<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/NCT04507217</url>
  </required_header>
  <id_info>
    <org_study_id>BGB-A317-2003-IIT</org_study_id>
    <nct_id>NCT04507217</nct_id>
  </id_info>
  <brief_title>Tislelizumab Combined With Pemetrexed/ Carboplatin in Patients With Brain Metastases of Non-squamous NSCLC</brief_title>
  <official_title>A Phase II, Open-Label, Multicenter, Prospective Clinical Study to Investigate the Efficacy and Safety of Tislelizumab Combined With Pemetrexed/ Carboplatin in Patients With Brain Metastases of Non-squamous Non-small Cell Lung Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sun Yat-sen University</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 phase II, Open-Label, Multicenter, Prospective Clinical Study to Investigate the&#xD;
      Efficacy and Safety of Tislelizumab Combined with Pemetrexed/ Carboplatin in Patients with&#xD;
      Brain Metastases of Non-squamous Non-small Cell Lung Cancer. The primary end point is PFS,&#xD;
      and secondary endpoint is ORR, OS, DoR and Neurocognitive impairment. during the study, the&#xD;
      exploratory objectives including (1) PD-L1 expression, TMB, and other potential predictive&#xD;
      biomarkers, correlated with response to treatment (2) Progression-free survival based on&#xD;
      intracranial response (iPFS) according to RECIST 1.1 and RANO-BM&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 15, 2020</start_date>
  <completion_date type="Actual">January 30, 2023</completion_date>
  <primary_completion_date type="Actual">November 15, 2022</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>
    <intervention_model_description>Tislelizumab Combined with Pemetrexed/ Carboplatin</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-Free Survival (PFS) rate at 12 months according to RECIST v1.1</measure>
    <time_frame>12months</time_frame>
    <description>Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR) according to RECIST v1.1</measure>
    <time_frame>36 months</time_frame>
    <description>ORR is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) according to RECIST v1.1</measure>
    <time_frame>12 months</time_frame>
    <description>Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>36 months</time_frame>
    <description>OS is defined as the time from the starting date of study drug to the date of death due to any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) according to RANO-BM</measure>
    <time_frame>36 months</time_frame>
    <description>PFS2 is defined as the time from first intracranial disease progression to second/subsequent disease progression (intracranial or extracranial) after initiation of new anti-cancer therapy, or death from any cause, whichever occurs first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) according to RECIST v1.1</measure>
    <time_frame>36 months</time_frame>
    <description>DoR is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence and severity of treatment-emergent AEs (TEAEs)</measure>
    <time_frame>36 months</time_frame>
    <description>TEAEs graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurocognitive impairment</measure>
    <time_frame>36 months</time_frame>
    <description>Neurocognitive impairment according to Hopkins Verbal Learning Test-Revised（HVLT-R）</description>
  </secondary_outcome>
  <other_outcome>
    <measure>PD-L1 expression, TMB, and other potential predictive biomarkers, correlated with response to treatment</measure>
    <time_frame>36 months</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>NSCLC Stage IV</condition>
  <condition>Brain Metastases</condition>
  <condition>PD-1 Antibody</condition>
  <arm_group>
    <arm_group_label>Eligible patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>tislelizumab (200mg) in combination with pemetrexed (500mg/m2) and carboplatin (AUC=5) intravenously on day 1 of a 3-week cycle for 4 cycles. Afterwards, patients without disease progression were treated with maintenance treatment with tislelizumab (200mg) plus pemetrexed (500mg/m2) every 3 weeks up to 24 months or until disease progression, unacceptable toxicity, or death.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tislelizumab, Carboplatin, Pemetrexed</intervention_name>
    <description>Tislelizumab: 200mg administered intravenously (IV) on Day 1 of each 21-day cycle&#xD;
Carboplatin: AUC 5 administered intravenously (IV) on Day 1 of each 21-day cycle, 4 cycles&#xD;
Pemetrexed: 500mg/m2 administered intravenously (IV) on Day 1 of each 21-day cycle</description>
    <arm_group_label>Eligible patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Disease-related inclusion criteria:&#xD;
&#xD;
          1. Histologically confirmed metastatic (Stage IV) not amenable to curative surgery or&#xD;
             radiotherapy, non-squamous NSCLC according to American Joint Committee on Cancer&#xD;
             (AJCC), 8th Edition.&#xD;
&#xD;
          2. Radiographically confirmed brain metastases;&#xD;
&#xD;
          3. No prior systemic treatment for stage IV NSCLC. (Bevacizumab administered for&#xD;
             improving radiation-induced encephaledema during irradiating intracranial lesions is&#xD;
