<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/NCT03784326</url>
  </required_header>
  <id_info>
    <org_study_id>2018-0678</org_study_id>
    <secondary_id>NCI-2018-02828</secondary_id>
    <secondary_id>2018-0678</secondary_id>
    <nct_id>NCT03784326</nct_id>
  </id_info>
  <brief_title>Phase I/II Study of Perioperative Chemotherapy Plus Immunotherapy Followed by Surgery in Localized Esophageal and Gastroesophageal Adenocarcinoma</brief_title>
  <official_title>Phase I/II Study of Perioperative Chemotherapy Plus Immunotherapy Followed by Surgery in Localized Esophageal and Gastroesophageal Adenocarcinoma</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      To learn if atezolizumab in combination with oxaliplatin and 5-fluorouracil (5-FU), when&#xD;
      given before surgery, can help to control esophageal and/or gastroesophageal cancer. To learn&#xD;
      if adding tiragolumab to the above drug combination can help to control the disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Objectives:&#xD;
&#xD;
        -  Atezolizumab +/- tiragolumab in combination with oxaliplatin and 5-fluorouracil&#xD;
           (modified FOLFOX) therapy in the neoadjuvant setting will achieve a pathological&#xD;
           complete response of approximately 20% in patients with localized esophageal and&#xD;
           gastroesophageal (GEJ) adenocarcinoma.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        -  To evaluate safety and toxicity profile of intravenous Atezolizumab +/- Tiragolumab in&#xD;
           combination with Oxaliplatin and 5-FU chemotherapy as neoadjuvant treatment for&#xD;
           resectable esophageal or GEJ adenocarcinoma.&#xD;
&#xD;
        -  To assess the efficacy of the combination by tumor regression grade scoring in the&#xD;
           surgical specimen.&#xD;
&#xD;
        -  To assess the overall safety and tolerability of adjuvant Atezolizumab +/- Tiragolumab&#xD;
           in subjects with resected esophageal and GEJ cancer&#xD;
&#xD;
        -  To evaluate disease free survival (DFS) and overall survival (OS) in cohort 1 and cohort&#xD;
           2&#xD;
&#xD;
        -  To explore changes in tumor stroma profile before and after immunotherapy in combination&#xD;
           with chemotherapy&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 19, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pathological complete response (PathCR)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The optimum two-stage design proposed by Simon will be implemented. The PathCR rate will be estimated along with the exact 95% confidence interval.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival (DFS)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The Kaplan-Meier method will be used to estimate the probabilities of DFS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The Kaplan-Meier method will be used to estimate the probabilities of OS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in tumor stroma profile after treatment</measure>
    <time_frame>Baseline up to 3 years</time_frame>
    <description>The changes in tumor stroma profile after treatment assessed through paired t-tests or Wilcoxon signed rank tests if normality assumption is not satisfied.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicities defined as any treatment-related grade 3 or greater non-hematologic adverse events (AEs) determined by CTCAE version v 4.03.</measure>
    <time_frame>From the start of study treatment up to 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor regression determined by CT or MRI</measure>
    <time_frame>Baseline up to 3 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Clinical Stage II Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage III Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage II Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage III Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8</condition>
  <arm_group>
    <arm_group_label>Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The combination of Atezolizumab with Oxaliplatin and 5-Fluorouracil IV on Days 1 and 15 of each 28-day cycle for total of 6 doses followed by surgery followed by Atezolizumab on Day 1 of each 21-day cycle for total of 24 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The combination of Atezolizumab + Tiragolumab with Oxaliplatin and 5-Flourouracil IV on Days 1 and 15 of each 28-day cycle for total of 6 doses followed by surgery followed by Atezolizumab + Tiragolumab on Day 1 of each 21-day cycle for a total of 48 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Given IV (vein)</description>
    <arm_group_label>Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <arm_group_label>Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <other_name>MPDL 3280A</other_name>
