Assessment of TK006 in Patients With Breast Cancer-related Bone Metastases

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: TK006


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients provide written informed consent voluntarily； 18 65 years old； Patients with pathology confirmed breast cancer radiological evidence with bone metastasis； Eastern Cooperative Oncology Group(ECOG) performance status≤2 Anticipated life span≥6-month； Adequate reservation of hematopoiesis, liver and kidney functions: Absolute neutrophil count (ANC) ≥1.5×10^9/L Absolute platelet count (PLT) ≥100×10^9/L Hemoglobin (Hb) ≥90 g/L Total bilirubin (TBIL) ≤1.0 time the upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0 ULN Serum creatinine (sCr) ≤2.0 ULN Albumin-adjusted calcium≥2.0 mmol/L, ≤2.9 mmol/ L(Calcium supplements are not allowed within 8 hours before examination). Exclusion Criteria: Hypersensitivity to any investigational medicine or supplements in this study. Women in Pregnancy or nursing. Anti-human immunodeficiency virus (HIV) antibody positive. Patients with hepatitis B virus DNA ≥10^5 copies/mL or active hepatitis C would not be selected. Stable hepatitis B or hepatitis C defined as AST/ALT≤2 ULN will not be selected as well if patients are not treated with antiviral therapy while receving immunosuppressive therapy or chemotherapy meanwhile. Prior malignancies (excluding the targeted breast cancer, basal cell carcinoma, or cervical cancer in situ) within 3 years. Uncontrolled systemic diseases, or organic or mental disorders that could affect compliance. Central nervous system metastasis that is symptomatic or require treatment. Unresolved toxicities ≥2 grades from previous chemo-therapy (excluding alopecia). Major surgery of bone or trauma within 4 weeks before the first dosing. Fracture of long bone within 90-day before the first dosing. Radiation therapy to bone within 2 weeks or treatment with radioisotopes within 8 weeks before the first dosing. Treatment with diphosphonate within 30-day or administration of calcitonin, parathyroid hormone-related peptides, mithramycin, gallium nitrate or strontium ranelate within 6-month before the first dosing. Plan to receive systemic treatment with glucocorticosteroids over a long period during the trial. Hyperthyroidism or hypothyroidism, unless hypothyroidism patients are receiving regular treatment with thyroid hormone and: 1) Thyroid stimulating hormone (TSH) is normal, or 2) TSH>4.78μIU/Ml, ≤10.0μIU/mL and thyroxine (T4) is normal. 14. Disorders of hypoparathyroidism or hyperparathyroidism, osteomalacia, rheumatoid arthritis, acute attack of osteoarthritis, gout, Paget's disease, malabsorption syndrome, ascites, or other diseases that could affect bone metabolism. 15. Previous or existing osteomyelitis or osteonecrosis of jaw, odontia or jaw diseases which are in active or require invasive operations, unhealing wound of oral surgery, or planned invasive dental operations during this trial. 16. Has been selected for the study of other test devices or test drugs, or the duration of the clinical studies that have taken less than 30 days or 5 half-lives or biological effects, whichever is longer. 17. Other situations which are not suitable for participation judged by the principal investigator (PI).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 60 mg single dose cohort<br>patients would receive a 60 mg single dose of TK006. | Biological: TK006<br>* Subcutaneous injection<br>* Other names: fully human monoclonal anti-RANKL antibody;|
| Experimental: 120 mg single dose cohort<br>patients would receive a 120 mg single dose of TK006. | Biological: TK006<br>* Subcutaneous injection<br>* Other names: fully human monoclonal anti-RANKL antibody;|
| Experimental: 180 mg single dose cohort<br>patients would receive a 180 mg single dose of TK006. | Biological: TK006<br>* Subcutaneous injection<br>* Other names: fully human monoclonal anti-RANKL antibody;|
| Experimental: 120 mg Q4W cohort<br>patients would receive 120 mg TK006 every 4 weeks, for a total of 3 doses. | Biological: TK006<br>* Subcutaneous injection<br>* Other names: fully human monoclonal anti-RANKL antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events (AEs) and serious adverse events (SAEs) which are related to TK006 assessed by CTCAE v4.03 | Collect the information of AEs and SAEs, vital sign, physical examination, laboratory examination and electrocardiogram during the trial. | single dose cohort：112 days, multiple dose cohort：140 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from time zero to time 'last' where last is the last time point after administration [AUClast] | Calculated by the linear trapezoidal method. | single dose cohort：112 days, multiple dose cohort：140 days | 
| Area under the plasma concentration-time curve from time zero to infinity [AUC0-inf] | Calculated by the linear trapezoidal and extrapolation method. | single dose cohort：112 days, multiple dose cohort：140 days | 
| Maximum observed maximum plasma concentration [Cmax] | The maximum (or peak) serum concentration that TK006 achieves after the drug has been administrated and before the administration of a second dose. | single dose cohort：112 days, multiple dose cohort：140 days | 
| Time to reach the maximum observed plasma concentration [Tmax] | The time at which the Cmax is observed. | single dose cohort：112 days, multiple dose cohort：140 days | 
| Terminal elimination half-life[T1/2] | 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. | single dose cohort：112 days, multiple dose cohort：140 days | 
| bioavailability corrected apparent volume of the central compartment cleared of drug per unit [Cl/F] | The apparent volume of the central compartment cleared of drug per unit time was estimated using the formula: Cl/F = Dose / AUC0-∞ | single dose cohort：112 days, multiple dose cohort：140 days | 
| bioavailability corrected apparent volume of distribution [Vd/F] | Apparent volume of distribution based on the terminal elimination phase. | single dose cohort：112 days, multiple dose cohort：140 days | 
| urine creatinine corrected cross-linked N-telopeptides of type I collagen [uNTX/Cr] | 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. | single dose cohort：112 days, multiple dose cohort：140 days | 
| serum bone alkaline phosphatase [bALP] | 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. | single dose cohort：112 days, multiple dose cohort：140 days | 
| anti-drug antibody [ADA] | 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. | single dose cohort：112 days, multiple dose cohort：140 days |