What side effects are associated with this type of intervention?

BET inhibitors like ZEN003694 can cause fatigue, gastrointestinal issues (nausea, diarrhea), and hematologic toxicities (anemia, thrombocytopenia). MEK inhibitors like Binimetinib commonly cause skin-related side effects (rash, acneiform dermatitis), gastrointestinal disturbances (diarrhea, nausea), and cardiovascular issues (hypertension). Both drug classes may also lead to increased creatine phosphokinase levels, indicating muscle damage.

What prior FDA approvals exist?

The FDA has approved several MEK inhibitors for cancer treatment, including Trametinib and Cobimetinib, which target the MEK1 and MEK2 proteins involved in cell signaling pathways that promote cancer cell growth. Trametinib, for instance, is approved for use in combination with Dabrafenib for the treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. While there are fewer BET inhibitors approved by the FDA, research and clinical trials are ongoing to explore their potential in cancer therapy. These inhibitors target bromodomain and extra-terminal (BET) proteins, which play a role in regulating gene expression involved in cancer progression.

What other types of research exist?

Promising alternatives to ZEN003694 and Binimetinib for cancer treatment in 2024 include: 1) mTOR inhibitors like Temsirolimus and Everolimus, which have shown potential in various cancers, 2) BCL2 inhibitors such as Venetoclax, particularly in combination therapies for hematologic malignancies, and 3) novel EGFR/HER2 inhibitors like TAK-788 and Pyrotinib, which are being investigated for their efficacy in specific mutations. These alternatives are in various stages of clinical trials and have shown encouraging results in terms of efficacy and safety.

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BET Bromodomain Inhibitor

ZEN003694 + Binimetinib for Advanced Solid Cancers

Phase 1

Waitlist Available

Led By Sarina A Piha-Paul

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age >= 18 years

Patients must have histologically confirmed advanced/metastatic or unresectable solid tumor that is refractory to standard therapy or has relapsed after standard therapy

Must not have

Patients with uncontrolled intercurrent illness

Prior therapy with specific inhibitors

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years from treatment start date

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing two drugs, ZEN003694 and binimetinib, to help stop the growth and spread of advanced cancers with specific genetic changes. Binimetinib targets patients whose cancers are hard to treat because they have spread or cannot be removed by surgery. The drugs work by blocking proteins and signals that cancer cells need to grow.

Who is the study for?

Adults with advanced/metastatic or unresectable solid tumors that have specific RAS alterations, including triple negative breast cancer. Participants must be in a stable condition, not pregnant or breastfeeding, and willing to use contraception. They should be beyond certain periods after previous treatments and agree to sign informed consent.

What is being tested?

The trial is testing the combination of ZEN003694 (a BET protein inhibitor) and binimetinib (a kinase inhibitor) on patients with solid tumors having RAS mutations. The study has two parts: finding the best dose without severe side effects and then giving this dose to more people to learn about its safety.

What are the potential side effects?

Potential side effects include issues related to organ inflammation, digestive system disturbances, blood disorders, fatigue, increased risk of infection due to immune system suppression, as well as possible reactions at the infusion site.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My cancer is advanced, cannot be surgically removed, and has not responded to standard treatments.

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My heart condition allows me to perform physical activities with slight limitations.

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I can take care of myself but might not be able to do heavy physical work.

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I have triple negative breast cancer or a solid tumor with specific genetic changes.

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I haven't had chemotherapy, radiotherapy, or investigational therapy for at least 4 weeks.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have any unmanaged ongoing illnesses.

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I have previously been treated with specific inhibitors.

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My cancer does not have PI3K pathway mutations.

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I do not have any conditions that affect how my body absorbs pills.

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I have had a stroke, heart attack, or severe chest pain in the last 6 months.

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My breast cancer has never been hormone receptor positive.

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I have had a blockage in the vein of my eye.

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I have had pneumonitis or lung disease affecting the tissue and space around the air sacs.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years from treatment start date

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years from treatment start date

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years from treatment start date for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

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

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

Secondary study objectives

Disease control rate (DCR)

Duration of response (DOR)

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

+3 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (ZEN-3694, binimetinib)Experimental Treatment6 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Magnetic Resonance Imaging

2017

Completed Phase 3

~1160

Binimetinib

2018

Completed Phase 3

~1250

Biopsy

2014

Completed Phase 4

~1090

Biospecimen Collection

2004

Completed Phase 3

~2020

Computed Tomography

2017

Completed Phase 2

~2740

0 / 14Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

BET inhibitors, like ZEN003694, work by targeting bromodomain and extra-terminal proteins that regulate genes essential for cancer cell growth and survival. MEK inhibitors, such as Binimetinib, block the MEK1 and MEK2 proteins in the MAPK/ERK pathway, which is often overactive in cancer cells, leading to uncontrolled proliferation. These targeted therapies are important for cancer patients because they can more precisely disrupt the specific pathways driving their cancer, potentially leading to better outcomes and fewer side effects compared to traditional chemotherapy.

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