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

Summary

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.