<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/NCT03248843</url>
  </required_header>
  <id_info>
    <org_study_id>KN035-JP-001</org_study_id>
    <nct_id>NCT03248843</nct_id>
  </id_info>
  <brief_title>A Study of PD-L1 Antibody KN035 in Japanese Subjects With Locally Advanced or Metastatic Solid Tumors</brief_title>
  <official_title>A Phase I, Open Label, Dose Escalation Study of The Safety and Pharmacokinetics of Anti-PD-L1 Monoclonal Antibody KN035 Administered in Subcutaneous Injection as A Single Agent to Japanese Subjects With Locally Advanced or Metastatic Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>3D Medicines (Sichuan) Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>3D Medicines</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>
      This is an open label, dose escalation study to evaluate the safety and tolerability of KN035&#xD;
      in Japanese patients with advanced and metastatic solid tumor. The dose escalation will&#xD;
      follow the widely used 3+3 design.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open label, dose escalation study to evaluate the safety and tolerability of KN035&#xD;
      in Japanese patients with advanced and metastatic solid tumor.&#xD;
&#xD;
      The dose escalation will follow the widely used 3+3 design. Cohorts of 3-6 subjects will be&#xD;
      enrolled sequentially at escalating doses of 1.0, 2.5, 5.0 and 10 mg/kg weekly. Dose&#xD;
      escalation will continue until identification of MTD up to a maximum dose of 10 mg/kg. MTD is&#xD;
      defined as the highest dose studied at which no more than 1 of 6 subjects has experienced a&#xD;
      dose-limiting toxicity (DLT) in Cycle 1. The enrolled patients are managed under&#xD;
      hospitalization for DLT observation period (C1 28 days). If no DLTs occur in a cohort of 3&#xD;
      subjects, a new cohort of 3 subjects will be treated at the next higher dose level. If 1 of 3&#xD;
      subjects in a cohort experiences a DLT, that cohort will be expanded to 6 subjects. If only 1&#xD;
      of the 6 subjects has a DLT, then the next cohort of 3 subjects will be treated at the next&#xD;
      higher dose level. If 2 or more DLTs occur within a cohort, then that dose level will be&#xD;
      above the MTD, and the previous lower (tolerated) dose level will be considered the MTD if ≤&#xD;
      1 in 6 subjects has a DLT.&#xD;
&#xD;
      A subject who withdraws from the study during Cycle 1 for reasons other than a DLT will be&#xD;
      replaced.&#xD;
&#xD;
      Subjects will be monitored for safety and efficacy throughout the study. After radiological&#xD;
      tumor assessment at Screening, the first radiological assessment of tumor response status&#xD;
      will be performed at Week 12 (± 1 week), unless there is clinical indication warranting&#xD;
      earlier radiologic imaging. The same imaging technique used at baseline has to be used&#xD;
      throughout the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 15, 2017</start_date>
  <completion_date type="Actual">March 31, 2020</completion_date>
  <primary_completion_date type="Actual">March 31, 2020</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>
    <intervention_model_description>Cohorts of 3-6 subjects will be enrolled sequentially at escalating doses of 1.0, 2.5, 5.0 and 10 mg/kg of KN035 weekly.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of dose limiting toxicities</measure>
    <time_frame>From screening to up to cycle 1 (28 days)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>KN035 safety and tolerability assessed by monitoring AEs per the NCI-CTC-AE Version 4.03, physical examination, electrocardiograms, laboratory measurements and severity of adverse events</measure>
    <time_frame>From screening to up to 1 months after the last dose of study drug (up to approximately 2 years</time_frame>
    <description>The safety of KN035 will be assessed throughout the study by monitoring adverse events (AEs) per the NCI-CTC-AE Version 4.03, physical examination, electrocardiograms, laboratory measurements and severity of adverse events.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak Plasma Concentration (Cmax) of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Time (Tmax) of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration versus time curve (AUC) of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>t1/2 of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough concentration of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma clearance (CL) of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation rate of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-Drug Antibody of KN035 in Japanese patients</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of lymphocyte Subtyping</measure>
    <time_frame>From Pre-dose of the first dose to up to 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of cytokine</measure>
    <time_frame>From Pre-dose of the first dose to up to 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>Up to 2 approximately years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>Up to 2 approximately years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-Free survival (PFS)</measure>
    <time_frame>Up to 2 approximately years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR)</measure>
    <time_frame>Up to 2 approximately years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Advanced or Metastatic Solid Tumors</condition>
