<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/NCT04400851</url>
  </required_header>
  <id_info>
    <org_study_id>SunYat-sen-Sintilimab</org_study_id>
    <nct_id>NCT04400851</nct_id>
  </id_info>
  <brief_title>Sintilimab in the Treatment of Advanced and Refractory Pediatric Malignant Tumors</brief_title>
  <official_title>Sintilimab in the Treatment of Advanced and Refractory Pediatric Malignant Tumors-A Phase I Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Innovent Biologics (Suzhou) Co. Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sun Yat-sen University</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 is a single center, single arm, open-label and phase I clinical study. The standard 3 +&#xD;
      3 group design was performed. Patients were enrolled by the design of phase I study standard.&#xD;
      Sintilimab was divided into three dose levels: 1 mg / kg, 3 mg / kg, and 10 mg / kg. Dose&#xD;
      escalation was carried out from the first level of sintilimab. The study is to evaluate the&#xD;
      safety, including dose limited toxicity (DLT) in the treatment of advanced, recurrent, and&#xD;
      refractory childhood cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Malignant tumors are the second leading cause of death in China after accidental casualties,&#xD;
      which is consistent with developed countries in Europe and America.&#xD;
&#xD;
      Sintilimab is a human monoclonal antibody against PD-1 receptor which was developed in China.&#xD;
      It can block the binding of PD-1 of T-lymphocyte and PD-L1 on the surface of tumor cells,&#xD;
      release the immunosuppression of tumor cells on immune cells, making immune cells play the&#xD;
      role of anti-tumor cell immunity again and kill tumor cells. In the past, the development of&#xD;
      immunocheckpoint drugs mainly focused on adult cancer. Immunocheckpoint inhibition has&#xD;
      achieved many successes in the adult population, including metastatic melanoma, non-small&#xD;
      cell lung cancer, Hodgkin's lymphoma, bladder cancer and head and neck cancer.&#xD;
&#xD;
      In the past, the development of immunocheckpoint drugs mainly focused on adult cancer.&#xD;
      Immunocheckpoint inhibition has achieved many successes in adult population. However, some&#xD;
      results of the clinical trials of immunocheckpoint inhibitors in children are also promising&#xD;
      especially in Hodgkin's lymphoma.&#xD;
&#xD;
      The investigators aimed to determine the maximum tolerable dose and effectiveness in&#xD;
      pediatric malignant tumors, so as to lay the foundation for the future phase II / III&#xD;
      clinical research.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 11, 2020</start_date>
  <completion_date type="Anticipated">December 10, 2021</completion_date>
  <primary_completion_date type="Anticipated">October 10, 2021</primary_completion_date>
  <phase>Phase 1</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>Maximum tolerable dose (MTD)</measure>
    <time_frame>From date of enrollment until the end of 1 cycle of treatment, assessed up to 3 weeks</time_frame>
    <description>Determine the appropriate dose of maximum tolerable dose (MTD) of sintilimab for further clinical study in this patient population</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]</measure>
    <time_frame>From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year</time_frame>
    <description>Hematology and non-hematology toxicity (NCI CTCAE v5.0 )</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective presponse rate (ORR)</measure>
    <time_frame>From the date of the treatment to the first evaluation (After 2 cycles of treatment assessed up to 6 weeks)</time_frame>
    <description>complete release and partial release</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Pediatric Cancer</condition>
  <arm_group>
    <arm_group_label>Sintilimab in advanced childhood cancer patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sintilimab</intervention_name>
    <description>Patients were enrolled by the design of phase I study standard. Sintilimab was divided into three dosage levels: 1 mg / kg, 3 mg / kg, and 10 mg / kg. The first level of sintilimab was followed by dose escalation</description>
    <arm_group_label>Sintilimab in advanced childhood cancer patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age: 1-18 years old;&#xD;
