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.
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
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
Single group
BET Bromodomain Inhibitor ZEN-3694
DrugGiven PO
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood samples
Cetuximab
Biological/VaccineGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Encorafenib
DrugGiven PO
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
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).
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.
Time to progression
Will be estimated according to Kaplan-Meier analysis.
Time to death
Will be estimated according to Kaplan-Meier analysis.
MAPK inhibition
MAPK inhibition, measured by phosphorylated ERK pharmacodynamic profiling, will be evaluated to determine efficacy of the combination.
Pharmacokinetic profile of ZEN003694 when combined with encorafenib
Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied.
Presence or absence of a given gene mutation
The presence or absence of a given gene mutation will be evaluated by next-generation sequencing.
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