    <other_name>MPDL 328OA</other_name>
    <other_name>MPDL-3280A</other_name>
    <other_name>MPDL3280A</other_name>
    <other_name>MPDL328OA</other_name>
    <other_name>RG7446</other_name>
    <other_name>RO5541267</other_name>
    <other_name>Tecentriq</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Conventional Surgery</intervention_name>
    <description>Undergo surgical resection</description>
    <arm_group_label>Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <arm_group_label>Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fluorouracil</intervention_name>
    <description>Given IV (vein)</description>
    <arm_group_label>Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <arm_group_label>Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)</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>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Given IV (vein)</description>
    <arm_group_label>Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
    <arm_group_label>Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)</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>Drug</intervention_type>
    <intervention_name>Tiragolumab</intervention_name>
    <description>Given IV (vein)</description>
    <arm_group_label>Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria (cohort 1 and cohort 2)&#xD;
&#xD;
          -  Signed Informed Consent Form&#xD;
&#xD;
          -  Age 18 years at time of signing Informed Consent Form&#xD;
&#xD;
          -  Ability to comply with the study protocol, in the investigator's judgment&#xD;
&#xD;
          -  Histologically or cytologically confirmed esophageal or gastroesophageal type I or II&#xD;
             adenocarcinoma&#xD;
&#xD;
          -  No prior therapy including chemotherapy or radiation therapy.&#xD;
&#xD;
          -  Patients with T1N1, and T2-3 with any N will be eligible.&#xD;
&#xD;
          -  ECOG Performance Status of 0-1&#xD;
&#xD;
          -  Adequate hematologic and end-organ function, defined by the following laboratory test&#xD;
             results, obtained within 14 days prior to initiation of study treatment:&#xD;
&#xD;
               -  ANC 1.5 109/L (1500/L) without granulocyte colony-stimulating factor support&#xD;
&#xD;
               -  Lymphocyte count 0.5 109/L (500/L)&#xD;
&#xD;
               -  Platelet count 100 109/L (100,000/L) without transfusion&#xD;
&#xD;
               -  Hemoglobin 90 g/L (9 g/dL) Patients may be transfused to meet this criterion.&#xD;
&#xD;
               -  AST, ALT, and alkaline phosphatase (ALP) 2.5 upper limit of normal (ULN)&#xD;
&#xD;
               -  Serum bilirubin 1.5 ULN with the following exception:&#xD;
&#xD;
        Patients with known Gilbert disease: serum bilirubin level 3 ULN&#xD;
&#xD;
          -  Serum creatinine 1.5 ULN [or] Creatinine clearance 70 mL/min (calculated using the&#xD;
             Cockcroft-Gault formula)}&#xD;
&#xD;
          -  Serum albumin 25 g/L (2.5 g/dL)&#xD;
&#xD;
          -  For patients not receiving therapeutic anticoagulation: INR and aPTT 1.5 ULN&#xD;
&#xD;
               -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen&#xD;
&#xD;
               -  Medically fit for surgery based on surgeon's assessment.SAE&#xD;
&#xD;
               -  No supraclavicular, or para-aortic nodal enlargement unless biopsy negative.&#xD;
&#xD;
               -  Male or Female but both sexes must practice adequate contraception while on&#xD;
                  therapy. (please see required contraception below)&#xD;
&#xD;
               -  Women of childbearing potential (WOCBP) must have a negative serum or urine&#xD;
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at&#xD;
                  screening, within 14 days prior to initiation of study treatment. Women must not&#xD;
                  be breastfeeding.&#xD;
&#xD;
               -  Availability of a representative tumor specimen that is suitable for&#xD;
                  determination of PDL-1 testing at MDA.&#xD;
&#xD;
        A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or&#xD;
        at least 10 slides containing unstained, freshly cut, serial sections should be submitted&#xD;
        along with an associated pathology report prior to study enrollment. If &lt;10 slides are&#xD;
        available, the patient may still be eligible for the study, after principal investigator&#xD;
        approval has been obtained. For Cohort 1: If archival tumor tissue is unavailable or is&#xD;
        determined to be unsuitable for required testing, tumor tissue must be obtained from a&#xD;
        biopsy performed at screening. Refer to Section 4.5.6 for additional information on tumor&#xD;
        specimens collected at screening.&#xD;
