<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/NCT03783936</url>
  </required_header>
  <id_info>
    <org_study_id>HCRN GI17-319</org_study_id>
    <nct_id>NCT03783936</nct_id>
  </id_info>
  <brief_title>Trial of mFOLFOX6 + Trastuzumab + Avelumab in Gastric and Esophageal Adenocarcinomas</brief_title>
  <official_title>A Single Arm, Multi-center Phase 2 Trial of mFOLFOX6 + Trastuzumab + Avelumab in First-line, Metastatic, HER2-amplified Gastric and Esophageal Adenocarcinomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Autumn McRee, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>EMD Serono</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hoosier Cancer Research Network</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The initial intent of the study was to be a multi-center single-arm open-label Simon's&#xD;
      two-stage Phase II clinical trial of first-line mFOLFOX6 + trastuzumab + avelumab in&#xD;
      metastatic HER2-amplified gastric and esophageal adenocarcinomas.&#xD;
&#xD;
      Accrual will halt after completion of Stage I (enrollment of 18 patients). This decision is&#xD;
      not due to safety issues. Subjects currently on treatment will continue until criteria as&#xD;
      defined in the protocol is met.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">January 24, 2019</start_date>
  <completion_date type="Anticipated">January 2022</completion_date>
  <primary_completion_date type="Actual">September 11, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <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>Best Objective Response Rate (bORR)</measure>
    <time_frame>24 weeks</time_frame>
    <description>The best objective response rate will be defined as the total number of patients whose best response by 24 weeks are either a CR or PR divided by the number of response evaluable patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>2 years</time_frame>
    <description>Progression Free Survival (PFS) by RECIST 1.1 will be defined as the time from the start date of treatment to the date of documented progression as determined by RECIST 1.1 or death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (iPFS)</measure>
    <time_frame>2 years</time_frame>
    <description>Progression Free Survival by iRECIST (iPFS) will be defined as the time from the start date of treatment to the date of documented progression as determined by iRECIST criteria or death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>2 years</time_frame>
    <description>Overall Survival (OS) will be defined as the time from start of treatment to the date of death. If the patient has not died, survival will be censored on last date the patient was known to be alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>24 weeks</time_frame>
    <description>Disease Control Rate (DCR) used to help determine clinical benefit will be defined as the total number of patients whose best responses are either a CR, PR, or SD divided by the number of response evaluable patients. Patients with best response of SD will need to maintain SD by 24 weeks to be considered to have received clinical benefit from the treatment regimen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess adverse events</measure>
    <time_frame>2 years</time_frame>
    <description>Adverse events will be summarized by frequency and severity using CTCAE version 5.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Gastric Adenocarcinoma</condition>
  <condition>Esophageal Adenocarcinoma</condition>
  <condition>Metastasis</condition>
  <condition>HER-2 Gene Amplification</condition>
  <arm_group>
    <arm_group_label>Induction and Maintenance</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Cycles 1-9; Induction; Cycle = 14 days&#xD;
mFOLFOX6&#xD;
oxaliplatin 85 mg/m2 IV Day 1 and&#xD;
leucovorin 400 mg/m2 IV Day 1 and&#xD;
5 fluorouracil 400 mg/m2 IV bolus and 2400 mg/m2 IV over 46 hours Day 1 and&#xD;
Trastuzumab 6 mg/kg IV loading dose C1D1 then Trastuzumab 4 mg/kg IV Day 1 and&#xD;
Avelumab 800 mg IV Day 1&#xD;
Cycles 10 and subsequent; Maintenance; Cycle = 14 days&#xD;
Trastuzumab 4 mg/kg Day 1 and Avelumab 800 mg Day 1</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Oxaliplatin 85 mg/m2</description>
    <arm_group_label>Induction and Maintenance</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>Leucovorin 400 mg/m2</description>
    <arm_group_label>Induction and Maintenance</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5 fluorouracil</intervention_name>
    <description>5 fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion</description>
    <arm_group_label>Induction and Maintenance</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trastuzumab</intervention_name>
    <description>Trastuzumab 6 mg/kg loading dose C1D1 then 4 mg/kg Day 1</description>
