PRIMARY OBJECTIVE:
I. To evaluate the efficacy of pembrolizumab (MK-3475) in combination with paclitaxel and
carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and
recurrent endometrial cancer.
SECONDARY OBJECTIVES:
I. To determine the nature, frequency and degree of toxicity as assessed by Common
Terminology Criteria for Adverse Events (CTCAE) for each treatment arm.
II. To evaluate blinded independent central review (BICR) assessed or investigator assessed
objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 by treatment arm and by mismatch repair (MMR) status in patients who enter the
study with measurable disease.
III. To evaluate BICR assessed or investigator assessed duration of response (DOR) by
treatment arm and by MMR status in patients who enter the study with measurable disease.
IV. To evaluate the effect of pembrolizumab on overall survival (OS) in patients with
mismatch repair protein proficient (pMMR) or mismatch repair deficiency (dMMR).
V. To determine whether the addition of pembrolizumab (MK-3475) to standard combination
chemotherapy is associated with improved patient reported physical function as measured with
the Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function scale
(short form), quality of life as measured with the Functional Assessment of Cancer Therapy
(FACT) - Endometrial Trial Outcome Index (En TOI) and worsened fatigue as measured with the
PROMIS-Fatigue scale (short form) in the pMMR patients.
VI. To determine concordance between institutional MMR immunohistochemistry (IHC) testing and
centralized MMR IHC.
EXPLORATORY OBJECTIVES:
I. To explore the correlation between patient-reported physical function as measured with the
PROMIS-physical function scale (short form) and quality of life as measure with the FACT-En
TOI.
II. To explore whether the addition of pembrolizumab (MK-3475) to standard combination
chemotherapy is associated with self-reported neurotoxicity as measured with the
FACT/Gynecologic Oncology Group Neurotoxicity (GOG-Ntx) subscale (short) and the extent to
which patients differ on their self-reported bother from side effects of cancer therapy in
the pMMR patients.
III. To evaluate the efficacy of pembrolizumab (MK-3475) in combination with paclitaxel and
carboplatin in patients with advanced stage (measurable stage III or IVA), stage IVB and
recurrent endometrial cancer by PD-L1 IHC (positive versus [vs] negative).
IV. To assess the association between PD-L1 IHC (positive vs negative) and mismatch repair
status (pMMR and dMMR).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I:
COMBINATION PHASE: Patients receive placebo intravenously (IV) over 30 minutes on day 1,
paclitaxel IV over 3 hours on day 1, and carboplatin IV over 30-60 minutes on day 1.
Treatment repeats every 3 weeks for 6 cycles in the absence of disease progression or
unacceptable toxicity. Patients with stable disease (SD) or partial response (PR) who still
have measurable disease may continue treatment for up to a total 10 cycles (if deemed
necessary by the treating physician) in the absence of disease progression or unacceptable
toxicity.
MAINTENANCE PHASE: Patients receive placebo IV over 30 minutes on day 1. Treatment repeats
every 6 weeks for up to 14 cycles in the absence of disease progression or unacceptable
toxicity.
ARM II:
COMBINATION PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1, paclitaxel IV
over 3 hours on day 1, and carboplatin IV over 30-60 minutes on day 1. Treatment repeats
every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity.
Patients with SD or PR who still have measurable disease may continue treatment for up to a
total of 10 cycles (if deemed necessary by the treating physician) in the absence of disease
progression or unacceptable toxicity.
MAINTENANCE PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment
repeats every 6 weeks for up to 14 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:
- Measurable stage III, measurable stage IVA, stage IVB (with or without measurable
disease) or recurrent (with or without measurable disease) endometrial cancer.
- Pathology report showing results of institutional MMR IHC testing. (This requirement
does not apply to sites in Japan.).
- 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, serous adenocarcinoma,
dedifferentiated/undifferentiated carcinoma, clear cell adenocarcinoma, mixed
epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.).
- Submission of tumor specimens for centralized MMR IHC testing is required after Step 1
and before Step 2 registration.
- In patients with measurable disease, lesions will be defined and monitored by RECIST
version (v) 1.1. Measurable disease is defined 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.
- Patients may have received
- NO prior chemotherapy for treatment of endometrial cancer OR
- Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a component
of concurrent chemotherapy and radiation therapy [with or without cisplatin])
provided adjuvant chemotherapy was completed >= 12 months prior to STEP 2
registration.
- 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 STEP 2 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 STEP 2
registration.
- 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 upper limit of normal (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.
- Thyroid stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid
patients on thyroid replacement therapy).
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of Step 2 registration are
eligible for this trial.
- For patients of child bearing potential: negative urine or serum pregnancy test. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
is required.
- Administration of study drugs (pembrolizumab, paclitaxel, carboplatin) may have an
adverse effect on pregnancy and poses a risk to the human fetus, including
embryo-lethality. Women of childbearing potential (WOCBP) must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) from at least
14 days prior to Step 2 registration (for oral contraceptives), during treatment, and
for 120 days after the last dose of study medication. Should a woman become pregnant
or suspect she is pregnant while she is participating in this study, she should inform
her treating physician immediately. Patients will be considered of nonreproductive
potential if they are either:
- Postmenopausal (defined as at least 12 months with no menses without an
alternative medical cause; in women < 45 years of age, a high follicle
stimulating hormone (FSH) level in the postmenopausal range may be used to
confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient); OR
- Have a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or
bilateral tubal ligation/occlusion, at least 6 weeks prior to Step 2
registration; OR
- Have a congenital or acquired condition that prevents childbearing.
- 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 with 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 pembrolizumab (MK-3475) and/or its excipients; and/or a severe
hypersensitivity reaction to paclitaxel and/or carboplatin
- Patients who are currently participating and receiving cancer-directed study therapy
or have participated in a study of an investigational agent and received
cancer-directed study therapy within 4 weeks prior to Step 2 registration.
- 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 Step 2
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.
- 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
they have been off steroids for at least 4 weeks prior to Step 2 registration and
remain clinically stable.
- 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 who have a history of (non-infectious) pneumonitis that required steroids, or
current pneumonitis.
- 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.
- 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.
- Pregnant or lactating patients.
