<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03776487</url>
  </required_header>
  <id_info>
    <org_study_id>2018-0012</org_study_id>
    <secondary_id>NCI-2018-02344</secondary_id>
    <secondary_id>2018-0012</secondary_id>
    <nct_id>NCT03776487</nct_id>
  </id_info>
  <brief_title>Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer</brief_title>
  <official_title>Pilot Study of Dual Checkpoint Inhibition Followed by Immuno-Chemoradiation in Patients With Resectable Gastric Adenocarcinoma (Concept ID 2016-NIV-0551)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>M.D. Anderson Cancer Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot phase I/II trial studies the side effects and how well nivolumab and ipilimumab in&#xD;
      combination with chemotherapy and radiation therapy work in treating patients with gastric&#xD;
      cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as&#xD;
      nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may&#xD;
      interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy,&#xD;
      such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor&#xD;
      cells, either by killing the cells, by stopping them from dividing, or by stopping them from&#xD;
      spreading. Intensity-modulated radiation therapy uses thin beams of radiation of different&#xD;
      strengths aimed at the tumor from many angles. This type of radiation therapy may reduce the&#xD;
      damage to healthy tissue near the tumor. Giving nivolumab, ipilimumab, chemotherapy and&#xD;
      radiation therapy may work better in treating patients with gastric cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the safety and toxicity profile of intravenous nivolumab in combination with&#xD;
      ipilimumab after standard chemotherapy and followed by intravenous nivolumab in combination&#xD;
      with fluoropyrimidine and intensity-modulated radiation therapy (IMRT) for the treatment of&#xD;
      localized gastroesophageal junction (GEJ) and/or gastric cancer.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the efficacy of double checkpoint inhibition (nivolumab + ipilimumab) followed&#xD;
      by nivolumab plus chemoradiation.&#xD;
&#xD;
      II. To assess the overall safety and tolerability of adjuvant nivolumab in subjects with&#xD;
      resected GEJ or gastric cancer.&#xD;
&#xD;
      III. To evaluate disease free survival (DFS).&#xD;
&#xD;
      IV. To explore changes in tumor stroma profile before and after immunotherapy and radiation&#xD;
      therapy.&#xD;
&#xD;
      V. To bank tumor and blood specimen for future correlative analysis, including, but not&#xD;
      limited to, biomarker analysis.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours and&#xD;
      fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses&#xD;
      in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.&#xD;
      Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease&#xD;
      progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil&#xD;
      IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients&#xD;
      undergo surgical resection 5-7 weeks after completing radiation therapy.&#xD;
&#xD;
      Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over&#xD;
      30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4&#xD;
      weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 and 84 days, every 12&#xD;
      weeks for 2 years, then every 6-12 months for up to 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 7, 2019</start_date>
  <completion_date type="Anticipated">September 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 30 days</time_frame>
    <description>The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rates</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Response rates will be estimated along with the corresponding exact 95% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events in patients with resected gastroesophageal junction (GEJ) or gastric cancer</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival</measure>
    <time_frame>From the date of surgery until disease relapse or death, whichever occurred first, assessed up to 5 years</time_frame>
    <description>Will be estimated using the method of Kaplan and Meier.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Clinical Stage 0 Gastric Cancer AJCC v8</condition>
  <condition>Clinical Stage 0 Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage I Gastric Cancer AJCC v8</condition>
  <condition>Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIB Gastric Cancer AJCC v8</condition>
  <condition>Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IVA Gastric Cancer AJCC v8</condition>
  <condition>Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Gastric Adenocarcinoma</condition>
  <condition>Localized Gastric Carcinoma</condition>
  <condition>Localized Gastroesophageal Junction Adenocarcinoma</condition>
  <condition>Pathologic Stage 0 Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage 0 Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage I Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage IA Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage IA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IB Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIA Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIB Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Gastric Cancer AJCC v8</condition>