    <arm_group_label>Induction and Maintenance</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Avelumab 800 mg</description>
    <arm_group_label>Induction and Maintenance</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent and HIPAA authorization for release of personal health&#xD;
             information prior to registration.&#xD;
&#xD;
          2. Age ≥ 18 years at the time of consent.&#xD;
&#xD;
          3. ECOG Performance Status of 0 or 1.&#xD;
&#xD;
          4. Histologically confirmed esophageal, gastroesophageal junction, or gastric&#xD;
             adenocarcinoma, with unresectable or metastatic disease documented on diagnostic&#xD;
             imaging studies.&#xD;
&#xD;
          5. HER2 amplification confirmed by standard of care testing of tumor specimen (3+ by&#xD;
             immunohistochemistry, or 2+ on IHC with ISH with HER2/CEP17 ratio ≥2).&#xD;
&#xD;
          6. Radiographically measurable disease according to RECIST 1.1 within 28 days prior to&#xD;
             registration.&#xD;
&#xD;
          7. Adequate organ function as defined in the table below. All screening labs to be&#xD;
             obtained within 28 days prior to registration.&#xD;
&#xD;
               -  Absolute Neutrophil Count ≥ 1.5 x 109/L&#xD;
&#xD;
               -  Hemoglobin (Hgb) ≥ 9 g/dL (may have been transfused)&#xD;
&#xD;
               -  Platelets ≥ 100 x 109/L OR ≥ 75 x 109/L for patients who received Cycle 1 of&#xD;
                  mFOLFOX6 +/- trastuzumab prior to registration&#xD;
&#xD;
               -  Calculated creatinine clearance1 ≥ 30 mL/min OR creatinine ≤ 1.5 × upper limit of&#xD;
                  normal (ULN)&#xD;
&#xD;
               -  Bilirubin ≤ 1.5 × upper limit of normal (ULN) (Subjects with Gilbert's syndrome&#xD;
                  may be enrolled despite a total bilirubin level &gt;1.5 mg/dL, if their conjugated&#xD;
                  bilirubin is &lt; 1.5× ULN)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) ≤ 2.5 × ULN OR ≤ 5x ULN in patients with known&#xD;
                  liver metastases&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) ≤ 2.5 × ULN OR ≤ 5x ULN in patients with known&#xD;
                  liver metastases&#xD;
&#xD;
          8. Left ventricular ejection fraction (LVEF) ≥ 50% or above the lower limit of the&#xD;
             institutional normal range, whichever is lower.&#xD;
&#xD;
          9. Females of childbearing potential must have a negative serum pregnancy test at&#xD;
             screening. NOTE: Females are considered of child bearing potential unless they are&#xD;
             surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or&#xD;
             bilateral oophorectomy) or they are naturally postmenopausal for at least 12&#xD;
             consecutive months.&#xD;
&#xD;
         10. Females of childbearing potential and males must be willing to abstain from&#xD;
             heterosexual activity or to use 2 forms of effective methods of contraception from the&#xD;
             time of informed consent until 210 days after treatment discontinuation. The two&#xD;
             contraception methods can be comprised of two barrier methods, or a barrier method&#xD;
             plus a hormonal method.&#xD;
&#xD;
         11. As determined by the enrolling physician or protocol designee, ability of the subject&#xD;
             to understand and comply with study procedures for the entire length of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous systemic therapy for stage IV disease - EXCEPT that patient may have received&#xD;
             one cycle of mFOLFOX6 +/- trastuzumab within the 4 weeks prior to registration.&#xD;
&#xD;
          2. Active infection requiring intravenous systemic therapy.&#xD;
&#xD;
          3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the&#xD;
             mother is being treated on study).&#xD;
&#xD;
          4. Treatment with any investigational drug within 28 days prior to registration.&#xD;
&#xD;
          5. Prior immune checkpoint inhibitor therapy (i.e. anti-CTLA-4, anti-PD-L1, anti-PD-1),&#xD;
             or HER2-directed therapy (including trastuzumab)&#xD;
&#xD;
          6. Evidence of interstitial lung disease or active, non-infectious pneumonitis&#xD;
&#xD;
          7. Untreated brain metastasis or brain metastasis treated within 4 weeks prior to&#xD;
             enrollment.&#xD;
&#xD;
          8. Known additional malignancy that is active and/or progressive requiring treatment;&#xD;
             exceptions include basal cell or squamous cell skin cancer, in situ cervical or&#xD;
             bladder cancer, or other cancer for which the subject has been disease-free for at&#xD;
             least five years.&#xD;
&#xD;
          9. Serious cardiovascular event within 6 months prior to study entry, including&#xD;
             myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic&#xD;
