<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/NCT03755739</url>
  </required_header>
  <id_info>
    <org_study_id>ZZITICI-004</org_study_id>
    <nct_id>NCT03755739</nct_id>
  </id_info>
  <brief_title>Trans-Artery/Intra-Tumor Infusion of Checkpoint Inhibitors Plus Chemodrug for Immunotherapy of Advanced Solid Tumors</brief_title>
  <official_title>A Phase II/III Trial of Comparison of Benefit of Administration of Checkpoint Inhibitors Plus Chemodrug Via Artery or Fine Needle to Tumor Versus Vein for Immunotherapy of Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Second Affiliated Hospital of Guangzhou Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Second Affiliated Hospital of Guangzhou Medical University</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This trial was designed to investigate the safety, response rates and survival outcomes of&#xD;
      patients with advanced solid tumors by trans-artery/intra-tumor infusion of PD1/PDL1 antibody&#xD;
      and/or CTLA4 antibody ipilimumab plus chemotherapeutic drug and to compare their differences.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Malignant solid tumors including lung and liver cancers are the most common malignancy&#xD;
      worldwide, and their mortality rates are very high. China has a huge population base, with&#xD;
      about 4,000,000 new cases each year. More than 60% of the solid tumors in China are diagnosed&#xD;
      at mid-to-late stage and have lost the chance of surgery. Recently a lot of therapeutic&#xD;
      strategies have been developed and applied to clinic including targeted therapy and&#xD;
      immunotherapy, but the overall efficiency is still low. It is difficult to be widely used in&#xD;
      patients with advanced solid cancers, and more alternative therapies are urgently needed.&#xD;
&#xD;
      Antibodies against PD1, PDL1 and CTLA4 are representative drugs for the check-points&#xD;
      inhibitory agents, and their clinical indications have been approved in various types of&#xD;
      tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and&#xD;
      classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma&#xD;
      patients, et al. Those drugs are regularly systemically administrated by vein infusion,&#xD;
      however, local delivery of those drugs via interventional radiology technique including&#xD;
      trans-artery or intra-tumor injection may increase the local drug concentration in the tumor,&#xD;
      improve the efficacy, and reduce systemic adverse reactions, through so called &quot;first pass&#xD;
      effect&quot; of drug on target organs. To the investigator's knowledge, no studies have been&#xD;
      developed on the efficacy and survival benefit of localized delivery of checkpoint inhibitors&#xD;
      for treatment of cancer patients. This phase II-III clinical trial was designed to compare&#xD;
      the effects of Pembrolizumab, Tecentriq, et al and/or ipilimumab plus chemotherapeutic drug&#xD;
      such as doxorubicin on the survival benefit of patients with advanced solid cancers,&#xD;
      including ORR, DCR, median survival time, and safety.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 1, 2018</start_date>
  <completion_date type="Anticipated">November 1, 2033</completion_date>
  <primary_completion_date type="Anticipated">November 1, 2033</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>5 years</time_frame>
    <description>Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complete response (CR) rate before or at Month 6</measure>
    <time_frame>4</time_frame>
    <description>Percentage of patients achieving complete response (CR) before or at Month 6</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>5 years</time_frame>
    <description>Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per mRECIST) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of remission (DOR)</measure>
    <time_frame>5 years</time_frame>
    <description>DOR will be defined as the duration of the cancer remission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate</measure>
    <time_frame>5 years</time_frame>
    <description>Disease control rate will be defined as objective response rate + steady disease rate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cause of death (COD) when appropriate</measure>
    <time_frame>5</time_frame>
    <description>Cause of death (COD) when appropriate</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Hepatocarcinoma</condition>
  <condition>Lung Cancer</condition>
  <condition>Melanoma</condition>
  <condition>Renal Cancer</condition>
  <condition>Head and Neck Cancer</condition>
  <condition>Pancreas Cancer</condition>
  <condition>Ovarian Cancer</condition>
  <condition>Colo-rectal Cancer</condition>
  <condition>Cervical Cancer</condition>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab via localized infusion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group dividied into two subgroups:&#xD;
Checkpoint inhibitor (CPI) such as Pembrolizumab ± Ipilimumab is administrated with a dose of 1-2mg/kg via sustained (10min) micro-pump infusion via artery, plus chemotherapy, every 3 weeks.&#xD;