  <condition>Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <arm_group>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.&#xD;
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy.&#xD;
Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fluorouracil</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
    <other_name>5-Fluoro-2,4(1H, 3H)-pyrimidinedione</other_name>
    <other_name>5-Fluorouracil</other_name>
    <other_name>5-Fluracil</other_name>
    <other_name>5-FU</other_name>
    <other_name>AccuSite</other_name>
    <other_name>Carac</other_name>
    <other_name>Fluoro Uracil</other_name>
    <other_name>Fluouracil</other_name>
    <other_name>Flurablastin</other_name>
    <other_name>Fluracedyl</other_name>
    <other_name>Fluracil</other_name>
    <other_name>Fluril</other_name>
    <other_name>Fluroblastin</other_name>
    <other_name>Ribofluor</other_name>
    <other_name>Ro 2-9757</other_name>
    <other_name>Ro-2-9757</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Intensity-Modulated Radiation Therapy</intervention_name>
    <description>Undergo IMRT</description>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
    <other_name>IMRT</other_name>
    <other_name>Intensity Modulated RT</other_name>
    <other_name>Intensity-Modulated Radiotherapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
    <other_name>Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody</other_name>
    <other_name>BMS-734016</other_name>
    <other_name>MDX-010</other_name>
    <other_name>MDX-CTLA4</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
    <other_name>1-OHP</other_name>
    <other_name>Ai Heng</other_name>
    <other_name>Aiheng</other_name>
    <other_name>Dacotin</other_name>
    <other_name>Dacplat</other_name>
    <other_name>Diaminocyclohexane Oxalatoplatinum</other_name>
    <other_name>Eloxatin</other_name>
    <other_name>Eloxatine</other_name>
    <other_name>JM-83</other_name>
    <other_name>Oxalatoplatin</other_name>
    <other_name>Oxalatoplatinum</other_name>
    <other_name>RP 54780</other_name>
    <other_name>RP-54780</other_name>
    <other_name>SR-96669</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Therapeutic Conventional Surgery</intervention_name>
    <description>Undergo partial or total gastrectomy and lymphadenectomy</description>
    <arm_group_label>Treatment (chemotherapy, immunotherapy, IMRT)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have signed and dated an Institutional Review Board (IRB)/Independent&#xD;
             Ethics Committee (IEC) approved written informed consent form in accordance with&#xD;
             regulatory and institutional guidelines. This must be obtained before the performance&#xD;
             of any protocol-related procedures that are not part of normal subject care. Subjects&#xD;
             must be willing and able to comply with scheduled visits, treatment schedule,&#xD;
             laboratory tests and other requirements of the study.&#xD;
&#xD;
          -  All subjects must have localized/eligible for surgery gastric cancer (GC) or GEJ&#xD;
             carcinoma type III, with negative peritoneal washing. Subjects must have&#xD;
             histologically confirmed predominant adenocarcinoma. The documentation of GEJ&#xD;
             involvement can include biopsy, endoscopy, or imaging.&#xD;
&#xD;
          -  Subject must be previously untreated with systemic treatment (including HER 2&#xD;
             inhibitors) given as primary therapy for advanced or metastatic disease. No prior&#xD;
             neoadjuvant chemotherapy, immunotherapy, radiotherapy and/or chemoradiotherapy are&#xD;
             permitted.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,500/mcL (within 28 days of treatment initiation).&#xD;
&#xD;
          -  Platelets &gt;=100,000/mcL (within 28 days of treatment initiation).&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL or &gt; 5.6 mmol/L; if patient is not actively bleeding and has&#xD;
             hemoglobin of &lt; 9g/dL, patient can receive blood transfusion to increase hemoglobin to&#xD;
             &gt;= 9g/dL (within 28 days of treatment initiation).&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 X upper limit of normal (ULN) OR measured or calculated&#xD;
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of&#xD;
             creatinine or creatinine clearance [CrCL]) &gt; 60 mL/min for subjects with creatinine&#xD;
             levels &gt; 1.5 x institutional ULN (measured via 24-hour urine collection) (within 28&#xD;
             days of treatment initiation). Creatinine clearance should be calculated per&#xD;
             institutional standard.&#xD;
&#xD;
          -  Serum total bilirubin =&lt; 1.5 X ULN (1.5 mg/dL or 25.65 umol/L) OR direct bilirubin &lt;&#xD;
             ULN for subjects with total bilirubin levels &lt; 1.5 X ULN. Except patients with&#xD;
             Gilbert's disease (&lt; 3 X ULN) (within 28 days of treatment initiation).&#xD;
&#xD;
          -  Aspartate aminotransferase AST (serum glutamic oxaloacetic transaminase [SGOT]) and&#xD;
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2.5 X&#xD;
             ULN OR &lt; 5 X ULN for subjects with liver metastases (within 28 days of treatment&#xD;
             initiation).&#xD;
&#xD;
          -  Albumin &gt;= 3 mg/dL (within 28 days of treatment initiation).&#xD;
&#xD;