&#xD;
        Options for female contraception&#xD;
&#xD;
        For women of childbearing potential: agreement to remain abstinent (refrain from&#xD;
        heterosexual intercourse) or use contraceptive, and agreement to refrain from donating&#xD;
        eggs, as defined below:&#xD;
&#xD;
        Women must remain abstinent or use contraceptive methods with a failure rate of 1% per year&#xD;
        during the treatment period and for 5 months after the last dose of Atezolizumab, 90 days&#xD;
        after the final dose of Tiragolumab, 4-9 months after the final dose of oxaliplatin and 6&#xD;
        months after the final dose of 5-FU. Women must refrain from donating eggs during this same&#xD;
        period. A woman is considered to be of childbearing potential if she is postmenarcheal, has&#xD;
        not reached a postmenopausal state ( 12 continuous months of amenorrhea with no identified&#xD;
        cause other than menopause), and has not undergone surgical sterilization (removal of&#xD;
        ovaries and/or uterus).&#xD;
&#xD;
        Examples of contraceptive methods with a failure rate of 1% per year include bilateral&#xD;
        tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation,&#xD;
        hormone-releasing intrauterine devices, and copper intrauterine devices.&#xD;
&#xD;
        Hormonal contraceptive methods must be supplemented by a barrier method. The reliability of&#xD;
        sexual abstinence should be evaluated in relation to the duration of the clinical trial and&#xD;
        the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar,&#xD;
        ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable&#xD;
        methods of contraception.&#xD;
&#xD;
        Options for contraception in male patients with pregnant female partners and/or with female&#xD;
        partners of childbearing potential. &quot;Recommendations related to contraception and pregnancy&#xD;
        testing in clinical trials&quot; and the Roche White Paper regarding contraception for males in&#xD;
        clinical trials. Atezolizumab +/- Tiragolumab does require male contraception or condom&#xD;
        use; guidelines below apply to other protocol-mandated study treatments.&#xD;
&#xD;
        • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a&#xD;
        condom, and agreement to refrain from donating sperm, as defined below: With female&#xD;
        partners of childbearing potential or pregnant female partners, men must remain abstinent&#xD;
        or use a condom plus an additional contraceptive method that together result in a failure&#xD;
        rate of 1% per year during the treatment period and for for 90 days after the final dose of&#xD;
        tiragolumab, 6 months after the final dose of oxaliplatin and 5-FU to avoid exposing the&#xD;
        embryo. Men must refrain from donating sperm during this same period.&#xD;
&#xD;
        The reliability of sexual abstinence should be evaluated in relation to the duration of the&#xD;
        clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence&#xD;
        (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not&#xD;
        acceptable methods of contraception.&#xD;
&#xD;
        Exclusion Criteria (cohort 1 and cohort 2)&#xD;
&#xD;
          -  Patients with T1aN0, T4b, or metastatic cancer will be excluded.&#xD;
&#xD;
          -  Squamous cell carcinoma histology&#xD;
&#xD;
          -  Invasion into nearby organs (T4b) with or increased risk for fistula&#xD;
&#xD;
          -  Significant comorbid conditions (defined as uncontrolled diabetes, active angina or&#xD;
             heart failure, uncontrolled hypertension (&gt;160 mmHg systolic or ≥100 mmHg diastolic)&#xD;
             or increased risk of prolonged QTc (QTc &gt; 500 ms), or active psychiatric condition&#xD;
             that prevents consistent participation and compliance).&#xD;
&#xD;
          -  More than grade 1 neuropathy.&#xD;
&#xD;
          -  Unable to comprehend the requirements of the study or comply with it.&#xD;
&#xD;
          -  Active bleeding from primary tumor requiring radiation therapy.&#xD;
&#xD;
          -  History of leptomeningeal disease&#xD;
&#xD;
          -  Uncontrolled tumor-related pain Patients requiring pain medication must be on a stable&#xD;
             regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases&#xD;
             causing nerve impingement) amenable to palliative radiotherapy should be treated prior&#xD;
             to enrollment. Patients should be recovered from the effects of radiation. There is no&#xD;
             required minimum recovery period.&#xD;
&#xD;
        Asymptomatic metastatic lesions that would likely cause functional deficits or intractable&#xD;
