Phase 2, randomized, trial of maintenance Letrozole/Abemaciclib vs Pembrolizumab after systemic therapy in patients with advanced or recurrent estrogen receptor positive, mismatch repair proficient, TP53 wild-type endometrial cancer

A standard treatment for endometrial cancer is chemotherapy and pembrolizumab together
followed by pembrolizumab maintenance for two years. This treatment regimen has shown
benefit in terms of delaying cancer progression in prior clinical trials, but the benefit
of the pembrolizumab maintenance treatment and whether all participants need it is
unclear. This research is being done on the maintenance portion of treatment to compare
the efficacy between the combination of letrozole + abemaciclib and pembrolizumab alone
following chemotherapy and pembrolizumab.

The names of the study drugs involved in this study are:

- Abemaciclib (a type of cyclin-dependent kinase (CDK) inhibitor)

- Letrozole (a type of aromatase inhibitor)

- Pembrolizumab (a type of monoclonal antibody)

Inclusion Criteria:

- Participants must have histologically confirmed either i) endometrioid endometrial
cancer or ii) endometrial carcinosarcoma with endometrioid epithelial component.

- Participants must have ER-positive disease, defined as ≥ 1 percent of tumor cell
nuclei being immunoreactive by immunohistochemistry (IHC). If multiple analyses have
been performed, judgment should be based on the most recent biopsy or pathology
specimen analyzed in a CLIA (Clinical Laboratory Improvement Amendments)-certified
laboratory.

- Tumor must be TP53 wild-type as determined by immunohistochemistry (IHC) or via
CLIA-certified targeted Next-Generation Sequencing (NGS); IHC assessment of p53
status is included in the NCCN guidelines of uterine neoplasms for the molecular
analysis of endometrial carcinoma.

- Participants must have mismatch repair proficient (MMRP) endometrial cancer as
determined by immunohistochemistry (IHC) or polymerase chain reaction (PCR) or any
CLIA-certified next generation sequencing assay.

- No known tumor mutational burden ≥ 10 mutations/megabase (Mb).

- Participants must have completed a minimum of 4 cycles and a maximum of 10 cycles of
combination carboplatin, paclitaxel, and pembrolizumab.

- Participants must be considered appropriate to proceed with maintenance
pembrolizumab monotherapy.

- Participants must have had measurable stage III, measurable stage IVA, stage IVB
(with or without measurable disease) or recurrent (with or without measurable
disease) endometrial cancer.

- Participants are permitted to have received:

- a. Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a
component of concurrent chemotherapy and radiation therapy [with or without
cisplatin])

- b. Prior radiation therapy for treatment of endometrial cancer. Prior radiation
therapy may have included pelvic radiation therapy, extended field
pelvic/paraaortic radiation therapy, intravaginal brachytherapy, and/or
palliative radiation therapy. All radiation therapy must have been completed at
least 4 weeks prior to registration.

- c. Prior hormonal therapy for treatment of endometrial cancer.

- Must be able to initiate study drug between 3 to 8 weeks (or 21 to 56 days) after
completion of their final dose of chemotherapy and pembrolizumab.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix A)

- Age ≥ 18 years

- Participants must have normal organ and bone marrow function within 2 weeks before
starting protocol therapy as defined below:

- System Laboratory Value

- Hematologic

- ANC ≥1.5 × 109 /L

- Platelets ≥100 × 109 /L

- Hemoglobin ≥8 g/dL Patients may receive erythrocyte transfusions to
achieve this hemoglobin level at the discretion of the investigator.
Initial treatment must not begin earlier than the day after the
erythrocyte transfusion.

- Hepatic

- Total bilirubin ≤1.5 × ULN Patients with Gilbert's syndrome with a total
bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are
permitted.

- ALT and AST ≤3 × ULN

- Creatinine ≤ 1.5 × institutional ULN, OR

- Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine
levels above 1.5 x institutional ULN.

- Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil
count; AST = aspartate aminotransferase; ULN = upper limit of normal.

- Ability to understand and the willingness to sign a written informed consent
document.

- Ability to swallow and retain oral medication.

- Participants must have archival tissue available for analysis in the form of a
formalinfixed paraffin embedded (FFPE) block or unstained slides. Note: confirmation
of availability of archival tissue is the only requirement for eligibility, archival
tissue does not need to be received by the study team prior to enrollment.

Exclusion Criteria:

- Participants who have received previous treatment with CDK4/6 inhibitors, including
but not limited to previous abemaciclib therapy.

- Any gastrointestinal dysfunctions that could interfere with the absorption of study
drugs (e.g., bowel obstruction, inability to swallow tablets, malabsorption
syndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 > grade 1).

- Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except
for residual alopecia or Grade 2 peripheral neuropathy prior to randomization.

- The patient has active systemic bacterial infection (requiring intravenous [IV]
antibiotics at time of initiating study treatment), fungal infection, or detectable
viral infection (such as known human immunodeficiency virus positivity or with known
active hepatitis B or C [for example, hepatitis B surface antigen positive].
Screening is not required for enrollment.

- Major injuries or surgery within 14 days prior to randomization and/or planned major
surgery during the on-treatment study period. Patients who received radiotherapy
must have completed and fully recovered from the acute effects of radiotherapy. A
washout period of at least 14 days is required between end of radiotherapy and
randomization.

- Other malignant disease with disease-free ≤ 3 years except: curatively treated
carcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductal
carcinoma in situ (DCIS) of the breast or any other cancer deemed by the
investigator to be at low risk for recurrence of that malignancy.

- Active brain metastases (e.g., stable for < 8 weeks, no adequate previous treatment
with radiotherapy and/or surgery, symptomatic, requiring treatment with
anti-convulsant therapy. Corticoid therapy is allowed if administered as stable dose
for at least 1 month before randomization).

- Females who are pregnant or lactating. The effects of the study agents on the
developing human fetus are unknown. For this reason, women of child-bearing
potential must agree to use a medically approved contraceptive method during the
treatment period and for 3 months following the last dose of study agent.
Contraceptive methods may include an intrauterine device (IUD) or barrier method. If
condoms are used as a barrier method, a spermicidal agent should be added as a
double barrier protection. Should a woman become pregnant or suspect she is pregnant
while she is participating in this study, she should inform her treating physician
immediately. A negative serum pregnancy test is required for study entry from women
of childbearing potential.

- The patient has serious and/or uncontrolled preexisting medical condition(s) that,
in the judgment of the investigator, would preclude participation in this study (for
example, interstitial lung disease/pneumonitis, severe dyspnea at rest or requiring
oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance
<30ml/min], history of major surgical resection involving the stomach or small
bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic
condition resulting in baseline Grade 2 or higher diarrhea).

- Participants who at the time of study enrollment are known to require concomitant
therapy with strong CYP3A4 inducers, or strong inhibitors of CYP3A4. Due to
potential drug interactions, concomitant use of these medications is not permitted
for the duration of treatment on trial. Participants are eligible for study entry if
an appropriate substitution is made prior to the first dose of study medication.

- Participants with personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including,
but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest.

- Individuals with a history of a different malignancy are ineligible with the
following exceptions: individuals who have been treated and are disease-free for a
minimum of 3 years prior to study enrollment, or individuals who are deemed by the
treating investigator to be at low risk for disease recurrence.