<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/NCT03800953</url>
  </required_header>
  <id_info>
    <org_study_id>201809084MIPC</org_study_id>
    <nct_id>NCT03800953</nct_id>
  </id_info>
  <brief_title>The Ave-CRT Study for Newly Diagnosed Metastatic Esophageal Squamous Cell Carcinoma</brief_title>
  <official_title>Chemotherapy/Avelumab Plus Radiotherapy to Primary Esophageal Tumor for Newly Diagnosed Metastatic Esophageal Squamous Cell Carcinoma: The Ave-CRT Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single institutional, single arm, open labeled phase II study to assess the overall&#xD;
      radiographic response of adding Avelumab to chemotherapy and palliative radiotherapy in&#xD;
      patients with metastatic advanced esophageal squamous cell carcinoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Avelumab belongs to the group of immune checkpoint blockade cancer therapies. Avelumab binds&#xD;
      to the programmed death-ligand 1 (PD-L1) and therefore inhibits binding to its receptor&#xD;
      programmed cell death 1 (PD-1). In the case of avelumab, the formation of PD-1/PDL1 ligand&#xD;
      pairs is blocked and CD8+ T cell immune response should be increased. This study comprises 2&#xD;
      phases, the concurrent immune-chemoradiotherapy (Ave-PF-CRT) phase and the&#xD;
      immune-chemotherapy (Ave-PF) phase. In the immune-chemoradiotherapy phase, patients are&#xD;
      treated with PF-CRT and concomitant Avelumab. In the immune-chemotherapy phase, patients are&#xD;
      treated with PF plus Avelumab. Overall radiological response, time to progression, overall&#xD;
      survival and adverse events will be evaluated. Subjects' health-related quality of life will&#xD;
      be assessed as well.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">March 20, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2021</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>overall radiographic response</measure>
    <time_frame>6 months</time_frame>
    <description>overall radiographic response at six-month will be determined by iRECIST</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best radiographic response</measure>
    <time_frame>up to 2 years</time_frame>
    <description>The best radiographic response of in-field irradiated and out-field non-irradiated (abscopal effect) target lesions will be determined by iRECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>up to 2 years</time_frame>
    <description>Kaplan-Meier survival estimator will be used to determine the median time to progression for study population (along with 95% confidence interval). The log-rank test will be performed to evaluate the equality of survivor functions across stage, and other covariates of interest on progression-free survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>up to 2 years</time_frame>
    <description>Kaplan-Meier survival estimator will be used to determine the median time to death for study population (along with 95% confidence interval). The log-rank test will be performed to evaluate the equality of survivor functions across stage, age, and other covariates of interest on overall survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of adverse events</measure>
    <time_frame>up to 2 years</time_frame>
    <description>The tabulations will count the number of subjects reporting individual adverse events. Adverse events are collected/assessed during treatment period (every week in the Ave-PF-CRT phase [one cycle, 4 weeks], the first and third week of each cycle in the Ave-PF phase [5 cycles, each cycle is 4 weeks]), every 3 months during evaluation, and in 2 years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heath-related quality of life</measure>
    <time_frame>up to 2 years</time_frame>
    <description>The self-reported health-related quality of life specific to esophageal cancer is a 44-item functioning scale captured using the Functional Assessment Of Cancer Therapy-Esophageal (FACT-E) Traditional Chinese version. Each question uses a 5-point Likert scale ranging from 0 to 4, and higher scores indicate better quality of life (0-176 for FACT-E total score). The FACT-E is assessed before treating is given, in the third week of Ave-PF-CRT phase (one cycle, 4 weeks), in the first week of every cycle (4 weeks) during the Ave-PF phase (5 cycles), and in the 2 years.&#xD;
Changes in total score of FACT-E from baseline to each assessment point will be calculated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New metastasis-free survival</measure>
    <time_frame>up to 2 years</time_frame>
    <description>Kaplan-Meier survival estimator will be used to determine the median time to development of new metastasis for study population (along with 95% confidence interval). The log-rank test will be performed to evaluate the equality of survivor functions across stage, and other covariates of interest on new metastasis-free survival.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">26</enrollment>
  <condition>Esophageal Tumor</condition>
  <condition>Metastatic Esophageal Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Avelumab (Bavencio)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a single arm, and open label study. All the subjects recruited will receive Avelumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>The study treatment comprises two phases, the concurrent immune-chemoradiotherapy (Ave-PF-CRT) phase and the immune-chemotherapy (Ave-PF) phase. All the subjects will receive Avelumab at both phases.</description>
    <arm_group_label>Avelumab (Bavencio)</arm_group_label>
    <other_name>Bavencio</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  To be eligible for inclusion, patients must fulfill the following criteria:&#xD;
&#xD;
               1. Histologically proved squamous cell carcinoma of esophagus&#xD;
&#xD;
               2. Metastatic disease, which are defined by TNM system of American Joint Committee&#xD;
                  on Cancer (AJCC) Cancer Staging System (8th edition) in 2017, involving distant&#xD;
                  lymph node (para-aortic or cervical) metastasis and/or visceral metastasis (lung,&#xD;
                  liver) documented by radiological examinations&#xD;
&#xD;
               3. Age ≥ 20 years&#xD;
&#xD;
               4. ECOG Performance Status 0 or 1&#xD;
&#xD;
               5. Adequate bone marrow reserves within 2 weeks prior to registration, defined as:a.&#xD;
                  absolute neutrophil count (ANC) ≥ 1.5×109/L (1,500/μl)b. platelets ≥ 100×109/L&#xD;
                  (100,000/µl)c. hemoglobin ≥ 9.0 g/dl (may have been transfused)&#xD;
&#xD;
               6. Adequate liver function reserves within 2 weeks prior to registration, defined&#xD;
                  as:&#xD;
&#xD;
