Trial Title:
Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer
NCT ID:
NCT05950464
Condition:
Endometrial Carcinoma
Endometrial Clear Cell Adenocarcinoma
Endometrial Endometrioid Adenocarcinoma
Endometrial Low Grade Endometrioid Adenocarcinoma
Ovarian Clear Cell Adenocarcinoma
Ovarian Endometrioid Adenocarcinoma
Ovarian High Grade Serous Adenocarcinoma
Ovarian Low Grade Endometrioid Adenocarcinoma
Platinum-Resistant Ovarian Carcinoma
Conditions: Official terms:
Carcinoma
Adenocarcinoma
Endometrial Neoplasms
Cystadenocarcinoma, Serous
Carcinoma, Endometrioid
Adenocarcinoma, Clear Cell
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
BET Bromodomain Inhibitor ZEN-3694
Description:
Given PO
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
BETi ZEN-3694
Other name:
ZEN 3694
Other name:
ZEN-3694
Other name:
ZEN003694
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood samples
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Electrocardiography
Description:
Undergo ECG
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
ECG
Other name:
EKG
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Drug
Intervention name:
Tuvusertib
Description:
Given PO
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
ATR Kinase Inhibitor M1774
Other name:
M 1774
Other name:
M-1774
Other name:
M1774
Intervention type:
Procedure
Intervention name:
X-Ray Imaging
Description:
Undergo x-ray
Arm group label:
Treatment (tuvusertib, BET bromodomain inhibitor ZEN-3694)
Other name:
Conventional X-Ray
Other name:
Diagnostic Radiology
Other name:
Medical Imaging, X-Ray
Other name:
Plain film radiographs
Other name:
Radiographic Imaging
Other name:
Radiographic imaging procedure (procedure)
Other name:
Radiography
Other name:
RG
Other name:
Static X-Ray
Other name:
X-Ray
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.
Detailed description:
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- 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
- 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.
- 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).
- 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.
- Hemoglobin >= 9 g/dL (in the absence of transfusion within 28 days prior to dosing)
- Absolute neutrophil count >= 1,500 cells/mm^3
- Platelet count >= 100,000 cells/mm^3
- Calculated creatinine clearance (CrCL) of >= 50 mL/min by the Cockcroft-Gault
formula
- 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)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x
institutional ULN
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Patients must be able to swallow oral medications (capsules and tablets) without
chewing, breaking, crushing, opening, or otherwise altering the product formulation.
- 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.
- 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).
Exclusion Criteria:
- 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.
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Augusta University Medical Center
Address:
City:
Augusta
Zip:
30912
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
706-721-2388
Email:
ga_cares@augusta.edu
Investigator:
Last name:
Sharad A. Ghamande
Email:
Principal Investigator
Facility:
Name:
University of Chicago Comprehensive Cancer Center
Address:
City:
Chicago
Zip:
60637
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
773-702-8222
Email:
cancerclinicaltrials@bsd.uchicago.edu
Investigator:
Last name:
Katherine C. Kurnit
Email:
Principal Investigator
Facility:
Name:
University of Iowa/Holden Comprehensive Cancer Center
Address:
City:
Iowa City
Zip:
52242
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-237-1225
Investigator:
Last name:
David P. Bender
Email:
Principal Investigator
Facility:
Name:
Wayne State University/Karmanos Cancer Institute
Address:
City:
Detroit
Zip:
48201
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
313-576-9790
Email:
ctoadmin@karmanos.org
Investigator:
Last name:
Ira S. Winer
Email:
Principal Investigator
Facility:
Name:
Case Western Reserve University
Address:
City:
Cleveland
Zip:
44106
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Cleveland Clinic Foundation
Address:
City:
Cleveland
Zip:
44195
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
866-223-8100
Email:
TaussigResearch@ccf.org
Investigator:
Last name:
Peter G. Rose
Email:
Principal Investigator
Facility:
Name:
Ohio State University Comprehensive Cancer Center
Address:
City:
Columbus
Zip:
43210
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-293-5066
Email:
Jamesline@osumc.edu
Investigator:
Last name:
John L. Hays
Email:
Principal Investigator
Facility:
Name:
University of Oklahoma Health Sciences Center
Address:
City:
Oklahoma City
Zip:
73104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
405-271-8777
Email:
ou-clinical-trials@ouhsc.edu
Investigator:
Last name:
Lauren E. Dockery
Email:
Principal Investigator
Facility:
Name:
NRG Oncology
Address:
City:
Philadelphia
Zip:
19103
Country:
United States
Status:
Recruiting
Contact:
Last name:
Fiona Simpkins
Email:
Fiona.Simpkins@pennmedicine.upenn.edu
Investigator:
Last name:
Fiona Simpkins
Email:
Principal Investigator
Facility:
Name:
University of Pennsylvania/Abramson Cancer Center
Address:
City:
Philadelphia
Zip:
19104
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
855-216-0098
Email:
PennCancerTrials@careboxhealth.com
Investigator:
Last name:
Fiona Simpkins
Email:
Principal Investigator
Facility:
Name:
Thomas Jefferson University Hospital
Address:
City:
Philadelphia
Zip:
19107
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
215-600-9151
Email:
ONCTrialNow@jefferson.edu
Investigator:
Last name:
Mitchell I. Edelson
Email:
Principal Investigator
Facility:
Name:
Women and Infants Hospital
Address:
City:
Providence
Zip:
02905
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
401-274-1122
Investigator:
Last name:
Cara A. Mathews
Email:
Principal Investigator
Facility:
Name:
Medical College of Wisconsin
Address:
City:
Milwaukee
Zip:
53226
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
414-805-3666
Investigator:
Last name:
William H. Bradley
Email:
Principal Investigator
Start date:
December 18, 2023
Completion date:
April 30, 2026
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Collaborator:
Agency:
NRG Oncology
Agency class:
Other
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05950464