          -  Prothrombin Time (PT) &lt; 1.5 X ULN unless subject is receiving anticoagulant therapy as&#xD;
             long as PT or partial thromboplastin time PTT is within therapeutic range of intended&#xD;
             use of anticoagulants. Activated partial thromboplastin Time (aPTT) &lt; 1.5 X ULN unless&#xD;
             subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic&#xD;
             range of intended use of anticoagulants (within 28 days of treatment initiation).&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy&#xD;
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin&#xD;
             [HCG]) within 24 hours prior to the start of study drug. Women must not be&#xD;
             breastfeeding.&#xD;
&#xD;
          -  Prior to chemotherapy and immunotherapy, WOCBP must agree to follow instructions for&#xD;
             method(s) of contraception for the duration of study treatment with nivolumab and 5&#xD;
             months after the last dose of study treatment (i.e. 30 days (duration of ovulatory&#xD;
             cycle plus the time required for the investigational drug to undergo approximately&#xD;
             five half-lives).&#xD;
&#xD;
          -  Males who are sexually active with WOCBP must agree to follow instructions for methods&#xD;
             of contraception for the duration of study treatment with nivolumab and 7 months after&#xD;
             the last dose of study treatment (i.e. 90 days (duration of sperm turnover) plus the&#xD;
             time required for the investigational drug to undergo approximately five half-lives).&#xD;
             In addition, male subjects must be willing to refrain from sperm donation during this&#xD;
             time.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants with an active, known or suspected autoimmune disease. Participants with&#xD;
             type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin&#xD;
             disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment,&#xD;
             or conditions not expected to recur in the absence of an external trigger are&#xD;
             permitted to enroll.&#xD;
&#xD;
          -  Participants with a condition requiring systemic treatment with either corticosteroids&#xD;
             (&gt; 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14&#xD;
             days of study treatment. Inhaled or topical steroids, and adrenal replacement steroid&#xD;
             doses &gt; 10 mg daily prednisone equivalent, are permitted in the absence of active&#xD;
             autoimmune disease.&#xD;
&#xD;
          -  Known history of positive test for human immunodeficiency virus (HIV) or known&#xD;
             acquired immunodeficiency syndrome (AIDS).&#xD;
&#xD;
               -  NOTE: Testing for HIV must be performed at sites where mandated locally.&#xD;
&#xD;
          -  White blood cell (WBC) &lt; 2000/uL.&#xD;
&#xD;
          -  Any positive test result for hepatitis B virus or hepatitis C virus indicating&#xD;
             presence of virus, e.g. hepatitis B surface antigen (HBsAg Australia antigen)&#xD;
             positive, or hepatitis C antibody (anti-HCV) positive (except if hepatitis C virus-&#xD;
             ribonucleic acid [HCV-RNA] negative).&#xD;
&#xD;
          -  History of allergy or hypersensitivity to study drug components.&#xD;
&#xD;
          -  Prior malignancy active within the previous 3 years except for locally curable cancers&#xD;
             that have been apparently cured, such as basal or squamous cell skin cancer,&#xD;
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.&#xD;
&#xD;
          -  Patients with serious or uncontrolled medical disorders.&#xD;
&#xD;
          -  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or&#xD;
             any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint&#xD;
             pathways.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mariela Blum</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>MD Anderson Cancer Center Website</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>September 7, 2023</last_update_submitted>
  <last_update_submitted_qc>September 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</mesh_term>
    <mesh_term>Stomach Neoplasms</mesh_term>
    <mesh_term>Esophageal Neoplasms</mesh_term>
    <mesh_term>Carcinoma in Situ</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03776487
org study id: 2018-0012
secondary id: NCI-2018-02344
secondary id: 2018-0012
nct id: NCT03776487
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This pilot phase I/II trial studies the side effects and how well nivolumab and ipilimumab in
      combination with chemotherapy and radiation therapy work in treating patients with gastric
      cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as
      nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may
      interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy,
      such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor
      cells, either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Intensity-modulated radiation therapy uses thin beams of radiation of different
      strengths aimed at the tumor from many angles. This type of radiation therapy may reduce the
      damage to healthy tissue near the tumor. Giving nivolumab, ipilimumab, chemotherapy and
      radiation therapy may work better in treating patients with gastric cancer.
PRIMARY OBJECTIVES:

