Testing the Combination of the Anticancer Drugs ZEN003694 and Binimetinib in Patients With Advanced/Metastatic or Unresectable Solid Tumors With RAS Alterations and Triple Negative Breast Cancer

NCT05111561 | Suspended Phase 1 FDA Drug

• 3 other identifiers: NCI-2021-1179310449UM1CA186688
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 4

Brief Summary

This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with binimetinib in treating patients with solid tumors that carry RAS alterations and that have spread to other places in the body (advanced/metastatic) or cannot be removed by surgery (unresectable). ZEN003694 is an oral medication with potential anticancer activity. It is an inhibitor of a family of proteins called bromodomain and extra-terminal (BET) which play important role during development and cellular growth. ZEN003694 may stop the growth of tumor cells that produce BET. Binimetinib is in a class of medications called kinase inhibitors. It works by blocking the action proteins called MEK1 and MEK2, that signal cancer cells to multiply. It may help keep cancer cells from growing and spreading. There is pre-clinical evidence that using ZEN003694 and binimetinib together may shrink or stabilize cancers studied in this trial. There are two parts of this study; dose escalation and dose expansion. In the dose escalation part of this study, different people will get different doses of the study drugs ZEN003694 and binimetinib. In the dose expansion part of this study, the highest dose with manageable side effects will be given to additional people. This will help to understand the side effects that may happen with this drug combination.

Conditions

Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm; Refractory Malignant Solid Neoplasm; Unresectable Malignant Solid Neoplasm; Triple-Negative Breast Carcinoma

Outcome Measures

Primary Outcomes (2)

• Incidence of dose limiting toxicities (Part 1 [Dose Escalation])

  Defined as the incidence of clinically significant adverse events or abnormal laboratory values thought to be at least possibly related to the study treatment occurring during the first cycle.

  Up to 28 days from treatment start date

• Incidence of adverse events (Part 2 [Dose Expansion])

  Including but not limited to treatment-emergent AEs, severe adverse events (SAEs), deaths, and clinical laboratory abnormalities, as assessed by the NCI CTCAE v5.0.

  Up to 30 days after last treatment dose

Secondary Outcomes (6)

• Incidence of adverse events (AEs) (Part 1 [Dose Escalation])

  Up to 30 days after last treatment dose

• Pharmacokinetic (PK) parameters (Part 1 [Dose Escalation])

  Days 2, 8, 15, and 16 of cycle 1

• Overall response rate (ORR)

  Up to 2 years from treatment start date

• Disease control rate (DCR)

  Up to 4 months from treatment start date

• Duration of response (DOR)

  Up to 2 years from treatment start date

Study Arms (1)

Treatment (ZEN-3694, binimetinib)

EXPERIMENTAL

Patients receive ZEN-3694 PO QD and binimetinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. During the dose expansion phase, patients will have two mandatory biopsies - one before beginning the study and the second at day 15 of cycle 1. The study biopsy takes small pieces of cancer tissue from patient's body to look for markers (substances made by, on, or in tumor cells) related to how the study treatment works. Patients also undergo collection of blood samples at screening and on study and undergo CT or MRI throughout the trial.

Drug: BET Bromodomain Inhibitor ZEN-3694; Drug: Binimetinib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging

Interventions

Binimetinib DRUG

Given PO

Also known as: ARRY 162, ARRY 438162, ARRY-162, ARRY-438162, ARRY162, ARRY438162, MEK 162, MEK-162, MEK162, Mektovi

Treatment (ZEN-3694, binimetinib)

Biopsy Procedure PROCEDURE

Undergo biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Treatment (ZEN-3694, binimetinib)

BET Bromodomain Inhibitor ZEN-3694 DRUG

Given PO

Also known as: BETi ZEN-3694, ZEN 3694, ZEN-3694, ZEN003694

Treatment (ZEN-3694, binimetinib)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (ZEN-3694, binimetinib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (ZEN-3694, binimetinib)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Treatment (ZEN-3694, binimetinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed advanced/metastatic or unresectable solid tumor that is refractory to standard therapy or has relapsed after standard therapy
• Patients must have one of the following:
• For Part 1 and 2 -
• Triple negative breast cancer (TNBC) (estrogen receptor =\< 1%, progesterone receptor =\< 1%, human epidermal growth factor receptor 2 0-1+ or non-amplified)
• Solid tumor with genomic alteration(s) activating RAS signaling including activating KRAS, NRAS, HRAS, or BRAF mutations, inactivating NF1 mutations, or BRAF fusions
• Genomic alterations should be identified locally by next generation sequencing (NGS). Patient genomic reports will be reviewed by the MD Anderson Cancer Center (MDACC) Precision Oncology Decision Support team prior to initiation of study treatment
• For Part 1, patients can have evaluable or measurable disease. For Part 2, patients must have measurable disease by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Patients must be \>= 4 weeks beyond treatment with any chemotherapy (6 weeks for nitrosoureas or mitomycin C) or other investigational therapy to include hormonal, biological, or targeted agents; or at least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter at the time of study treatment initiation. Patients must be \>= 4 weeks beyond radiotherapy
• Age \>= 18 years. Because no dosing or adverse events (AE) data are currently available on the use of binimetinib and ZEN003694 (ZEN-3694) 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 \>= 125,000/mcL
• Hemoglobin \>= 8 g/dL or \>= 5.6 mmol/L
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) OR \< 2.0 x ULN in patients with documented Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN

You may not qualify if:

• Patients who have not recovered from adverse events (AEs) due to prior anticancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia and peripheral neuropathy
• Patients who are receiving any other investigational agents
• Breast cancer patients with a prior history of hormone receptor positivity will not be eligible
• Patients with known PI3K pathway activating genomic alterations including inactivating mutations/deletions in PTEN and PIK3R1, amplifications in PIK3CA, and activating mutations in PIK3CA, Akt, or mTOR will not be eligible
• Prior therapy with BET, RAF, MEK, or ERK inhibitor
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694) and binimetinib
• Patients requiring therapeutic doses of anticoagulation are excluded. Patients taking low-dose (prophylactic) anticoagulation (e.g., low-molecular weight heparin, low-dose warfarin, fondaparinux) are allowed. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers). 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. Patients should avoid medications that prolong the QT
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because ZEN003694 (ZEN-3694) and binimetinib are a BETi and MEK inhibitor agent, respectively, with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with ZEN003694 (ZEN-3694) and binimetinib, breastfeeding should be discontinued if the mother is treated with ZEN003694 (ZEN-3694) and binimetinib
• Patient has a history of cerebrovascular accident, myocardial infarction, or unstable angina within the previous 6 months prior to study treatment initiation
• Patients with any medical condition or diagnosis that would likely impair absorption of an orally administered drug (e.g., gastrectomy, ileal bypass, chronic diarrhea, gastroparesis) are excluded
• Patient has a history of retinal vein occlusion
• Patient has a history of pneumonitis or interstitial lung disease

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Texas Medical Branch

Galveston, Texas, 77555-0565, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis; Triple Negative Breast Neoplasms

Interventions

binimetinib; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Sarina A Piha-Paul

  University of Texas MD Anderson Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2021
• First Posted: November 8, 2021
• Study Start: August 2, 2022
• Primary Completion (Estimated): March 14, 2027
• Study Completion (Estimated): March 14, 2027
• Last Updated: May 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (4)