M1774 + ZEN-3694 for Ovarian and Endometrial Cancer

Recruiting at 12 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective doses of two drugs, Tuvusertib (also known as M1774) and BET Bromodomain Inhibitor ZEN-3694, for treating recurrent ovarian and endometrial cancers. These drugs may inhibit tumor growth by blocking enzymes essential for cancer cell growth. The trial seeks patients whose ovarian or endometrial cancer has returned and who have not responded to other treatments. Participants should have specific cancer types resistant to certain treatments and must be able to swallow pills. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research shows that tuvusertib has been safely tested in patients with various solid tumors. In studies involving 55 patients, researchers carefully monitored side effects, and the drug was generally well-tolerated. This indicates that while side effects occurred, they were manageable and did not halt further testing.

For ZEN-3694, more than 550 patients have participated in various studies. Results indicate that it functions as expected without causing serious issues. Researchers are also testing this drug to determine if it can block proteins that promote tumor growth.

Both drugs have been tolerated by patients when tested separately. The current trial aims to assess their safety when used together. As a phase 1 trial, it is early in the testing process, with the main goal of finding a safe dose and identifying any side effects. Although both drugs have been tolerated individually, using them together is new, and safety will be closely monitored. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of tuvusertib and the BET bromodomain inhibitor ZEN-3694 for ovarian and endometrial cancer because it offers a novel approach to treatment. Unlike traditional chemotherapy, which targets rapidly dividing cells, ZEN-3694 works by inhibiting BET bromodomains, proteins that play a crucial role in regulating gene expression in cancer cells. This new mechanism could potentially disrupt cancer cell growth and survival more effectively. Additionally, combining ZEN-3694 with tuvusertib, another promising agent, might enhance the overall anti-cancer effects, offering hope for improved outcomes in challenging cases where standard therapies fall short.

What evidence suggests that this trial's treatments could be effective for ovarian and endometrial cancer?

Research has shown that using M1774 (tuvusertib) with ZEN-3694, which participants in this trial will receive, may help treat ovarian and endometrial cancer. Studies have found that these drugs kill ovarian tumor cells more effectively together than separately. Tuvusertib blocks enzymes that aid cancer cell growth, and early research suggests patients tolerate it well. ZEN-3694 targets proteins that help cancer cells survive and has slowed tumor growth in other advanced cancers. This combined treatment could potentially offer a stronger attack against recurring ovarian and endometrial cancers. ^{3 4 6 7 8}

Who Is on the Research Team?

Fiona Simpkins, MD

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03408

Testing Different Amounts of the Combination of Drugs ... M1774 and ZEN-3694 combined together has demonstrated to be better than either drug alone in killing ovarian tumor cells. Eligibility Criteria ...

2. uchicagomedicine.org uchicagomedicine.org/find-a-clinical-trial/clinical-trial/cirb240232

CLINICAL TRIAL / NCT05950464 M1774 and ZEN-3694 combined together has demonstrated to be better than either drug alone in killing ovarian tumor cells. Detailed Description.

3. withpower.com withpower.com/trial/phase-1-carcinoma-7-2023-e2dcd

M1774 + ZEN-3694 for Ovarian and Endometrial Cancer 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 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05327010

NCT05327010 | Testing the Combination of the Anti-cancer ... Combination therapy with ZEN-3694 and talazoparib may be effective at slowing or stopping tumor growth in patients with advanced cancer. Detailed Description.

5. 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, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04840589

Study Details | NCT04840589 | Testing the Combination of ... This phase I/Ib trial is to find out the best dose, possible benefits and/or side effects of BET bromodomain inhibitor ZEN-3694 (ZEN003694) when given in ...

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-02915

Trial ZEN-3694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that overproduce BET ...

8. careacross.com careacross.com/clinical-trials/trial/NCT05950464

Testing Different Amounts of the Combination of Drugs ... Summary: 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 ...