             not considered as systemic therapy for stage IV NSCLC)&#xD;
&#xD;
          4. Patients with asymptomatic BM or symptoms can be controlled by low dose&#xD;
             corticosteroids (≤ 10 mg/day of prednisone or equivalent) or antiepileptics drugs;&#xD;
&#xD;
          5. Patients with previous local treatment to BMs should be stable and suitable to receive&#xD;
             the systemic treatment;&#xD;
&#xD;
          6. ECOG PS: 0 ~ 1&#xD;
&#xD;
          7. Extracranial measurable target lesions (per RECIST v1.1)&#xD;
&#xD;
          8. Life expectancy ≥ 3 months&#xD;
&#xD;
             Have adequate hematology, clinical chemistry, and organ function as indicated by the&#xD;
             following laboratory values (confirmed within 7 days prior to the first dose):&#xD;
&#xD;
          9. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥&#xD;
             90 g/L.&#xD;
&#xD;
         10. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × upper limit of&#xD;
             normal [ULN].&#xD;
&#xD;
         11. Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.&#xD;
&#xD;
         12. Serum total bilirubin ≤ 1.5 × ULN (total bilirubin must be &lt; 3 × ULN for patients with&#xD;
             Gilbert's syndrome).&#xD;
&#xD;
         13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN or AST&#xD;
             and ALT ≤ 5 × ULN for patients with liver metastases.&#xD;
&#xD;
             General inclusion criteria:&#xD;
&#xD;
         14. Able to provide written ICF signed by patient or by his/her legally authorized&#xD;
             representative or guardian and can understand and agree to comply with the study&#xD;
             protocol and follow-up procedures.&#xD;
&#xD;
         15. Male or female, aged 18 ~ 75 years on the day of signing ICF. Female patients of&#xD;
             childbearing potential and non-sterile male patients must be willing to use a highly&#xD;
             effective method of birth control for the duration of the study and for at least 120&#xD;
             days after the last dose of tislelizumab.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Disease-related exclusion criteria:&#xD;
&#xD;
          1. Received prior therapies targeting PD-1, PD-L1, CTLA-4 or other immune checkpoints&#xD;
             inhibitors.&#xD;
&#xD;
          2. Received prior systemic chemotherapy for advanced disease.&#xD;
&#xD;
          3. Have EGFR mutation or ALK gene translocation.&#xD;
&#xD;
          4. Patients iwith BMs that have received systemic treatment with corticosteroids (&gt;10&#xD;
             mg/day of prednisone or equivalent) or other drugs to relieve or prevent symptoms of&#xD;
             BMs.&#xD;
&#xD;
          5. Patients with intracranial metastases that are locally amenable.&#xD;
&#xD;
          6. Have received any approved systemic anticancer therapy or systemic immunomodulators&#xD;
             (including but not limited to interferon, interleukin-2, and tumor necrosis factor)&#xD;
             within 4 weeks prior to the first dose of study drug.&#xD;
&#xD;
          7. Have clinically uncontrolled pleural effusion or ascites that requires pleurocentesis&#xD;
             or abdominal tapping for drainage within 2 weeks prior to the first dose of study&#xD;
             drugs.&#xD;
&#xD;
          8. Active leptomeningeal metastasis.&#xD;
&#xD;
             Exclusion criteria related to study drugs:&#xD;
&#xD;
          9. History of allergic reactions to any study drugs and their excipients.&#xD;
&#xD;
         10. Creatinine clearance (Ccr) &lt; 45 mL/min.&#xD;
&#xD;
         11. Patients with active viral hepatitis that requires treatment as judged by the&#xD;
             investigator: a. chronic hepatitis B virus carriers with HBV DNA ≥ 500 IU/mL (2500&#xD;
             copies/mL) (The HBV DNA test will be performed only for patients who have a positive&#xD;
             antibody to hepatitis B core antigen (anti-HBc antibody) test); b. patients who have&#xD;
             positive hepatitis C virus (HCV) RNA results (The HCV RNA test will be performed only&#xD;
             for patients testing positive for HCV antibody).&#xD;
&#xD;
         12. Active autoimmune diseases that requires systemic treatment and may impact study&#xD;
             treatment as assessed by investigator.&#xD;
&#xD;
         13. Any condition that required extensive chronic treatment with either corticosteroids or&#xD;
             any other immunosuppressive medications that may impact study treatment as assessed by&#xD;
             investigator.&#xD;
&#xD;
             General exclusion criteria:&#xD;
&#xD;
         14. Severe chronic or active infections requiring systemic antibacterial, antifungal, or&#xD;
             antiviral therapy, including tuberculosis infection, etc.; 1) Serious infections&#xD;
             within 4 weeks before first dose, including but not limited to hospitalization for&#xD;
             complications of infection, bacteremia, or severe pneumonia; 2) Receive therapeutic&#xD;
             oral or intravenous antibiotics within 2 weeks before first dose. With history of&#xD;
             interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic&#xD;
             diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases,&#xD;
