Healthy
Conditions
Brief summary
This is a 12-week, randomized, double-blind, single-dose pharmacokinetic (PK) study. Approximately 114 healthy male participants (screening occurred within 28 days prior to dosing) will be randomized 1:1:1 to either TRS003, China-approved bevacizumab, and US-licensed Avastin® groups. Study drug will be dispensed as a single 3 mg/kg dose for intravenous infusion within 90 minutes. PK and immunogenicity samples will be collected and safety will be assessed. The primary objective of this study was to demonstrate pharmacokinetic similarity between TRS003, China-approved bevacizumab and US-licensed Avastin®, as measured by AUC0-inf in healthy male participants after a single 3 mg/kg dose.
Detailed description
The primary assessment of PK similarity will be based upon a 90 percentage confidence interval (CI) for the ratio of the geometric means (TRS003, China-approved bevacizumab and US-licensed Avastin®) for AUC0-inf on PK analysis set. If the 90 percentage CI of the ratio of the geometric means for AUC0-inf is within the range of 80-125 percentage, then PK similarity will be concluded. Secondary PK parameters such as but not limited to Cmax, AUClast will be analyzed using the same statistical approach. A nonparametric approach, for example, Wilcoxon signed-rank test, will be taken to evaluate parameters such as t1/2. Exploratory analyses may be performed for other PK parameters as deemed appropriate. All adverse events (AEs) will be listed and summarized using descriptive methodology. The incidence of AEs for each treatment will be presented by severity and association with the study drugs. Clinical laboratory parameters, vital signs, and electrocardiogram (ECG) parameters will be listed and summarized using descriptive statistics. The number and percentage of participants testing positive for anti-drug antibodies (ADAs) will be summarized by treatment and time point.
Interventions
BIOLOGICALTRS003
25mg/mL (4 mL/vial) Injection，Single dose of 3mg/kg Intravenous infusion for 90 minutes
BIOLOGICALChina-approved Bevacizumab
25mg/mL (4 mL/vial) Injection，Single dose of 3mg/kg Intravenous infusion for 90 minutes
BIOLOGICALUS-licensed Avastin
25mg/mL (4 mL/vial) Injection，Single dose of 3mg/kg Intravenous infusion for 90 minutes
Sponsors
Zhejiang Teruisi Pharmaceutical Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
double-blind
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy, male participants, 18-55 years old with no significant medical history, and in good health as determined by detailed medical history, full physical examination, vital signs, 12-lead electrocardiogram (ECG), urinalysis and laboratory tests at screening. * Body mass index of 17.5-30.5 kg/m\^2 and body weight of 50-95 kg. * Protocol-specified hematology, coagulation, blood chemistry and urinalysis within the laboratory normal range at screening, unless deemed not clinically significant by the Investigator. * Participants must have adequate organ function according to the following laboratory values: 1. Bone marrow function (absolute neutrophil count ≥1500/mm\^3 and platelet count ≥100,000/mm\^3) 2. Adequate liver function \[alanine aminotransferase (ALT) ≤3 × upper limit normal (ULN) and alkaline phosphatase ≤2 × ULN, total bilirubin ≤1.5 mg/dL\] 3. Adequate renal function creatinine clearance ≥60 mL/min based on Cockcroft-Gault equation * Participants must agree to use an acceptable form of birth control throughout the study and for at least 18 weeks after the study is over.
