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

ConditionsRecurrent Endometrial CarcinomaRecurrent Endometrial Clear Cell AdenocarcinomaRecurrent Endometrial Endometrioid AdenocarcinomaRecurrent Endometrial Low Grade Endometrioid AdenocarcinomaRecurrent Ovarian Clear Cell AdenocarcinomaRecurrent Ovarian Endometrioid AdenocarcinomaRecurrent Ovarian High Grade Serous AdenocarcinomaRecurrent Ovarian Low Grade Endometrioid AdenocarcinomaRecurrent Platinum-Resistant Ovarian Carcinoma
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexFemale
Age18+
SponsorNational Cancer Institute (NCI)

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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.

Trial design

Design model

Sequential

Treatments tested in this trial

  • BET Bromodomain Inhibitor ZEN-3694

    Drug

    Given PO

  • Biopsy Procedure

    Procedure/Surgery

    Undergo biopsy

  • Biospecimen Collection

    Procedure/Surgery

    Undergo collection of blood samples

  • Computed Tomography

    Procedure/Surgery

    Undergo CT

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Tuvusertib

    Drug

    Given PO

  • X-Ray Imaging

    Procedure/Surgery

    Undergo x-ray

Treatment groups

65 Participants
are divided into 1 treatment group
Group A: Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)Experimental treatment 7 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
Within the first cycle of study treatment (up to 28 days)
2

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.

Time frame
Within the first 2 cycles of study treatment (up to 56 days)
3

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.

Time frame
Baseline and cycle 1, day 8 (C1D8)
4

Incidence of adverse events (Part I and II)

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

Time frame
Up to 5 years

Secondary outcomes

1

Measurements for c-myc (Part II)

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.

Time frame
Baseline and C1D8
2

Measurements for gammaH2AX (Part II)

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

Time frame
Baseline and C1D8
3

Measurements for ARID1A protein and pathogenic alteration status (Part II)

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.

Time frame
Baseline, C1D8, and at progression
4

Objective response rate (Part II)

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).

Time frame
At 6 months

Other outcomes

1

Measurements of blood pharmacokinetics (PK) for ZEN003694 and ZEN003791 (Part I)

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.

Time frame
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)
2

Measurements for ARID1A protein (Part I)

ARID1A status and molecular profiles will be tabulated retrospectively.

Time frame
Baseline
3

Objective response rate (Part I)

Time frame
At 6 months
4

Progression-free survival (Part I)

Time frame
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

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

NRG Oncology

Collaborator

Source ClinicalTrials.gov
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