<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/NCT04494009</url>
  </required_header>
  <id_info>
    <org_study_id>MC20-01</org_study_id>
    <nct_id>NCT04494009</nct_id>
  </id_info>
  <brief_title>Randomized Phase II Trial of a PD-1 Inhibitor INCMGA00012 as Consolidation Therapy After Definitive Concurrent Chemoradiotherapy(RHAPSODY)</brief_title>
  <official_title>Randomized Phase II Trial of a PD-1 Inhibitor INCMGA00012 as Consolidation Therapy After Definitive Concurrent Chemoradiotherapy for Patients With Locally Advanced Esophageal Squamous Cell Carcinoma (RHAPSODY)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Asan Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Asan Medical Center</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a randomized, multi-center, open-label, phase II study of a PD-1 inhibitor&#xD;
      (INCMGA00012) versus observation as consolidation therapy after definitive concurrent&#xD;
      chemoradiotherapy in patients with locally advanced ESCC who have not progressed following&#xD;
      definitive chemoradiotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a randomized, multi-center, open-label, phase II study of a PD-1 inhibitor&#xD;
      (INCMGA00012) versus observation as consolidation therapy after definitive concurrent&#xD;
      chemoradiotherapy in patients with locally advanced ESCC who have not progressed following&#xD;
      definitive chemoradiotherapy.&#xD;
&#xD;
      Patients must have received definitive concurrent chemoradiotherapy for locally advanced ESCC&#xD;
      (cT1b N1-3 M0 or T2-4b N0-3 M0 according to the 8th American Joint Committee on Cancer [AJCC]&#xD;
      staging system) because of unresectable disease status (such as cervical esophageal cancer&#xD;
      and cTb), medically inoperable status, or patient's refusal of undergoing surgery.&#xD;
&#xD;
      Patients must not have progressed following definitive chemoradiotherapy consisting of&#xD;
      fluoropyrimidine or taxane plus platinum chemotherapy (including, but not limited to&#xD;
      fluorouracil plus cisplatin, capecitabine plus cisplatin, and paclitaxel plus carboplatin&#xD;
      according to the institute standard of care regimens) concurrent with radiation therapy (a&#xD;
      total dose of at least 50 Gy). One or two cycles of induction chemotherapy before&#xD;
      chemoradiotherapy is allowed, but chemotherapy after concurrent chemoradiotherapy is not&#xD;
      allowed.&#xD;
&#xD;
      Approximately 110 patients who have not progressed following definitive chemoradiotherapy for&#xD;
      locally advanced ESCC will be randomly assigned within 4-8 weeks after completing&#xD;
      chemoradiotherapy in a 1:1 ratio to the INCMGA00012 arm or observation arm.&#xD;
&#xD;
        -  INCMGA00012 arm (500 mg iv every 4 weeks for up to 12 months)&#xD;
&#xD;
        -  Observation arm (followed-up every 3 months) Randomization will be stratified by Eastern&#xD;
           Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2), clinical response to&#xD;
           definitive chemoradiation (complete response [CR] vs. non-CR), and institute.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">July 30, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2026</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival per RECIST 1.1</measure>
    <time_frame>5 Years</time_frame>
    <description>Every 12 weeks during the first two years after randomization then every 24 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>5 Years</time_frame>
    <description>every visit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival per iRECIST</measure>
    <time_frame>5 Years</time_frame>
    <description>Every 12 weeks during the first two years after randomization then every 24 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time To Progression per RECIST 1.1</measure>
    <time_frame>5 Years</time_frame>
    <description>Every 12 weeks during the first two years after randomization then every 24 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time To Progression per iRECIST Time To Progression per iRECIST</measure>
    <time_frame>5 Years</time_frame>
    <description>Every 12 weeks during the first two years after randomization then every 24 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To compare pattern of first cause of progression</measure>
    <time_frame>5 Years</time_frame>
    <description>Every 12 weeks during the first two years after randomization then every 24 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To compare the safety and tolerability(NCI-CTCAE version 5.0)</measure>
    <time_frame>5 Years</time_frame>
    <description>every visit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HRQoL, time to deterioration</measure>
    <time_frame>5 Years</time_frame>
    <description>Every 12 weeks during the first two years after randomization then every 24 weeks</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">110</enrollment>
  <condition>Esophageal Cancer</condition>
  <arm_group>
    <arm_group_label>INCMGA00012 군</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>INCMGA00012 500 mg iv every 4 weeks for up to 12 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Observation arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>followed up every 12 weeks for up to 12 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>INCMGA00012</intervention_name>
    <description>INCMGA00012 (also known as MGA012) is a humanized, hinge-stabilized IgG4 monoclonal antibody against human PD-1, which blocks the interaction of PD-1 with PD-L1 and PD-L2, interrupting PD-1 signaling, enhances antigen-induced interferon-γ release, and has a favorable preclinical profile.</description>
