<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/NCT04425226</url>
  </required_header>
  <id_info>
    <org_study_id>Renji-IIT-2020-0005</org_study_id>
    <nct_id>NCT04425226</nct_id>
  </id_info>
  <brief_title>Pembrolizumab and LENvatinib in Participants With Hepatocellular Carcinoma (HCC) Before Liver Transplant</brief_title>
  <acronym>PLENTY202001</acronym>
  <official_title>Safety and Efficacy Study of Pembrolizumab in Combination With LENvatinib in Participants With Hepatocellular Carcinoma (HCC) Before Liver Transplant as Neoadjuvant TherapY--PLENTY Randomized Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>RenJi Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>RenJi Hospital</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Objectives of Study：This study will evaluate the safety and efficacy of pembrolizumab in&#xD;
      combination with lenvatinib as neoadjuvant therapy in participants with hepatocellular&#xD;
      carcinoma (HCC) exceeding Milan criteria before liver transplant.&#xD;
&#xD;
      The primary hypothesis of this study are that neoadjuvant pembrolizumab plus lenvatinib is&#xD;
      superior to regularly waiting in the list with respect to: 1) recurrence-free survival (RFS)&#xD;
      as assessed by blinded independent central review (BICR); and 2) Objective Response Rate&#xD;
      (ORR).The investigators design a clinical study to explore whether the combination above as a&#xD;
      neoadjuvant treatment in patients with advanced HCC before liver transplant could reduce&#xD;
      postoperative recurrence and to analyze potential immune biomarker of therapeutic response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participates would be randomly assigned (1:1) to experimental or Comparator/Control by&#xD;
      computer-generated allocation based on the envelope method and the hierarchical block&#xD;
      randomization method(hierarchy: BCLC stage and AFP level). The envelopes are sealed opaque,&#xD;
      and sequentially numbered.Randomization is performed by the trial coordinator.The random&#xD;
      number table and the block assignment number table will be kept confidential by the full-time&#xD;
      secretary of this project.Center-stratified block-permuted randomization is used in this&#xD;
      trial. Then permuted block randomization is used for each stratum with a block size of 4.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 6, 2020</start_date>
  <completion_date type="Anticipated">December 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2022</primary_completion_date>
  <phase>N/A</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recurrence-Free Survival (RFS)</measure>
    <time_frame>Up to ~4 years</time_frame>
    <description>RFS is defined as the time from randomization to first documentation of disease recurrence (local, regional, or distant) as assessed by BICR or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>one year</time_frame>
    <description>Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants who Experience an Adverse Event (AE)</measure>
    <time_frame>one year</time_frame>
    <description>An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants who Discontinue Study Treatment due to an AE</measure>
    <time_frame>Up to ~1 year</time_frame>
    <description>An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>one year</time_frame>
    <description>Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">192</enrollment>
  <condition>Liver Transplant; Complications</condition>
  <condition>Hepatocellular Carcinoma Recurrent</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab plus Lenvatinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants receive intravenous (IV) pembrolizumab at 200 mg on Day 1 of each 21-day cycle. Number of cycles: until &gt;42 days before liver transplantation or unacceptable toxicity develops. Patients receive Lenvatinib 8-12mg(basing on weight), once a day, oral at least 38 days of each 6 weeks cycle until &gt;7 days before liver transplantation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Comparator</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants are advised to stay as healthy as possible and wait regularly</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab Injection [Keytruda]</intervention_name>
    <description>Pembrolizumab (Keytruda, MSD China) is a recombinant anti-human PD-1 monoclonal antibody.</description>
    <arm_group_label>Pembrolizumab plus Lenvatinib</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>MK-3475</other_name>
    <other_name>Pembrolizumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenvatinib Oral Product</intervention_name>
    <description>Lenvatinib (Lenvima, Eisai China) is a novel angiogenesis inhibitor which targets vascular endothelial growth factor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor β, RET and KIT</description>
    <arm_group_label>Pembrolizumab plus Lenvatinib</arm_group_label>
    <other_name>LENVIMA</other_name>
    <other_name>Lenvatinib</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have pathologically or cytologically or by radiological criteria proven&#xD;
             hepatocellular carcinoma（exceeding Milan criteria）; known mixed histology (e.g.&#xD;
             hepatocellular carcinoma plus cholangiocarcinoma) or fibrolamellar variant is not&#xD;
             allowed&#xD;
&#xD;
          -  Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and&#xD;
             CT or MRI of the pelvis) &lt;1 week before the treatment of pembrolizumab in combination&#xD;
             with lenvatinib. Randomization needs to occur within 1 weeks after recruitment in the&#xD;