             etc.&#xD;
&#xD;
         15. Major surgery requiring general anesthesia within 4 weeks before first dose.&#xD;
&#xD;
         16. Underlying medical conditions or alcohol or drug abuse or dependence that are to be&#xD;
             unfavorable for the administration of study drugs or may have affected the&#xD;
             interpretation of the results or rendered the patient at high risk from treatment&#xD;
             complications.&#xD;
&#xD;
         17. Concurrent participation in another therapeutic clinical study. Female patients who&#xD;
             are pregnant, breastfeeding, or males and females patients planning to have child&#xD;
             during the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Cancer Center of Sun-Yat Sen University (CCSYSU)</name>
      <address>
        <city>GuangZhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Guangxi Medical University Affiliated Tumor Hospital</name>
      <address>
        <city>Nanning</city>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>August 6, 2020</study_first_submitted>
  <study_first_submitted_qc>August 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2020</study_first_posted>
  <last_update_submitted>May 23, 2023</last_update_submitted>
  <last_update_submitted_qc>May 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
    <investigator_full_name>Li Zhang, MD</investigator_full_name>
    <investigator_title>Professor, Chief Physician</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Pemetrexed</mesh_term>
    <mesh_term>Tislelizumab</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/NCT04507217
org study id: BGB-A317-2003-IIT
nct id: NCT04507217
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a phase II, Open-Label, Multicenter, Prospective Clinical Study to Investigate the
      Efficacy and Safety of Tislelizumab Combined with Pemetrexed/ Carboplatin in Patients with
      Brain Metastases of Non-squamous Non-small Cell Lung Cancer. The primary end point is PFS,
      and secondary endpoint is ORR, OS, DoR and Neurocognitive impairment. during the study, the
      exploratory objectives including (1) PD-L1 expression, TMB, and other potential predictive
      biomarkers, correlated with response to treatment (2) Progression-free survival based on
      intracranial response (iPFS) according to RECIST 1.1 and RANO-BM
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Tislelizumab Combined with Pemetrexed/ Carboplatin
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-Free Survival (PFS) rate at 12 months according to RECIST v1.1
time frame: 12months
description: Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first
measure: Objective Response Rate (ORR) according to RECIST v1.1
time frame: 36 months
description: ORR is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).
measure: Progression-free survival (PFS) according to RECIST v1.1
time frame: 12 months
description: Progression-free survival is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.
measure: Overall Survival (OS)
time frame: 36 months
description: OS is defined as the time from the starting date of study drug to the date of death due to any cause
measure: Progression-free survival (PFS) according to RANO-BM
time frame: 36 months
description: PFS2 is defined as the time from first intracranial disease progression to second/subsequent disease progression (intracranial or extracranial) after initiation of new anti-cancer therapy, or death from any cause, whichever occurs first
measure: Duration of Response (DoR) according to RECIST v1.1
time frame: 36 months
description: DoR is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first
measure: Incidence and severity of treatment-emergent AEs (TEAEs)
time frame: 36 months
description: TEAEs graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
measure: Neurocognitive impairment
time frame: 36 months
description: Neurocognitive impairment according to Hopkins Verbal Learning Test-Revised（HVLT-R）
measure: PD-L1 expression, TMB, and other potential predictive biomarkers, correlated with response to treatment
time frame: 36 months
arm group label: Eligible patients
arm group type: Experimental
description: tislelizumab (200mg) in combination with pemetrexed (500mg/m2) and carboplatin (AUC=5) intravenously on day 1 of a 3-week cycle for 4 cycles. Afterwards, patients without disease progression were treated with maintenance treatment with tislelizumab (200mg) plus pemetrexed (500mg/m2) every 3 weeks up to 24 months or until disease progression, unacceptable toxicity, or death.
intervention type: Drug
intervention name: Tislelizumab, Carboplatin, Pemetrexed
description: Tislelizumab: 200mg administered intravenously (IV) on Day 1 of each 21-day cycle
Carboplatin: AUC 5 administered intravenously (IV) on Day 1 of each 21-day cycle, 4 cycles
Pemetrexed: 500mg/m2 administered intravenously (IV) on Day 1 of each 21-day cycle
arm group label: Eligible patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Li Zhang, MD
investigator title: Professor, Chief Physician
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
mesh term: Carboplatin
mesh term: Pemetrexed
mesh term: Tislelizumab