<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/NCT03816553</url>
  </required_header>
  <id_info>
    <org_study_id>B2018-169-01</org_study_id>
    <nct_id>NCT03816553</nct_id>
  </id_info>
  <brief_title>SHR-1210 in Combination With Apatinib in Patients With Metastatic, Persistent, or Recurrent Cervical Cancer</brief_title>
  <official_title>SHR-1210, a Novel Anti-pd-1 Antibody, in Combination With Apatinib in Patients With Metastatic, Persistent, or Recurrent Cervical Cancer: a Single-arm, Open Label, Multi-center, Phase II Study</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>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>
      The purpose of this study is to explore the efficacy and safety of SHR-1210 in combination&#xD;
      with apatinib in treating patients with metastatic, persistent, or recurrent cervical cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      SHR-1210 is a humanized monoclonal antibody against Programmed death 1(PD-1). Apatinib is a&#xD;
      small-molecule tyrosine kinase inhibitor (TKI) selectively inhibits Vascular Endothelial&#xD;
      Growth Factor Receptor 2 (VEGFR-2). Patients with metastatic, persistent, or recurrent&#xD;
      cervical cancer who failed to first-line chemotherapy +/- bevacizumab will received SHR-1210&#xD;
      200mg (3mg/kg for underweight patients) iv every 2 weeks and apatinib 250mg orally once&#xD;
      daily. The efficacy and safety will be observed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 19, 2019</start_date>
  <completion_date type="Actual">August 31, 2022</completion_date>
  <primary_completion_date type="Actual">April 30, 2020</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>Up to approximately 12 months</time_frame>
    <description>ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>Progression-free survival is defined as the duration from date of enrollment to the first occurrence of progression of disease or death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>Overall survival is defined as the duration from date of enrollment to the date of death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6-month PFS rate</measure>
    <time_frame>From date of enrollment up to 6 months</time_frame>
    <description>The rate of 6-month PFS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>9-month OS rate</measure>
    <time_frame>From date of enrollment up to 9 months</time_frame>
    <description>The rate of 9-month OS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DCR)</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>DCR is defined as the percentage of participants in the analysis population who have a CR, PR or stable disease (SD) per RECIST 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR)</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events (AEs) in the treatment of SHR1210 in combination with apatinib</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>Number of participants with adverse events occurring up to 30 days after the last administration are evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Impact of the treatment on Quality of Life (QOL) measured by the Functional Assessment of Cancer Therapy (FACT)-Cervical Trial Outcome of Index (FACT-Cx TOI)</measure>
    <time_frame>Baseline, every other cycle (each cycle is 28 days) and up to approximately 24 months</time_frame>
    <description>The FACT-Cx TOI is a scale for assessing general QOL of cervical cancer patients consisting of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Cervical Cancer subscale (15 items). Each item in the FACT-Cx TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative statements (or questions), reversal was performed prior to score calculation. The score ranges 0-116 with a large score suggesting better QOL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pain assessed by Brief Pain Inventory (BPI)</measure>
    <time_frame>Baseline, every other cycle (each cycle is 28 days) and up to approximately 24 months</time_frame>
    <description>Single item from the BPI assessing &quot;worst pain&quot; in the past 24 hours, on a 0-10 scale with a higher score indicating more pain than a low score.</description>
  </other_outcome>
  <other_outcome>
    <measure>PD-L1 expression on tumor and immune cells</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>The efficacy of the combination of SHR-1210 and apatinib as measured by objective response, will be described in patients according to PD-L1 positive and PD-L1 negative.</description>
  </other_outcome>
  <other_outcome>