Checkpoint inhibitor (CPI) such as Pembrolizumab ± Ipilimumab is administrated with a total dose of 150mg via intra-tumor fine needle injection in 5 min, plus doxorubicin, every 3 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Checkpoint inhibitor (CPI) Pembrolizumab plus chemotherapy via vein infusion</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Checkpoint inhibitor (CPI) such as Pembrolizumab is administrated with a total dose of 2mg/kg via vein infusion (30 min), plus chemotherpy every 3 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Checkpoint inhibitor (CPI) such as Pembrolizumab plus chemotherapy</intervention_name>
    <description>vein, artery, or intra-tumor infusion of checkpoint inhibitor (CPI) such as Pembrolizumab and/or Ipilimumab, plus chemotherapy to destroy cancer cells and release tumor antigen for improving CPI therapeutic efficacy.</description>
    <arm_group_label>Checkpoint inhibitor (CPI) Pembrolizumab plus chemotherapy via vein infusion</arm_group_label>
    <arm_group_label>Pembrolizumab via localized infusion</arm_group_label>
    <other_name>Checkpoint inhibitor (CPI) such as Keytruda plus chemotherapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Cytohistological confirmation is required for diagnosis of cancer.&#xD;
&#xD;
          2. Signed informed consent before recruiting.&#xD;
&#xD;
          3. Age above 18 years with estimated survival over 3 months.&#xD;
&#xD;
          4. Child-Pugh class A or B/Child score &gt; 7; ECOG score &lt; 2&#xD;
&#xD;
          5. Tolerable coagulation function or reversible coagulation disorders&#xD;
&#xD;
          6. Laboratory examination test within 7 days prior to procedure: WBC≥3.0×10E9/L;&#xD;
             Hb≥90g/L； PLT ≥50×10E9/L；INR &lt; 2.3 or PT &lt; 6 seconds above control；Cr ≤ 145.5&#xD;
             umul/L；Albumin &gt; 28 g/L；Total bilirubin &lt; 51 μmol/L&#xD;
&#xD;
          7. At least one tumor lesion meeting measurable disease criteria as determined by RECIST&#xD;
             v1.1.&#xD;
&#xD;
          8. Birth control.&#xD;
&#xD;
          9. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients participated in clinical trials of equipment or drugs (signed informed&#xD;
             consent) within 4 weeks;&#xD;
&#xD;
          2. Patients accompany by ascites, hepatic encephalopathy and esophageal and gastric&#xD;
             varices bleeding;&#xD;
&#xD;
          3. Any serious accompanying disease, which is expected to have an unknown, impact on the&#xD;
             prognosis, include heart disease, inadequately controlled diabetes and psychiatric&#xD;
             disorders;&#xD;
&#xD;
          4. Patients accompanied with other tumors or past medical history of malignancy;&#xD;
&#xD;
          5. Pregnant or lactating patients, all patients participating in this trial must adopt&#xD;
             appropriate birth control measures during treatment;&#xD;
&#xD;
          6. Patients have poor compliance.&#xD;
&#xD;
             Any contraindications for hepatic arterial infusion procedure:&#xD;
&#xD;
             A.Impaired clotting test (platelet count &lt; 60000/mm3, prothrombin activity &lt; 50%).&#xD;
&#xD;
             B.Renal failure / insufficiency requiring hemo-or peritoneal dialysis. C.Known severe&#xD;
             atheromatosis. D.Known uncontrolled blood hypertension (&gt; 160/100 mm/Hg).&#xD;
&#xD;
          7. Allergic to contrast agent;&#xD;
&#xD;
          8. Any agents which could affect the absorption or pharmacokinetics of the study drugs&#xD;
&#xD;
          9. Other conditions that investigator decides not suitable for the trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zhenfeng Zhang, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Second Affiliated Hospital of Guangzhou Medical University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Zhenfeng Zhang, MD,PhD</last_name>
    <phone>02034153532</phone>
    <email>zhangzhf@gzhmu.edu.cn</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Deji Chen, MD,PhD</last_name>
    <phone>02034153532</phone>
    <email>chendeji2003@163.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>The Second Affiliated Hospital of Guangzhou Medical University</name>
      <address>
        <city>Guanzhou</city>
        <state>Guangdong</state>
        <zip>51260</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Zhenfeng Zhang, MD,PhD</last_name>
      <phone>02034153532</phone>
      <email>zhangzhf@gzhmu.edu.cn</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>November 3, 2018</study_first_submitted>
  <study_first_submitted_qc>November 25, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>February 26, 2023</last_update_submitted>
  <last_update_submitted_qc>February 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Solid cancers</keyword>
  <keyword>Check-point inhibitors</keyword>
  <keyword>Interventional Radiology</keyword>
  <keyword>Trans-artery infusion</keyword>
  <keyword>Intra-tumor injection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pancreatic Neoplasms</mesh_term>
    <mesh_term>Kidney Neoplasms</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>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03755739
org study id: ZZITICI-004
nct id: NCT03755739
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This trial was designed to investigate the safety, response rates and survival outcomes of
      patients with advanced solid tumors by trans-artery/intra-tumor infusion of PD1/PDL1 antibody
      and/or CTLA4 antibody ipilimumab plus chemotherapeutic drug and to compare their differences.