                    1. hepatic transaminases (AST and ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤&#xD;
                       5 × ULN for subjects with documented metastatic disease to liver&#xD;
&#xD;
                    2. serum total bilirubin ≤ 2.5 × upper limit of normal (ULN)&#xD;
&#xD;
               7. Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5&#xD;
                  mg/dL&#xD;
&#xD;
               8. Negative serum or urine pregnancy test for women of childbearing potential&#xD;
&#xD;
               9. Women of childbearing potential and male participants must practice highly&#xD;
                  effective contraception throughout the study and for at least 30 days after last&#xD;
                  avelumab treatment administration if the risk of conception exists&#xD;
&#xD;
              10. Patients must be able to comply with the study protocol and follow-up schedules&#xD;
                  and provide study-specific informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients fulfill any of the following criteria will be excluded from this trial&#xD;
&#xD;
               1. Prior radiotherapy to head and neck, chest, or abdomen&#xD;
&#xD;
               2. Tumor invasion to adjacent structures (T4 lesion)&#xD;
&#xD;
               3. Adenocarcinoma of esophagus or gastroesophageal junction.&#xD;
&#xD;
               4. No measurable metastatic target lesion(s) by RECIST criteria&#xD;
&#xD;
               5. Synchronously or metachronously diagnosed squamous cell carcinoma of&#xD;
                  aerodigestive way, other than esophageal cancer&#xD;
&#xD;
               6. Prior invasive malignancy&#xD;
&#xD;
               7. Prior organ transplantation including allogenic stem-cell transplantation&#xD;
&#xD;
               8. Current use of immunosuppressive medication, EXCEPT for the following:&#xD;
&#xD;
                    1. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,&#xD;
                       intra-articular injection)&#xD;
&#xD;
                    2. systemic corticosteroids at physiologic doses '≤ 10 mg/day of prednisone or&#xD;
                       equivalent&#xD;
&#xD;
                    3. steroids as premedication for hypersensitivity reactions (e.g., CT scan&#xD;
                       premedication).&#xD;
&#xD;
               9. Active autoimmune disease that might deteriorate when receiving an&#xD;
                  immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or&#xD;
                  hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are&#xD;
                  eligible.&#xD;
&#xD;
              10. Severe, active comorbidities which, in the judgment of the investigator, would&#xD;
                  make the patient inappropriate for entry into this study or interfere&#xD;
                  significantly with the proper assessment of safety and adverse events of the&#xD;
                  protocol, or limit compliance with study requirements, defined as follows:&#xD;
&#xD;
                    1. Uncontrolled active infection requiring intravenous antibiotics at the time&#xD;
                       of registration&#xD;
&#xD;
                    2. Transmural myocardial infarction &lt; 6 months prior to registration&#xD;
&#xD;
                    3. Unstable angina or congestive heart failure requiring hospitalization &lt; 6&#xD;
                       months prior to registration&#xD;
&#xD;
                    4. Life-threatening uncontrolled clinically significant cardiac arrhythmias&#xD;
&#xD;
                    5. Cerebral vascular accident/stroke (&lt; 6 months prior to enrollment)&#xD;
&#xD;
                    6. Congestive heart failure (≥ New York Heart Association Classification Class&#xD;
                       II), or serious cardiac arrhythmia requiring medication.&#xD;
&#xD;
                    7. Hepatic insufficiency resulting in clinical jaundice and/or coagulation&#xD;
                       defects&#xD;
&#xD;
                    8. Chronic obstructive pulmonary disease exacerbation or other respiratory&#xD;
                       illness including pulmonary fibrosis requiring hospitalization or precluding&#xD;
                       study therapy at the time of registration&#xD;
&#xD;
                    9. Uncontrolled psychiatric disorder including recent (within the past year) or&#xD;
                       active suicidal ideation or behavior&#xD;
&#xD;
                   10. Laboratory abnormalities that may increase the risk associated with study&#xD;
                       participation or study treatment administration or may interfere with the&#xD;
                       interpretation of study results&#xD;
&#xD;
                   11. Immune colitis, inflammatory bowel disease, immune pneumonitis&#xD;
&#xD;
              11. Known history of testing positive for HIV or known acquired immunodeficiency&#xD;
                  syndrome.&quot;&#xD;
&#xD;
              12. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening&#xD;
                  (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test&#xD;
                  positive)&#xD;
&#xD;
              13. 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;
              14. Known prior severe hypersensitivity to investigational product or any component&#xD;
                  in its formulations, including known severe hypersensitivity reactions to&#xD;
                  monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)&quot;&#xD;
&#xD;
              15. Women of childbearing potential and male participants who are sexually active and&#xD;
                  not willing/able to use medically acceptable forms of contraception; this&#xD;
                  exclusion is necessary because the radiation treatment involved in this study may&#xD;
                  be significantly teratogenic&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chia-Hsien Cheng</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Taiwan University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Taiwan University Hospital, Taiwan</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>September 6, 2021</last_update_submitted>
  <last_update_submitted_qc>September 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 8, 2021</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>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Esophageal Squamous Cell Carcinoma</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>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/NCT03800953
org study id: 201809084MIPC
nct id: NCT03800953
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a single institutional, single arm, open labeled phase II study to assess the overall
      radiographic response of adding Avelumab to chemotherapy and palliative radiotherapy in
      patients with metastatic advanced esophageal squamous cell carcinoma.
