ZEN003694 + Binimetinib for Advanced Solid Cancers

Recruiting at 3 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

42 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug ZEN-3694 in combination with Binimetinib for advanced solid cancers?

Research shows that ZEN-3694, a BET inhibitor, has shown activity in treating prostate cancer resistant to other treatments, and BET inhibitors in general have demonstrated effectiveness in various solid tumors and blood cancers. This suggests potential for ZEN-3694 in combination with other drugs like Binimetinib for advanced solid cancers. ^{1 2 3 4 5}

What safety data exists for ZEN-3694 and Binimetinib in humans?

ZEN-3694, a BET inhibitor, has been studied in combination with other drugs for cancer treatment, and some trials have reported adverse events like thrombocytopenia (low blood platelet count) and gastrointestinal issues. These side effects have been noted in trials with similar BET inhibitors, indicating potential safety concerns. ^{1 6 7 8 9}

What makes the drug ZEN003694 + Binimetinib unique for treating advanced solid cancers?

ZEN003694 is a BET bromodomain inhibitor that works by interfering with proteins that help cancer cells grow, while Binimetinib targets a specific pathway involved in cell division. This combination is unique because it targets cancer growth through two different mechanisms, potentially offering a new option for patients with advanced solid cancers. ^{1 3 6 10 11}

Research Team

Sarina A Piha-Paul

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

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.

I am 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

1. United States 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies. [2023]

3. England 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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Discovery of N-Ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)-5-(1-hydroxy-1-methyl-ethyl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (ABBV-744), a BET Bromodomain Inhibitor with Selectivity for the Second Bromodomain. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

A dose escalation study of RO6870810/TEN-10 in patients with acute myeloid leukemia and myelodysplastic syndrome. [2021]

6. United States 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. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family. [2021]

8. England 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. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC). [2019]