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Nivolumab and Ipilimumab in Treating Patients With Esophageal and Gastroesophageal Junction Adenocarcinoma Undergoing Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03604991
Recruitment Status : Recruiting
First Posted : July 30, 2018
Last Update Posted : January 15, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Clinical Stage II Esophageal Adenocarcinoma AJCC v8 Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8 Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8 Clinical Stage IIB 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 Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage II Esophageal Adenocarcinoma AJCC v8 Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage III Esophageal Adenocarcinoma AJCC v8 Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8 Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Drug: Carboplatin Biological: Ipilimumab Biological: Nivolumab Drug: Paclitaxel Radiation: Radiation Therapy Phase 2 Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 278 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II/III Study of Peri-Operative Nivolumab and Ipilimumab in Patients With Locoregional Esophageal and Gastroesophageal Junction Adenocarcinoma
Actual Study Start Date : January 17, 2019
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm A (carboplatin, paclitaxel, radiation therapy)
Patients receive carboplatin 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.
 Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
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. Cycles repeat every week for up to 5 weeks in the absence of disease progression or unacceptable toxicity.
 Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
Experimental: Arm C (nivolumab)
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.
 Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
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, 4, 7, and 10. Treatment repeats every 2 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
 Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo


Outcome Measures
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Primary Outcome Measures :
  1. Pathologic complete response (Step I) [ Time Frame: Up to 5 weeks ]
    The study with compare the pathologic complete response of Arm A and Arm B using a one-sided 0.10 level chi-squared test for proportions.

  2. Disease-free survival (DFS) (Step 2) [ Time Frame: From the adjuvant treatment randomization assessed for up to 7 years ]
    DFS measured from the adjuvant treatment randomization will be the endpoint of the adjuvant portion of the study and to achieve the desired power it is expected that patients will be followed for an additional year post completion of accrual to the adjuvant portion. The DFS comparison will be between patients randomized to Arm C (nivolumab) versus Arm D (nivolumab plus ipilimumab) using a one-sided 0.10 level stratified log rank test.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 7 years ]
    Graded according to Common Terminology Criteria for Adverse Events version 5.0. Toxicity will be evaluated among all treated patients regardless of eligibility and interim analyses of toxicity are performed twice yearly. The study will have sufficient precision to provide 95% confidence intervals on toxicity

  2. Overall survival [ Time Frame: From the time of first randomization up to 7 years ]
    Analyses will be descriptive in nature and will not follow any formal interim monitoring.

  3. DFS [ Time Frame: From the time of first randomization up to 7 years ]
    The DFS comparison will be between patients randomized to Arm C (nivolumab) versus Arm D (nivolumab plus ipilimumab) using a one-sided 0.10 level stratified log rank test.


Other Outcome Measures:
  1. Percent change in mean volumetric apparent diffusion coefficient (ADC) [ Time Frame: Baseline to mid-treatment ]
    The study will assess the area under the receiver operating characteristic curve of the changes of ADC value.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03604991


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jennifer R Eads ECOG-ACRIN Cancer Research Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03604991    
Other Study ID Numbers: NCI-2018-01575
NCI-2018-01575 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA2174 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA2174 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: July 30, 2018    Key Record Dates
Last Update Posted: January 15, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
 Paclitaxel
Carboplatin
Nivolumab
Albumin-Bound Paclitaxel
Ipilimumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological