Nivolumab and Ipilimumab in Treating Patients With Esophageal and Gastroesophageal Junction Adenocarcinoma Undergoing Surgery
Purpose
This phase II/III trial studies the usefulness of treatment with nivolumab and ipilimumab in addition to standard of care chemotherapy and radiation therapy in patients with esophageal and gastroesophageal junction adenocarcinoma who are undergoing surgery. Immunotherapy with antibodies, such as nivolumab and ipilimumab, may remove the brake on the body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy and radiation therapy may reduce the tumor size and the amount of normal tissue that needs to be removed during surgery. A combined treatment with nivolumab and ipilimumab, chemotherapy, and radiation therapy might be more effective in patients with esophageal and gastroesophageal junction adenocarcinoma who are undergoing surgery.
Conditions
- Clinical Stage II Esophageal Adenocarcinoma AJCC v8
- Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
- Clinical Stage III Esophageal Adenocarcinoma AJCC v8
- Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
- Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8
- Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
- Esophageal Adenocarcinoma
- Gastroesophageal Junction Adenocarcinoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- STEP 1 RANDOMIZATION: Patients must be age >= 18 years
- STEP 1 RANDOMIZATION: Patients must have histologically confirmed T1N1-3M0 or
T2-3N0-2M0 esophageal or gastroesophageal junctional adenocarcinoma (Siewert I and
II)
- STEP 1 RANDOMIZATION: Patients must have an Eastern Cooperative Oncology Group
(ECOG) performance status 0-1
- STEP 1 RANDOMIZATION: Patents must be deemed a surgical candidate by a thoracic
surgeon, surgical oncologist, or surgeon who is qualified to perform an
esophagectomy
- STEP 1 RANDOMIZATION: Absolute neutrophil count >= 1,500/mcL (within less than or
equal to 14 days prior to randomization)
- STEP 1 RANDOMIZATION: Platelets >= 100,000/mcL (within less than or equal to 14 days
prior to randomization)
- STEP 1 RANDOMIZATION: Total bilirubin =< institutional upper limit of normal (ULN)
(within less than or equal to 14 days prior to randomization)
- STEP 1 RANDOMIZATION: 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 RANDOMIZATION: Serum creatinine =< 1.5 x institutional ULN (within less than
or equal to 14 days prior to randomization)
- STEP 1 RANDOMIZATION: Hemoglobin (Hgb) >= 9 g/dL (within less than or equal to 14
days prior to randomization)
- STEP 1 RANDOMIZATION: Leukocytes >= 3,000/mm^3 (within less than or equal to 14 days
prior to randomization)
- STEP 1 RANDOMIZATION: Patients may not have received prior chemotherapy or radiation
therapy for management for this malignancy
- STEP 1 RANDOMIZATION: Patients may not have received prior immunotherapy for
management of this malignancy or for any other past malignancy
- STEP 1 RANDOMIZATION: Patients must have no contraindication to receiving either
carboplatin or paclitaxel chemotherapy
- STEP 1 RANDOMIZATION: Patients must have no contraindication to receiving radiation
therapy
- STEP 1 RANDOMIZATION: 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, must 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 must 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 must be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be
eligible
- STEP 1 RANDOMIZATION: 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 RANDOMIZATION: 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
- Date of last evidence of disease
- STEP 1 RANDOMIZATION: 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 RANDOMIZATION: Patients must have 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 RANDOMIZATION: For patients with evidence of uncontrolled CHF, myocardial
infarction (MI), cardiomyopathy, or myositis, require a cardiac evaluation and
clearance including lab tests and cardiology consultation (EKG, creatinine
phosphokinase [CPK], troponin, and echocardiogram)
- STEP 1 RANDOMIZATION: 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 RANDOMIZATION: 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 RANDOMIZATION: Patients must not be receiving any other investigational
agents
- STEP 1 RANDOMIZATION: 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 RANDOMIZATION: Patients must not be pregnant or breast-feeding due to
potential harm to an unborn fetus and possible risk for adverse events in nursing
infants from carboplatin, paclitaxel, ipilimumab or nivolumab
- All patients of childbearing potential must have a blood test or urine study
done within 2 weeks prior to randomization 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 patient of childbearing potential is defined as anyone, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has achieved menarche at some point 2) has not undergone
a hysterectomy or bilateral oophorectomy; or 3) 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 RANDOMIZATION: Patients of childbearing potential must not expect to conceive
children by either abstaining from sexual intercourse for the duration of their
participation in the study or by agreeing to use both double barrier contraception
and birth control pills or implants for at least one month prior to the start of the
study drug and continuing for 5 months after the last dose of study drug.
