto study and progression, withdraw, or death, assessed up to 3 years
|
Will be estimated according to Kaplan-Meier analysis. |
Time between consent onto study and progression, withdraw, or death, assessed up to 3 years
|
|
Time to death
Periodo de tiempo: Time between consent onto study and death, assessed up to 3 years
|
Will be estimated according to Kaplan-Meier analysis. |
Time between consent onto study and death, assessed up to 3 years
|
|
Overall survival (OS)
Periodo de tiempo: Up to 3 years
|
Median OS will be estimated according to Kaplan-Meier analysis. |
Up to 3 years
|
|
Progression-free survival (PFS)
Periodo de tiempo: From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years
|
Median PFS will be estimated according to Kaplan-Meier analysis. |
From start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years
|
|
MAPK inhibition
Periodo de tiempo: Baseline and cycle 1 day 14 (C1D14)
|
MAPK inhibition, measured by phosphorylated ERK pharmacodynamic profiling, will be evaluated to determine efficacy of the combination. |
Baseline and cycle 1 day 14 (C1D14)
|
|
Pharmacokinetic profile of ZEN003694 when combined with encorafenib
Periodo de tiempo: 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
|
Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied. |
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
|
Otras medidas de resultado
Otras medidas de resultado
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Presence or absence of a given gene mutation
Periodo de tiempo: At pre-treatment and post-progression
|
The presence or absence of a given gene mutation will be evaluated by next-generation sequencing. |
At pre-treatment and post-progression
|
Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Patrocinador
Investigadores
Investigadores
- Investigador principal: Salvador Alonso Martinez, University of Texas MD Anderson Cancer Center LAO
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
- 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.
- 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.
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio (Actual)
Inicio del estudio
5 de junio de 2024
Finalización primaria (Estimado)
Finalización primaria
30 de enero de 2027
Finalización del estudio (Estimado)
Finalización del estudio
30 de enero de 2027
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
25 de octubre de 2023
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
25 de octubre de 2023
Publicado por primera vez (Actual)
Publicado por primera vez
26 de octubre de 2023
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización publicada
30 de octubre de 2026
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
29 de octubre de 2026
Última verificación
Última verificación
1 de septiembre de 2026
Más información
Términos relacionados con este estudio
Términos MeSH relevantes adicionales
- Neoplasias por sitio
- Neoplasias
- Enfermedades intestinales
- Neoplasias Gastrointestinales
- Neoplasias del Sistema Digestivo
- Enfermedades del Sistema Digestivo
- Enfermedades Gastrointestinales
- Neoplasias Intestinales
- Enfermedades Rectales
- Enfermedades del Colon
- Neoplasias colorrectales
- Aminoácidos, péptidos y proteínas
- Proteínas
- Técnicas de investigación
- Técnicas de laboratorio clínico
- Técnicas y procedimientos de diagnóstico
- Diagnóstico
- Procedimientos quirúrgicos, operativo
- Técnicas citológicas
- Citodiagnóstico
- Anticuerpos, monoclonales, humanizados
- Anticuerpos, monoclonal
- Anticuerpos
- Inmunoglobulinas
- Inmunoproteínas
- Proteínas de la sangre
- Globulinas séricas
- Globulinas
- Técnicas de diagnóstico, quirúrgico
- Técnicas de química, analítica
- Análisis de espectro
- Cetuximab
- Biopsia
- Manejo de muestras
- Espectroscopía de resonancia magnética
- encorafenib
- (225) AC-DOTA-C (RGDYK)
Otros números de identificación del estudio
Otros números de identificación del estudio
- NCI-2023-08787
- UM1CA186688 (Subvención/contrato del NIH de EE. UU.)
- 10605 (Otro identificador: CTEP)
- NCI-2023-08787 (Identificador de registro: CTRP (Clinical Trial Reporting Program))
- 2024-0120
- 10605 (Otro identificador: University of Texas MD Anderson Cancer Center LAO)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
SÍ
Descripción del plan IPD
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.
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Sí
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
No
producto fabricado y exportado desde los EE. UU.
No
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .