| Eligibility |
Inclusion Criteria:
Participants are eligible to be included in the study only if they meet all of the
following criteria, as applicable:
Applicable to All Participants
1. Is capable of providing signed informed consent as described in Section 10.1.1, which
includes compliance with the requirements and restrictions listed in the study
informed consent form (ICF) and in this protocol.
2. Is at least 18 years of age, or the legal age of consent in the jurisdiction in which
the study is taking place, at the time of providing signed informed consent.
3. Has confirmed Grade 1 or Grade 2 (ie, low-grade histology) endometrioid endometrial
adenocarcinoma.
• Note: Mixed tumor histology is permitted, provided that the non-endometrioid
component is < 5%.
4. Is treatment-naïve for Endometrial Cancer (EC) in the advanced/metastatic setting.
5. Is naïve to prior endocrine therapy for EC.
6. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
7. Has adequate organ function, as defined by all of the following:
- Absolute neutrophil count = 1.5 × 10^9/L
- Platelets = 100 × 10^9/L
- Hemoglobin = 8.0 g/dL
- International Normalized Ratio (INR) = 1.5, unless participant is receiving
chronic anti-coagulation therapy as noted below.
Note: Therapeutic INR is higher in individuals on chronic anti-coagulation treatment.
Any such participant whose INR exceeds 1.5 may be considered eligible per Investigator
judgment if otherwise meeting the study entry criteria.
- Creatinine clearance (CLcr) = 45/mL/min, as estimated by Cockcroft-Gault equation
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both < 2.5 ×
the upper limit of normal (ULN)
- Total bilirubin = 1.5 × ULN, in participants with well-documented absence of
Gilbert's Syndrome
8. Has QTc interval with Fridericia's correction (QTcF) of < 480 ms
9. Is able to swallow oral medications (or, for selected participants, to receive them by
PEG tube as noted below).
• Note: At the discretion of the Investigator, selected participants with a
percutaneous endoscopic gastrostomy (PEG) tube may be eligible. For any such
participant, the PEG must allow for the safe and adequate administration of tablets
(ie, without crushing or otherwise damaging them).
10. Has a life expectancy of at least 12 weeks.
11. Is medically postmenopausal, as confirmed by the Investigator by meeting one or more
of the following criteria:
- Has undergone bilateral oophorectomy.
- Is = 60 years of age.
- Is < 60 years of age and without menses for = 1 year, in the absence of ovarian
suppression agents, chemotherapy, tamoxifen, or other agents which may interfere
with ovarian function, with laboratory confirmation by Follicle Stimulating
Hormone (FSH).
12. If Screening pregnancy testing is clinically indicated per judgment of the
Investigator, must have a negative pregnancy test at Screening
13. Must adhere to contraceptive use consistent with local regulations regarding the
methods of contraception for those participating in clinical studies
14. Agrees not to donate ova (as applicable) from the time of the first administration of
any study intervention until 28 days after the last dose of any study intervention.
Applicable to Participants with Recurrent Disease
15. Participants with recurrent disease should meet all of the following criteria:
- Has disease that is measurable according to RECIST v1.1 and outside an irradiated
field.
- Is not eligible for curative intent therapy.
- Has not received prior anticancer therapy in the recurrent setting.
Note:
• Participants are permitted to have received prior adjuvant chemotherapy and/or
radiation therapy, provided that such therapy was completed = 6 months before study
enrollment
Applicable to Participants with Advanced/Metastatic Disease
16. Participants with advanced/metastatic disease should meet all of the following
criteria:
- Has disease that is either:
- FIGO Stage III/IV, measurable according to RECIST v1.1, and outside an irradiated
field (as applicable), or
- FIGO Stage IVB (either measurable or nonmeasurable).
- Is not eligible for curative intent therapy.
- Is considered eligible for hormonal therapy.
Exclusion Criteria:
Participants are excluded from this study if they meet any of the following criteria, as
applicable:
Applicable to All Participants
1. Tumor histology includes any non-endometrioid component of = 5%.
2. Has EC that meets either of the following criteria:
- Is amenable to curative intent therapy (ie, surgery, radiation, etc).
- Was previously treated with systemic therapy (eg, chemotherapy) in the
advanced/metastatic setting.
- Note: Prior adjuvant chemotherapy is allowed, provided that it was completed = 6
months before study enrollment.
