Recruiting

Phase 1

M1774 & ZEN-3694Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer

Sponsor:

National Cancer Institute (NCI)

Code:

NCT05950464

Conditions

Recurrent Endometrial Carcinoma

Recurrent Endometrial Clear Cell Adenocarcinoma

Recurrent Endometrial Endometrioid Adenocarcinoma

Recurrent Endometrial Low Grade Endometrioid Adenocarcinoma

Recurrent Ovarian Clear Cell Adenocarcinoma

Eligibility Criteria

Sex: Female

Age: 18+

Healthy Volunteers: Not accepted

Interventions

BET Bromodomain Inhibitor ZEN-3694

Biopsy Procedure

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Study Details

Brief 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 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.

Conditions

Recurrent Endometrial Carcinoma

Recurrent Endometrial Clear Cell Adenocarcinoma

Recurrent Endometrial Endometrioid Adenocarcinoma

Recurrent Endometrial Low Grade Endometrioid Adenocarcinoma

Recurrent Ovarian Clear Cell Adenocarcinoma

Study ID

NCT05950464

Start date

Dec 18, 2023

Status verified date

Jun, 2026

Completion date

Jun 30, 2027

Anticipated

Primary completion date

Jun 30, 2027

Anticipated

Eligibility Criteria

Sex: Female

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

Patients must have pathologically confirmed:

PART I: Recurrent clear cell or endometrioid ovarian carcinoma (at least 50% morphology of clear cell and endometrioid required), recurrent clear cell and low grade endometrioid endometrial carcinoma (The International Federation of Gynecology and Obstetrics \[FIGO\] grade 1), or recurrent platinum resistant high grade serous ovarian carcinoma
NOTE: platinum-resistant disease is defined as progression within < 6 months from completion of platinum-based therapy. The date should be calculated from the last administered dose of platinum therapy
NOTE: Institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian cancer.
NOTE: Patients with recurrent endometrial carcinoma must not be eligible for or decline treatment with curative intent.
PART II: Recurrent clear cell or endometrioid ovarian carcinoma (at least 50% tumor morphology of clear cell and endometrioid required). Recurrent clear cell or FIGO Grade 1 endometrioid endometrial carcinoma. Next Generation Sequencing (NGS) by Clinical Laboratory Improvement Act (CLIA) approved lab required for ARID1A status. Tumor will be determined as ARID1A pathologic alteration or likely pathologic alteration (Cohort I) or ARID1A wildtype by NGS (Cohort II). The number of patients in PART II cohort with clear cell or endometrioid EMCA will be capped at 33% (5 patients per cohort). Institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian cancer.
Age >= 18
Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 2
Prior Treatment

1-3 prior cytotoxic therapies

NOTE: For platinum-resistant HGSOC (PART 1) may have received up to 3 prior cytotoxic therapies after developing platinum resistant disease.
Subjects with microsatellite instability- high (MSI-H) and/or mismatch repair protein deficient (dMMR) endometrioid endometrial cancer must have previously received an immune checkpoint inhibitor.
Unlimited prior hormonal therapy, targeted therapy (including immunotherapy), and/or antiangiogenic therapy will be permitted.
Washout periods (due to risk of myelosuppression):

Cytotoxic chemotherapy - 3 weeks.
Radiation therapy - 2 weeks (NOTE: patients with radiation to > 25% of the bone marrow are NOT eligible).
Disease status:

For PART I, evaluable disease or measurable disease required. NOTE: evaluable disease: defined as disease related abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions.
For PART II, measurable disease by RECIST 1.1 is required. Patients will be required to undergo biopsy, which may be a non-target lesion but should not be the only RECIST measurable lesion.

NOTE: Patients for PART II are required to undergo paired tumor biopsies. If at time of biopsy the biopsy is deemed unsafe by interventional radiology or attempted and is unsuccessful, patients may still enroll.

Hemoglobin >= 9 g/dL (in the absence of transfusion within 28 days prior to dosing)
Absolute neutrophil count >= 1,500 cells/mm\^3
Platelet count >= 100,000 cells/mm\^3
Calculated creatinine clearance (CrCL) of >= 50 mL/min by the Cockcroft-Gault formula
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level =< 3 x ULN may be enrolled)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional ULN
Patients with known history or current symptoms of cardiac disease or history of treatment with cardiotoxic agents should be New York Heart Association (NYHA) Functional Classification of class I or II.
The effects of M1774 and ZEN003694 on the developing human fetus are unknown. For this reason and because BETi agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Women of reproductive potential should use effective contraception treatment with M1774 and ZEN003694 and for at least 6 months following the last dose. Women should be advised not to breastfeed while taking M1774 and ZEN003694 and for 1 month after cessation of treatment.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression, are off steroids, and are stable for at least 1 month.
The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.
PART II only: Participants must have known mutational status (wild-type or pathogenic or likely pathogenic alteration) for ARID1A by Next-Generation Sequencing. This can be determined according to local testing generated by an assay with appropriate regulatory status.
Patients must be able to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening, or otherwise altering the product formulation.
Patients with co-morbidities:

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
For patients with evidence of chronic Hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Patients with a history of Hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Resolution of all toxicities of prior therapy or surgical procedures to baseline or grade 1 (except for hypothyroidism requiring medication, which must have resolved to Grade =< 2), alopecia, and other toxicities considered clinically nonsignificant and/or stable on supportive therapy as determined by the investigator).