        pain with further growth (e.g., epidural metastasis that is not currently associated with&#xD;
        spinal cord compression) should be considered for loco-regional therapy if appropriate&#xD;
        prior to enrollment.&#xD;
&#xD;
          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent&#xD;
             drainage procedures (once monthly or more frequently) Patients with indwelling&#xD;
             catheters (e.g., PleurX) are allowed.&#xD;
&#xD;
          -  Uncontrolled or symptomatic hypercalcemia ( 1.5 mmol/L ionized calcium or calcium 12&#xD;
             mg/dL or corrected serum calcium ULN)&#xD;
&#xD;
          -  Active or history of autoimmune disease or immune deficiency, including, but not&#xD;
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus&#xD;
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid&#xD;
             antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré&#xD;
             syndrome, or multiple sclerosis with the following exceptions:&#xD;
&#xD;
        Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement&#xD;
        hormone are eligible for the study.&#xD;
&#xD;
        Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are&#xD;
        eligible for the study.&#xD;
&#xD;
        Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic&#xD;
        manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for&#xD;
        the study provided all of following conditions are met:&#xD;
&#xD;
          -  Rash must cover 10% of body surface area&#xD;
&#xD;
          -  Disease is well controlled at baseline and requires only low-potency topical&#xD;
             corticosteroids&#xD;
&#xD;
          -  No occurrence of acute exacerbations of the underlying condition requiring psoralen&#xD;
             plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral&#xD;
             calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12&#xD;
             months&#xD;
&#xD;
               -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,&#xD;
                  bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,&#xD;
                  or evidence of active pneumonitis on screening chest computed tomography (CT)&#xD;
                  scan&#xD;
&#xD;
               -  Positive HIV test at screening&#xD;
&#xD;
               -  Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a&#xD;
                  positive hepatitis B surface antigen (HBsAg) test at screening Patients with a&#xD;
                  negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test&#xD;
                  at screening, , an HBV DNA test should be performe before determining if patient&#xD;
                  is eligible for the study. (63)&#xD;
&#xD;
               -  Active hepatitis C virus (HCV) infection, defined as having a positive HCV&#xD;
                  antibody test followed by a positive HCV RNA test at screening The HCV RNA test&#xD;
                  will be performed only for patients who have a positive HCV antibody test.&#xD;
&#xD;
               -  Active tuberculosis&#xD;
&#xD;
               -  Significant cardiovascular disease, such as New York Heart Association Class II&#xD;
                  or greater cardiac disease, myocardial infarction, or cerebrovascular accident&#xD;
                  within 3 months prior to initiation of study treatment, unstable arrhythmia, or&#xD;
                  unstable angina&#xD;
&#xD;
               -  Major surgical procedure other than for diagnosis within 4 weeks prior to&#xD;
                  initiation of study treatment, or anticipation of need for a major surgical&#xD;
                  procedure during the course of the study&#xD;
&#xD;
               -  History of other malignancy within 5 years prior to screening, with the exception&#xD;
                  of those with a negligible risk of metastasis or death (e.g., 5-year OS of 90%),&#xD;
                  such as adequately treated carcinoma in situ of the cervix, non-melanoma skin&#xD;
                  carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I&#xD;
                  uterine cancer&#xD;
&#xD;
               -  Severe infection within 4 weeks prior to initiation of study treatment,&#xD;
                  including, but not limited to, hospitalization for complications of infection,&#xD;
                  bacteremia, or severe pneumonia&#xD;
&#xD;
               -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to&#xD;
                  initiation of study treatment Patients receiving prophylactic antibiotics (e.g.,&#xD;
                  to prevent a urinary tract infection or chronic obstructive pulmonary disease&#xD;
                  exacerbation) are eligible for the study.&#xD;
&#xD;
               -  Any other disease, metabolic dysfunction, physical examination finding, or&#xD;
