<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/NCT03239756</url>
  </required_header>
  <id_info>
    <org_study_id>Tmab-TK006-102</org_study_id>
    <nct_id>NCT03239756</nct_id>
  </id_info>
  <brief_title>Assessment of TK006 in Patients With Breast Cancer-related Bone Metastases</brief_title>
  <official_title>Phase 1 Trial of a Fully Human Monoclonal Antibody of Receptor Activator for Nuclear Factor-κ B Ligand (RNAKL, TK006) Safety, Pharmacokinetics, and Pharmacodynamics in Patients With Breast Cancer-related Bone Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jiangsu T-Mab Biopharma Co.,Ltd</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Jiangsu T-Mab Biopharma Co.,Ltd</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 single-center, open-label, dose-escalating study to evaluate the safety,&#xD;
      pharmacokinetics, immunogenicity, and preliminary efficacy of single and multiple&#xD;
      subcutaneous injection TK006 in patients with breast cancer-related bone metastases.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an single-center, open-label, dose-escalating study to evaluate the safety,&#xD;
      pharmacokinetics, immunogenicity, and preliminary efficacy of single and multiple&#xD;
      subcutaneous injection TK006 in patients with breast cancer-related bone metastases. It&#xD;
      contains 4 cohorts：60 mg single-dose conhort, 120 mg single-dose conhort, 180 mg single-dose&#xD;
      conhort and 120 mg Q4W （one dose every 4 weeks, 3 dose totally） conhort.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 20, 2017</start_date>
  <completion_date type="Anticipated">August 2018</completion_date>
  <primary_completion_date type="Anticipated">August 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Frequency of adverse events (AEs) and serious adverse events (SAEs) which are related to TK006 assessed by CTCAE v4.03</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>Collect the information of AEs and SAEs, vital sign, physical examination, laboratory examination and electrocardiogram during the trial.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero to time 'last' where last is the last time point after administration [AUClast]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>Calculated by the linear trapezoidal method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero to infinity [AUC0-inf]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>Calculated by the linear trapezoidal and extrapolation method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum observed maximum plasma concentration [Cmax]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>The maximum (or peak) serum concentration that TK006 achieves after the drug has been administrated and before the administration of a second dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach the maximum observed plasma concentration [Tmax]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>The time at which the Cmax is observed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal elimination half-life[T1/2]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>The time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>bioavailability corrected apparent volume of the central compartment cleared of drug per unit [Cl/F]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>The apparent volume of the central compartment cleared of drug per unit time was estimated using the formula: Cl/F = Dose / AUC0-∞</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>bioavailability corrected apparent volume of distribution [Vd/F]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>Apparent volume of distribution based on the terminal elimination phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>urine creatinine corrected cross-linked N-telopeptides of type I collagen [uNTX/Cr]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>For singel dose cohort, detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28, day 56, day 84 and day 112 For multiple dose cohort：detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28 (before dosing), day 56 (before dosing), day 84 and day 140.&#xD;
Assessing the change of uNTX level to baseline and the uNTX should be corrected by urine creatinine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>serum bone alkaline phosphatase [bALP]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>Assessing the change of serum bALP level to baseline. For singel dose cohort, detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28, day 56, day 84 and day 112 For multiple dose cohort：detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28 (before dosing), day 56 (before dosing), day 84 and day 140.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>anti-drug antibody [ADA]</measure>
    <time_frame>single dose cohort：112 days, multiple dose cohort：140 days</time_frame>
    <description>Quantitative assay the ADA. For single cohort, the ADA titer would be detected at day 0 (before dosing) and day 56.&#xD;
For multiple dose cohort, the ADA titer would be detected at day 0 (before dosing), day 28 (before dosing), day 56 (before dosing), day 84 and day 140.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>60 mg single dose cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients would receive a 60 mg single dose of TK006.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>120 mg single dose cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients would receive a 120 mg single dose of TK006.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>180 mg single dose cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients would receive a 180 mg single dose of TK006.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>120 mg Q4W cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients would receive 120 mg TK006 every 4 weeks, for a total of 3 doses.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TK006</intervention_name>
    <description>Subcutaneous injection</description>
