M1774 + ZEN-3694 for Ovarian and Endometrial Cancer

Recruiting at 13 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proton pump inhibitors, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Breastfeeding, Genetic disorders, others

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

Compensation: Varies

Number of Visits: 4

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participating. Proton pump inhibitors must be stopped 7 days before starting the trial, and strong inhibitors or inducers of CYP3A4 must be stopped at least 7 days before the first dose. Factor Xa and Factor IIa inhibitors are discouraged, but low molecular weight heparin is allowed.

What data supports the effectiveness of the drug ZEN-3694 for ovarian and endometrial cancer?

Research shows that BET inhibitors like ZEN-3694 can slow down the growth and spread of ovarian cancer cells by targeting specific cancer-driving pathways. They can also make resistant ovarian cancer cells more responsive to existing cancer treatments, which has been confirmed in animal studies. ^{1 2 3 4 5}

Is the treatment with M1774 + ZEN-3694 generally safe for humans?

The safety of ZEN-3694, a BET inhibitor, has been evaluated in clinical trials for other cancers, such as prostate cancer, where it was combined with enzalutamide. While BET inhibitors show promise in treating various cancers, a study on a similar BET inhibitor, BAY 1238097, was terminated early due to unexpected toxicity, indicating potential safety concerns. ^{1 2 3 5 6}

What makes the drug ZEN-3694 unique for treating ovarian and endometrial cancer?

ZEN-3694 is a BET bromodomain inhibitor that targets specific proteins involved in gene regulation, which can disrupt cancer cell growth pathways like FoxM1 in ovarian cancer. This drug is unique because it can potentially re-sensitize resistant cancer cells to existing treatments, offering a new strategy for tackling these cancers. ^{1 2 3 4 7}

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects, and best dose of M1774 when given with ZEN-3694 in treating patients with ovarian and endometrial cancer that has come back (recurrent). M1774 and ZEN-3694 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. M1774 and ZEN-3694 combined together has demonstrated to be better than either drug alone in killing ovarian tumor cells.

Research Team

Fiona Simpkins, MD

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for adults with recurrent ovarian or endometrial cancer who've had 1-3 prior treatments. They must be able to swallow pills, have stable brain metastases if present, and not be pregnant. Excluded are those on certain heart medications, with severe illnesses, gastrointestinal issues that affect drug absorption, or a history of allergic reactions to similar drugs.

Inclusion Criteria

I have another cancer that won't affect this treatment's safety or results.

My cancer's ARID1A mutation status is known through sequencing.

I can swallow pills without needing to change their form.

Exclusion Criteria

I am not taking any strong medication that affects liver enzymes.

You are currently taking any other experimental medications.

I have previously been treated with specific inhibitors like ATR, ATM, or PI3K.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose-Escalation Treatment

Patients receive tuvusertib and BET bromodomain inhibitor ZEN-3694 orally. ECG, blood samples, and imaging are conducted.

4 weeks

Weekly visits (in-person)

Dose-Expansion Treatment

Continuation of treatment with additional biopsies and imaging. Focus on safety and tolerability in ARID1A cohorts.

8 weeks

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

Every 3 months for 2 years, then every 6 months for 3 years

Treatment Details

Interventions

• BET Bromodomain Inhibitor ZEN-3694
• Biopsy
• Biospecimen Collection
• Computed Tomography
• Electrocardiography
• Magnetic Resonance Imaging
• Tuvusertib
• X-Ray Imaging

Trial Overview The trial tests the safety and optimal dosages of M1774 combined with ZEN-3694 in patients whose ovarian or endometrial cancer has returned. These drugs may block enzymes needed for tumor cell growth and could work better together than alone.

Participant Groups

Group I: Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694) Experimental Treatment 8 Interventions

Patients receive tuvusertib and BET bromodomain inhibitor ZEN-3694 PO on study. Patients in the dose-escalation phase of the trial also undergo ECG during screening, collection of blood samples on study, and x-ray, CT, or MRI throughout the trial. Patients in the dose-expansion phase of the trial also undergo ECG during screening, biopsies during screening and on study, and x-ray, CT, or MRI, and collection of blood samples throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

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]

BET proteins, particularly BRD4, are important in regulating oncogenic drivers in ovarian cancer, and their inhibition can reduce cancer cell growth and spread by targeting key pathways like FOXM1 and JAK/STAT.

Preclinical studies suggest that BET inhibitors can make resistant ovarian cancer cells more sensitive to existing treatments like cisplatin and PARP inhibitors, and ongoing Phase I/II clinical trials are evaluating their safety and efficacy in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical perspectives of BET inhibition in ovarian cancer. Andrikopoulou, A., Liontos, M., Koutsoukos, K., et al.[2021]

The study identified BRD4 as a promising therapeutic target in ovarian cancer, showing that small-molecule BET inhibitors like JQ1 and I-BET151 can effectively suppress tumor growth across various ovarian cancer subclasses.

Inhibition of BRD4 disrupts the FoxM1 pathway, a critical driver of ovarian cancer, suggesting that targeting this epigenetic vulnerability could lead to new treatment strategies and warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1. Zhang, Z., Ma, P., Jing, Y., et al.[2018]

Ovarian clear cell carcinoma (OCCC) cells are particularly sensitive to the knockdown of BET proteins BRD2 and BRD3, suggesting these proteins as promising therapeutic targets for this chemo-resistant cancer subtype.

Combination therapies using the BET inhibitor CPI0610 alongside PI3K or AKT inhibitors showed synergistic effects in inducing cell death, indicating a potential new treatment strategy for OCCC that warrants further preclinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma. Shigeta, S., Lui, GYL., Shaw, R., et al.[2022]

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]

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]

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]

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. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical perspectives of BET inhibition in ovarian cancer. [2021]

3. Australia pubmed.ncbi.nlm.nih.gov

BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1. [2018]

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

Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma. [2022]

5. 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]

6. 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]

7. 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]