Nivolumab and Ipilimumab in Treating Patients With Esophageal and Gastroesophageal Junction Adenocarcinoma Undergoing Surgery
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| ClinicalTrials.gov Identifier: NCT03604991 |
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Recruitment Status :
Suspended
(End of Initial Phase of Multi-phase protocol)
First Posted : July 30, 2018
Last Update Posted : January 31, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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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 IIB Esophageal 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 | Drug: Carboplatin Procedure: Computed Tomography Biological: Ipilimumab Biological: Nivolumab Drug: Paclitaxel Procedure: Positron Emission Tomography Radiation: Radiation Therapy | Phase 2 Phase 3 |
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| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 514 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
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Carboplatin
Given IV
Other Names:
Procedure: Computed Tomography Undergo CT scan
Other Names:
Drug: Paclitaxel Given IV
Other Names:
Procedure: Positron Emission Tomography Undergo PET scan
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
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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.
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Drug: Carboplatin
Given IV
Other Names:
Procedure: Computed Tomography Undergo CT scan
Other Names:
Biological: Nivolumab Given IV
Other Names:
Drug: Paclitaxel Given IV
Other Names:
Procedure: Positron Emission Tomography Undergo PET scan
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
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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 during screening, on study, and during follow-up.
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Procedure: Computed Tomography
Undergo CT scan
Other Names:
Biological: Nivolumab Given IV
Other Names:
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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 during screening, on study, and during follow-up.
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Procedure: Computed Tomography
Undergo CT scan
Other Names:
Biological: Ipilimumab Given IV
Other Names:
Biological: Nivolumab Given IV
Other Names:
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Primary Outcome Measures :
- 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.
- 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 :
- 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
- 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.
- 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:
- 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.
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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 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 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 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: 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 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 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)
Exclusion Criteria:
- 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 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
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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 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 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
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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 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
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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
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
Show 494 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Jennifer R Eads | ECOG-ACRIN Cancer Research Group |
| 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 31, 2023 |
| Last Verified: | January 2023 |
| 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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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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 Immune Checkpoint Inhibitors |