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Test sull'aggiunta del farmaco antitumorale ZEN003694 al consueto trattamento chemioterapico Cetuximab più Encorafenib per il cancro del colon-retto

29 ottobre 2026 aggiornato da: National Cancer Institute (NCI)

Uno studio di fase 1 su ZEN003694 (ZEN-3694) in combinazione con cetuximab ed encorafenib in pazienti con carcinoma colorettale metastatico BRAF V600E refrattario

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.

Panoramica dello studio

Stato

Reclutamento

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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 di studio

Interventistico

Iscrizione (Stimato)

30

Fase

  • Fase 1

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Stati Uniti
    • California
      • Costa Mesa, California, Stati Uniti, 92627
        • Reclutamento
        • UC Irvine Health Cancer Center-Newport
        • Investigatore principale:
          • Farshid Dayyani
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-827-8839
      • Irvine, California, Stati Uniti, 92612
        • Reclutamento
        • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-827-8839
          • Email: ucstudy@uci.edu
        • Investigatore principale:
          • Farshid Dayyani
      • Los Angeles, California, Stati Uniti, 90033
        • Reclutamento
        • USC / Norris Comprehensive Cancer Center
        • Investigatore principale:
          • Heinz-Josef Lenz
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 323-865-0451
      • Los Angeles, California, Stati Uniti, 90033
        • Sospeso
        • Los Angeles General Medical Center
      • Orange, California, Stati Uniti, 92868
        • Reclutamento
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-827-8839
          • Email: ucstudy@uci.edu
        • Investigatore principale:
          • Farshid Dayyani
    • Colorado
      • Aurora, Colorado, Stati Uniti, 80045
        • Reclutamento
        • UCHealth University of Colorado Hospital
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 720-848-0650
        • Investigatore principale:
          • Alexis D. Leal
    • Kansas
      • Fairway, Kansas, Stati Uniti, 66205
        • Attivo, non reclutante
        • University of Kansas Clinical Research Center
      • Kansas City, Kansas, Stati Uniti, 66160
        • Attivo, non reclutante
        • University of Kansas Cancer Center
      • Overland Park, Kansas, Stati Uniti, 66211
        • Attivo, non reclutante
        • University of Kansas Hospital-Indian Creek Campus
      • Westwood, Kansas, Stati Uniti, 66205
        • Attivo, non reclutante
        • University of Kansas Hospital-Westwood Cancer Center
    • Louisiana
      • New Orleans, Louisiana, Stati Uniti, 70121
        • Attivo, non reclutante
        • Ochsner Medical Center Jefferson
    • Ohio
      • Columbus, Ohio, Stati Uniti, 43210
        • Reclutamento
        • Ohio State University Comprehensive Cancer Center
        • Investigatore principale:
          • Shafia Rahman
        • Contatto:
    • Oklahoma
      • Oklahoma City, Oklahoma, Stati Uniti, 73104
        • Reclutamento
        • University of Oklahoma Health Sciences Center
        • Contatto:
        • Investigatore principale:
          • Susanna V. Ulahannan
    • Texas
      • Houston, Texas, Stati Uniti, 77030
        • Reclutamento
        • UT MD Anderson Cancer Center
        • Contatto:
        • Investigatore principale:
          • Salvador Alonso Martinez
    • Virginia
      • Charlottesville, Virginia, Stati Uniti, 22908
      • Richmond, Virginia, Stati Uniti, 23298
        • Reclutamento
        • VCU Massey Comprehensive Cancer Center
        • Investigatore principale:
          • Khalid Matin
        • Contatto:

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

18 anni e precedenti (Adulto, Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: N / A
  • Modello interventistico: Assegnazione di gruppo singolo
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: 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.
Procedura: Computed Tomography

Undergo CT

Altri nomi:
  • CT
  • GATTO
  • TAC
  • Tomografia assiale computerizzata
  • Tomografia computerizzata
  • tomografia
  • Tomografia assiale computerizzata (procedura)
  • Scansione tomografia computerizzata (CT).
  • Scansione CAT diagnostica
  • Tipo di servizio di scansione CAT diagnostica
Procedura: Magnetic Resonance Imaging