&#xD;
          2. ECOG PS score: 0-1;&#xD;
&#xD;
          3. Pediatric malignant tumors confirmed by histopathology include Hodgkin's lymphoma,&#xD;
             mediastinal large B-cell lymphoma, NK / T-cell lymphoma, nasopharyngeal carcinoma,&#xD;
             malignant melanoma, neuroblastoma, hepatoblastoma, sarcoma, brain tumor, etc;&#xD;
&#xD;
          4. Late stage patients who failed to receive standard treatment;&#xD;
&#xD;
          5. There must be at least one measurable lesion defined by RECIST or who standard;&#xD;
&#xD;
          6. Estimated survival time ≥ 6 months;&#xD;
&#xD;
          7. Heart function:&#xD;
&#xD;
               1. LVEF ≥ 50% by color Doppler echocardiography;&#xD;
&#xD;
               2. EKG showed no myocardial ischemia;&#xD;
&#xD;
               3. There was no history of arrhythmia requiring drug intervention before admission;&#xD;
&#xD;
          8. Patients must fully recover from the acute toxicity of all previous anticancer&#xD;
             chemotherapy;&#xD;
&#xD;
               1. Myelosuppression chemotherapy: at least 21 days after the last myelosuppression&#xD;
                  chemotherapy (42 days if nitrosourea was used in the earlier stage);&#xD;
&#xD;
               2. Experimental drug or anti-cancer therapy other than chemotherapy: it can not be&#xD;
                  used within the first 28 days before the planned start of the use of sintilimab,&#xD;
                  and must be clearly recovered from the clinically significant toxicity of the&#xD;
                  therapy;&#xD;
&#xD;
               3. Immunotherapy: at least 42 days after completion of any type of immunotherapy&#xD;
                  (excluding steroids), including immunocheckpoint inhibitors and tumor vaccines;&#xD;
&#xD;
               4. X-ray therapy (XRT): at least 14 days after local palliative XRT (small oral&#xD;
                  area); in case of other substantial bone marrow (BM) irradiation, including pre&#xD;
                  radioiodinated m-iodobenzidine (131I-MIBG) treatment, at least 42 days must be&#xD;
                  ended;&#xD;
&#xD;
               5. Stem cell infusion without total body irradiation (TBI): there is no evidence of&#xD;
                  active graft-versus-host disease. At least 56 days must elapse after&#xD;
                  transplantation or stem cell infusion;&#xD;
&#xD;
          9. Patients who have previously received CTLA-4 antibody must meet the following&#xD;
             conditions to be admitted to the group&#xD;
&#xD;
             a) More than 12 weeks after the last administration; b）No history of serious immune&#xD;
             related adverse events (CTCAE V4.03 G3 or G4);&#xD;
&#xD;
         10. For patients with known no BM involvement:&#xD;
&#xD;
               1. Neutrophil absolute count (ANC) ≥ One ×109/L；&#xD;
&#xD;
               2. Platelet count ≥ one hundred ×109/L；&#xD;
&#xD;
               3. Hemoglobin ≥ 90 g / L;&#xD;
&#xD;
         11. Liver and kidney function should meet the following standards:&#xD;
&#xD;
               1. Bilirubin (combined + unconjugated sum) ≤ Two point five * upper limit of normal&#xD;
                  value (ULN) (corresponding to age), patients who have been confirmed as Gilbert's&#xD;
                  syndrome can be judged according to the researchers;&#xD;
&#xD;
               2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ Two point&#xD;
                  five ×ULN；&#xD;
&#xD;
               3. Estimated glomerular filtration rate ≥ 30 ml / min/ one point seven three M2 or&#xD;
                  serum creatinine (CR) ≤ One point five ×ULN；&#xD;
&#xD;
         12. During the period of participating in the study, be able to follow the outpatient&#xD;
             treatment, laboratory monitoring and necessary clinical visits;&#xD;
&#xD;
         13. The parents / guardians of the child or adolescent subjects have the ability to&#xD;
             understand, agree and sign the study informed consent form (ICF) and the applicable&#xD;
             child consent form before initiating any program related procedures; the subjects have&#xD;
             the ability to express their consent (when applicable) with the consent of the parents&#xD;
             / guardians.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Received anti-PD-1 or anti-PD-L1 monoclonal antibody or related pathway targeted&#xD;