    <arm_group_label>120 mg Q4W cohort</arm_group_label>
    <arm_group_label>120 mg single dose cohort</arm_group_label>
    <arm_group_label>180 mg single dose cohort</arm_group_label>
    <arm_group_label>60 mg single dose cohort</arm_group_label>
    <other_name>fully human monoclonal anti-RANKL antibody</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients provide written informed consent voluntarily；&#xD;
&#xD;
          2. 18~65 years old；&#xD;
&#xD;
          3. Patients with pathology confirmed breast cancer radiological evidence with bone&#xD;
             metastasis；&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group(ECOG) performance status≤2&#xD;
&#xD;
          5. Anticipated life span≥6-month；&#xD;
&#xD;
          6. Adequate reservation of hematopoiesis, liver and kidney functions:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥1.5×10^9/L&#xD;
&#xD;
               -  Absolute platelet count (PLT) ≥100×10^9/L&#xD;
&#xD;
               -  Hemoglobin (Hb) ≥90 g/L&#xD;
&#xD;
               -  Total bilirubin (TBIL) ≤1.0 time the upper limit of normal (ULN)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0 ULN&#xD;
&#xD;
               -  Serum creatinine (sCr) ≤2.0 ULN&#xD;
&#xD;
          7. Albumin-adjusted calcium≥2.0 mmol/L, ≤2.9 mmol/ L(Calcium supplements are not allowed&#xD;
             within 8 hours before examination).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Hypersensitivity to any investigational medicine or supplements in this study.&#xD;
&#xD;
          2. Women in Pregnancy or nursing.&#xD;
&#xD;
          3. Anti-human immunodeficiency virus (HIV) antibody positive.&#xD;
&#xD;
          4. Patients with hepatitis B virus DNA ≥10^5 copies/mL or active hepatitis C would not be&#xD;
             selected. Stable hepatitis B or hepatitis C defined as AST/ALT≤2 ULN will not be&#xD;
             selected as well if patients are not treated with antiviral therapy while receving&#xD;
             immunosuppressive therapy or chemotherapy meanwhile.&#xD;
&#xD;
          5. Prior malignancies (excluding the targeted breast cancer, basal cell carcinoma, or&#xD;
             cervical cancer in situ) within 3 years.&#xD;
&#xD;
          6. Uncontrolled systemic diseases, or organic or mental disorders that could affect&#xD;
             compliance.&#xD;
&#xD;
          7. Central nervous system metastasis that is symptomatic or require treatment.&#xD;
&#xD;
          8. Unresolved toxicities ≥2 grades from previous chemo-therapy (excluding alopecia).&#xD;
&#xD;
          9. Major surgery of bone or trauma within 4 weeks before the first dosing.&#xD;
&#xD;
         10. Fracture of long bone within 90-day before the first dosing.&#xD;
&#xD;
         11. Radiation therapy to bone within 2 weeks or treatment with radioisotopes within 8&#xD;
             weeks before the first dosing.&#xD;
&#xD;
         12. Treatment with diphosphonate within 30-day or administration of calcitonin,&#xD;
             parathyroid hormone-related peptides, mithramycin, gallium nitrate or strontium&#xD;
             ranelate within 6-month before the first dosing. Plan to receive systemic treatment&#xD;
             with glucocorticosteroids over a long period during the trial.&#xD;
&#xD;
         13. Hyperthyroidism or hypothyroidism, unless hypothyroidism patients are receiving&#xD;
             regular treatment with thyroid hormone and:&#xD;
&#xD;
        1) Thyroid stimulating hormone (TSH) is normal, or 2) TSH&gt;4.78μIU/Ml, ≤10.0μIU/mL and&#xD;
        thyroxine (T4) is normal. 14. Disorders of hypoparathyroidism or hyperparathyroidism,&#xD;
        osteomalacia, rheumatoid arthritis, acute attack of osteoarthritis, gout, Paget's disease,&#xD;
        malabsorption syndrome, ascites, or other diseases that could affect bone metabolism.&#xD;
&#xD;
        15. Previous or existing osteomyelitis or osteonecrosis of jaw, odontia or jaw diseases&#xD;
        which are in active or require invasive operations, unhealing wound of oral surgery, or&#xD;
        planned invasive dental operations during this trial.&#xD;
&#xD;
        16. Has been selected for the study of other test devices or test drugs, or the duration of&#xD;
        the clinical studies that have taken less than 30 days or 5 half-lives or biological&#xD;
        effects, whichever is longer.&#xD;
&#xD;
        17. Other situations which are not suitable for participation judged by the principal&#xD;
        investigator (PI).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jiang H Y</last_name>
    <role>Study Director</role>
    <affiliation>Jiangsu T-Mab Biopharma Co.,Ltd</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yu M X</last_name>
    <phone>15021830072</phone>
    <email>yumingxia@sh-qingfeng.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jiang H B</last_name>
    <phone>13062892252</phone>
    <email>jianghaibiao@sh-qingfeng.net</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>the first affiliated hospital with Nanjing University</name>
      <address>
        <city>Nanjing</city>
        <state>Jiangsu</state>
        <zip>210029</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yin Y M</last_name>
      <phone>13951842727</phone>
      <email>ym.yin@hotmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>July 28, 2017</study_first_submitted>
  <study_first_submitted_qc>August 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2017</study_first_posted>
  <last_update_submitted>August 21, 2017</last_update_submitted>
  <last_update_submitted_qc>August 21, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast 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/NCT03239756
org study id: Tmab-TK006-102
nct id: NCT03239756
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a single-center, open-label, dose-escalating study to evaluate the safety,
      pharmacokinetics, immunogenicity, and preliminary efficacy of single and multiple
      subcutaneous injection TK006 in patients with breast cancer-related bone metastases.
