Trial Title:
Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer
NCT ID:
NCT06102902
Condition:
Metastatic Colorectal Adenocarcinoma
Recurrent Colorectal Adenocarcinoma
Refractory Colorectal Adenocarcinoma
Stage IV Colorectal Cancer AJCC v8
Conditions: Official terms:
Colorectal Neoplasms
Adenocarcinoma
Antineoplastic Agents, Immunological
Cetuximab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
BET Bromodomain Inhibitor ZEN-3694
Description:
Given PO
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
BETi ZEN-3694
Other name:
ZEN 3694
Other name:
ZEN-3694
Other name:
ZEN003694
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood samples
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Biological
Intervention name:
Cetuximab
Description:
Given IV
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
C 225
Other name:
C-225
Other name:
C225
Other name:
Cetuximab Biosimilar CDP-1
Other name:
Cetuximab Biosimilar CMAB009
Other name:
Cetuximab Biosimilar KL 140
Other name:
Chimeric Anti-EGFR Monoclonal Antibody
Other name:
Chimeric MoAb C225
Other name:
Chimeric Monoclonal Antibody C225
Other name:
Erbitux
Other name:
IMC-C225
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
EC
Intervention type:
Drug
Intervention name:
Encorafenib
Description:
Given PO
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
Braftovi
Other name:
LGX 818
Other name:
LGX-818
Other name:
LGX818
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Treatment (ZEN003694, cetuximab, encorafenib)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNV Scan
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
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.
Detailed description:
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.
EXPLORATORY OBJECTIVE:
I. To characterize pharmacodynamics and potential mechanisms of resistance to therapy via
whole exome sequencing (WES), reverse phase protein array (RPPA), 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. 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically confirmed and radiographically measurable
metastatic colorectal adenocarcinoma with known BRAF V600E mutation, confirmed in a
Clinical Laboratory Improvement Act (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. For those with previous exposure to
encorafenib and cetuximab, they must have tolerated the combination at doses planned
for the study
- 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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
USC / Norris Comprehensive Cancer Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
323-865-0451
Investigator:
Last name:
Heinz-Josef Lenz
Email:
Principal Investigator
Facility:
Name:
Ohio State University Comprehensive Cancer Center
Address:
City:
Columbus
Zip:
43210
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-293-5066
Email:
Jamesline@osumc.edu
Investigator:
Last name:
Shafia Rahman
Email:
Principal Investigator
Facility:
Name:
University of Oklahoma Health Sciences Center
Address:
City:
Oklahoma City
Zip:
73104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
405-271-8777
Email:
ou-clinical-trials@ouhsc.edu
Investigator:
Last name:
Susanna V. Ulahannan
Email:
Principal Investigator
Facility:
Name:
M D Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-632-6789
Email:
askmdanderson@mdanderson.org
Investigator:
Last name:
Edmund S. Kopetz
Email:
Principal Investigator
Facility:
Name:
University of Virginia Cancer Center
Address:
City:
Charlottesville
Zip:
22908
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
434-243-6303
Email:
uvacancertrials@hscmail.mcc.virginia.edu
Investigator:
Last name:
Paul Kunk
Email:
Principal Investigator
Facility:
Name:
Virginia Commonwealth University/Massey Cancer Center
Address:
City:
Richmond
Zip:
23298
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Email:
CTOclinops@vcu.edu
Investigator:
Last name:
Khalid Matin
Email:
Principal Investigator
Start date:
June 5, 2024
Completion date:
June 30, 2025
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06102902
