Clinical Trials /

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

NCT03604991

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Ipilimumab in Treating Patients With Esophageal and Gastroesophageal Junction Adenocarcinoma Undergoing Surgery
  • Official Title: A Phase II/III Study of Peri-Operative Nivolumab and Ipilimumab in Patients With Locoregional Esophageal and Gastroesophageal Junction Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01575
  • SECONDARY ID: NCI-2018-01575
  • SECONDARY ID: EA2174
  • SECONDARY ID: EA2174
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT03604991

Conditions

  • 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

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (carboplatin, paclitaxel, radiation therapy)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm D (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm B (carboplatin, paclitaxel, radiation therapy, nivolumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (carboplatin, paclitaxel, radiation therapy)

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (carboplatin, paclitaxel, radiation therapy)ExperimentalPatients 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.
  • Carboplatin
  • Paclitaxel
Arm B (carboplatin, paclitaxel, radiation therapy, nivolumab)ExperimentalPatients 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.
  • Carboplatin
  • Nivolumab
  • Paclitaxel
Arm C (nivolumab)ExperimentalPatients 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.
  • Nivolumab
Arm D (nivolumab, ipilimumab)ExperimentalPatients 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.
  • Ipilimumab
  • Nivolumab

Eligibility 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: 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 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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response (Step I)
Time Frame:Up to 5 weeks
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 7 years
Safety Issue:
Description: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
Measure:Overall survival
Time Frame:From the time of first randomization up to 7 years
Safety Issue:
Description:Analyses will be descriptive in nature and will not follow any formal interim monitoring.
Measure:DFS
Time Frame:From the time of first randomization up to 7 years
Safety Issue:
Description: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.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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