Avelumab belongs to the group of immune checkpoint blockade cancer therapies. Avelumab binds
      to the programmed death-ligand 1 (PD-L1) and therefore inhibits binding to its receptor
      programmed cell death 1 (PD-1). In the case of avelumab, the formation of PD-1/PDL1 ligand
      pairs is blocked and CD8+ T cell immune response should be increased. This study comprises 2
      phases, the concurrent immune-chemoradiotherapy (Ave-PF-CRT) phase and the
      immune-chemotherapy (Ave-PF) phase. In the immune-chemoradiotherapy phase, patients are
      treated with PF-CRT and concomitant Avelumab. In the immune-chemotherapy phase, patients are
      treated with PF plus Avelumab. Overall radiological response, time to progression, overall
      survival and adverse events will be evaluated. Subjects' health-related quality of life will
      be assessed as well.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: overall radiographic response
time frame: 6 months
description: overall radiographic response at six-month will be determined by iRECIST
measure: Best radiographic response
time frame: up to 2 years
description: The best radiographic response of in-field irradiated and out-field non-irradiated (abscopal effect) target lesions will be determined by iRECIST.
measure: Progression-free survival
time frame: up to 2 years
description: Kaplan-Meier survival estimator will be used to determine the median time to progression for study population (along with 95% confidence interval). The log-rank test will be performed to evaluate the equality of survivor functions across stage, and other covariates of interest on progression-free survival.
measure: Overall survival
time frame: up to 2 years
description: Kaplan-Meier survival estimator will be used to determine the median time to death for study population (along with 95% confidence interval). The log-rank test will be performed to evaluate the equality of survivor functions across stage, age, and other covariates of interest on overall survival.
measure: Frequency of adverse events
time frame: up to 2 years
description: The tabulations will count the number of subjects reporting individual adverse events. Adverse events are collected/assessed during treatment period (every week in the Ave-PF-CRT phase [one cycle, 4 weeks], the first and third week of each cycle in the Ave-PF phase [5 cycles, each cycle is 4 weeks]), every 3 months during evaluation, and in 2 years.
measure: Heath-related quality of life
time frame: up to 2 years
description: The self-reported health-related quality of life specific to esophageal cancer is a 44-item functioning scale captured using the Functional Assessment Of Cancer Therapy-Esophageal (FACT-E) Traditional Chinese version. Each question uses a 5-point Likert scale ranging from 0 to 4, and higher scores indicate better quality of life (0-176 for FACT-E total score). The FACT-E is assessed before treating is given, in the third week of Ave-PF-CRT phase (one cycle, 4 weeks), in the first week of every cycle (4 weeks) during the Ave-PF phase (5 cycles), and in the 2 years.
Changes in total score of FACT-E from baseline to each assessment point will be calculated.
measure: New metastasis-free survival
time frame: up to 2 years
description: Kaplan-Meier survival estimator will be used to determine the median time to development of new metastasis for study population (along with 95% confidence interval). The log-rank test will be performed to evaluate the equality of survivor functions across stage, and other covariates of interest on new metastasis-free survival.
arm group label: Avelumab (Bavencio)
arm group type: Experimental
description: This is a single arm, and open label study. All the subjects recruited will receive Avelumab.
intervention type: Drug
intervention name: Avelumab
description: The study treatment comprises two phases, the concurrent immune-chemoradiotherapy (Ave-PF-CRT) phase and the immune-chemotherapy (Ave-PF) phase. All the subjects will receive Avelumab at both phases.
arm group label: Avelumab (Bavencio)
other name: Bavencio
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Chia-Hsien Cheng
role: Principal Investigator
affiliation: National Taiwan University Hospital
facility: 
country: Taiwan
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Esophageal Squamous Cell Carcinoma
mesh term: Esophageal Neoplasms
mesh term: Avelumab
sharing ipd: Undecided