Investigators shall counsel patients of childbearing potential on the importance of
pregnancy prevention and the implications of an unexpected pregnancy
- STEP 2 RANDOMIZATION: Patient registration must not exceed 12 weeks from time of
esophagectomy
- STEP 2 RANDOMIZATION: Patients must have a post-operative ECOG performance status of
0-2
- STEP 2 RANDOMIZATION: Absolute neutrophil count >= 1,500/mcL (within less than or
equal to 14 days prior to randomization)
- STEP 2 RANDOMIZATION: Platelets >= 100,000/mcL (within less than or equal to 14 days
prior to randomization)
- STEP 2 RANDOMIZATION: Total bilirubin =< institutional upper limit of normal (ULN)
(within less than or equal to 14 days prior to randomization)
- STEP 2 RANDOMIZATION: AST (SGOT)/ ALT (SGPT) =< 2.5 x institutional ULN (within less
than or equal to 14 days prior to randomization)
- STEP 2 RANDOMIZATION: Serum creatinine =< 1.5 x institutional ULN (within less than
or equal to 14 days prior to randomization)
- STEP 2 RANDOMIZATION: Patients must be disease free following esophagectomy as is
demonstrated by having no evidence of disease on a post-surgical CT scan. Patients
must also have a negative surgical margin (R0 resection)
- STEP 2 RANDOMIZATION: 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 RANDOMIZATION: 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 RANDOMIZATION: Patients must not be receiving any other investigational
agents
- STEP 2 RANDOMIZATION: 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 RANDOMIZATION: Patients must not be pregnant or breast-feeding due to
potential harm to an unborn fetus and possible risks for adverse events in nursing
infants from nivolumab or ipilimumab
- All patients 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 randomization 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 RANDOMIZATION: Patients of childbearing potential must not expect to conceive
children by either abstaining from sexual intercourse for the duration of their
participation in the study or by agreeing to use both double barrier contraception
and birth control pills or implants for at least one month prior to the start of the
study drug and continuing for 5 months after the last dose of study drug.
Investigators shall counsel patients of childbearing potential on the importance of
pregnancy prevention and the implications of an unexpected pregnancy
Study Design
- Phase
- Phase 2/Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Arm A (carboplatin, paclitaxel, radiation therapy) |
Patients receive carboplatin IV and paclitaxel IV once weekly and undergo radiation therapy QD (Monday-Friday) beginning on day 1 of each cycle. Cycles repeat every week for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or PET scan during screening and follow-up and undergo collection of blood samples throughout the trial. |
|
|
Experimental Arm B (carboplatin, paclitaxel, radiation therapy, nivolumab) |
Patients receive carboplatin, paclitaxel, and radiation therapy as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every week for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or PET scan during screening and follow-up and undergo collection of blood samples throughout the trial. |
|
|
Experimental Arm C (nivolumab) |
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 4 weeks for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan and collection of blood samples throughout the trial. |
|
|
Experimental Arm D (nivolumab, ipilimumab) |
Patients receive nivolumab as in Arm C and receive ipilimumab IV over 90 minutes on day 1 of cycles 1 and 4 and day 15 of cycles 2 and 5. Treatment repeats every 4 weeks for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan and collection of blood samples throughout the trial. |
|
More Details
- Status
- Suspended
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed Description
PRIMARY OBJECTIVES: I. To assess the pathologic complete response (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. 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 (QD) (Monday-Friday) beginning on day 1 of each cycle. Cycles repeat every week for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) or positron emission tomography (PET) scan during screening and follow-up and undergo collection of blood samples throughout the trial. 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 of each cycle. Cycles repeat every week for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or PET scan during screening and follow-up and undergo collection of blood samples throughout the trial. 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 of each cycle. Treatment repeats every 4 weeks for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan and collection of blood samples throughout the trial. ARM D: Patients receive nivolumab as in Arm C and receive ipilimumab IV over 90 minutes on day 1 of cycles 1 and 4 and day 15 of cycles 2 and 5. Treatment repeats every 4 weeks for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan and collection of blood samples throughout the trial. 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.