      I. To evaluate the safety and toxicity profile of intravenous nivolumab in combination with
      ipilimumab after standard chemotherapy and followed by intravenous nivolumab in combination
      with fluoropyrimidine and intensity-modulated radiation therapy (IMRT) for the treatment of
      localized gastroesophageal junction (GEJ) and/or gastric cancer.

      SECONDARY OBJECTIVES:

      I. To assess the efficacy of double checkpoint inhibition (nivolumab + ipilimumab) followed
      by nivolumab plus chemoradiation.

      II. To assess the overall safety and tolerability of adjuvant nivolumab in subjects with
      resected GEJ or gastric cancer.

      III. To evaluate disease free survival (DFS).

      IV. To explore changes in tumor stroma profile before and after immunotherapy and radiation
      therapy.

      V. To bank tumor and blood specimen for future correlative analysis, including, but not
      limited to, biomarker analysis.

      OUTLINE:

      INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours and
      fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses
      in the absence of disease progression or unacceptable toxicity.

      Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.
      Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease
      progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil
      IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients
      undergo surgical resection 5-7 weeks after completing radiation therapy.

      Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over
      30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4
      weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 84 days, every 12
      weeks for 2 years, then every 6-12 months for up to 3 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events
time frame: Up to 30 days
description: The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately.
measure: Response rates
time frame: Up to 5 years
description: Response rates will be estimated along with the corresponding exact 95% confidence interval.
measure: Incidence of adverse events in patients with resected gastroesophageal junction (GEJ) or gastric cancer
time frame: Up to 5 years
description: The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately.
measure: Disease-free survival
time frame: From the date of surgery until disease relapse or death, whichever occurred first, assessed up to 5 years
description: Will be estimated using the method of Kaplan and Meier.
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
arm group type: Experimental
description: INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy.
Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Fluorouracil
description: Given IV
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
other name: 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
other name: 5-Fluorouracil
other name: 5-Fluracil
other name: 5-FU
other name: AccuSite
other name: Carac
other name: Fluoro Uracil
other name: Fluouracil
other name: Flurablastin
other name: Fluracedyl
other name: Fluracil
other name: Fluril
other name: Fluroblastin
other name: Ribofluor
other name: Ro 2-9757
other name: Ro-2-9757
intervention type: Radiation
intervention name: Intensity-Modulated Radiation Therapy
description: Undergo IMRT
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
other name: IMRT
other name: Intensity Modulated RT
other name: Intensity-Modulated Radiotherapy
intervention type: Biological
intervention name: Ipilimumab
description: Given IV
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
other name: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
other name: BMS-734016
other name: MDX-010
other name: MDX-CTLA4
other name: Yervoy
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
other name: BMS-936558
other name: MDX-1106
other name: NIVO
other name: ONO-4538
other name: Opdivo
intervention type: Drug
intervention name: Oxaliplatin
description: Given IV
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
other name: 1-OHP
other name: Ai Heng
other name: Aiheng
other name: Dacotin
other name: Dacplat
other name: Diaminocyclohexane Oxalatoplatinum
other name: Eloxatin
other name: Eloxatine
other name: JM-83
other name: Oxalatoplatin
other name: Oxalatoplatinum
other name: RP 54780
other name: RP-54780
other name: SR-96669
intervention type: Procedure
intervention name: Therapeutic Conventional Surgery
description: Undergo partial or total gastrectomy and lymphadenectomy
arm group label: Treatment (chemotherapy, immunotherapy, IMRT)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mariela Blum
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
country: United States
url: http://www.mdanderson.org
description: MD Anderson Cancer Center Website
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Stomach Neoplasms
mesh term: Esophageal Neoplasms
mesh term: Carcinoma in Situ
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Nivolumab
mesh term: Ipilimumab