    <measure>Tumor Mutation Burden (TMB)</measure>
    <time_frame>Up to approximately 24 months</time_frame>
    <description>The impact of TMB on efficacy of the combination of SHR-1210 and apatinib will be explored.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">45</enrollment>
  <condition>Recurrent Cervical Carcinoma</condition>
  <condition>Metastatic Cervical Cancer</condition>
  <arm_group>
    <arm_group_label>SHR-1210 + Apatinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants receive SHR-1210 200mg (3mg/kg for underweight patients) intravenously every 2 weeks and apatinib 250mg orally once daily until disease progression or unacceptable toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SHR-1210</intervention_name>
    <description>SHR-1210 will be administered as a 30-minute IV infusion Q2W at a dose of 200mg (3mg/kg for underweight patients).</description>
    <arm_group_label>SHR-1210 + Apatinib</arm_group_label>
    <other_name>Camrelizumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apatinib</intervention_name>
    <description>Apatinib will be administered 250mg orally, once daily until progression.</description>
    <arm_group_label>SHR-1210 + Apatinib</arm_group_label>
    <other_name>Apatinib Mesylate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients must have metastatic, recurrent or persistent squamous cell carcinoma,&#xD;
             adenosquamous carcinoma, or adenocarcinoma of the cervix which is not amenable to&#xD;
             curative treatment with surgery and/or radiation therapy;&#xD;
&#xD;
          2. Age ≥ 18 years and ≤ 70 years;&#xD;
&#xD;
          3. Patients must have measurable disease per RECIST 1.1; measurable lesions are defined&#xD;
             as those that can be accurately measured in at least one dimension (longest diameter&#xD;
             to be recorded as ≥ 10 mm with computed tomography (CT) scan, magnetic resonance&#xD;
             imaging (MRI),; a lymph node must be ≥ 15 mm in short axis. Tumors within a previously&#xD;
             irradiated field will be designated as &quot;non-target&quot; lesions unless progression is&#xD;
             documented or a biopsy is obtained to confirm persistence at least 90 days following&#xD;
             completion of radiation therapy.&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          5. Life expectancy exceeds 3 months;&#xD;
&#xD;
          6. Patients must have had at least one prior systemic chemotherapeutic regimen for&#xD;
             management of recurrent, persistent or metastatic carcinoma of the cervix.&#xD;
&#xD;
             Note: Prior adjuvant therapy is NOT counted as a systemic chemotherapeutic regimen for&#xD;
             management of recurrent, persistent or metastatic carcinoma of the cervix; adjuvant&#xD;
             therapy includes cisplatin given concurrent with primary radiation therapy (CCRT) and&#xD;
             adjuvant chemotherapy given following the completion of concurrent chemotherapy and&#xD;
             radiation therapy&#xD;
&#xD;
          7. Patients must have adequate organ function&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.5×10^9/L&#xD;
&#xD;
               -  Platelet count ≥ 80 × 10^9/L&#xD;
&#xD;
               -  Hemoglobin ≥ 90 g/L&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN&#xD;
                  (however, patients with known liver metastasis who have AST or ALT level ≤ 5 ×&#xD;
                  ULN may be enrolled)&#xD;
&#xD;
               -  Creatinine ≤ 1.5 × ULN or creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault&#xD;
                  formula)&#xD;
&#xD;
               -  Baseline albumin ≥ 28 g/L&#xD;
&#xD;
               -  Thyroid-stimulating hormone (TSH) levels ≤ 1 × ULN (however, patients with free&#xD;
                  Triiodothyronine [FT3] or free Thyroxine [FT4] levels ≤ 1 × ULN may be enrolled)&#xD;
&#xD;
          8. Written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Histopathologic diagnoses of tumors other than squamous cell carcinoma, adenosquamous&#xD;
             carcinoma, or adenocarcinoma.&#xD;
&#xD;
          2. Participated in other clinical trials, or finish other clinical trials within 4 weeks.&#xD;
&#xD;
          3. Prior exposure to immune checkpoint inhibitors, including but not limited to other&#xD;
             anti-PD-1 and anti-PD-L1 antibodies, or prior exposure to apatinib.&#xD;
&#xD;
          4. Known history of hypersensitivity to any components of the SHR-1210 formulation, or&#xD;
             other monoclonal antibody.&#xD;
&#xD;
