RESOLVE: letRozole abEmaciclib combinationS in endOmetriaL and oVarian cancEr: A Multi-Cohort Phase 2 Study of Letrozole/Abemaciclib alone and in Combination with Metformin and Zotatifin

NOT ENROLLING
Protocol # :
18-301
Conditions
Endometrial Cancer
Phase
II
Disease Sites
Soft Tissue
Cervix
Other Female Genital
Principal Investigator
Konstantinopoulos, Panagiotis, A.
Site Investigator
Castro, Cesar, Martin
Shea, Meghan
Spriggs, David, R.
Site Research Nurses
Belavusava, Vera
Bowers, Mary, Ellen
Bowes, Brittany, N.
Colella, Tina
Creaton, Eileen
Doherty, Kelsie
Gotthardt, Susan, Jean
Hindenach, Sarah
Hurley-Whalen, Christin
Keis, Rylee
Markt, Denise, A.
McNamara, Taylor
Morrissey, Stephanie, C.
Neals, Allison
Thistle, Katrina, M.

Trial Description

This research study is studying a combination of targeted therapies as a possible treatment
for estrogen-receptor positive (ER+) endometrial cancer.

The drugs involved in this study are:

- Abemaciclib (also known as Verzenio™)

- Letrozole (also known as Femara®)

- Metformin (also known as Glucophage®)

Eligibility Requirements

Inclusion Criteria:

- Participants must have cytologically or histologically confirmed endometrial cancer
that is recurrent or metastatic and/or resistant to standard therapies, or for which
no standard therapy is available.Participants enrolled in the second stage of Cohort
1A, or into Cohort 3, 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-certified laboratory.

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.

- Age ≥ 18 years

- ECOG performance status of 0 or 1

- Participants must have normal organ and bone marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN). Patients with
Gilbert's syndrome with a total bilirubin within normal limits are permitted.

- AST(SGOT)/ALT(SGPT) ≤ 3× institutional ULN

- Creatinine ≤ 1.5 × institutional ULN, OR

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

- 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.

- 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
formalin-fixed 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 had chemotherapy, immune therapy, other investigational therapy,
or major surgery within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the
first dose of study medication. Previous hormonal therapy, including prior letrozole,
is allowed and there is no required washout period for hormonal therapy.

- Participants who have had tyrosine kinase inhibitor (TKI) therapy within 5 half-lives
of study entry.

- Participants who have had radiation therapy within 2 weeks of the first dose of study
medication.

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

- Participants who are currently receiving metformin therapy (if enrolling to Cohort 3).

- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to the study agents that the participant will be administered.

- Participants who at the time of study enrollment are known to require concomitant
therapy with moderate or 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.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Participants with histories or evidence of cardiovascular risk including any of the
following: acute coronary syndromes (i.e. myocardial infarction or angina), coronary
angioplasty, or stenting within 6 months prior to study enrollment.

- Pregnant women are excluded from this study because the study agents are anti-cancer
agents with the potential for teratogenic or abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with the study agents, breastfeeding must be discontinued if
the mother is treated on trial.

- 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 5
years prior to study enrollment, or individuals who are deemed by the treating
investigator to be at low risk for disease recurrence. Additionally, individuals with
the following cancers are eligible if diagnosed and treated within the past 5 years:
basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in
situ.

- Known HIV-positive participants are ineligible because of the increased risk of lethal
infections when treated with marrow-suppressive therapy.

- Participants with a history of uncontrolled hypertension despite optimal medical
management, defined as systolic blood pressure > 150 mmHg or diastolic blood pressure
> 90 mmHg

18-301