                  clinical laboratory finding that contraindicates the use of an investigational&#xD;
                  drug, may affect the interpretation of the results, or may render the patient at&#xD;
                  high risk from treatment complications&#xD;
&#xD;
               -  Prior allogeneic stem cell or solid organ transplantation&#xD;
&#xD;
               -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of&#xD;
                  study treatment, or anticipation of need for such a vaccine during study&#xD;
                  treatment, within 90 days after the final dose of tiragolumab, or within 5 months&#xD;
                  after the final dose of atezolizumab&#xD;
&#xD;
               -  Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM)&#xD;
                  test at screening An EBV PCR test should be performed as clinically indicated to&#xD;
                  screen for acute infection or suspected chronic active infection. Patients with a&#xD;
                  positive EBV PCR test are excluded.&#xD;
&#xD;
               -  Treatment with investigational therapy within 28 days prior to initiation of&#xD;
                  study treatment&#xD;
&#xD;
               -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies,&#xD;
                  including antiCTLA-4, anti PD-1, anti-TIGIT and anti PD-L1 therapeutic antibodies&#xD;
&#xD;
               -  Treatment with systemic immunostimulatory agents (including, but not limited to,&#xD;
                  interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the&#xD;
                  drug (whichever is longer) prior to initiation of study treatment&#xD;
&#xD;
               -  Treatment with systemic immunosuppressive medication (including, but not limited&#xD;
                  to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide,&#xD;
                  and antiTNF- agents) within 2 weeks prior to initiation of study treatment, or&#xD;
                  anticipation of need for systemic immunosuppressive medication during the course&#xD;
                  of the study, with the following exceptions:&#xD;
&#xD;
        Patients who received acute, low-dose systemic immunosuppressant medication or a one-time&#xD;
        pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for&#xD;
        a contrast allergy) are eligible for the study after Principal Investigator approval&#xD;
        Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for&#xD;
        chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for&#xD;
        orthostatic hypotension or adrenal insufficiency are eligible for the study.&#xD;
&#xD;
          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies&#xD;
             or fusion proteins&#xD;
&#xD;
          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of&#xD;
             the atezolizumab formulation&#xD;
&#xD;
          -  Known allergy or hypersensitivity to any component of the oxaliplatin or 5-FU&#xD;
             formulation&#xD;
&#xD;
          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within&#xD;
             5 months for atezolizumab+/- tiragolumab&#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>
  <overall_contact>
    <last_name>Mariela Blum</last_name>
    <phone>713-792-2828</phone>
    <email>mblum1@mdanderson.org</email>
  </overall_contact>
  <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>
    <status>Recruiting</status>
    <contact>
      <last_name>Mariela Blum</last_name>
      <phone>713-792-2828</phone>
    </contact>
    <investigator>
      <last_name>Mariela Blum</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>M D Anderson Cancer Center</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>December 13, 2018</study_first_submitted>
  <study_first_submitted_qc>December 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 21, 2018</study_first_posted>
  <last_update_submitted>September 1, 2023</last_update_submitted>
  <last_update_submitted_qc>September 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 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>Esophageal Neoplasms</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>Atezolizumab</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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/NCT03784326
org study id: 2018-0678
secondary id: NCI-2018-02828
secondary id: 2018-0678
nct id: NCT03784326
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
To learn if atezolizumab in combination with oxaliplatin and 5-fluorouracil (5-FU), when
      given before surgery, can help to control esophageal and/or gastroesophageal cancer. To learn
      if adding tiragolumab to the above drug combination can help to control the disease.
