| Eligibility |
Inclusion Criteria:
- Patients with measurable or non-measurable (detectable) recurrent endometrial cancer
- Measurable disease will be defined and monitored by RECIST v 1.1. Measurable disease
is defined per RECIST 1.1 criteria as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded). Each lesion must
be >= 10 mm when measured by computed tomography (CT) or magnetic resonance imaging
(MRI). Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI
- Non-measurable (detectable) disease in a patient is defined in this protocol per
RECIST 1.1 criteria as one who does not have measurable disease but has at least one
of the following conditions:
- All other lesions (or sites of disease), including small lesions (longest
diameter <10 mm or pathological lymph nodes with >= 10 to < 15 mm short axis),
are considered non-measurable disease
- Ascites and/or pleural effusion attributed to tumor
- Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST
1.1 definitions for target lesions
- Patients must have endometrial cancer with deficient mismatch repair system. All
patients must have institutional immunohistochemistry (IHC) and/or microsatellite
instability (MSI) testing to determine mismatch repair (MMR) status. MMR deficiency is
defined as lack of expression of one or more mismatch repair proteins (MLH1, PMS2,
MSH2, MSH6, EPCAM) by immunohistochemistry and/or presence of microsatellite
instability high using the National Cancer Institute (NCI)-5plex and Promega v1.2
assays, or institutional standards (e.g. next-generation sequencing [NGS] panel)
- Method(s) of detection of MMR deficiency will be recorded for each patient. An
institutional pathology report, and additional reports if available, documenting
these results must be submitted. Patients with "equivocal" results on MMR testing
by immunohistochemistry may be eligible if they have documented evidence of
microsatellite instability by MSI testing or by next generation sequencing
assays. MMR testing by IHC may be used to resolve equivocal/indeterminate MSI
results
- Histologic confirmation of the original primary tumor is required (submission of
pathology report(s) is required). Patients with the following histologic types are
eligible: Endometrioid adenocarcinoma, mucinous adenocarcinoma,
dedifferentiated/undifferentiated carcinoma, clear cell adenocarcinoma, mixed
epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.)
- Patients may have received 1-2 prior lines of systemic therapy:
- Prior anti-PD1/PD-L1 therapy is allowed if given in combination with chemotherapy
or radiation therapy in adjuvant or primary metastatic/recurrent settings.
Patients must have had a complete response and have disease progression/relapse
with treatment-free interval of 12 months or more from last dose of therapy with
immune check inhibition
- 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 registration
- Patients may have received prior hormonal therapy for treatment of endometrial cancer.
All hormonal therapy must be discontinued at least three weeks prior to registration
- Any other prior therapy directed at the malignant tumor including chemotherapy,
targeted agents, biologic agents, immunologic agents, and any investigational agents,
must be discontinued at least 4 weeks prior to registration (6 weeks for nitrosoureas
or mitomycin C)
- Age >= 18
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Platelets >= 100,000/mcl
- Absolute neutrophil count (ANC) >= 1,500/mcl
- Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN)
- Total serum bilirubin level =< 1.5 x ULN (patients with known Gilbert's disease who
have bilirubin level =<3 x ULN may be enrolled)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN
- Adequate oxygen saturation via pulse oximeter (CTCAE v.5.0 hypoxia < grade 2 within 28
days prior to registration)
- Thyroid-stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid
patients on thyroid replacement therapy). TSH testing is only required if clinically
indicated
- Patients must have recovered from effects of recent surgery, radiotherapy or
chemotherapy. At least 4 weeks must have elapsed since major surgery
- As clinically indicated, patients with known history or current symptoms of cardiac
disease, or history of treatment with cardiotoxic agents, should have a clinical risk
assessment of cardiac function using the New York Heart Association Functional
Classification. To be eligible for this trial, patients should be class 2B or better
and have a corrected QT (QTc) interval < 450 msec
- The effects of nivolumab, and ipilimumab on the developing human fetus are unknown.
For this reason and because nivolumab and ipilimumab are known to be teratogenic,
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
5 months after the last dose of investigational drug. Women of childbearing potential
must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the
start of nivolumab. Women must not be breastfeeding. Women who are not of childbearing
potential (i.e., who are postmenopausal or surgically sterile) do not require
contraception
- WOCBP is defined as any female who has experienced menarche and who has not
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who
is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea
in a woman over 45 in the absence of other biological or physiological causes. In
addition, women under the age of 55 must have a documented serum follicle
stimulating hormone (FSH) level less than 40 mIU/mL
- 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
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of registration are eligible for
this trial
- Patients with evidence of chronic hepatitis B virus (HBV) infection must have an
undetectable HBV viral load 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
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression and the
patient is stable off steroids for at least one month
- 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
- Patients 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
Exclusion Criteria:
- Patients with a diagnosis of endometrial serous carcinoma or carcinosarcoma
- Patients who received prior anti-PD1/PD-L1 therapy and had grade 3-4 or recurring
grade 2 immune-related toxicities that led to dose delay or discontinuation of
immunotherapy due to those toxicities
- Patients who received anti-CTLA-4 therapy or other immunotherapeutic agents
- Patients on chronic steroid therapy except those on replacement therapy at a daily
dose of 10mg or less prednisone or equivalent
- Patients on immunosuppressive therapy, with the exception of:
- Intra-nasal, inhaled, topical or local steroid injections
- Premedication for hypersensitivity reaction
- 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 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 should be
excluded because of the risk of recurrence or exacerbation of disease
- Patients with known immune impairment who may be unable to respond to anti-CTLA-4
antibody
- Patients with 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
- Women who are pregnant or unwilling to discontinue nursing
- Prior therapy with CTLA-4 inhibitors, or any other antibody or drug specifically
targeting T-cell co-stimulation or immune checkpoint pathways
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab, and/or ipilimumab including severe hypersensitivity
reactions to any monoclonal antibody
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