Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer
A Phase 1B Study of Combination ATR (M1774) and BET Inhibition (ZEN003694) to Exploit ARID1A Loss in Recurrent Ovarian and Endometrial Cancer
3 other identifiers
interventional
65
1 country
14
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Dec 2023
Typical duration for phase_1
14 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 15, 2023
CompletedFirst Posted
Study publicly available on registry
July 18, 2023
CompletedStudy Start
First participant enrolled
December 18, 2023
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 30, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
June 30, 2027
June 12, 2026
June 1, 2026
3.5 years
July 15, 2023
June 11, 2026
Conditions
Outcome Measures
Primary Outcomes (4)
Dose-limiting toxicities (DLTs) (Part I)
DLT is defined as any adverse events considered possibly, probably or definitely related to study drug combination as evaluated by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. A Bayesian Optimal Interval (BOIN) design will be used to determine the MTD (Yuan et al. 2016). Will be summarized by dose level.
Within the first cycle of study treatment (up to 28 days)
DLTs (Part II)
DLT is defined as any adverse events considered possibly, probably or definitely related to study drug combination as evaluated by NCI CTCAE v5.0. Within the ARID1A cohorts, the number of patients with DLTs will be summarized, and adverse events tabulated using the highest observed grade for each system organ class or preferred term, using CTCAE v5.0 criteria by cohort.
Within the first 2 cycles of study treatment (up to 56 days)
Measurements for gammaH2AX (PART II)
GammaH2AX will be assessed by immunohistochemistry (IHC) from tumor samples. Will be summarized using descriptive statistics (e.g., mean, standard deviation, median) by cohort and collection time point. One-sided Wilcoxon signed rank tests will be used for testing whether there is a change in gammaH2AX expression in the pre-treatment vs on-treatment tumor in the patients who have been treated at the recommended phase 2 dose (RP2D) and have evaluable bio-specimen by cohort, respectively.
Baseline and cycle 1, day 8 (C1D8)
Incidence of adverse events (Part I and II)
The frequency and severity of adverse events will be assessed by CTCAE v5.
Up to 5 years
Secondary Outcomes (5)
Measurements for c-myc (Part II)
Baseline and C1D8
Measurements for gammaH2AX (Part II)
Baseline and C1D8
Measurements for ARID1A protein and pathogenic alteration status (Part II)
Baseline, C1D8, and at progression
Objective response rate (Part II)
At 6 months
Progression-free survival (Part II)
From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed at 6 months
Other Outcomes (11)
Measurements of blood pharmacokinetics (PK) for ZEN003694 and ZEN003791 (Part I)
C1D1 (Pre-dose, 0.5, 1, 1.5, 2, 3, 4, & 8 hours [hrs]); C1D8 (Pre-dose, 0.5, 1, 1.5, 2, 3, 4, & 8 hrs)
Measurements for ARID1A protein (Part I)
Baseline
Objective response rate (Part I)
At 6 months
- +8 more other outcomes
Study Arms (1)
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
EXPERIMENTALPatients 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
Given PO
Undergo biopsy
Undergo collection of blood samples
Undergo MRI
Given PO
Undergo x-ray
Undergo CT
Eligibility Criteria
You may qualify if:
- 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
- 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.
- +23 more criteria
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- National Cancer Institute (NCI)lead
- NRG Oncologycollaborator
Study Sites (14)
Augusta University Medical Center
Augusta, Georgia, 30912, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242, United States
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201, United States
University of New Mexico Cancer Center
Albuquerque, New Mexico, 87106, United States
Case Western Reserve University
Cleveland, Ohio, 44106, United States
Cleveland Clinic Foundation
Cleveland, Ohio, 44195, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
NRG Oncology
Philadelphia, Pennsylvania, 19103, United States
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, 19104, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107, United States
Women and Infants Hospital
Providence, Rhode Island, 02905, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Fiona Simpkins
NRG Oncology
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 15, 2023
First Posted
July 18, 2023
Study Start
December 18, 2023
Primary Completion (Estimated)
June 30, 2027
Study Completion (Estimated)
June 30, 2027
Last Updated
June 12, 2026
Record last verified: 2026-06
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.