Exclusion criteria
* Participants unable to give voluntary informed consent. * Evidence or history of clinically significant disease, cancer other than adequately treated basal cell or squamous cell carcinoma of the skin. * Participants on anticoagulant drugs, anemic or with known bleeding diatheses. * Participants with a history of severe, uncontrolled hypertension, heart disease, cerebrovascular incidents, gastrointestinal bleeding, hemoptysis, frequent epistaxis or gingival bleeding. * History clinically significant orthostatic hypotension, fainting spells, vasovagal syncope. * Uncontrolled severe hypertension (140/90 mm Hg). * Previous treatment with an anti-VEGF antibody or any other antibody or protein targeting the VEGF receptor. * Use of any prescription, investigational drugs, herbal supplements or nonprescription drugs within 1 month or 5 half-lives (whichever is longer) prior to the first dose, or dietary supplements within 1 week prior to the first dose. If needed, paracetamol/acetaminophen may be used, but must be documented in the Concomitant medications/Significant non-drug therapies page of the case report form (CRF). * Serious unhealed wound, cutaneous ulcer or bone fracture at the time of screening. * Major surgery or major dental procedure or significant traumatic injury within 2 months prior to screening, or any planned surgery or procedure within 3 months after investigational treatment administration. Participants must have recovered from all acute surgery- or trauma-related complications. * Participant's medical and family history of recent or recurrent thromboembolism or other clotting and coagulation disorders. * Donated blood over 400 mL within 3 months. * History of relevant and clinically significant intra-abdominal inflammation, gastrointestinal perforation or gall bladder perforation. * History of severe allergic or anaphylactic reaction to a therapeutic drug or severe seasonal allergies. * Recent (within the last three \[3\] years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated). * A positive hepatitis B, hepatitis C or HIV tests at screening indicative of a current or past infection. * Current use of tobacco or nicotine-containing products. Concomitant treatment was given only if Investigator believes strictly necessary and should be documented. * Current use of any biologic drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-inf，Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity | Pre-dose, 0 hour (End of infusion, EOI), 0.5 hour, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours, 336 hours, 672 hours, 1008 hours, 1344 hours, 1680 hours, and 2016 hours post EOI | The primary assessment of PK similarity will be based upon a 90 percentage CI for the ratio of the geometric means (TRS003, China-approved bevacizumab and US-licensed Avastin®) for AUC0-inf on PK analysis set. If the 90 percentage CI of the ratio of the geometric means for AUC0-inf is within the range of 80-125 percentage, then PK similarity will be concluded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax, Maximum Drug Concentration | Pre-dose, 0 hour (End of infusion, EOI), 0.5 hour, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours, 336 hours, 672 hours, 1008 hours, 1344 hours, 1680 hours, and 2016 hours post EOI | To assess other PK parameters such as Cmax, following a single dose of TRS003, China-approved bevacizumab and US-licensed Avastin® in healthy male participants. If the 90 percentage CI of the ratio of the geometric means for Cmax is within the range of 80-125 percentage, then PK similarity will be concluded. |
| AUC0-last, Area Under the Serum Concentration-time Curve，Time 0 to Last | Pre-dose, 0 hour (End of infusion, EOI), 0.5 hour, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours, 336 hours, 672 hours, 1008 hours, 1344 hours, 1680 hours, and 2016 hours post EOI | To assess other PK parameters such as AUClast, following a single dose of TRS003, China-approved bevacizumab and US-licensed Avastin® in healthy male participants. If the 90 percentage CI of the ratio of the geometric means for AUC0-last is within the range of 80-125 percentage, then PK similarity will be concluded. |
| Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | Pre-dose, 336 hours, 672 hours, 1344 hours and 2016 hours after EOI (End of infusion) | To determine the number of participants with immunogenicity against TRS003, China-approved bevacizumab, and US-licensed Avastin® in healthy male participants, blood samples will be collected for ADA analyses. |
| Number of Participants With Adverse Events (AEs) | Within 85 days following the drug administration | Adverse events will be classified using the MedDRA classification system. The severity of the toxicities will be graded according to the NCI CTCAE version 4.03. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TRS003 Proposed biosimilar of bevacizumab，Intravenous administration
TRS003: 25mg/mL (4 mL/vial) Injection，Single dose of 3mg/kg Intravenous infusion for 90 minutes | 38 |
