Phase I - Pharmacokinetic Comparability Study in Healthy Male Volunteers

Study Overview
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Brief Summary
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Double-blind, single-dose, three-treatment, parallel group design PK comparability study of MYL-1402O solution manufactured for Mylan compared to US and EU marketed Avastin® solution (bevacizumab).

Detailed Description
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Double-blind, single-dose, three-treatment, parallel group design PK comparability study of MYL-1402O solution manufactured for Mylan compared to US and EU marketed Avastin® solution (bevacizumab) in a total of 111 healthy, adult male volunteers (37 subjects per treatment arm). After randomization, subjects will receive one of the following treatments: A single 1 mg/kg dose administered by i.v. infusion (25 mL over approximately 90 minutes) of MYL-1402O, an equivalent i.v. infusion of US marketed Avastin® (1 mg/kg), or an equivalent i.v. infusion of EU marketed Avastin® (1 mg/kg).

Official Title
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A Single Center, Randomized, Double-blind, 3-arm Parallel Phase1 Study to Assess PK, Safety, and Tolerability of a Single 90 Min iv Infusion of 1 mg/kg MYL-1402O, EU Avastin®, and US Avastin® in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: MYL-1402O
* Drug: US marketed Avastin(R)
* Drug: EU marketed Avastin(R)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males aged 18-55 yrs. (inclusive) BMI: 19.0 to 30.0 kg/m2 (inclusive) Weight: ≥ 60kg and ≤100kg Subjects should be willing to use adequate contraception and not donate sperm from admission to clinical research center until 6 months post dosing. All intermittent medications should have be stopped at least 14days prior to admission to the clinical research center. All intermittent non topical medication must be stopped at least 30days prior to admission to the clinical research center. Ability and willingness to abstain from ETOH 48hrs prior to admission to the clinical research center. Medical history without significant findings per the PI Resting supine systolic BP of ≤140mmHg and diastolic BP of ≤90mmHg ECGs (via 12 lead) showing NCS findings per PI All clinical laboratory tests of blood and urine, WNL and/or without clinically significant findings Willing/able to sign ICF Normal bowel habits Negative medical history regarding fecal blood positivity Normal and/or NCS spot protein/creatinine (PCR) ratio. Exclusion Criteria: Previous participation in the current study History of prior exposure to bevacizumab Evidence of clinically significant findings Cognitive and / or mentally impaired handicaps that would affect ability to make an informed consent and/or remain compliant to the requirements of this trial. History of relevant drug and/or food related allergies. History of or known hypersensitivity to bevacizumab or other recombinant human or humanized antibodies or inactive ingredients. Tobacco product use w/I 1 yr. prior to drug administration. History of ETOH and or drug abuse/addiction Positive urine drug and ETOH screen for opiates, methadone, cocaine, amphetamines including XTC, cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants and ETOH. Average intake of more than 24 units of ETOH / wk. (1 unit of ETOH equals  250mL of beer, 100mL of wine or 35mL of spirits). Consumption of any foods containing poppy seeds w/I 48 hrs. prior to screening and admission to the clinical research center Positive screen for Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) antibodies or anti-human immunodeficiency virus (HIV) 1 and 2 antibodies. Participation in a drug study w/I 60days or 5 half-lives of the previous drug. Participation in more than 3 other drug studies in the 10months prior to drug administration in the current protocol. Donation or loss of more than 100mL of blood w/I 60days prior to drug administration. Donation or loss of more than 1.5liters of blood w/I the 10months prior to drug administration. Strenuous exercise w/I 96 hrs. Prior to admission to the clinical research center. Significant or acute illness w/I 5days prior to drug administration that may impact safety assessments per the judgement of the PI. Unsuitable veins for infusion and/or venepuncture Surgery including surgery with suturing via a dental procedure or would dehiscence w/I 28days of dosing. Any planned surgery or dental procedures during the study and for at least 30days after follow up. Presence of a non-healing wound or fracture. History of bleeding disorders History of thromboembolic conditions History of gastrointestinal perforations or any fistulae. History of orthostatic hypotension, fainting spells, blackouts for any reasons. History of hypertension Medically significant dental disease or dental neglect with signs and or symptoms of local or systemic infection that would likely require a dental procedure during the course of study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MYL-1402O<br>MYL-1402O (bevacizumab), single 1mg/kg i.v. infusion over 90 minutes. | Drug: MYL-1402O<br>* Treatment A - single 1mg/kg dose of MYL-14020 IV infusion over 90 mins.<br>* Other names: Bevacizumab;|
| Active Comparator: US Marketed Avastin (R)<br>US Marketed Avastin(R) (bevacizumab), single 1mg/kg i.v. infusion over 90 minutes. | Drug: US marketed Avastin(R)<br>* Treatment B - single 1mg/kg dose of US marketed Avastin® IV infusion over 90mins<br>* Other names: Bevacizumab;|
| Active Comparator: EU Marketed Avastin(R)<br>EU Marketed Avastin(R) (bevacizumab), single 1mg/kg i.v. infusion over 90 minutes. | Drug: EU marketed Avastin(R)<br>* Treatment C - single 1mg/kg dose of EU marketed Avastin® IV infusion over 90mins.<br>* Other names: Bevacizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) for bevacizumab. | Area under the plasma concentration versus time curve (AUC) for bevacizumab | pre-dose and 0.33, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 264, 336, 504, 672, 1008, 1344, 1680, 2016, and 2352 hours after start of infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) for bevacizumab | Area under the plasma concentration versus time curve (AUC) for bevacizumab | pre-dose and 0.33, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 264, 336, 504, 672, 1008, 1344, 1680, 2016, and 2352 hours after start of infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, tolerability, immunogenicity, MYL-1402O, PK, Avastin®, biosimilarity, male