             congestive heart failure (≥ New York Heart Association Classification Class II),&#xD;
             cerebral vascular accident, transient ischemic attack, or serious cardiac arrhythmia&#xD;
             requiring medication.&#xD;
&#xD;
         10. History of organ allograft or allogeneic stem cell transplantation&#xD;
&#xD;
         11. Active autoimmune disease requiring systemic treatment in the past 3 months (for&#xD;
             example with disease modifying agents, corticosteroids, or immunosuppressive drugs).&#xD;
&#xD;
             Exceptions Include:&#xD;
&#xD;
               -  Subjects with endocrine diseases stable on replacement therapy (e.g., thyroxine,&#xD;
                  insulin, or physiologic corticosteroid replacement therapy for adrenal or&#xD;
                  pituitary insufficiency, etc.) or hormone suppression.&#xD;
&#xD;
               -  Subjects that require intermittent use of bronchodilators, local steroid&#xD;
                  injections, or inhaled or topical steroids&#xD;
&#xD;
               -  Subjects with vitiligo, psoriasis, Sjogren's syndrome, or resolved childhood&#xD;
                  asthma/atopy&#xD;
&#xD;
         12. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,&#xD;
             inhaled, topical steroids, or local steroid injection (e.g., intra-articular&#xD;
             injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone&#xD;
             or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT&#xD;
             scan premedication).&#xD;
&#xD;
         13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.&#xD;
&#xD;
         14. Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.&#xD;
             Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.&#xD;
&#xD;
         15. Vaccination within 4 weeks of the first dose of avelumab and while on trials is&#xD;
             prohibited except for administration of inactivated vaccines.&#xD;
&#xD;
         16. Known prior severe hypersensitivity to investigational product or any component in its&#xD;
             formulations, including known severe hypersensitivity reactions to monoclonal&#xD;
             antibodies (NCI CTCAE v5 Grade ≥ 3).&#xD;
&#xD;
         17. Persisting toxicity related to prior therapy (NCI CTCAE v5 Grade &gt; 1); however,&#xD;
             alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety&#xD;
             risk based on investigator's judgment are acceptable.&#xD;
&#xD;
         18. Other severe acute or chronic medical conditions including immune colitis,&#xD;
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric&#xD;
             conditions including recent (within the past year) or active suicidal ideation or&#xD;
             behavior; or laboratory abnormalities that may increase the risk associated with study&#xD;
             participation or study treatment administration or may interfere with informed&#xD;
             consent, the interpretation of study results and, in the judgment of the investigator,&#xD;
             would make the patient inappropriate for entry into this study.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Autumn McRee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina, Chapel Hill</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Winship Cancer Insititute of Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University Feinberg School of Medicine</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospital and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Atlantic Health System</name>
      <address>
        <city>Morristown</city>
        <state>New Jersey</state>
        <zip>07960</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Roswell Park Cancer Institute</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of North Carolina at Chapel Hill</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>December 19, 2018</study_first_submitted>
  <study_first_submitted_qc>December 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 21, 2018</study_first_posted>
  <last_update_submitted>May 10, 2021</last_update_submitted>
  <last_update_submitted_qc>May 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Hoosier Cancer Research Network</investigator_affiliation>
    <investigator_full_name>Autumn McRee, MD</investigator_full_name>
    <investigator_title>Sponsor-Investigator</investigator_title>
  </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>Leucovorin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Avelumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03783936
org study id: HCRN GI17-319
nct id: NCT03783936
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The initial intent of the study was to be a multi-center single-arm open-label Simon's
      two-stage Phase II clinical trial of first-line mFOLFOX6 + trastuzumab + avelumab in
      metastatic HER2-amplified gastric and esophageal adenocarcinomas.

