PRIMARY OBJECTIVES:
I. To assess the pathologic complete response rate (pathCR) rate following administration of
neoadjuvant carboplatin, paclitaxel and radiation therapy versus neoadjuvant carboplatin,
paclitaxel, radiation therapy and nivolumab in patients with a resected locoregionally
advanced esophageal or gastroesophageal junction adenocarcinoma.
II. To assess the disease-free survival (DFS) following administration of adjuvant nivolumab
and ipilimumab versus adjuvant nivolumab in patients with a resected locoregionally advanced
esophageal or gastroesophageal junction adenocarcinoma who received neoadjuvant treatment
with carboplatin, paclitaxel and radiation therapy with or without nivolumab.
SECONDARY OBJECTIVES:
I. To assess the overall survival (OS) following administration of adjuvant nivolumab and
ipilimumab versus nivolumab in patients with a resected locoregional esophageal or
gastroesophageal junctional adenocarcinoma who received neoadjuvant treatment with
carboplatin, paclitaxel and radiation therapy with or without nivolumab.
II. To assess the disease free survival (DFS) following administration of neoadjuvant
carboplatin, paclitaxel, and radiation therapy with or without nivolumab in patients with a
locoregional esophageal or gastroesophageal junction adenocarcinoma III. To assess the
toxicity associated with the administration of neoadjuvant nivolumab in combination with
carboplatin, paclitaxel and radiation therapy in patients with a locoregional esophageal or
gastroesophageal junction adenocarcinoma.
IV. To assess the toxicity associated with the administration of adjuvant nivolumab and
ipilimumab versus adjuvant nivolumab in patients with a resected locoregional esophageal or
gastroesophageal junction adenocarcinoma who received neoadjuvant treatment with carboplatin,
paclitaxel and radiation therapy with or without nivolumab.
IMAGING OBJECTIVES:
I. To determine if the percent change in mean volumetric apparent diffusion coefficient
(ADC), measured from pre-treatment to mid-treatment, is predictive of pathCR in patients with
a locoregional esophageal or gastroesophageal junctional adenocarcinoma undergoing chemo and
chemoradiotherapy plus (+)/minus (-) nivolumab.
II. To identify an optimal delta ADC cutoff in predicting pathCR.
OUTLINE:
STEP I: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive carboplatin intravenously (IV) and paclitaxel IV once weekly and
undergo radiation therapy once daily (Monday-Friday) beginning on day 1. Cycles repeat every
week for up to 5 weeks in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive carboplatin, paclitaxel, and radiation therapy as in Arm A. Patients
also receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every week for up
to 5 weeks in the absence of disease progression or unacceptable toxicity.
STEP II: Patients are randomized to 1 of 2 arms following standard of care surgery.
ARM C: Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2
weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
ARM D: Patients receive nivolumab as in Arm C and receive ipilimumab IV over 90 minutes on
day 1 of cycles 1, 4, 7, and 10. Treatment repeats every 2 weeks for up to 12 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 up to 5 years.
Inclusion Criteria:
- STEP 1: Patients must have histologically confirmed T1N1-3M0 or T2-3N0-2M0 esophageal
or gastroesophageal junctional adenocarcinoma (Siewert I and II)
- STEP 1: Patients must have an Eastern Cooperative Oncology Group (ECOG) performance
status 0-1
- STEP 1: Patents must be deemed a surgical candidate by a thoracic surgeon, surgical
oncologist, or surgeon who is qualified to perform an esophagectomy
- STEP 1: Absolute neutrophil count >= 1,500/mcL (within less than or equal to 14 days
prior to randomization)
- STEP 1: Platelets >= 100,000/mcL (within less than or equal to 14 days prior to
randomization)
- STEP 1: Total bilirubin =< institutional upper limit of normal (ULN) (within less than
or equal to 14 days prior to randomization)
- STEP 1: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (within less than or equal to 14 days prior to
randomization)
- STEP 1: Serum creatinine =< 1.5 x institutional ULN (within less than or equal to 14
days prior to randomization)
- STEP 1: Hemoglobin (Hgb) >= 9 g/dL (within less than or equal to 14 days prior to
randomization)
- STEP 1: Leukocytes >= 3,000/mm^3 (within less than or equal to 14 days prior to
randomization)
- STEP 1: Patients may not have received prior chemotherapy or radiation therapy for
management for this malignancy
- STEP 1: Patients may not have received prior immunotherapy for management of this
malignancy or for any other past malignancy
- STEP 1: Patients must have no contraindication to receiving either carboplatin or
paclitaxel chemotherapy
- STEP 1: Patients must have no contraindication to receiving radiation therapy
- STEP 1: 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 disease, 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
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
- STEP 1: 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)
- STEP 1: Patient must NOT have previous or concurrent malignancy. Exceptions are made
for patients who meet any of the following conditions:
- Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or
breast cancer in situ OR
- Prior malignancy completely excised or removed and patient has been continuously
disease free for > 5 years OR
- Prior malignancy completely excised or removed and patient has been continuously
disease free for > 5 years
- Date of last evidence of disease
- STEP 1: Patients must not have a condition requiring systemic treatment with either
corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration. Inhaled or topical steroids
and adrenal replacement doses =< 10 mg/day prednisone equivalents are permitted in the