             waiting list.&#xD;
&#xD;
          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7&#xD;
             days prior to Cycle 1, Day 1.&#xD;
&#xD;
          -  Has a Child-Pugh A-B7 liver score (5 to 7 points) within 7 days prior to Cycle 1, Day&#xD;
             1.&#xD;
&#xD;
          -  Has controlled hepatitis B (Hep B)&#xD;
&#xD;
          -  The estimate time length between enrollment and liver transplantation should be at&#xD;
             least 3 months&#xD;
&#xD;
          -  No prior systemic therapy, local therapy (TACE etc.)&gt;6w&#xD;
&#xD;
          -  If female, is not pregnant or breastfeeding, and at least one of the following&#xD;
             conditions applies: 1) Is not a woman of childbearing potential (WOCBP); or 2) Is a&#xD;
             WOCBP and using a contraceptive method that is highly effective or be abstinent from&#xD;
             heterosexual intercourse as their preferred and usual lifestyle (a WOCBP must have a&#xD;
             negative pregnancy test within 72 hours before the first dose of study treatment).&#xD;
&#xD;
          -  Has adequate organ function.&#xD;
&#xD;
          -  Granulocytes &gt;= 1,500/uL&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.5 g/dL; patients with recent or ongoing gastrointestinal bleed may not&#xD;
             be transfused to reach the entry hemoglobin of 8.5 g/dL; physicians should ensure&#xD;
             patients requiring transfusion prior to registration do not have an occult or&#xD;
             clinically apparent gastrointestinal bleed&#xD;
&#xD;
          -  Platelets &gt;= 75,000/uL&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x upper limit of normal (ULN) (or creatinine clearance calculated &gt;=&#xD;
             60 cc/minute)&#xD;
&#xD;
          -  Bilirubin =&lt; 3 mg/dL&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =&lt; 5 x ULN&#xD;
&#xD;
          -  Prothrombin time (PT)-international normalized ratio (INR) =&lt; 1.7 (not required for&#xD;
             patients on anticoagulation agents; patients who are being therapeutically&#xD;
             anticoagulated with an agent such as Coumadin or heparin will be allowed to&#xD;
             participate provided that no prior evidence of underlying abnormality in these&#xD;
             parameters exists)&#xD;
&#xD;
          -  Patients with a history of hypertension should be well controlled (&lt; 140/90 mmHg) on a&#xD;
             regimen of anti-hypertensive therapy&#xD;
&#xD;
          -  Significant history of cardiac disease is not allowed:&#xD;
&#xD;
          -  Congestive heart failure &gt; class II New York Heart Association (NYHA) Myocardial&#xD;
             infarction within 6 months prior to registration Serious myocardial dysfunction,&#xD;
             defined as scintigraphically (multigated acquisition scan [MUGA], myocardial&#xD;
             scintigram) determined absolute left ventricular ejection fraction (LVEF) below 45% or&#xD;
             an LVEF on echocardiogram (ECHO) below the normal limit at the individual institution&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Surgery within the past 3 years.&#xD;
&#xD;
          -  Has had esophageal or gastric variceal bleeding within the last 6 months.&#xD;
&#xD;
          -  Has clinically apparent ascites on physical examination.&#xD;
&#xD;
          -  Has had clinically diagnosed hepatic encephalopathy in the last 6 months.&#xD;
&#xD;
          -  Has received liver ablation, radiofrequency or microwave ablation, radiotherapy in the&#xD;
             last 6 months.&#xD;
&#xD;
          -  Has a history of (noninfectious) pneumonitis that required steroids or has current&#xD;
             pneumonitis&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy.&#xD;
&#xD;
          -  Has dual active Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection at study&#xD;
             entry.&#xD;
&#xD;
          -  Has a known history of human immunodeficiency virus (HIV) infection.&#xD;
&#xD;
          -  Has known active tuberculosis (TB; Bacillus tuberculosis).&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with&#xD;
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,&#xD;
             OX-40, CD137).&#xD;
&#xD;
          -  Has received prior systemic anti-cancer therapy for HCC including investigational&#xD;
             agents.&#xD;
&#xD;
          -  Is receiving any of the following prohibited concomitant therapies:1) Antineoplastic&#xD;
             systemic chemotherapy or biological therapy; 2) Immunotherapy not specified in this&#xD;
             protocol; 3) Investigational agents other than pembrolizumab; 4) Radiation therapy; 5)&#xD;
             Oncological surgical therapy; or systemic glucocorticoids for any purpose other than&#xD;
             to modulate symptoms from an AE that is suspected to have an immunologic etiology.&#xD;
&#xD;
          -  Has received a live vaccine within 30 days prior to the first dose of study treatment.&#xD;
&#xD;
          -  Is currently participating in or has participated in a study of an investigational&#xD;
             agent or has used an investigational device within 4 weeks prior to Cycle 1, Day 1.&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy&#xD;
             or any other form of immunosuppressive therapy within 7 days prior to Cycle 1, Day 1.&#xD;
&#xD;
          -  Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.&#xD;
&#xD;
          -  Has an active autoimmune disease that has required systemic treatment in past 2 years.&#xD;
&#xD;
          -  Has a known psychiatric or substance abuse disorder that would interfere with the&#xD;