| China-approved Bevacizumab Intravenous administration
China-approved Bevacizumab: 25mg/mL (4 mL/vial) Injection，Single dose of 3mg/kg Intravenous infusion for 90 minutes | 38 |
| US-licensed Avastin Intravenous administration
US-licensed Avastin: 25mg/mL (4 mL/vial) Injection，Single dose of 3mg/kg Intravenous infusion for 90 minutes | 38 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 0 | 0 |
| Overall Study | schedule conflict | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | TRS003 | China-approved Bevacizumab | US-licensed Avastin | Total |
|---|---|---|---|---|
| Age, Customized Pharmacokinetic Population <18 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Pharmacokinetic Population 18-40 | 26 Participants | 30 Participants | 25 Participants | 81 Participants |
| Age, Customized Pharmacokinetic Population >40 | 12 Participants | 8 Participants | 13 Participants | 33 Participants |
| Age, Customized Safety Population <18 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Safety Population 18-40 | 26 Participants | 30 Participants | 25 Participants | 81 Participants |
| Age, Customized Safety Population >40 | 12 Participants | 8 Participants | 13 Participants | 33 Participants |
| BMI | 26.09 kg/m^2 | 26.21 kg/m^2 | 25.84 kg/m^2 | 26.05 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 27 Participants | 25 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 11 Participants | 13 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 175.37 cm | 173.09 cm | 174.62 cm | 174.36 cm |
| Race/Ethnicity, Customized Race Am Indian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 4 Participants | 6 Participants | 4 Participants | 14 Participants |
| Race/Ethnicity, Customized Race Black | 18 Participants | 8 Participants | 9 Participants | 35 Participants |
| Race/Ethnicity, Customized Race Hawaiian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Multi-racial | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 15 Participants | 22 Participants | 25 Participants | 62 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 38 Participants | 38 Participants | 38 Participants | 114 Participants |
| Weight | 80.16 kg | 78.55 kg | 78.82 kg | 79.18 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 38 | 0 / 38 |
| other Total, other adverse events | 6 / 38 | 12 / 38 | 11 / 38 |
| serious Total, serious adverse events | 0 / 38 | 0 / 38 | 0 / 38 |
Outcome results
Primary
AUC0-inf，Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity
The primary assessment of PK similarity will be based upon a 90 percentage CI for the ratio of the geometric means (TRS003, China-approved bevacizumab and US-licensed Avastin®) for AUC0-inf on PK analysis set. If the 90 percentage CI of the ratio of the geometric means for AUC0-inf is within the range of 80-125 percentage, then PK similarity will be concluded.
Time frame: Pre-dose, 0 hour (End of infusion, EOI), 0.5 hour, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours, 336 hours, 672 hours, 1008 hours, 1344 hours, 1680 hours, and 2016 hours post EOI
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TRS003 | AUC0-inf，Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity | 30308695.01 hr*ng/mL | Standard Deviation 4780171.58 |
| China-approved Bevacizumab | AUC0-inf，Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity | 28449241.04 hr*ng/mL | Standard Deviation 5232124.54 |
| US-licensed Avastin | AUC0-inf，Area Under the Serum Concentration Versus Time Curve，Time 0 to Infinity | 29050169.73 hr*ng/mL | Standard Deviation 4476342.82 |
Secondary
AUC0-last, Area Under the Serum Concentration-time Curve，Time 0 to Last
To assess other PK parameters such as AUClast, following a single dose of TRS003, China-approved bevacizumab and US-licensed Avastin® in healthy male participants. If the 90 percentage CI of the ratio of the geometric means for AUC0-last is within the range of 80-125 percentage, then PK similarity will be concluded.
Time frame: Pre-dose, 0 hour (End of infusion, EOI), 0.5 hour, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours, 336 hours, 672 hours, 1008 hours, 1344 hours, 1680 hours, and 2016 hours post EOI
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TRS003 | AUC0-last, Area Under the Serum Concentration-time Curve，Time 0 to Last | 29146948.37 hr*ng/mL | Standard Deviation 4383124.3 |
| China-approved Bevacizumab | AUC0-last, Area Under the Serum Concentration-time Curve，Time 0 to Last | 27446018.92 hr*ng/mL | Standard Deviation 4716128.56 |
| US-licensed Avastin | AUC0-last, Area Under the Serum Concentration-time Curve，Time 0 to Last | 27951588.98 hr*ng/mL | Standard Deviation 4089884.99 |
Secondary
Cmax, Maximum Drug Concentration
To assess other PK parameters such as Cmax, following a single dose of TRS003, China-approved bevacizumab and US-licensed Avastin® in healthy male participants. If the 90 percentage CI of the ratio of the geometric means for Cmax is within the range of 80-125 percentage, then PK similarity will be concluded.