             drugs;&#xD;
&#xD;
          2. Known to be allergic to PD-1 monoclonal antibody or any of its adjuvants; known to&#xD;
             have a history of allergic diseases or severe allergic constitution;&#xD;
&#xD;
          3. Patients with other malignant tumor diseases other than those treated by the&#xD;
             Institute, except for patients who has been cured and with no recurrence within 3&#xD;
             years before the study was selected, completely removed basal cell and squamous cell&#xD;
             skin cancer, completely removed any type of carcinoma in situ;&#xD;
&#xD;
          4. Active central nervous system metastasis (whether or not treated), including&#xD;
             symptomatic brain metastasis or meningeal metastasis or spinal cord compression, etc.;&#xD;
             except: asymptomatic brain metastasis (no progress within at least 4 weeks after&#xD;
             radiotherapy and / or no neurological symptoms or signs after surgical resection, no&#xD;
             need for dexamethasone or mannitol treatment).&#xD;
&#xD;
          5. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated&#xD;
             drainage;&#xD;
&#xD;
          6. The toxicity of previous treatment is still more than grade 1 (CTCAE V4.03 Standard),&#xD;
             except hair loss and neurotoxicity;&#xD;
&#xD;
          7. Having a history of mental disorders;&#xD;
&#xD;
          8. Those who have a history of drug use or drug abuse upon inquiry;&#xD;
&#xD;
          9. History of idiopathic pulmonary fibrosis or pneumonia;&#xD;
&#xD;
         10. The complications that need to be treated with immunosuppressive drugs, or the&#xD;
             complications that need to be treated with systemic or local corticosteroids according&#xD;
             to the dose with immunosuppressive effect (prednisone &gt; 10 mg / day or equivalent dose&#xD;
             of similar drugs).&#xD;
&#xD;
         11. Have a history of autoimmune diseases, including but not limited to systemic lupus&#xD;
             erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease,&#xD;
             Hashimoto's thyroiditis, etc., except for: type I diabetes, hypothyroidism that can be&#xD;
             controlled only through hormone replacement therapy, skin diseases that do not need&#xD;
             systemic treatment (such as vitiligo, psoriasis), controlled celiac disease, or&#xD;
             Disease that does not recur without external stimulus;&#xD;
&#xD;
         12. Patients with active TB infection before or now;&#xD;
&#xD;
         13. Active infection requiring systemic treatment;&#xD;
&#xD;
         14. Uncontrolled hypertension (systolic ≥ 140 mmHg and / or diastolic ≥ 90 MmHg) or&#xD;
             pulmonary hypertension or unstable angina pectoris; myocardial infarction or bypass or&#xD;
             stent operation within 6 months before administration; history of chronic heart&#xD;
             failure meeting NYHA level 3-4; valvular disease of clinical significance; serious&#xD;
             arrhythmia requiring treatment (excluding atrial fibrillation and paroxysmal&#xD;
             supraventricular tachycardia), including QTc interval male ≥ 450ms , female ≥ 470ms&#xD;
             (calculated by friderica formula), cerebrovascular accident (CVA) or transient&#xD;
             ischemic attack (TIA) within 6 months before administration, etc;&#xD;
&#xD;
         15. Serious medical diseases, including but not limited to: uncontrolled diabetes, active&#xD;
             peptic ulcer, active bleeding, etc;&#xD;
&#xD;
         16. Anti HIV, TP AB and HCV AB were positive, HBV AG was positive and HBV DNA copy number&#xD;
             was higher than the upper limit of normal value of detection unit;&#xD;
&#xD;
         17. Thyroid function was abnormal (FT3, FT4, T3, T4);&#xD;
&#xD;
         18. Major surgery is expected within 28 days before administration or during treatment;&#xD;
&#xD;
         19. Live vaccine or attenuated vaccine is expected to be given 4 weeks before&#xD;
             administration, during treatment or within 5 months after the last administration;&#xD;
&#xD;
         20. Participate in another clinical trial and receive the trial drug treatment within 30&#xD;
             days before administration;&#xD;
&#xD;
         21. According to the judgment of the investigator, patients who are not suitable for the&#xD;