Malignant solid tumors including lung and liver cancers are the most common malignancy
      worldwide, and their mortality rates are very high. China has a huge population base, with
      about 4,000,000 new cases each year. More than 60% of the solid tumors in China are diagnosed
      at mid-to-late stage and have lost the chance of surgery. Recently a lot of therapeutic
      strategies have been developed and applied to clinic including targeted therapy and
      immunotherapy, but the overall efficiency is still low. It is difficult to be widely used in
      patients with advanced solid cancers, and more alternative therapies are urgently needed.

      Antibodies against PD1, PDL1 and CTLA4 are representative drugs for the check-points
      inhibitory agents, and their clinical indications have been approved in various types of
      tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and
      classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma
      patients, et al. Those drugs are regularly systemically administrated by vein infusion,
      however, local delivery of those drugs via interventional radiology technique including
      trans-artery or intra-tumor injection may increase the local drug concentration in the tumor,
      improve the efficacy, and reduce systemic adverse reactions, through so called "first pass
      effect" of drug on target organs. To the investigator's knowledge, no studies have been
      developed on the efficacy and survival benefit of localized delivery of checkpoint inhibitors
      for treatment of cancer patients. This phase II-III clinical trial was designed to compare
      the effects of Pembrolizumab, Tecentriq, et al and/or ipilimumab plus chemotherapeutic drug
      such as doxorubicin on the survival benefit of patients with advanced solid cancers,
      including ORR, DCR, median survival time, and safety.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival
time frame: 5 years
description: Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study.
measure: Complete response (CR) rate before or at Month 6
time frame: 4
description: Percentage of patients achieving complete response (CR) before or at Month 6
measure: Progression-free survival
time frame: 5 years
description: Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per mRECIST) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment.
measure: Duration of remission (DOR)
time frame: 5 years
description: DOR will be defined as the duration of the cancer remission
measure: Disease control rate
time frame: 5 years
description: Disease control rate will be defined as objective response rate + steady disease rate.
measure: Cause of death (COD) when appropriate
time frame: 5
description: Cause of death (COD) when appropriate
arm group label: Pembrolizumab via localized infusion
arm group type: Experimental
description: This group dividied into two subgroups:
Checkpoint inhibitor (CPI) such as Pembrolizumab ± Ipilimumab is administrated with a dose of 1-2mg/kg via sustained (10min) micro-pump infusion via artery, plus chemotherapy, every 3 weeks.
Checkpoint inhibitor (CPI) such as Pembrolizumab ± Ipilimumab is administrated with a total dose of 150mg via intra-tumor fine needle injection in 5 min, plus doxorubicin, every 3 weeks.
arm group label: Checkpoint inhibitor (CPI) Pembrolizumab plus chemotherapy via vein infusion
arm group type: Active Comparator
description: Checkpoint inhibitor (CPI) such as Pembrolizumab is administrated with a total dose of 2mg/kg via vein infusion (30 min), plus chemotherpy every 3 weeks.
intervention type: Drug
intervention name: Checkpoint inhibitor (CPI) such as Pembrolizumab plus chemotherapy
description: vein, artery, or intra-tumor infusion of checkpoint inhibitor (CPI) such as Pembrolizumab and/or Ipilimumab, plus chemotherapy to destroy cancer cells and release tumor antigen for improving CPI therapeutic efficacy.
arm group label: Checkpoint inhibitor (CPI) Pembrolizumab plus chemotherapy via vein infusion
arm group label: Pembrolizumab via localized infusion
other name: Checkpoint inhibitor (CPI) such as Keytruda plus chemotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Zhenfeng Zhang, MD,PhD
role: Principal Investigator
affiliation: Second Affiliated Hospital of Guangzhou Medical University
last name: Zhenfeng Zhang, MD,PhD
phone: 02034153532
email: zhangzhf@gzhmu.edu.cn
last name: Deji Chen, MD,PhD
phone: 02034153532
email: chendeji2003@163.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Pancreatic Neoplasms
mesh term: Kidney Neoplasms
mesh term: Carcinoma, Hepatocellular
mesh term: Pembrolizumab
sharing ipd: No