ZEN003694 + Binimetinib for Advanced Solid Cancers

Not currently recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Hormone receptor positive breast cancer, PI3K pathway alterations, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the safety of combining two drugs, BET Bromodomain Inhibitor ZEN-3694 (ZEN003694) and binimetinib, for patients with advanced solid tumors that have specific genetic changes. ZEN003694 may slow cancer growth by targeting a protein family crucial for cell growth, while binimetinib blocks signals that prompt cancer cells to multiply. The trial seeks participants with advanced cancers, such as certain types of breast cancer or tumors with RAS gene changes, that have not responded to standard treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking any strong inhibitors or inducers of CYP3A4 at least 7 days before starting the study drugs. Other medications may need to be reviewed for potential interactions, so it's important to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, over 550 patients received ZEN003694. The study found that the drug is generally safe, even with long-term use. However, like all BET inhibitors, ZEN003694 can cause thrombocytopenia, which means having fewer platelets in the blood than normal, and this could be a concern.

Binimetinib is already approved for treating certain types of skin cancer called melanoma. Research has shown it is safe when used with other treatments. However, some reports suggest it might not always help people live longer with certain cancers.

Since this trial is in an early stage, it mainly focuses on testing how safe the combination of these two drugs is for patients. The goal is to find the best dose with the fewest side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ZEN-3694 and binimetinib for advanced solid cancers because it offers a unique approach compared to current treatments. Unlike traditional therapies that often target specific cancer pathways, ZEN-3694 is a BET bromodomain inhibitor, which means it disrupts the expression of cancer-related genes by targeting the proteins that help regulate them. Binimetinib, on the other hand, is a MEK inhibitor, which blocks a different pathway crucial for cancer cell growth. Together, these drugs may provide a more comprehensive attack on cancer cells, potentially leading to better outcomes for patients with fewer side effects.

What evidence suggests that the combination of ZEN003694 and binimetinib might be an effective treatment for advanced solid cancers?

This trial will evaluate the combination of ZEN003694, a BET bromodomain inhibitor, and binimetinib for advanced solid cancers. Research has shown that ZEN003694 may stop certain tumor cells from growing by targeting proteins involved in cell growth, potentially slowing cancer spread. Early results suggest it works well with other treatments. Studies have found that binimetinib blocks proteins that allow cancer cells to multiply and has shown benefits when combined with other drugs, especially in cancers with specific genetic changes. Using these two drugs together in this trial might enhance their ability to stop cancer growth. ^{1 2 5 6 7}

Who Is on the Research Team?

Sarina A Piha-Paul

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

Your corrected QT interval must be less than 450 milliseconds.

My cancer's genetic changes were identified using advanced DNA testing.

Patients must agree to use adequate contraception if of childbearing potential

Exclusion Criteria

Patients who are receiving any other investigational agents

Pregnant or breastfeeding women are excluded from this study

Patients with psychiatric illness/social situations that would limit compliance with study requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Escalation

Participants receive ZEN-3694 and binimetinib to determine the maximum tolerated dose and recommended Phase 2 dose

28 days per cycle

Multiple visits for dose adjustments and monitoring

Dose Expansion

Participants receive the highest dose with manageable side effects to evaluate safety and toxicity

28 days per cycle

Biopsies on day 1 and day 15 of cycle 1, regular monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• BET Bromodomain Inhibitor ZEN-3694
• Binimetinib

Trial Overview 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.

How Is the Trial Designed?

Group I: Treatment (ZEN-3694, binimetinib) Experimental Treatment 6 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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a Phase Ia/Ib study involving 77 patients with advanced solid tumors, the novel BET inhibitor BI 894999 showed a maximum tolerated dose of 1.5 mg, 2.5 mg, and 6.0/3.0 mg across different dosing schedules, indicating its potential for safe administration.

Disease control was achieved in approximately 24% of patients across all dosing schedules, with partial responses in 9.5% and 4% of patients for specific schedules, suggesting that BI 894999 may have therapeutic efficacy in treating advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours. Schöffski, P., Machiels, JP., Rottey, S., et al.[2023]

ABBV-744, a selective inhibitor targeting the second bromodomain of BET proteins, shows significant antiproliferative activity in cancer cell lines, particularly in acute myeloid leukemia and prostate cancer, indicating its potential as an effective treatment option.

In preclinical models, ABBV-744 demonstrated comparable antitumor efficacy to broader pan-BET inhibitors but with a better safety profile, especially when combined with the BCL-2 inhibitor venetoclax, suggesting a promising therapeutic strategy for enhancing treatment outcomes in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective Inhibition of the Second Bromodomain of BET Family Proteins Results in Robust Antitumor Activity in Preclinical Models of Acute Myeloid Leukemia. Zhang, L., Cai, T., Lin, X., et al.[2022]

In a phase Ib/IIa study involving 75 patients with metastatic castration-resistant prostate cancer (mCRPC) resistant to prior treatments, ZEN-3694 combined with enzalutamide showed acceptable safety, with only 18.7% experiencing grade ≥3 toxicities.

The treatment demonstrated potential efficacy, with a median radiographic progression-free survival of 9.0 months, particularly benefiting patients with lower androgen receptor transcriptional activity in their tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer. Aggarwal, RR., Schweizer, MT., Nanus, DM., et al.[2023]

The phase I study of the BET inhibitor BAY 1238097 involved 8 patients with advanced malignancies and aimed to determine safety and maximum tolerated dose, but was terminated early due to dose-limiting toxicities (DLTs) occurring at a lower dose than expected.

Despite a linear pharmacokinetic response and some patients showing prolonged stable disease, the study found that the adverse effects, including severe nausea and headaches, limited the potential for effective dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity. Postel-Vinay, S., Herbschleb, K., Massard, C., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05422794

NCT05422794 | Testing the Addition of Anti-Cancer Drug ... ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05372640

Study Details | NCT05372640 | Testing the Safety and ... This phase I trial tests the safety, side effects, and best dose of a ZEN003694 when given together with abemaciclib in treating patients with NUT carcinoma ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/bet-bromodomain-inhibitor-zen-3694?pn=1

Clinical Trials Using BET Bromodomain Inhibitor ZEN-3694 Review the clinical trials studying bet bromodomain inhibitor zen-3694 on this list and use the filters to refine the results by age and location.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5346709/

The BET bromodomain inhibitor exerts the most potent ... The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs.

5. targetedonc.com targetedonc.com/view/fda-awards-orphan-drug-status-to-zen-3694-for-nut-carcinoma

FDA Awards Orphan Drug Status to ZEN-3694 for NUT ... FDA designates ZEN-3694 as an orphan drug, offering hope for patients with NUT carcinoma with no current approved therapies.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7870522/

Safety and Efficacy of Bromodomain and Extra-Terminal ... All BET inhibitors reviewed in our study exhibited exposure-dependent thrombocytopenia, which may limit their clinical application.

7. cancernetwork.com cancernetwork.com/view/zen-3694-earns-fda-orphan-drug-designation-in-nut-carcinoma

ZEN-3694 Earns FDA Orphan Drug Designation in NUT ... Across more than 550 patients who have received ZEN-3694 to date, developers have observed robust signs of on-target safety, chronic dosing, ...