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Ovarian Cancer

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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.

BET Bromodomain Inhibitor ZEN-3694

Biopsy

Biospecimen Collection

Computed Tomography

Electrocardiography

Magnetic Resonance Imaging

Tuvusertib

X-Ray Imaging

Site Public Contact

Sharad A. Ghamande

David P. Bender

Ira S. Winer

Lindsay Ferguson

Peter G. Rose

John L. Hays

Lauren E. Dockery

Fiona Simpkins

Mitchell I. Edelson

Cara A. Mathews

William H. Bradley

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.

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.

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 (ZEN00-3694) to Exploit ARID1A Loss in Recurrent Ovarian and Endometrial Cancer

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PK endpoints (area under the curve \[AUC\], maximum concentration \[Cmax\] and metabolic ratio of ZEN003694 and active metabolite ZEN003791, and M1774) will be summarized using descriptive statistics by dose level.

ARID1A status and molecular profiles will be tabulated retrospectively.

Will assess profiles by Next Generation Sequencing from somatic tumor, correlate other molecular alterations (e.g., PIK3CA, C-Myc) with response by RECIST 1.1 and CA-125 by Gynecological Cancer Intergroup (GCIG).

Will be summarized using descriptive statistics by dose level and non-linear model techniques.

Objective tumor response (complete or partial response) by RECIST 1.1 and GCIG CA-125 will be tabulated by cohort, respectively, and the proportion of patients with response will be estimated and compared between the two cohorts by Fisher's exact test.

Descriptive statistics or mixed modeling approaches may be used to explore the corresponding associations of pharmacodynamic biomarkers with PK plasma concentration for ZEN003694.

Will assess ARID1A protein level (IHC and DSP), gammaH2AX (IHC and DSP), c-myc (DSP), total ATM (DSP), HEXIM1 by ribonucleic acid sequencing (RNASeq) in tumor biopsies, and correlation with objective response rate, and progression-free survival. Will be explored by Spearman's correlation coefficient, respectively.

Summary statistics for ARID1A genetic status from pre-treatment blood specimen will be provided, and the associations of it with tumor ARID1A genetic status and protein expression from pre-treatment biopsies, and objective tumor response will be explored by appropriate non-parametric methods, e.g., Spearman's correlation coefficient methods for ordinal-type data.

Will be assessed by NGS (gene alteration) and IHC from archival tumor and compare to most recent pre-treatment biopsy. The ARID1A genetic status and protein in archival tumor and most recent pre-treatment biopsy will be summarized by time, and the corresponding changes will be explored using Wilcoxon's signed rank tests or repeated measures methods.

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.

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.

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.

The frequency and severity of adverse events will be assessed by CTCAE v5.

Will be assessed by Digital Spatial Profiling (DSP) using tumor samples. Will be summarized using descriptive statistics (e.g., mean, standard deviation, median) by cohort, biospecimen type, and collection time point. One-sided Wilcoxon signed rank tests will be applied to examine whether there is a change in c-myc expression in the pre-treatment vs on-treatment tumor in the patients who have been treated at the RP2D and have evaluable bio-specimen by cohort, respectively.

Will be assessed by DSP using tumor samples. Analyses will be performed in similar approach to the primary endpoint gammaH2AX expression by IHC.

Summary statistics (e.g., mean and standard deviation, median) for ARID1A protein by IHC and DSP in pre-treatment tumor will be provided for the 12-point score (measure of ARID1A positive staining cells by IHC) by cohort and mutation status (Khalique et al, 2018). ARID1A pathogenic alteration means there is loss of ARID1A protein as assessed by IHC and DSP. ARID1A wildtype means there is no mutation and ARID1A protein is present. The relationship between ARID1A protein and ARID1A pathogenic alteration status will be investigated by Wilcoxon rank-sum test.

Objective response rate (ORR) is defined as the binomial proportion of evaluable patients with best overall response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of complete or partial response (CR or PR).

Progression-free survival at six months (PFS) is defined as the binomial proportion of evaluable patients who survive without documentation of disease progression (RECIST 1.1) at least 6 months after starting study entry.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer	NCT05950464	Endometrial Car... Endometrial Cle... Endometrial End... Endometrial Low... Ovarian Clear C... Ovarian Endomet... Ovarian High Gr... Ovarian Low Gra... Platinum-Resist...	BET Bromodomain... Biopsy Biospecimen Col... Computed Tomogr... Electrocardiogr... Magnetic Resona... Tuvusertib X-Ray Imaging	18 Years -	National Cancer Institute (NCI)
Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer	NCT05950464	Endometrial Car... Endometrial Cle... Endometrial End... Endometrial Low... Ovarian Clear C... Ovarian Endomet... Ovarian High Gr... Ovarian Low Gra... Platinum-Resist...	BET Bromodomain... Biopsy Biospecimen Col... Computed Tomogr... Electrocardiogr... Magnetic Resona... Tuvusertib X-Ray Imaging	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for endometrial low grade endometrioid adenocarcinoma