Exclusion Criteria:

Patients who are receiving any other investigational agents.
Patients who have received prior ATR, ATM, CHK, BET, EZH2, and/or PI3K inhibitors.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 or M1774 used in study.
Patients taking proton pump inhibitors given decreased solubility of M1774 with increased pH. Proton pump inhibitors must be discontinued 7 days prior to initiating the trial.
Patients with corrected QT (QTc) over 450msec that does not correct with correction of electrolyte abnormalities or family history of long QT syndrome.
Patients with severe, active co-morbidity defined as follows:

No active infection requiring parenteral antibiotics.
Known hereditary diseases characterized by genetic defects of DNA repair mechanisms, including ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.
Pregnant and breastfeeding women are excluded from this study because ZEN003694 has the potential for teratogenic or abortifacient effects and M1774 is genotoxic in in vivo nonclinical studies. Patients who discontinue breastfeeding are eligible for enrollment and may not resume breastfeeding until 1 month off treatment.
Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors or inducers of CYP3A4 must be discontinued at least 7 days prior to the first dose of ZEN003694. Moderate inhibitors of CYP3A4 should be avoided. If alternative is not available, the use of moderate CYP3A4 inhibitors is permitted with careful monitoring and approval by study team. At the discretion of the provider, additional monitoring (labs, toxicity checks) may be implemented for use of moderate CYP3A4 inhibitors. Substrates of CYP1A2 with narrow therapeutic window also must be avoided white taking ZEN003694. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
Patients receiving any medications or substances that are Factor Xa inhibitors are discouraged given concerns for thrombocytopenia (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed. If patients are not willing to switch to low molecular heparin, they must obtain approval by study team.
Serious gastrointestinal bleeding within 3 months, refractory nausea and vomiting, uncontrolled diarrhea, known malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes, presence of drainage gastrostomy tube, other chronic gastrointestinal disease, and/or other situations that may preclude absorption of oral medications M1774 and/or ZEN003694.
M1774 restrictions:

Patients who cannot discontinue drugs that are strong inhibitors of CYP3A4 or CYP1A2.
Patients who cannot discontinue drugs that use hMATE1 or hMATE2-K substrates.

Study Design

Enrollment

65 participants

Anticipated

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)

Patients receive tuvusertib PO QD either on days 2-14 of cycle 1 and days 1-14 of subsequent cycles or days 1-14 of each cycle and BET bromodomain inhibitor ZEN-3694 PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients in the dose-escalation phase of the trial also undergo 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 biopsies during screening and on study, and x-ray, CT, or MRI, and collection of blood samples throughout the trial.

Interventions

BET Bromodomain Inhibitor ZEN-3694

Given PO

Biopsy Procedure

Undergo biopsy

Biospecimen Collection

Undergo collection of blood samples

Computed Tomography

Undergo CT

Magnetic Resonance Imaging

Undergo MRI

Tuvusertib

Given PO

X-Ray Imaging

Undergo x-ray

Primary outcome measure

Dose-limiting toxicities (DLTs) (Part I) [ Time Frame: Within the first cycle of study treatment (up to 28 days) ]
DLTs (Part II) [ Time Frame: Within the first 2 cycles of study treatment (up to 56 days) ]
Measurements for gammaH2AX (PART II) [ Time Frame: Baseline and cycle 1, day 8 (C1D8) ]
Incidence of adverse events (Part I and II) [ Time Frame: Up to 5 years ]

Central Contacts and Locations

Locations

University of Chicago Comprehensive Cancer Center

Recruiting

Chicago, Illinois, United States, 60637

Contacts

Site Public Contact

773-702-8222 cancerclinicaltrials@bsd.uchicago.edu

Principal Investigator:

Katherine C. Kurnit

University of Iowa/Holden Comprehensive Cancer Center

Recruiting

Iowa City, Iowa, United States, 52242

Contacts

Site Public Contact

800-237-1225

Principal Investigator:

David P. Bender

University of New Mexico Cancer Center

Recruiting

Albuquerque, New Mexico, United States, 87106

Contacts

Site Public Contact

505-925-0348 HSC-ClinicalTrialInfo@salud.unm.edu

Principal Investigator:

Carolyn Y. Muller

Cleveland Clinic Foundation

Recruiting

Cleveland, Ohio, United States, 44195

Contacts

Site Public Contact

866-223-8100 TaussigResearch@ccf.org

Principal Investigator:

Peter G. Rose

Ohio State University Comprehensive Cancer Center

Recruiting

Columbus, Ohio, United States, 43210

Contacts

Site Public Contact

800-293-5066 Jamesline@osumc.edu

Principal Investigator:

John L. Hays

University of Oklahoma Health Sciences Center

Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contacts

Site Public Contact

405-271-8777 ou-clinical-trials@ouhsc.edu

Principal Investigator:

Lauren E. Dockery

NRG Oncology

Recruiting

Philadelphia, Pennsylvania, United States, 19103

Contacts

Fiona Simpkins

Fiona.Simpkins@pennmedicine.upenn.edu

Principal Investigator:

Fiona Simpkins

University of Pennsylvania/Abramson Cancer Center

Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contacts

Site Public Contact

215-349-8245 PMCancerResearch@pennmedicine.upenn.edu

Principal Investigator:

Fiona Simpkins

Thomas Jefferson University Hospital

Recruiting

Philadelphia, Pennsylvania, United States, 19107

Contacts

Site Public Contact

215-600-9151 ONCTrialNow@jefferson.edu

Principal Investigator:

Mitchell I. Edelson

Women and Infants Hospital

Recruiting

Providence, Rhode Island, United States, 02905

Contacts

Site Public Contact

401-274-1122

Principal Investigator:

Cara A. Mathews

Medical College of Wisconsin

Recruiting

Milwaukee, Wisconsin, United States, 53226

Contacts

Site Public Contact

414-805-3666

Principal Investigator:

William H. Bradley

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Sep 3, 2026

Last verified

Jun, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-09-03.