This is an single-center, open-label, dose-escalating study to evaluate the safety,
      pharmacokinetics, immunogenicity, and preliminary efficacy of single and multiple
      subcutaneous injection TK006 in patients with breast cancer-related bone metastases. It
      contains 4 cohorts：60 mg single-dose conhort, 120 mg single-dose conhort, 180 mg single-dose
      conhort and 120 mg Q4W （one dose every 4 weeks, 3 dose totally） conhort.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Frequency of adverse events (AEs) and serious adverse events (SAEs) which are related to TK006 assessed by CTCAE v4.03
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: Collect the information of AEs and SAEs, vital sign, physical examination, laboratory examination and electrocardiogram during the trial.
measure: Area under the plasma concentration-time curve from time zero to time 'last' where last is the last time point after administration [AUClast]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: Calculated by the linear trapezoidal method.
measure: Area under the plasma concentration-time curve from time zero to infinity [AUC0-inf]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: Calculated by the linear trapezoidal and extrapolation method.
measure: Maximum observed maximum plasma concentration [Cmax]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: The maximum (or peak) serum concentration that TK006 achieves after the drug has been administrated and before the administration of a second dose.
measure: Time to reach the maximum observed plasma concentration [Tmax]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: The time at which the Cmax is observed.
measure: Terminal elimination half-life[T1/2]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: The time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose.
measure: bioavailability corrected apparent volume of the central compartment cleared of drug per unit [Cl/F]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: The apparent volume of the central compartment cleared of drug per unit time was estimated using the formula: Cl/F = Dose / AUC0-∞
measure: bioavailability corrected apparent volume of distribution [Vd/F]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: Apparent volume of distribution based on the terminal elimination phase.
measure: urine creatinine corrected cross-linked N-telopeptides of type I collagen [uNTX/Cr]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: For singel dose cohort, detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28, day 56, day 84 and day 112 For multiple dose cohort：detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28 (before dosing), day 56 (before dosing), day 84 and day 140.
Assessing the change of uNTX level to baseline and the uNTX should be corrected by urine creatinine.
measure: serum bone alkaline phosphatase [bALP]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: Assessing the change of serum bALP level to baseline. For singel dose cohort, detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28, day 56, day 84 and day 112 For multiple dose cohort：detecting the level of uNTX at screening period, day 0 (before dosing)、day 1, day 7, day 14, day 28 (before dosing), day 56 (before dosing), day 84 and day 140.
measure: anti-drug antibody [ADA]
time frame: single dose cohort：112 days, multiple dose cohort：140 days
description: Quantitative assay the ADA. For single cohort, the ADA titer would be detected at day 0 (before dosing) and day 56.
For multiple dose cohort, the ADA titer would be detected at day 0 (before dosing), day 28 (before dosing), day 56 (before dosing), day 84 and day 140.
arm group label: 60 mg single dose cohort
arm group type: Experimental
description: patients would receive a 60 mg single dose of TK006.
arm group label: 120 mg single dose cohort
arm group type: Experimental
description: patients would receive a 120 mg single dose of TK006.
arm group label: 180 mg single dose cohort
arm group type: Experimental
description: patients would receive a 180 mg single dose of TK006.
arm group label: 120 mg Q4W cohort
arm group type: Experimental
description: patients would receive 120 mg TK006 every 4 weeks, for a total of 3 doses.
intervention type: Biological
intervention name: TK006
description: Subcutaneous injection
arm group label: 120 mg Q4W cohort
arm group label: 120 mg single dose cohort
arm group label: 180 mg single dose cohort
arm group label: 60 mg single dose cohort
other name: fully human monoclonal anti-RANKL antibody
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Jiang H Y
role: Study Director
affiliation: Jiangsu T-Mab Biopharma Co.,Ltd
last name: Yu M X
phone: 15021830072
email: yumingxia@sh-qingfeng.net
last name: Jiang H B
phone: 13062892252
email: jianghaibiao@sh-qingfeng.net
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Breast Neoplasms