Time frame: Pre-dose, 0 hour (End of infusion, EOI), 0.5 hour, 4 hours, 8 hours, 24 hours, 48 hours, 96 hours, 168 hours, 336 hours, 672 hours, 1008 hours, 1344 hours, 1680 hours, and 2016 hours post EOI
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TRS003 | Cmax, Maximum Drug Concentration | 86051.02 ng/mL | Standard Deviation 14888.99 |
| China-approved Bevacizumab | Cmax, Maximum Drug Concentration | 84748.14 ng/mL | Standard Deviation 12592.56 |
| US-licensed Avastin | Cmax, Maximum Drug Concentration | 82509.03 ng/mL | Standard Deviation 13197.95 |
Secondary
Number of Participants Who Develop Detectable Anti-drug Antibody (ADA)
To determine the number of participants with immunogenicity against TRS003, China-approved bevacizumab, and US-licensed Avastin® in healthy male participants, blood samples will be collected for ADA analyses.
Time frame: Pre-dose, 336 hours, 672 hours, 1344 hours and 2016 hours after EOI (End of infusion)
Population: In TRS003, four subjects were lost to follow-up and one subject elected to withdraw due to schedule conflict, resulting in 13 samples missing.~In China-approved bevacizumab, three subjects were lost to follow-up, resulting in 4 samples missing.~In US-licensed Avastin, two subjects were lost to follow-up, resulting in 2 sample missing.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 1344 hour | Negative | 33 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 336 hour | Negative | 36 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 2016 hour | Negative | 35 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 0 hour | Negative | 37 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 2016 hour | Positive | 0 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 1344 hour | Positive | 0 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 336 hour | Positive | 0 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 0 hour | Positive | 1 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 672 hour | Negative | 35 Participants |
| TRS003 | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 672 hour | Positive | 0 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 1344 hour | Negative | 34 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 336 hour | Positive | 0 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 1344 hour | Positive | 2 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 336 hour | Negative | 37 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 672 hour | Positive | 0 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 2016 hour | Negative | 35 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 0 hour | Negative | 37 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 672 hour | Negative | 37 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 2016 hour | Positive | 3 Participants |
| China-approved Bevacizumab | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 0 hour | Positive | 1 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 2016 hour | Positive | 0 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 0 hour | Negative | 38 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 0 hour | Positive | 0 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 336 hour | Negative | 37 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 336 hour | Positive | 0 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 672 hour | Negative | 37 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 672 hour | Positive | 0 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 1344 hour | Negative | 38 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 1344 hour | Positive | 0 Participants |
| US-licensed Avastin | Number of Participants Who Develop Detectable Anti-drug Antibody (ADA) | 2016 hour | Negative | 38 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
Adverse events will be classified using the MedDRA classification system. The severity of the toxicities will be graded according to the NCI CTCAE version 4.03.
Time frame: Within 85 days following the drug administration
Population: 110 subjects completed the study. Three subjects who received Treatment A (Subject Nos. Subject Nos. 1-119, 1-120, and 1-177) were lost to follow-up and 1 subject (Subject No. 1-138) who received Treatment A was withdrawn from the study due to other reason (schedule conflict).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TRS003 | Number of Participants With Adverse Events (AEs) | 6 Participants |
| China-approved Bevacizumab | Number of Participants With Adverse Events (AEs) | 12 Participants |
| US-licensed Avastin | Number of Participants With Adverse Events (AEs) | 11 Participants |