Primary Objectives: To assess the antitumor activity (proportion of objective response by
RECIST 1.1 criteria) of pembrolizumab with objective tumor response in patients with
persistent, recurrent or metastatic endometrial cancer harboring an ultra-mutated or
hyper-mutated (MMR gene-defective) phenotype identified by next generation sequencing (NGS)
and comprehensive genomic profiling (CGP). To determine the nature and degree of toxicity of
pembrolizumab as assessed by CTCAE in patients with persistent, recurrent or metastatic
endometrial carcinoma. Secondary Objective(s): To estimate the duration of progression-free
survival (PFS) and overall survival (OS).
1. Patients must have histologically confirmed endometrial cancer that is recurrent or
progressive following at least one prior chemotherapy regimen.
2. Patients with the following histologic epithelial cell types are eligible:
Endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma,
undifferentiated carcinoma, mixed epithelial carcinoma, carcinosarcoma, and
adenocarcinoma not otherwise specified (N.O.S.).
3. Tumors must demonstrate ultramutation (POLE/POLD1-mutation) and/or hyper-mutation (due
to MMR gene defect) in a representative primary or metastatic tumor site by next
generation sequencing (NGS) and Comprehensive Genomic Profiling (CGP) testing, and/or
standard PCR-based DNA microsatellite instability (MSI) and immunohistochemistry
4. All patients must have measurable disease by RECIST 1.1.
5. Patients must have a ECOG performance status of 0 or 1.
6. Women of childbearing potential must have a negative urine and serum pregnancy test
within 72 hours prior to receiving first dose and must be willing to use contraceptive
through 120 days of last dose of Pembrolizumab.
7. Patients must have recovered from effects of recent surgery, radiotherapy, or
chemotherapy. Patients with ≥ Grade 2 neuropathy are eligible.
8. Patients may have received prior radiation therapy for treatment of endometrial
cancer. Prior radiation therapy may have included pelvic radiation therapy, extended
field pelvic/para-aortic radiation therapy, intravaginal brachytherapy and/or
palliative radiation therapy. All radiation therapy must be completed at least 4 weeks
prior to the first date of study therapy.
9. Patients may have received prior hormonal therapy for treatment of endometrial
carcinoma. All hormonal therapy must be discontinued at least one week prior to the
first date of study therapy.
10. Patients may have received prior therapy (including chemotherapy, biologic/targeted
therapy and immunotherapy) for treatment of endometrial cancer. All therapy must be
discontinued at least 3 weeks prior to the first date of study therapy. Any
investigational agent must be discontinued at least 30 days prior to the first date of
11. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer
WILL be counted as a systemic chemotherapy regimen.
12. Patients are allowed to receive, but not required to receive, up to 4 additional lines
13. At least 4 weeks must have elapsed since the patient underwent any major surgery
(e.g., major: laparotomy, laparoscopy) There is no delay in treatment for minor
procedures (e.g., tumor FNA or core biopsy, venous access device placement).
14. Have demonstrated adequate organ function. All screen labs should be performed within
14 days of treatment initiation
15. Patients must have signed an approved informed consent and authorization permitting
release of personal health information.
16. Patients must be 18 years or older
1. Patients who have had prior therapy with nivolumab, pembrolizumab or with an
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune check point pathways.
2. History of severe hypersensitivity reaction to any monoclonal antibody.
3. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure and unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.
4. Patients who are pregnant or nursing. The effects of pembrolizumab on the developing
human fetus are unknown. For this reason, women of child-bearing potential (WOCBP)
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. WOCBP
should use an adequate method to avoid pregnancy for 23 weeks after the last dose of
investigational drug. WOCBP must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IV/L or equivalent units of HCG) within 24 hours prior to the
start ofpembrolizumab. Women must not be breastfeeding.
5. Women who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile or have undergone definitive radiation) do not require
6. Patients with known brain metastases or leptomeningeal metastases are excluded unless
the following conditions are met: Metastases have been treated and there is no
evidence of progression by CT scan or magnetic resonance imaging (MRI) prior to the
first dose of pembrolizumab administration). There must also be no requirement for
immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone
equivalents) for at least 1 week prior to study drug administration.
7. Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
Patients should be excluded if they have a positive test for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection (e.g., HCV RNA [qualitative] is detected).
8. 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, should be excluded. These include but are 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 SLE, connective tissue diseases,
scleroderma, inflammatory bowel disease (IRB), Crohn's, ulcerative colitis, hepatitis;
and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson
syndrome, or phospholipid syndrome should be excluded because of the risk of
recurrence or exacerbation of disease. Patient with vitiligo, endocrine deficiencies
including 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.
NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event).
9. Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (>10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease. Patients are permitted to use
topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with
minimal systemic absorption). Physiologic replacement doses of systemic
corticosteroids are permitted, even if <10 mg/day prednisone equivalents. A brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen) is permitted.
10. Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, abdominal/pelvic fistula, gastrointestinal perforation, GI obstruction and/or
who require parenteral hydration and/or nutrition..
11. Has a known history of active TB (Bacillus Tuberculosis)
12. Hypersensitivity to pembrolizumab or any of its excipients.
13. Prior invasive malignancy (except non-melanomatous skin cancer such as basal cell
carcinoma of the skin or squamous cell carcinoma of the skin that has undergone
potentially curative therapy or in situ cervical cancer) unless disease free for a
minimum of 3 years.
14. Has a history of (non-infectious) pneumonitis that required steroids or current
15. Has an active infection requiring intravenous systemic therapy.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
18. Has not recovered from adverse events to <Grade 1 or prior treatment level due to a
previously administered agent. Subjects with Grade <2 neuropathy or alopecia of any
grade are an exception to this criterion and may qualify for the study.
19. Has a known additional malignancy that progressed or required active treatment within
the last five years. Exceptions include basal cell carcinoma of the skin, squamous
cell carcinoma of the skin that has undergone potentially curative therapy or in situ
20. Is pregnant or breastfeeding, or expecting to conceive children within the projected
duration of the trial, starting with the pre-screening or screening visit through 120
days after the last dose of trial treatment.
21. Patients should not have used investigational agents or device within 4 weeks prior to
22. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.