  <arm_group>
    <arm_group_label>KN035</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohorts of 3-6 subjects will be enrolled sequentially at escalating doses of 1.0, 2.5, 5.0 and 10 mg/kg weekly. Dose escalation will continue until identification of MTD up to a maximum dose of 10 mg/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>KN035</intervention_name>
    <description>Four cohorts dosed at 1.0 mg/kg, 2.5 mg/kg, 5.0 mg/kg, and 10 mg/kg weekly. All cohorts are administered by subcutaneous injection (SC).</description>
    <arm_group_label>KN035</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have a histological or cytological diagnosis of any type of carcinoma,&#xD;
             progressive metastatic disease, or progressive locally advanced disease not amenable&#xD;
             to local therapy. Subjects must have no standard anti-cancer therapy option, who&#xD;
             failed established standard medical anti-cancer therapies for a given tumor type.&#xD;
&#xD;
          -  Subject is male or female and ≥ 18 years of age on the day of signing informed&#xD;
             consent. However, in case a subject is younger than 20 years old, written informed&#xD;
             consent will be obtained from both a subject and a legal representative.&#xD;
&#xD;
          -  Subject must have a performance status of 0 to 1 on the Eastern Cooperative Oncology&#xD;
             Group (ECOG) Performance Scale.&#xD;
&#xD;
          -  Subject must have adequate hematologic and organ function.&#xD;
&#xD;
          -  Subject has voluntarily agreed to participate by giving written informed consent.&#xD;
&#xD;
          -  Women able to get pregnant has a negative urine or serum pregnancy test. If the urine&#xD;
             test is positive or cannot be confirmed as negative, a serum pregnancy test will be&#xD;
             required. The serum pregnancy test must be negative for the subject to be eligible.&#xD;
&#xD;
          -  Female subjects enrolled in the study must be willing to use either 2 adequate barrier&#xD;
             methods or a barrier method plus a hormonal method of contraception to prevent&#xD;
             pregnancy or to abstain from heterosexual activity throughout the study, starting with&#xD;
             Informed Consent through 120 days after the last dose of study therapy. Women who have&#xD;
             had a surgical hysterectomy and/or bilateral oophorectomy, or who are postmenopausal&#xD;
             and have not had a menstrual cycle for 12 consecutive months without medical/medicinal&#xD;
             reasons are not considered to be of childbearing potential. Approved contraceptive&#xD;
             methods include for example; intra uterine device, diaphragm with spermicide*,&#xD;
             cervical cap* with spermicide*, male condoms, or female condom *with spermicide* and&#xD;
             hormonal method of contraception. Spermicides alone are not an acceptable method of&#xD;
             contraception. *: not approved/certified in Japan.&#xD;
&#xD;
        Male subjects must agree to use an adequate method of contraception starting with Informed&#xD;
        Consent through 120 days after the last dose of study therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject who not recovered from the effects of any prior chemotherapy, radioactive, or&#xD;
             biological cancer therapy prior to the first dose of study therapy (for prior cancer&#xD;
             therapy drugs, a washout of 5 half-lives or 28 days whichever is shorter is required),&#xD;
             or who has not recovered to CTCAE Grade 1 or better from the adverse events due to&#xD;
             cancer therapeutics administered more than 4 weeks earlier. Subject who has had&#xD;
             erlotinib, gefitinib, afatinib, or crizotinib within 1 week prior to the first dose of&#xD;
             study therapy, or who has not recovered to CTCAE Grade 1 or better from the adverse&#xD;
             events due to any of these drugs administered more than 1 week earlier. Grade 2&#xD;
             alopecia is allowed to enter.&#xD;
&#xD;
          -  Subject is expected to require any other form of antineoplastic therapy while on study&#xD;
             (including maintenance therapy with another agent for NSCLC).&#xD;
&#xD;
          -  Subject had prior treatment targeting PD-L1. Subjects with prior treatment targeting&#xD;
             PD-1 are allowed to enroll if the subject has a washout time of at least 4 weeks.&#xD;
             Examples of such anti-PD-L1 agents include (but are not limited to): BMS-936559 (MDX&#xD;
             1105); MPDL3280A (RG7446); and MEDI4736.&#xD;
&#xD;
          -  Subject has a medical condition that requires chronic systemic steroid therapy or&#xD;
             requires any other form of immunosuppressive medication. However, subjects using&#xD;
             physiologic replacement doses of hydrocortisone, or its equivalent, will be considered&#xD;
             eligible for this study: up to 20 mg of hydrocortisone (or 5 mg of prednisone) in the&#xD;
             morning and 10 mg of hydrocortisone (or 2.5 mg of prednisone) in the evening. Topical,&#xD;
             intraocular, and intranasal steroids are allowed.&#xD;
&#xD;
          -  Subject has risk factors for bowel obstruction or bowel perforation (examples include&#xD;
             but not limited to a history of acute diverticulitis, intra-abdominal abscess, or&#xD;