absence of active autoimmune disease
- STEP 1: Adequate cardiac function including electrocardiogram (EKG) and echocardiogram
for any patient with a history of congestive heart failure (CHF) or at risk because of
underlying cardiovascular disease or exposure to cardiotoxic drugs
- STEP 1: For patients with evidence of CHF, myocardial infarction (MI), cardiomyopathy,
or myositis, cardiac evaluation including lab tests and cardiology consultations
including EKG, creatine phosphokinase (CPK), troponin, and echocardiogram
- STEP 1: Patients must not have a positive test result for hepatitis B virus surface
antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or
chronic infection. Testing should be conducted to determine eligibility
- STEP 1: Patients with a known history of testing positive for human immunodeficiency
virus (HIV) or known acquired immunodeficiency syndrome (AIDS) must have no detectable
viral load on a stable anti-viral regimen
- STEP 1: Patients must not be receiving any other investigational agents
- STEP 1: Patients with an uncontrolled intercurrent illness such as 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 will be excluded
- STEP 1: Women must not be pregnant or breast-feeding due to potential harm to the
fetus from carboplatin, paclitaxel, or nivolumab. All females of childbearing
potential must have a blood test or urine study done within 2 weeks prior to
registration to rule out pregnancy. Those enrolled on Arm B with nivolumab must agree
to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [HCG]) within 24 hours of starting nivolumab to rule out
pregnancy. A female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)
- STEP 1: Women of childbearing potential (WOCBP) and sexually active males must either
abstain from sexual intercourse for the duration of their participation in the study
or agree to use both double barrier contraception and birth control pills or implants
for at least one month (female patients) or one week (male patients) prior to the
start of the study drug and continuing for 5 months after the last dose of study drug
(for female patients) and for 7 months after the last dose of study drug (for male
patients who are sexually active with WOCBP). Investigators shall counsel WOCBP and
male subjects who are sexually active with WOCBP on the importance of pregnancy
prevention and the implications of an unexpected pregnancy
- STEP 1: If patient says 'Yes' to "I choose to take part in the imaging study and will
have the diffusion weighted magnetic resonance imaging (MRI) scans": patients must be
able to tolerate MRI scans:
- No history of untreatable claustrophobia
- No magnetic resonance (MR) incompatible implants/devices or metallic foreign
bodies
- Weight compatible with limits imposed by the MRI scanner table
- STEP 2: Patient registration must not exceed 12 weeks from time of esophagectomy
- STEP 2: Patients must have a post-operative ECOG performance status of 0-2
- STEP 2: Absolute neutrophil count >= 1,500/mcL (within less than or equal to 14 days
prior to randomization)
- STEP 2: Platelets >= 100,000/mcL (within less than or equal to 14 days prior to
randomization)
- STEP 2: Total bilirubin =< institutional upper limit of normal (ULN) (within less than
or equal to 14 days prior to randomization)
- STEP 2: AST (SGOT)/ ALT (SGPT) =< 2.5 x institutional ULN (within less than or equal
to 14 days prior to randomization)
- STEP 2: Serum creatinine =< 1.5 x institutional ULN (within less than or equal to 14
days prior to randomization)
- STEP 2: Patients must be disease free following esophagectomy as is demonstrated by
having no evidence of disease on a post-surgical computed tomography (CT) scan.
Patients must also have a negative surgical margin (R0 resection)
- STEP 2: Patients must not have an active, known or suspected autoimmune disease or a
condition requiring treatment with steroids or immunosuppressive agents. 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
- STEP 2: Patients must not have a condition requiring systemic treatment with either
corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive
medications with 14 days of study drug administration. Inhaled or topical steroids and
adrenal replacement doses > 10 mg/day prednisone equivalents are permitted in the
absence of active autoimmune disease
- STEP 2: Patients must not be receiving any other investigational agents
- STEP 2: Patients with an uncontrolled intercurrent illness such as 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 will be excluded
- STEP 2: Women must not be pregnant or breast-feeding due to potential harm to the
fetus from nivolumab or ipilimumab. All females of childbearing potential must have a
blood test or urine study done (minimum sensitivity 25 IU/L or equivalent units of
HCG) within 2 weeks prior to registration to rule out pregnancy. All patients must
also agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units
of HCG) within 24 hours of starting nivolumab to rule out pregnancy. Those enrolled on
Arm D with ipilimumab must agree to have pregnancy tests within 72 hours of each
ipilimumab administration to rule out pregnancy
- STEP 2: Women of childbearing potential (WOCBP) and sexually active males must either
abstain from sexual intercourse for the duration of their participation in the study
or agree to use both double barrier contraception and birth control pills or implants
for at least one month (female patients) or one week (male patients) prior to the
start of the study drug and continuing for 5 months after the last dose of study drug
(for female patients) and for 7 months after the last dose of study drug (for male
patients who are sexually active with WOCBP). Investigators shall counsel WOCBP and
male subjects who are sexually active with WOCBP on the importance of pregnancy
prevention and the implications of an unexpected pregnancy