          5. Concurrent medical condition requiring the use of immunosuppressive medications, or&#xD;
             immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses &gt; 10&#xD;
             mg/day prednisone or equivalent are prohibited within 2 weeks before study drug&#xD;
             administration.&#xD;
&#xD;
          6. Patients with any active autoimmune disease or history of autoimmune disease,&#xD;
             including but not limited to the following: hepatitis, pneumonitis, uveitis, colitis&#xD;
             (inflammatory bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism,&#xD;
             and hypothyroidism, except for subjects with vitiligo or resolved childhood&#xD;
             asthma/atopy. Asthma that requires intermittent use of bronchodilators or other&#xD;
             medical intervention should also be excluded.&#xD;
&#xD;
          7. Clinically significant cardiovascular diseases, including but not limited to&#xD;
             congestive heart failure (New York heart association (NYHA) class &gt; 2), unstable or&#xD;
             severe angina, severe acute myocardial infarction within 1 year before enrollment,&#xD;
             supraventricular or ventricular arrhythmia which need medical intervention, or QT&#xD;
             interval male ≥ 450 ms, female ≥ 470 ms.&#xD;
&#xD;
          8. Arterial thrombus or phlebothrombosis within 6 months.&#xD;
&#xD;
          9. Hypertension that can not be well controlled through antihypertensive drugs (systolic&#xD;
             pressure ≥ 140 mm Hg and/or diastolic pressure ≥ 90 mm Hg)&#xD;
&#xD;
         10. Proteinuria ≥ (++) or 24 hours total urine protein &gt; 1.0 g.&#xD;
&#xD;
         11. Coagulation abnormalities (INR&gt;2.0、PT&gt;16s), with bleeding tendency or are receiving&#xD;
             thrombolytic or anticoagulant therapy.&#xD;
&#xD;
         12. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events (except for&#xD;
             alopecia) due to a previously administered agent.&#xD;
&#xD;
         13. Has known active central nervous system metastases.&#xD;
&#xD;
         14. Patients with a prior invasive malignancy who have had any evidence of disease within&#xD;
             the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell&#xD;
             carcinoma of the skin, or in situ cervical cancer that has undergone potentially&#xD;
             curative therapy.&#xD;
&#xD;
         15. Has an active infection requiring systemic therapy.&#xD;
&#xD;
         16. History of immunodeficiency including seropositivity for human immunodeficiency virus&#xD;
             (HIV), or other acquired or congenital immune-deficient disease.&#xD;
&#xD;
         17. Hepatitis B virus (HBV) &gt;2000 IU/ml or DNA ≥ 1×10^4/ml; or hepatitis C virus (HCV) RNA&#xD;
             ≥ 1×10^3/ml).&#xD;
&#xD;
         18. Has received a live vaccine within 4 weeks prior to the first dose of trial treatment.&#xD;
             Note: Injection of inactivated viral vaccines against seasonal influenza are allowed.&#xD;
&#xD;
         19. Any other medical, psychiatric, or social condition deemed by the investigator to be&#xD;
             likely to interfere with a subject's rights, safety, welfare, or ability to sign&#xD;
             informed consent, cooperate, and participate in the study or would interfere with the&#xD;
             interpretation of the results.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Sun Yat-sen University Cancer Center</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Guangzhou Panyu Central Hospital</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>511400</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First affiliated Hospital of Sun Yat-sen University</name>
      <address>
        <city>Guanzhou</city>
        <state>Guangdong</state>
        <zip>510080</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>January 13, 2019</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>April 8, 2023</last_update_submitted>
  <last_update_submitted_qc>April 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 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>Xin Huang</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>Uterine Cervical Neoplasms</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apatinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03816553
org study id: B2018-169-01
nct id: NCT03816553
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to explore the efficacy and safety of SHR-1210 in combination
      with apatinib in treating patients with metastatic, persistent, or recurrent cervical cancer.