             participant's ability to cooperate with the requirements of the study.&#xD;
&#xD;
          -  Is pregnant or breastfeeding or expecting to conceive or father children within the&#xD;
             projected duration of the study, starting with the screening visit through 120 days&#xD;
             after the last dose of study treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Qiang Xia, MD., Ph.D.</last_name>
    <role>Study Chair</role>
    <affiliation>Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hao Feng, MD., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Hao Feng, MD., Ph.D.</last_name>
    <phone>008615000901110</phone>
    <email>surgeonfeng@live.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University</name>
      <address>
        <city>Shanghai</city>
        <zip>200127</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hao Feng, MD, PhD</last_name>
      <email>surgeonfeng@live.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>August 12, 2020</last_update_submitted>
  <last_update_submitted_qc>August 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2020</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, Hepatocellular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Lenvatinib</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/NCT04425226
org study id: Renji-IIT-2020-0005
nct id: NCT04425226
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Objectives of Study：This study will evaluate the safety and efficacy of pembrolizumab in
      combination with lenvatinib as neoadjuvant therapy in participants with hepatocellular
      carcinoma (HCC) exceeding Milan criteria before liver transplant.

      The primary hypothesis of this study are that neoadjuvant pembrolizumab plus lenvatinib is
      superior to regularly waiting in the list with respect to: 1) recurrence-free survival (RFS)
      as assessed by blinded independent central review (BICR); and 2) Objective Response Rate
      (ORR).The investigators design a clinical study to explore whether the combination above as a
      neoadjuvant treatment in patients with advanced HCC before liver transplant could reduce
      postoperative recurrence and to analyze potential immune biomarker of therapeutic response.
Participates would be randomly assigned (1:1) to experimental or Comparator/Control by
      computer-generated allocation based on the envelope method and the hierarchical block
      randomization method(hierarchy: BCLC stage and AFP level). The envelopes are sealed opaque,
      and sequentially numbered.Randomization is performed by the trial coordinator.The random
      number table and the block assignment number table will be kept confidential by the full-time
      secretary of this project.Center-stratified block-permuted randomization is used in this
      trial. Then permuted block randomization is used for each stratum with a block size of 4.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recurrence-Free Survival (RFS)
time frame: Up to ~4 years
description: RFS is defined as the time from randomization to first documentation of disease recurrence (local, regional, or distant) as assessed by BICR or by pathology consistent with HCC if required per the site's standard of care, or death due to any cause (both cancer and non-cancer causes of death)
measure: Disease Control Rate (DCR)
time frame: one year
description: Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.
measure: Percentage of Participants who Experience an Adverse Event (AE)
time frame: one year
description: An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
measure: Percentage of Participants who Discontinue Study Treatment due to an AE
time frame: Up to ~1 year
description: An AE is defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined.
measure: Objective Response Rate (ORR)
time frame: one year
description: Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.
arm group label: Pembrolizumab plus Lenvatinib
arm group type: Experimental
description: Participants receive intravenous (IV) pembrolizumab at 200 mg on Day 1 of each 21-day cycle. Number of cycles: until >42 days before liver transplantation or unacceptable toxicity develops. Patients receive Lenvatinib 8-12mg(basing on weight), once a day, oral at least 38 days of each 6 weeks cycle until >7 days before liver transplantation.
arm group label: Comparator
arm group type: No Intervention
description: Participants are advised to stay as healthy as possible and wait regularly
intervention type: Drug
intervention name: Pembrolizumab Injection [Keytruda]
description: Pembrolizumab (Keytruda, MSD China) is a recombinant anti-human PD-1 monoclonal antibody.
arm group label: Pembrolizumab plus Lenvatinib
other name: Keytruda
other name: MK-3475
other name: Pembrolizumab
intervention type: Drug
intervention name: Lenvatinib Oral Product
description: Lenvatinib (Lenvima, Eisai China) is a novel angiogenesis inhibitor which targets vascular endothelial growth factor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor β, RET and KIT
arm group label: Pembrolizumab plus Lenvatinib
other name: LENVIMA
other name: Lenvatinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Qiang Xia, MD., Ph.D.
role: Study Chair
affiliation: Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU
last name: Hao Feng, MD., Ph.D.
role: Principal Investigator
affiliation: Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU
last name: Hao Feng, MD., Ph.D.
phone: 008615000901110
email: surgeonfeng@live.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Pembrolizumab
mesh term: Lenvatinib