      Accrual will halt after completion of Stage I (enrollment of 18 patients). This decision is
      not due to safety issues. Subjects currently on treatment will continue until criteria as
      defined in the protocol is met.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Best Objective Response Rate (bORR)
time frame: 24 weeks
description: The best objective response rate will be defined as the total number of patients whose best response by 24 weeks are either a CR or PR divided by the number of response evaluable patients
measure: Progression Free Survival (PFS)
time frame: 2 years
description: Progression Free Survival (PFS) by RECIST 1.1 will be defined as the time from the start date of treatment to the date of documented progression as determined by RECIST 1.1 or death from any cause.
measure: Progression Free Survival (iPFS)
time frame: 2 years
description: Progression Free Survival by iRECIST (iPFS) will be defined as the time from the start date of treatment to the date of documented progression as determined by iRECIST criteria or death from any cause.
measure: Overall Survival (OS)
time frame: 2 years
description: Overall Survival (OS) will be defined as the time from start of treatment to the date of death. If the patient has not died, survival will be censored on last date the patient was known to be alive.
measure: Disease Control Rate (DCR)
time frame: 24 weeks
description: Disease Control Rate (DCR) used to help determine clinical benefit will be defined as the total number of patients whose best responses are either a CR, PR, or SD divided by the number of response evaluable patients. Patients with best response of SD will need to maintain SD by 24 weeks to be considered to have received clinical benefit from the treatment regimen
measure: Assess adverse events
time frame: 2 years
description: Adverse events will be summarized by frequency and severity using CTCAE version 5.
arm group label: Induction and Maintenance
arm group type: Other
description: Cycles 1-9; Induction; Cycle = 14 days
mFOLFOX6
oxaliplatin 85 mg/m2 IV Day 1 and
leucovorin 400 mg/m2 IV Day 1 and
5 fluorouracil 400 mg/m2 IV bolus and 2400 mg/m2 IV over 46 hours Day 1 and
Trastuzumab 6 mg/kg IV loading dose C1D1 then Trastuzumab 4 mg/kg IV Day 1 and
Avelumab 800 mg IV Day 1
Cycles 10 and subsequent; Maintenance; Cycle = 14 days
Trastuzumab 4 mg/kg Day 1 and Avelumab 800 mg Day 1
intervention type: Drug
intervention name: Oxaliplatin
description: Oxaliplatin 85 mg/m2
arm group label: Induction and Maintenance
intervention type: Drug
intervention name: Leucovorin
description: Leucovorin 400 mg/m2
arm group label: Induction and Maintenance
intervention type: Drug
intervention name: 5 fluorouracil
description: 5 fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion
arm group label: Induction and Maintenance
intervention type: Drug
intervention name: Trastuzumab
description: Trastuzumab 6 mg/kg loading dose C1D1 then 4 mg/kg Day 1
arm group label: Induction and Maintenance
intervention type: Drug
intervention name: Avelumab
description: Avelumab 800 mg
arm group label: Induction and Maintenance
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Autumn McRee, MD
role: Principal Investigator
affiliation: University of North Carolina, Chapel Hill
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Hoosier Cancer Research Network
investigator full name: Autumn McRee, MD
investigator title: Sponsor-Investigator
mesh term: Adenocarcinoma
mesh term: Esophageal Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Trastuzumab
mesh term: Avelumab
sharing ipd: Undecided