    <arm_group_label>INCMGA00012 군</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be willing and able to provide written informed consent for the trial.&#xD;
&#xD;
          2. Be ≥19 years of age on the day of signing the informed consent.&#xD;
&#xD;
          3. Have ECOG performance status 0-2 (Appendix 1).&#xD;
&#xD;
          4. Have histologically proven esophageal squamous cell carcinoma (ESCC).&#xD;
&#xD;
          5. Have demonstrated cT1b N1-3 M0 or T2-4b N0-3 M0 (8th AJCC staging system) before&#xD;
             definitive chemoradiotherapy (Appendix 2).&#xD;
&#xD;
          6. Have completed definitive concurrent chemoradiotherapy for esophageal cancer due to&#xD;
             unresectable disease status (such as cervical esophageal cancer and T4b), medically&#xD;
             inoperable status, or patient's refusal of undergoing surgery.&#xD;
&#xD;
          7. Have received fluoropyrimidine or taxane plus platinum chemotherapy (including, but&#xD;
             not limited to fluorouracil plus cisplatin, capecitabine plus cisplatin, and&#xD;
             paclitaxel plus carboplatin according to the institute standard of care regimens)&#xD;
             concurrent with radiation therapy. One or two cycles of induction chemotherapy before&#xD;
             chemoradiotherapy is allowed, but chemotherapy after concurrent chemoradiotherapy is&#xD;
             not allowed.&#xD;
&#xD;
          8. Have received a total dose of radiation of at least 50 Gy as part of concurrent&#xD;
             chemoradiotherapy.&#xD;
&#xD;
          9. Have not progressed following definitive chemoradiotherapy assessed by 18F-FDG-PET (or&#xD;
             PET-CT) scan, esophagogastroduodenoscopy (EGD), and chest CT. Clinical response should&#xD;
             be evaluated within 4 to 8 weeks after completing definitive chemoradiotherapy, and&#xD;
             within 3 weeks before randomization.&#xD;
&#xD;
         10. Have available pre-treatment tumor tissue for biomarker analyses. Either 1&#xD;
             formalin-fixed paraffin embedded (FFPE) tumor tissue block or 20 unstained tumor&#xD;
             tissue slides must be submitted for biomarker evaluation. Post-chemoradiation biopsy&#xD;
             should be performed if it is technically feasible and is not associated with&#xD;
             unacceptable clinical risk, and in case of pathologic residual cancer, tumor tissue&#xD;
             for biomarker analyses should be submitted (Either 1 FFPE tumor tissue block or 20&#xD;
             unstained tumor tissue slides).&#xD;
&#xD;
         11. Have adequate major organ functions as demonstrated by following laboratory results&#xD;
             obtained within 14 days prior to randomization (these lab criteria should be also met&#xD;
             within 7 days before initiation of study drug):&#xD;
&#xD;
               -  Adequate bone marrow function as defined by absolute neutrophil count (ANC) ≥&#xD;
                  1,000/mm3 and platelet count ≥ 75,000/mm3 without receiving growth factors or&#xD;
                  blood transfusion within 7 days before the laboratory testing.&#xD;
&#xD;
               -  Adequate renal function with serum creatinine ≤ 1.5 x upper limit of normal (ULN)&#xD;
                  or creatinine clearance ≥50 mL/minute by calculation using the Cockcroft-Gault&#xD;
                  formula (Appendix 3) or measurement using a preferred method per institute&#xD;
                  standard of care.&#xD;
&#xD;
               -  Adequate hepatic function with alanine aminotransferase (ALT) and aspartate&#xD;
                  aminotransferase (AST) ≤ 2.5 x ULN, and serum total bilirubin ≤ 1.5 x ULN except&#xD;
                  for subjects with Gilbert syndrome (persistent or recurrent hyperbilirubinemia&#xD;
                  that is predominantly unconjugated in the absence of hemolysis or hepatic&#xD;
                  pathology) who may be enrolled despite a total bilirubin level &gt; 1.5 x ULN.&#xD;
&#xD;
         12. Female subjects of childbearing potential must have a negative urine or serum&#xD;
             pregnancy test within 14 days prior to randomization. If the urine test is positive or&#xD;
             cannot be confirmed as negative, a serum pregnancy test will be required.&#xD;
&#xD;
         13. Female subjects of childbearing potential randomized to the INCMGA00012 arm must be&#xD;
             willing to use an adequate method of contraception for the duration of study treatment&#xD;
             and 90 days after the last dose of study treatment.&#xD;
&#xD;
         14. Non-sterile male subjects randomized to the INCMGA00012 arm and who have female sexual&#xD;
             partner(s) of childbearing potential must agree to use an adequate method of&#xD;
             contraception for the duration of study treatment and 90 days after the last dose of&#xD;
             study treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Has demonstrated disease progression while or after completion of definitive&#xD;
             chemoradiotherapy for locally advanced ESCC.&#xD;
&#xD;
          2. Has received sequential chemotherapy or chemoradiotherapy after completion of&#xD;
             concurrent chemoradiotherapy for locally advanced ESCC.&#xD;
&#xD;
          3. Has received any immunotherapy or investigational drug within 4 weeks prior to&#xD;
             randomization.&#xD;
&#xD;
          4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
