PRIMARY OBJECTIVE:
I. To compare the 3-year recurrence-free survival of women with high intermediate risk (HIR)
stage I/II mismatch repair deficient (dMMR) endometrioid endometrial cancer treated with
radiation and pembrolizumab (MK-3475) versus radiation alone.
SECONDARY OBJECTIVES:
I. To describe the safety and tolerability of concurrent pembrolizumab (MK-3475) and
radiation compared to radiation alone in patients with MMR deficient high intermediate risk
endometrial cancer (HIR EC).
II. To describe the recurrence patterns in each group. III. To measure recurrence free
survival at 5 years in each group. IV. To estimate disease specific overall survival in each
group. V. To determine whether the addition of pembrolizumab (MK-3475) to radiation, compared
with radiation alone is associated with decreased quality of life at 6- and 24-weeks, as
measured with the Functional Assessment of Cancer Therapy (FACT)-Endometrial (En) Trial
Outcome Index (TOI), increased gastrointestinal (GI) symptoms as measured with the GI
subscale, and increased fatigue as measured with the Patient Reported Outcomes Measurement
Information System (PROMIS)-Fatigue scale (short form).
VI. To validate the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator
(FACT-ICM) subscale, which assesses in cancer patients on immunotherapy.
EXPLORATORY OBJECTIVES:
I. To explore the baseline tumor genetic and microenvironment parameters predictive of
clinical benefit or resistance to immunotherapy.
II. To determine whether the addition of pembrolizumab (MK-3475) to radiation, compared with
radiation alone, is associated with decreased quality of life as measured with the Functional
Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM subscale) and more
self-reported bother from side effects as measured with a single item GP5 "I am bothered by
side effects," a question from the FACT-En TOI.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo pelvic external beam radiation therapy (EBRT) daily for 5-6 weeks and
vaginal brachytherapy completed within 7 days after completion of EBRT in the absence of
disease progression or unacceptable toxicity.
ARM II: Patients undergo EBRT and brachytherapy as in Arm I. Within 7 days prior to the start
of radiation therapy, patients also receive pembrolizumab intravenously (IV) over 30 minutes
on day 1. Treatment with pembrolizumab repeats every 6 weeks for up to 1 year (9 cycles) in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
Inclusion Criteria:
- Patients must have:
- Stage I endometrioid endometrial cancer and a combination of age and risk factors
as listed below:
- Age >= 70 and 1 or more risk factors
- Age 50 - < 70 and 2 or more risk factors
- Age < 50 and 3 risk factors
- Risk factors:
- Myometrial invasion >= 50%
- Lymphovascular space invasion
- Grade 2 or 3 OR
- Stage II endometrioid endometrial cancer
- Note: Patients with isolated tumor cells in sentinel lymph nodes are
eligible (considered N0i) as long as there is no evidence of micro- or
macro-metastases in any lymph nodes
- Computed tomography (CT) or magnetic resonance imaging (MRI) abdomen or pelvis and
either chest X-ray or CT chest demonstrating no evidence of disease outside of the
uterus. Imaging can be performed pre-operatively or post-operatively. CT with contrast
is the preferred modality. PET/CT is NOT to be used for any disease assessment or
reassessment unless there is documentation that PET/CT is of diagnostic quality equal
to CT with contrast
- Patients must have deficient mismatch repair as demonstrated by lack of expression of
at least one mismatch repair protein by immunohistochemistry (IHC) and/or evidence of
microsatellite instability (MSI) high. The institutional pathology report documenting
MMR deficiency must be submitted
- Patients must have undergone surgical staging with at least hysterectomy, removal of
cervix, bilateral (if both are present) salpingo-oophorectomy, and either sentinel
lymph node assessment or complete pelvic +/- aortic lymphadenectomy. Secondary staging
is allowed to determine stage. Patients with isolated tumor cells in sentinel lymph
nodes are eligible (considered N0i) as long as there is no evidence of micro- or
macro-metastases in any lymph nodes
- Patients must have received no prior therapy for endometrial cancer, including
hormonal therapy, chemotherapy, targeted therapy, immunotherapy or radiation therapy
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Platelets >= 100,000/mcl (within 14 days prior to registration)
- Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)
- Creatinine =< 1.5 x laboratory upper limit of normal (ULN) (within 14 days prior to
registration)
- Bilirubin =< 1.5 x ULN (within 14 days prior to registration) (patients with known
Gilbert's disease who have bilirubin level =< 3 x ULN may be enrolled)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within
14 days prior to registration)
- Thyroid stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid
patients on thyroid replacement therapy)
- Patients must be registered between 1 and 8 weeks after initial (staging) surgery
performed for the combined purpose of diagnosis and staging
- Human immunodeficiency virus (HIV) testing is not required by protocol unless
clinically indicated. Known HIV positive patients on effective anti-retroviral therapy
with undetectable viral load within 6 months are eligible for this trial
- 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
- 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
Exclusion Criteria:
- Patients who are currently participating and receiving cancer-directed study therapy
for endometrial cancer or have participated in a study of an investigational agent and
received cancer-directed study therapy for endometrial cancer within 4 weeks prior to
registration
- Patients who have received prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4
therapeutic antibody or other similar agents
- Patients who have a history of a severe hypersensitivity reaction to monoclonal
antibody or MK-3475 (pembrolizumab) and/or its excipients
- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids. This includes, but is not limited to, patients
with a history of immune related neurologic disease, multiple sclerosis, autoimmune
(demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic
autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue
diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis,
hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence
or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including
type I diabetes mellitus, thyroiditis managed with replacement hormones including
physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other
arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and
patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
antibodies should be evaluated for the presence of target organ involvement and
potential need for systemic treatment but should otherwise be eligible
- Patients with a history of (non-infectious) pneumonitis that required steroids, or
current pneumonitis
- Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to
registration:
- Patients who have received steroids as CT scan contrast premedication may be
enrolled
- The use of inhaled or topical corticosteroids is allowed
- The use of mineralocorticoids (e.g., fludrocortisone) for patients with
orthostatic hypotension or adrenocortical insufficiency is allowed
- The use of physiologic doses of corticosteroids may be approved after
consultation with the study chair (e.g. 10 mg of prednisone used for replacement
therapy for adrenal insufficiency)
- Patients who are lactating
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; and cirrhosis. 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
- Uncontrolled intercurrent illness including, but not limited to: ongoing or active
infection (except for uncomplicated urinary tract infection), interstitial lung
disease or active, non-infectious pneumonitis, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements
- Patients who have received any of the prohibited medications