SHR-1210 is a humanized monoclonal antibody against Programmed death 1(PD-1). Apatinib is a
      small-molecule tyrosine kinase inhibitor (TKI) selectively inhibits Vascular Endothelial
      Growth Factor Receptor 2 (VEGFR-2). Patients with metastatic, persistent, or recurrent
      cervical cancer who failed to first-line chemotherapy +/- bevacizumab will received SHR-1210
      200mg (3mg/kg for underweight patients) iv every 2 weeks and apatinib 250mg orally once
      daily. The efficacy and safety will be observed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate (ORR)
time frame: Up to approximately 12 months
description: ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
measure: Progression-free Survival (PFS)
time frame: Up to approximately 24 months
description: Progression-free survival is defined as the duration from date of enrollment to the first occurrence of progression of disease or death from any cause
measure: Overall survival (OS)
time frame: Up to approximately 24 months
description: Overall survival is defined as the duration from date of enrollment to the date of death from any cause.
measure: 6-month PFS rate
time frame: From date of enrollment up to 6 months
description: The rate of 6-month PFS
measure: 9-month OS rate
time frame: From date of enrollment up to 9 months
description: The rate of 9-month OS
measure: Duration of Response (DCR)
time frame: Up to approximately 24 months
description: DCR is defined as the percentage of participants in the analysis population who have a CR, PR or stable disease (SD) per RECIST 1.1.
measure: Duration of Response (DOR)
time frame: Up to approximately 24 months
description: DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
measure: Incidence of Adverse Events (AEs) in the treatment of SHR1210 in combination with apatinib
time frame: Up to approximately 24 months
description: Number of participants with adverse events occurring up to 30 days after the last administration are evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
measure: Impact of the treatment on Quality of Life (QOL) measured by the Functional Assessment of Cancer Therapy (FACT)-Cervical Trial Outcome of Index (FACT-Cx TOI)
time frame: Baseline, every other cycle (each cycle is 28 days) and up to approximately 24 months
description: The FACT-Cx TOI is a scale for assessing general QOL of cervical cancer patients consisting of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Cervical Cancer subscale (15 items). Each item in the FACT-Cx TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative statements (or questions), reversal was performed prior to score calculation. The score ranges 0-116 with a large score suggesting better QOL.
measure: Pain assessed by Brief Pain Inventory (BPI)
time frame: Baseline, every other cycle (each cycle is 28 days) and up to approximately 24 months
description: Single item from the BPI assessing "worst pain" in the past 24 hours, on a 0-10 scale with a higher score indicating more pain than a low score.
measure: PD-L1 expression on tumor and immune cells
time frame: Up to approximately 24 months
description: The efficacy of the combination of SHR-1210 and apatinib as measured by objective response, will be described in patients according to PD-L1 positive and PD-L1 negative.
measure: Tumor Mutation Burden (TMB)
time frame: Up to approximately 24 months
description: The impact of TMB on efficacy of the combination of SHR-1210 and apatinib will be explored.
arm group label: SHR-1210 + Apatinib
arm group type: Experimental
description: Participants receive SHR-1210 200mg (3mg/kg for underweight patients) intravenously every 2 weeks and apatinib 250mg orally once daily until disease progression or unacceptable toxicity
intervention type: Drug
intervention name: SHR-1210
description: SHR-1210 will be administered as a 30-minute IV infusion Q2W at a dose of 200mg (3mg/kg for underweight patients).
arm group label: SHR-1210 + Apatinib
other name: Camrelizumab
intervention type: Drug
intervention name: Apatinib
description: Apatinib will be administered 250mg orally, once daily until progression.
arm group label: SHR-1210 + Apatinib
other name: Apatinib Mesylate
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
facility: 
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Xin Huang
investigator title: Professor
mesh term: Uterine Cervical Neoplasms
mesh term: Recurrence
mesh term: Apatinib
sharing ipd: Undecided