             abdominal carcinomatosis).&#xD;
&#xD;
          -  Subject has a known history of a hematologic malignancy, malignant primary brain tumor&#xD;
             or malignant sarcoma, or of another malignant primary solid tumor, unless the subject&#xD;
             has undergone potentially curative therapy with no evidence of that disease for 5&#xD;
             years.&#xD;
&#xD;
          -  Subject has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis. Subjects with previously treated brain metastases may participate provided&#xD;
             they are clinically stable for at least 4 weeks prior to study entry, have no evidence&#xD;
             of new or enlarging brain metastases and are off steroids for at least 7 days from&#xD;
             first dose of KN035.&#xD;
&#xD;
          -  Subject previously had a severe hypersensitivity reaction to treatment with another&#xD;
             mAb.&#xD;
&#xD;
          -  Subject has a history of pneumonitis or interstitial lung disease irrespective of&#xD;
             causes (For the purpose of screening of interstitial lung disease, chest X-ray,&#xD;
             Sialylated carbohydrate antigen (KL-6) (hereafter, KL-6), percutaneous arterial blood&#xD;
             oxygen saturation (hereafter, SpO2) and auscultation are conducted).&#xD;
&#xD;
          -  Subject has an active autoimmune disease or a documented history of autoimmune disease&#xD;
             or syndrome that requires systemic steroids or immunosuppressive agents. Subjects with&#xD;
             vitiligo or resolved childhood asthma/atopy would be exception to this rule. Subjects&#xD;
             that require intermittent use of bronchodilators or local steroid injections would not&#xD;
             be excluded from the study. Subjects with hypothyroidism that is stable on hormone&#xD;
             replacement will not be excluded from the study.&#xD;
&#xD;
          -  Subject has an active infection requiring therapy.&#xD;
&#xD;
          -  Subject is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),&#xD;
             active hepatitis B (HBsAg reactive) or hepatitis C (HCV RNA (qualitative) is&#xD;
             detected); subjects with negative hepatitis C antibody testing may not need RNA&#xD;
             testing.&#xD;
&#xD;
          -  Subject has a history or current evidence of any condition, therapy, or laboratory&#xD;
             abnormality that might confound the results of the study, interfere with the subject's&#xD;
             participation for the full duration of the study, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating Investigator.&#xD;
&#xD;
          -  Subject has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Subject has a marked baseline prolongation of QT/QTc (Fridericia's formula) interval&#xD;
             (e.g., repeated demonstration of a QTc interval &gt;450 milliseconds (ms) as a guidance&#xD;
             considering the patient's background of physiological conditions), or a history of&#xD;
             additional risk factors for torsade de pointes (TdP, e.g., heart failure, hypokalemia,&#xD;
             family history of Long QT Syndrome), or is using concomitant medications that prolong&#xD;
             the QT/QTc interval.&#xD;
&#xD;
          -  Subject is, at the time of signing informed consent, a regular user (including&#xD;
             &quot;recreational use&quot;) of any illicit drugs or had a recent history (within the last&#xD;
             year) of substance abuse (including alcohol).&#xD;
&#xD;
          -  Subjects with symptomatic ascites or pleural effusion. A subject who is clinically&#xD;
             stable following treatment for these conditions (including therapeutic thoraco- or&#xD;
             paracentesis) is eligible.&#xD;
&#xD;
          -  Subject is pregnant or breastfeeding, or expecting to conceive or father children&#xD;
             within the projected duration of the study. However, breastfeeding female subject who&#xD;
             stopped breastfeeding can be included only if she agrees to stop breastfeeding during&#xD;
             the treatment of the investigational drug and to restart breastfeeding 120 days after&#xD;
             the last dose of the investigational drug.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>St. Marianna University School of Medicine Hospital</name>
      <address>
        <city>Kawasaki</city>
        <zip>216-8511</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Cancer Center Hospital</name>
      <address>
        <city>Tokyo</city>
        <zip>104-0045</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>August 7, 2017</study_first_submitted>
  <study_first_submitted_qc>August 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 14, 2017</study_first_posted>
  <last_update_submitted>February 7, 2022</last_update_submitted>
  <last_update_submitted_qc>February 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>KN035</keyword>
  <keyword>Solid tumors</keyword>
  <keyword>Phase 1</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_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/NCT03248843
org study id: KN035-JP-001
nct id: NCT03248843
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is an open label, dose escalation study to evaluate the safety and tolerability of KN035
      in Japanese patients with advanced and metastatic solid tumor. The dose escalation will
      follow the widely used 3+3 design.