3. Has leptomeningeal carcinomatosis or central nervous system (CNS) metastases, unless
the participant meets all of the following criteria:
- Has completed prior therapy for CNS tumor at least 4 weeks before initiating
study treatment.
- Has stable CNS tumor at Screening.
- Is not receiving steroids and/or enzyme-inducing anti-epileptic medications for
brain metastases.
4. Is known to exhibit loss of retinoblastoma protein (Rb) on genetic testing of tumor
tissue, if identified per one of the following methods prior to enrollment (note that
Rb testing is not an enrollment requirement):
- PCR
- Next-generation sequencing
- Peripheral blood testing
5. Currently has, or has had within the past 3 years, any invasive cancer, except the
following:
- Any prior in situ cancer treated with curative intent
- Non-melanoma skin cancer, including basal cell carcinoma of the skin
6. Has undergone major surgical intervention within 21 days prior to study entry or minor
surgical intervention within 14 days prior to study entry, or is expected to undergo
either at any time during the study.
7. Has received within 21 days prior to study entry, is currently receiving, or is
expected to receive at any time during the study any radiation therapy, except as
palliative therapy for a solitary nontarget lesion.
8. Has received within the 6 months prior to study entry any anti-PD-1/anti-PD-L1
checkpoint inhibitor therapy for any disease.
9. Is currently receiving any of the following substances, and the substance cannot be
discontinued within 14 days prior to the first administration of any study
intervention:
- Known strong or moderate CYP3A inducer or strong inhibitor of CYP3A, with the
following exception:
- Note: Participants may receive strong/moderate CYP3A inducers/inhibitors for
short periods of time (ie, ritonavir-based treatments for SARS-CoV-2), but the
study drug dosing plan during that period of time must be discussed with the
Sponsor Medical Monitor.
- Substances with a narrow therapeutic window that are predominantly metabolized
through CYP3A4/5
10. Is currently receiving, is expected to receive at any time during the study, or has
discontinued within 14 days prior to study entry any exogenous reproductive hormone
therapy (eg, hormone replacement therapy).
11. Has experienced within the 3 months prior to study entry any thromboembolic event or
event of intracranial hemorrhage.
12. Has an ejection fraction (EF) of = 45% on any echocardiogram performed within the past
12 months, or has a documented history of congestive heart failure with reduced EF.
13. Has any clinically significant, uncontrolled heart disease and/or cardiac
repolarization abnormality.
14. Has a history of prolonged QT syndrome or Torsades de Pointes.
15. Has a history of any of the following:
- Syncope of cardiovascular etiology
- Ventricular arrhythmia of pathological origin
- Sudden cardiac arrest
- Unprovoked venous thromboembolism or known underlying hypercoagulability, with
the following additional consideration:
- Note: Participants with prior deep vein thrombosis may be eligible, provided that
they are currently on a stable dose of an anticoagulant and do not pose a
bleeding risk in the opinion of the Investigator.
16. Has evidence of active bacterial infection, fungal infection, or viral infection
(including SARS-CoV-2 or uncontrolled human immunodeficiency virus [HIV], as noted
below) which would preclude safe enrollment in the judgment of the Investigator.
- Notes:
- The study SARS-CoV-2 requirements are determined by institutional standards (and
local/country regulations, as applicable).
- At Investigator discretion, any participant who tests positive and/or is
symptomatic for SARS-CoV-2 during Screening may either be excluded from the study
or delay enrollment until active infection has been excluded per institutional
standards.
- During the study, any SARS-CoV-2 testing is to be performed as clinically
indicated for the individual participant. The Investigator must document the
results of all tests performed. Any confirmed infection is to be recorded as an
AE or, in the event that clinical manifestation warrants such, recorded and
handled as an SAE
- Participants with uncontrolled HIV may be eligible for re-screening after
initiating highly active antiretroviral therapy (HAART).
17. Has interstitial pneumonia, or has severe impairment of lung function as defined by
either of the following:
- Vital capacity and diffusing capacity of the lung for carbon monoxide (DLCO) are
= 50% of the normal predicted values.
- Oxygen (O2) saturation at rest in ambient environment is = 88%.
18. Has, or shows evidence of, any other active infection, significant medical illness,
serious underlying medical condition, abnormal laboratory finding, or psychiatric
illness/social situation that might, in the Investigator's judgment, prevent the
participant from receiving study treatment or being followed in this study; or which
otherwise renders the participant inappropriate for the study as judged by the
Investigator.
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