Primary Objectives:

        -  Atezolizumab +/- tiragolumab in combination with oxaliplatin and 5-fluorouracil
           (modified FOLFOX) therapy in the neoadjuvant setting will achieve a pathological
           complete response of approximately 20% in patients with localized esophageal and
           gastroesophageal (GEJ) adenocarcinoma.

      Secondary Objectives:

        -  To evaluate safety and toxicity profile of intravenous Atezolizumab +/- Tiragolumab in
           combination with Oxaliplatin and 5-FU chemotherapy as neoadjuvant treatment for
           resectable esophageal or GEJ adenocarcinoma.

        -  To assess the efficacy of the combination by tumor regression grade scoring in the
           surgical specimen.

        -  To assess the overall safety and tolerability of adjuvant Atezolizumab +/- Tiragolumab
           in subjects with resected esophageal and GEJ cancer

        -  To evaluate disease free survival (DFS) and overall survival (OS) in cohort 1 and cohort
           2

        -  To explore changes in tumor stroma profile before and after immunotherapy in combination
           with chemotherapy
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pathological complete response (PathCR)
time frame: Up to 3 years
description: The optimum two-stage design proposed by Simon will be implemented. The PathCR rate will be estimated along with the exact 95% confidence interval.
measure: Disease-free survival (DFS)
time frame: Up to 3 years
description: The Kaplan-Meier method will be used to estimate the probabilities of DFS.
measure: Overall survival (OS)
time frame: Up to 3 years
description: The Kaplan-Meier method will be used to estimate the probabilities of OS.
measure: Changes in tumor stroma profile after treatment
time frame: Baseline up to 3 years
description: The changes in tumor stroma profile after treatment assessed through paired t-tests or Wilcoxon signed rank tests if normality assumption is not satisfied.
measure: Incidence of toxicities defined as any treatment-related grade 3 or greater non-hematologic adverse events (AEs) determined by CTCAE version v 4.03.
time frame: From the start of study treatment up to 3 months
measure: Tumor regression determined by CT or MRI
time frame: Baseline up to 3 years
arm group label: Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)
arm group type: Experimental
description: The combination of Atezolizumab with Oxaliplatin and 5-Fluorouracil IV on Days 1 and 15 of each 28-day cycle for total of 6 doses followed by surgery followed by Atezolizumab on Day 1 of each 21-day cycle for total of 24 weeks
arm group label: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)
arm group type: Experimental
description: The combination of Atezolizumab + Tiragolumab with Oxaliplatin and 5-Flourouracil IV on Days 1 and 15 of each 28-day cycle for total of 6 doses followed by surgery followed by Atezolizumab + Tiragolumab on Day 1 of each 21-day cycle for a total of 48 weeks.
intervention type: Drug
intervention name: Atezolizumab
description: Given IV (vein)
arm group label: Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)
arm group label: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)
other name: MPDL 3280A
other name: MPDL 328OA
other name: MPDL-3280A
other name: MPDL3280A
other name: MPDL328OA
other name: RG7446
other name: RO5541267
other name: Tecentriq
intervention type: Procedure
intervention name: Conventional Surgery
description: Undergo surgical resection
arm group label: Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)
arm group label: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)
intervention type: Drug
intervention name: Fluorouracil
description: Given IV (vein)
arm group label: Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)
arm group label: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)
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: Drug
intervention name: Oxaliplatin
description: Given IV (vein)
arm group label: Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU)
arm group label: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)
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: Drug
intervention name: Tiragolumab
description: Given IV (vein)
arm group label: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU)
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
last name: Mariela Blum
phone: 713-792-2828
email: mblum1@mdanderson.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.mdanderson.org
description: M D Anderson Cancer Center
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Esophageal Neoplasms
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Atezolizumab
mesh term: Antibodies, Monoclonal