This is an open label, dose escalation study to evaluate the safety and tolerability of KN035
      in Japanese patients with advanced and metastatic solid tumor.

      The dose escalation will follow the widely used 3+3 design. Cohorts of 3-6 subjects will be
      enrolled sequentially at escalating doses of 1.0, 2.5, 5.0 and 10 mg/kg weekly. Dose
      escalation will continue until identification of MTD up to a maximum dose of 10 mg/kg. MTD is
      defined as the highest dose studied at which no more than 1 of 6 subjects has experienced a
      dose-limiting toxicity (DLT) in Cycle 1. The enrolled patients are managed under
      hospitalization for DLT observation period (C1 28 days). If no DLTs occur in a cohort of 3
      subjects, a new cohort of 3 subjects will be treated at the next higher dose level. If 1 of 3
      subjects in a cohort experiences a DLT, that cohort will be expanded to 6 subjects. If only 1
      of the 6 subjects has a DLT, then the next cohort of 3 subjects will be treated at the next
      higher dose level. If 2 or more DLTs occur within a cohort, then that dose level will be
      above the MTD, and the previous lower (tolerated) dose level will be considered the MTD if ≤
      1 in 6 subjects has a DLT.

      A subject who withdraws from the study during Cycle 1 for reasons other than a DLT will be
      replaced.

      Subjects will be monitored for safety and efficacy throughout the study. After radiological
      tumor assessment at Screening, the first radiological assessment of tumor response status
      will be performed at Week 12 (± 1 week), unless there is clinical indication warranting
      earlier radiologic imaging. The same imaging technique used at baseline has to be used
      throughout the study.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Cohorts of 3-6 subjects will be enrolled sequentially at escalating doses of 1.0, 2.5, 5.0 and 10 mg/kg of KN035 weekly.
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of dose limiting toxicities
time frame: From screening to up to cycle 1 (28 days)
measure: KN035 safety and tolerability assessed by monitoring AEs per the NCI-CTC-AE Version 4.03, physical examination, electrocardiograms, laboratory measurements and severity of adverse events
time frame: From screening to up to 1 months after the last dose of study drug (up to approximately 2 years
description: The safety of KN035 will be assessed throughout the study by monitoring adverse events (AEs) per the NCI-CTC-AE Version 4.03, physical examination, electrocardiograms, laboratory measurements and severity of adverse events.
measure: Peak Plasma Concentration (Cmax) of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Peak Time (Tmax) of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Area under the plasma concentration versus time curve (AUC) of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: t1/2 of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Trough concentration of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Plasma clearance (CL) of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Apparent volume of distribution of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Accumulation rate of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Anti-Drug Antibody of KN035 in Japanese patients
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Changes of lymphocyte Subtyping
time frame: From Pre-dose of the first dose to up to 48 weeks
measure: Changes of cytokine
time frame: From Pre-dose of the first dose to up to 6 months
measure: Objective Response Rate (ORR)
time frame: Up to 2 approximately years
measure: Disease Control Rate (DCR)
time frame: Up to 2 approximately years
measure: Progression-Free survival (PFS)
time frame: Up to 2 approximately years
measure: Duration of Response (DOR)
time frame: Up to 2 approximately years
arm group label: KN035
arm group type: Experimental
description: Cohorts of 3-6 subjects will be enrolled sequentially at escalating doses of 1.0, 2.5, 5.0 and 10 mg/kg weekly. Dose escalation will continue until identification of MTD up to a maximum dose of 10 mg/kg.
intervention type: Drug
intervention name: KN035
description: Four cohorts dosed at 1.0 mg/kg, 2.5 mg/kg, 5.0 mg/kg, and 10 mg/kg weekly. All cohorts are administered by subcutaneous injection (SC).
arm group label: KN035
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Neoplasms
sharing ipd: No