          5. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy,&#xD;
             investigational agent, or local treatment (except for stent insertion or feeding&#xD;
             enterostomy for palliative intent) for cancer treatment.&#xD;
&#xD;
          6. Any unresolved toxicities CTCAE grade ≥2 from prior therapy with the exception of&#xD;
             alopecia, fatigue, and neuropathy.&#xD;
&#xD;
          7. Has undergone major surgery within 4 weeks prior to entry into the study.&#xD;
&#xD;
          8. Has an active autoimmune disease that has required systemic treatment within the 2&#xD;
             years prior to entry into the study (i.e., with use of disease-modifying agents,&#xD;
             corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine,&#xD;
             insulin, or physiologic corticosteroid replacement therapy for adrenal insufficiency&#xD;
             of pituitary insufficiency) is not considered a form of systemic treatment and is&#xD;
             allowed.&#xD;
&#xD;
          9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,&#xD;
             ulcerative colitis)&#xD;
&#xD;
         10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy&#xD;
             (&gt;10 mg/day prednisolone or equivalents) or any other form of immunosuppressive&#xD;
             therapy within 14 days prior to entry into the study. Note: A use of topical, ocular,&#xD;
             intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic&#xD;
             absorption) is allowed. A brief course of corticosteroids for prophylaxis (e.g.,&#xD;
             contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,&#xD;
             delayed-type hypersensitivity reaction caused by contact allergen) is permitted.&#xD;
&#xD;
         11. Has a history of organ transplant, including stem cell allograft.&#xD;
&#xD;
         12. Has received a live vaccine within 30 days prior to entry into the study. Examples of&#xD;
             live vaccines include, but are not limited to, the following: measles, mumps, rubella,&#xD;
             varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG),&#xD;
             and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed&#xD;
             virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,&#xD;
             FluMist®) are live attenuated vaccines and are not allowed.&#xD;
&#xD;
         13. Has an active infection requiring systemic therapy.&#xD;
&#xD;
         14. Has known history of Human Immunodeficiency Virus (HIV) infection.&#xD;
&#xD;
         15. Has active HBV (detectable HBsAg or HBV DNA) or HCV infection (detectable HCV RNA):&#xD;
&#xD;
             o For the subject receiving antiviral agents for HBV at screening, if the subject has&#xD;
             been treated for &gt; 2 weeks and HBV DNA is &lt;500 IU/mL (or 2,500 copies/mL) prior to&#xD;
             randomization, the subject will be allowed to be enrolled in the study. Antiviral&#xD;
             agent should be continued for 6 months after study drug treatment discontinuation.&#xD;
&#xD;
         16. Has known history of, or any evidence of interstitial lung disease, non-infectious&#xD;
             pneumonitis, or pulmonary fibrosis diagnosed based on imaging or clinical findings.&#xD;
             Note: Subjects with radiation pneumonitis may be enrolled if the radiation pneumonitis&#xD;
             has been confirmed as stable (beyond acute phase) and is unlikely to recur.&#xD;
&#xD;
         17. Has history of another primary malignancy requiring active treatment within the&#xD;
             previous 3 years except for adequately treated basal or squamous cell skin cancer,&#xD;
             superficial bladder cancer, or carcinoma in situ (e.g., of cervix, breast, prostate).&#xD;
&#xD;
         18. Has medical or psychiatric conditions that compromise the subject's ability to give&#xD;
             informed consent or to complete the protocol or a history of non-compliance.&#xD;
&#xD;
         19. Has significant cardiovascular impairment within 6 months prior to entry to the study&#xD;
             such as history of congestive heart failure meeting New York Heart Association (NYHA)&#xD;
             Class III or IV, unstable angina, myocardial infarction, cerebrovascular accident, or&#xD;
             cardiac arrhythmia associated with hemodynamic instability.&#xD;
&#xD;
         20. Has a history of severe hypersensitivity to antibody products.&#xD;
&#xD;
         21. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
         22. Is a pregnant or breastfeeding woman.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Sook Ryun Park, Ph.D</last_name>
    <phone>82-2-3010-3206</phone>
    <email>srpark@amc.seoul.kr</email>
  </overall_contact>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2020</study_first_posted>
  <last_update_submitted>July 27, 2020</last_update_submitted>
  <last_update_submitted_qc>July 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 31, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Asan Medical Center</investigator_affiliation>
    <investigator_full_name>Sook Ryun Park</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <!-- 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/NCT04494009
org study id: MC20-01
nct id: NCT04494009
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This study is a randomized, multi-center, open-label, phase II study of a PD-1 inhibitor
      (INCMGA00012) versus observation as consolidation therapy after definitive concurrent
      chemoradiotherapy in patients with locally advanced ESCC who have not progressed following
      definitive chemoradiotherapy.
