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.

Objectives

PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) for combination of tuvusertib (ATR inhibitor [M1774]) and BET bromodomain inhibitor ZEN-3694 (BET inhibitor [ZEN003694]) in women with recurrent clear cell, endometrioid, and platinum resistant high grade serous ovarian carcinoma (HGSOC) and clear cell and endometrioid endometrial carcinoma irrespective of ARID1A status (PART I).
II. To determine safety and tolerability in ARID1A pathogenic alteration (ARID1A^MUTATION [MUT]) and ARID1A wildtype (ARID1A^WT) cohorts (ARID1A is an integral biomarker) in an expansion phase (PART II).
III. To determine change in pharmacodynamic biomarker expression of gammaH2AX (for ATR inhibition, integral biomarker) from pre-treatment and on-treatment tumor samples in ARID1A^MUT and ARID1A^WT expansion cohorts by immunohistochemistry (IHC) (PART II).

SECONDARY OBJECTIVES:
I. To evaluate change in pharmacodynamic biomarker expression of cmyc (for BET inhibition, integrated biomarker) from pre-treatment and on-treatment tumor samples in ARID1A^MUT and ARID1A^WT expansion cohorts by Digital Spatial Profiling (DSP) (PART II).
II. To evaluate change in pharmacodynamic biomarker expression of gammaH2AX (for ATR inhibition, integrated biomarker) from pre-treatment and on-treatment tumor samples in ARID1A^MUT and ARID1A^WT expansion cohorts by DSP (PART II).
III. To investigate if ARID1A protein by IHC and DSP correlates with ARID1A pathogenic alteration in pre-treatment tumor biopsy samples (PART II).
IV. To estimate objective response rate (ORR) and progression free survival (PFS) at 6 months in ARID1A pathogenic alteration and wildtype cohorts (PART II).

EXPLORATORY OBJECTIVES:
I. To evaluate the pharmacokinetics of ZEN003694 and its active metabolite, ZEN003791, when the drug is taken alone and in combination with M1774, as well as M1774 pharmacokinetics in the combination (PART I).
II. To assess if ARID1A pathogenic alteration status by Next Generation Sequencing (NGS) correlates with ARID1A protein by IHC utilizing existing archival tissue and evaluate retrospectively (PART I).
III. To evaluate objective response rate (ORR) and progression free survival (PFS) at 6 months and to evaluate if these correlate with ARID1A pathogenic alteration status by Next Generation Sequencing (NGS) and with ARID1A protein by IHC (PART I).
IV. In patients with prior somatic tumor testing by Next Generation Sequencing, will obtain results and correlate molecular profiles (i.e., ARID1A pathogenic alteration, PIK3CA pathogenic alteration, C-myc amplification, ATM pathogenic alteration) with response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or CA-125 by Gynecological Cancer Intergroup (GCIG) (Rustin et al., 2011) (PART I).
V. To evaluate the pharmacokinetics of ZEN003694 and its active metabolite, ZEN003791, when the drug is taken alone and in combination with M1774, as well as M1774 pharmacokinetics in the combination (PART II).
VI. To assess if there is a greater overall response by RECIST 1.1 and CA-125 by GCIG (Rustin et al. 2011) in ARID1A pathogenic alteration cohort (ARID1A^MUT ) compared to ARID1A wildtype (ARID1A^WT ) cohort (PART II).
VII. To correlate pharmacodynamics and pharmacokinetics in ARID1A^MUT and ARID1A^WT expansion cohorts at the MTD (determine if drug levels affect drug target engagement and expression (e.g., gamma [g]H2AX and MYC)) (PART II).
VIII. To estimate overall survival (OS) in ARID1A pathogenic alteration versus (vs) wildtype cohorts (PART II).
IX. To identify biomarkers of response we will correlate ORR and PFS with ARID1A gene alteration, ARID1A protein level (IHC and DSP), gammaH2AX (IHC and DSP), C-myc (DSP), and total (tot) ATM (DSP), and HEXIM1 by ribonucleic acid (RNA) sequencing (Seq) in tumor biopsies (PART II).
X. To explore if liquid biopsies are a good surrogate for tumor ARID1A pathogenic alteration (PART II).
XI. To evaluate if ARID1A expression changes over time, we will compare ARID1A expression by NGS (gene alteration) and IHC (protein) using existing archival tumor to most recent pre-treatment biopsy samples required for PART II expansion cohort (PART II).

OUTLINE: This is a dose-escalation study of tuvusertib followed by a dose-expansion study.

Patients receive tuvusertib and BET bromodomain inhibitor ZEN-3694 orally (PO) on study. Patients in the dose-escalation phase of the trial also undergo electrocardiography (ECG) during screening, collection of blood samples on study, and x-ray, computed tomography (CT), or magnetic resonance imaging (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.

After study completion, patients are followed every 3 months for 2 years and then every 6 months for 3 years, or until the study is terminated.

Eligibility

1. 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.
2. Age >= 18
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 2
4. 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.
5. 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).
6. 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.
7. Hemoglobin >= 9 g/dL (in the absence of transfusion within 28 days prior to dosing)
8. Absolute neutrophil count >= 1,500 cells/mm^3
9. Platelet count >= 100,000 cells/mm^3
10. Calculated creatinine clearance (CrCL) of >= 50 mL/min by the Cockcroft-Gault formula
11. 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)
12. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional ULN
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. Patients must be able to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening, or otherwise altering the product formulation.
20. 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.
21. 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).

Treatment Sites in Georgia