             trial due to other reasons.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Yizhuo Zhang</last_name>
    <phone>020-87342459</phone>
    <email>zhangyzh@sysucc.org.cn</email>
  </overall_contact>
  <location>
    <facility>
      <name>Yizhuo Zhang</name>
      <address>
        <city>Guangzhou</city>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yizhuo Zhang</last_name>
      <phone>020-87342459</phone>
      <email>zhangyzh@sysucc.org.cn</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>May 19, 2020</study_first_submitted>
  <study_first_submitted_qc>May 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>September 1, 2020</last_update_submitted>
  <last_update_submitted_qc>September 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
    <investigator_full_name>Yizhuo Zhang</investigator_full_name>
    <investigator_title>professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_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/NCT04400851
org study id: SunYat-sen-Sintilimab
nct id: NCT04400851
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
This is a single center, single arm, open-label and phase I clinical study. The standard 3 +
      3 group design was performed. Patients were enrolled by the design of phase I study standard.
      Sintilimab was divided into three dose levels: 1 mg / kg, 3 mg / kg, and 10 mg / kg. Dose
      escalation was carried out from the first level of sintilimab. The study is to evaluate the
      safety, including dose limited toxicity (DLT) in the treatment of advanced, recurrent, and
      refractory childhood cancer.
Malignant tumors are the second leading cause of death in China after accidental casualties,
      which is consistent with developed countries in Europe and America.

      Sintilimab is a human monoclonal antibody against PD-1 receptor which was developed in China.
      It can block the binding of PD-1 of T-lymphocyte and PD-L1 on the surface of tumor cells,
      release the immunosuppression of tumor cells on immune cells, making immune cells play the
      role of anti-tumor cell immunity again and kill tumor cells. In the past, the development of
      immunocheckpoint drugs mainly focused on adult cancer. Immunocheckpoint inhibition has
      achieved many successes in the adult population, including metastatic melanoma, non-small
      cell lung cancer, Hodgkin's lymphoma, bladder cancer and head and neck cancer.

      In the past, the development of immunocheckpoint drugs mainly focused on adult cancer.
      Immunocheckpoint inhibition has achieved many successes in adult population. However, some
      results of the clinical trials of immunocheckpoint inhibitors in children are also promising
      especially in Hodgkin's lymphoma.

      The investigators aimed to determine the maximum tolerable dose and effectiveness in
      pediatric malignant tumors, so as to lay the foundation for the future phase II / III
      clinical research.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerable dose (MTD)
time frame: From date of enrollment until the end of 1 cycle of treatment, assessed up to 3 weeks
description: Determine the appropriate dose of maximum tolerable dose (MTD) of sintilimab for further clinical study in this patient population
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
time frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year
description: Hematology and non-hematology toxicity (NCI CTCAE v5.0 )
measure: Objective presponse rate (ORR)
time frame: From the date of the treatment to the first evaluation (After 2 cycles of treatment assessed up to 6 weeks)
description: complete release and partial release
arm group label: Sintilimab in advanced childhood cancer patients
arm group type: Experimental
intervention type: Drug
intervention name: Sintilimab
description: Patients were enrolled by the design of phase I study standard. Sintilimab was divided into three dosage levels: 1 mg / kg, 3 mg / kg, and 10 mg / kg. The first level of sintilimab was followed by dose escalation
arm group label: Sintilimab in advanced childhood cancer patients
criteria: 
gender: All
minimum age: 1 Year
maximum age: 18 Years
healthy volunteers: No
last name: Yizhuo Zhang
phone: 020-87342459
email: zhangyzh@sysucc.org.cn
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Yizhuo Zhang
investigator title: professor
mesh term: Neoplasms