This study is a randomized, multi-center, open-label, phase II study of a PD-1 inhibitor
      (INCMGA00012) versus observation as consolidation therapy after definitive concurrent
      chemoradiotherapy in patients with locally advanced ESCC who have not progressed following
      definitive chemoradiotherapy.

      Patients must have received definitive concurrent chemoradiotherapy for locally advanced ESCC
      (cT1b N1-3 M0 or T2-4b N0-3 M0 according to the 8th American Joint Committee on Cancer [AJCC]
      staging system) because of unresectable disease status (such as cervical esophageal cancer
      and cTb), medically inoperable status, or patient's refusal of undergoing surgery.

      Patients must not have progressed following definitive chemoradiotherapy consisting of
      fluoropyrimidine or taxane plus platinum chemotherapy (including, but not limited to
      fluorouracil plus cisplatin, capecitabine plus cisplatin, and paclitaxel plus carboplatin
      according to the institute standard of care regimens) concurrent with radiation therapy (a
      total dose of at least 50 Gy). One or two cycles of induction chemotherapy before
      chemoradiotherapy is allowed, but chemotherapy after concurrent chemoradiotherapy is not
      allowed.

      Approximately 110 patients who have not progressed following definitive chemoradiotherapy for
      locally advanced ESCC will be randomly assigned within 4-8 weeks after completing
      chemoradiotherapy in a 1:1 ratio to the INCMGA00012 arm or observation arm.

        -  INCMGA00012 arm (500 mg iv every 4 weeks for up to 12 months)

        -  Observation arm (followed-up every 3 months) Randomization will be stratified by Eastern
           Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2), clinical response to
           definitive chemoradiation (complete response [CR] vs. non-CR), and institute.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Care Provider)
measure: Progression Free Survival per RECIST 1.1
time frame: 5 Years
description: Every 12 weeks during the first two years after randomization then every 24 weeks
measure: Overall Survival
time frame: 5 Years
description: every visit
measure: Progression Free Survival per iRECIST
time frame: 5 Years
description: Every 12 weeks during the first two years after randomization then every 24 weeks
measure: Time To Progression per RECIST 1.1
time frame: 5 Years
description: Every 12 weeks during the first two years after randomization then every 24 weeks
measure: Time To Progression per iRECIST Time To Progression per iRECIST
time frame: 5 Years
description: Every 12 weeks during the first two years after randomization then every 24 weeks
measure: To compare pattern of first cause of progression
time frame: 5 Years
description: Every 12 weeks during the first two years after randomization then every 24 weeks
measure: To compare the safety and tolerability(NCI-CTCAE version 5.0)
time frame: 5 Years
description: every visit
measure: HRQoL, time to deterioration
time frame: 5 Years
description: Every 12 weeks during the first two years after randomization then every 24 weeks
arm group label: INCMGA00012 군
arm group type: Experimental
description: INCMGA00012 500 mg iv every 4 weeks for up to 12 months
arm group label: Observation arm
arm group type: No Intervention
description: followed up every 12 weeks for up to 12 months
intervention type: Drug
intervention name: INCMGA00012
description: INCMGA00012 (also known as MGA012) is a humanized, hinge-stabilized IgG4 monoclonal antibody against human PD-1, which blocks the interaction of PD-1 with PD-L1 and PD-L2, interrupting PD-1 signaling, enhances antigen-induced interferon-γ release, and has a favorable preclinical profile.
arm group label: INCMGA00012 군
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Sook Ryun Park, Ph.D
phone: 82-2-3010-3206
email: srpark@amc.seoul.kr
responsible party type: Principal Investigator
investigator affiliation: Asan Medical Center
investigator full name: Sook Ryun Park
investigator title: Professor