Undergo MRI

Altri nomi:
  • Risonanza magnetica
  • Scansione di immagini a risonanza magnetica
  • Imaging medico, risonanza magnetica/risonanza magnetica nucleare
  • SIG
  • Imaging RM
  • Scansione MRI
  • Imaging NMR
  • RMN
  • Risonanza Magnetica Nucleare
  • Imaging a risonanza magnetica (MRI)
  • sMRI
  • Imaging a risonanza magnetica (procedura)
  • RM strutturale
Procedura: Echocardiography Test

Undergo ECHO

Altri nomi:
  • Ecocardiografia
  • CE
Procedura: Multigated Acquisition Scan

Undergo MUGA

Altri nomi:
  • Scansione della pozza di sangue
  • Angiografia con radionuclidi di equilibrio
  • Imaging del pool di sangue recintato
  • MUGA
  • Ventricolografia con radionuclidi
  • RNVG
  • Scansione SIMA
  • Scansione di acquisizione multigate sincronizzata
  • Scansione MUGA
  • Scansione di acquisizione multi-gate
  • Scansione del ventricologramma con radionuclidi
  • Scansione del pool cardiaco recintato
  • Scansione RNV
Procedura: Biopsy Procedure

Undergo biopsy

Altri nomi:
  • Bx
  • BIOPSY_TYPE
  • Biopsia
Procedura: Biospecimen Collection

Undergo collection of blood samples

Altri nomi:
  • Raccolta di campioni biologici
  • Biocampione raccolto
  • Raccolta di campioni
  • Raccolta campione
Biologico: Cetuximab

Given IV

Altri nomi:
  • C225
  • Erbitux
  • IMC-C225
  • Cetuximab biosimilare CDP-1
  • Cetuximab biosimilare CMAB009
  • Cetuximab Biosimilare KL 140
  • Anticorpo monoclonale chimerico anti-EGFR
  • Chimerico MoAb C225
  • Anticorpo monoclonale chimerico C225
  • C-225
  • Cetuximab-cetu
  • Cetuxa
  • ENZ 124
  • ENZ-124
  • ENZ124
Droga: BET Bromodomain Inhibitor ZEN-3694

Given PO

Altri nomi:
  • BETi ZEN-3694
  • Zen 3694
  • ZEN-3694
  • ZEN003694
Droga: Encorafenib

Given PO

Altri nomi:
  • Braftovi
  • LGX 818
  • LGX-818
  • LGX818

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Maximum tolerated dose (dose escalation cohort)
Lasso di tempo: 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)
Lasso di tempo: 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

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Time to progression
Lasso di tempo: 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
Lasso di tempo: 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)
Lasso di tempo: Up to 3 years

Median OS will be estimated according to Kaplan-Meier analysis.
Up to 3 years
Progression-free survival (PFS)
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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

Altre misure di risultato

Misura del risultato
Misura Descrizione
Lasso di tempo
Presence or absence of a given gene mutation
Lasso di tempo: 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

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

National Cancer Institute (NCI)

Investigatori

  • Investigatore principale: Salvador Alonso Martinez, University of Texas MD Anderson Cancer Center LAO

Pubblicazioni e link utili

La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.

Pubblicazioni generali

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Effettivo)

5 giugno 2024

Completamento primario (Stimato)

30 gennaio 2027

Completamento dello studio (Stimato)

30 gennaio 2027

Date di iscrizione allo studio

Primo inviato

25 ottobre 2023

Primo inviato che soddisfa i criteri di controllo qualità

25 ottobre 2023

Primo Inserito (Effettivo)

26 ottobre 2023

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

30 ottobre 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

29 ottobre 2026

Ultimo verificato

1 settembre 2026

Maggiori informazioni

Termini relativi a questo studio

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • NCI-2023-08787
  • UM1CA186688 (Sovvenzione/contratto NIH degli Stati Uniti)
  • 10605 (Altro identificatore: CTEP)
  • NCI-2023-08787 (Identificatore di registro: CTRP (Clinical Trial Reporting Program))
  • 2024-0120
  • 10605 (Altro identificatore: University of Texas MD Anderson Cancer Center LAO)

Piano per i dati dei singoli partecipanti (IPD)

Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?

SÌ

Descrizione del piano 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.

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

Sì

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

prodotto fabbricato ed esportato dagli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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