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Trial registered on ANZCTR


Registration number
ACTRN12619001287123
Ethics application status
Approved
Date submitted
3/09/2019
Date registered
18/09/2019
Date last updated
11/11/2020
Date data sharing statement initially provided
18/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Evaluate the Safety and Pharmacokinetics of Bevacizumab After a Single Dose in Healthy Males
Scientific title
A Randomized, Double-Blind, Parallel, Comparative Assessment of the Pharmacokinetics, Safety, and Immunogenicity of Three Preparations of Bevacizumab, Following a Single I.V. Dose of 1 mg/kg in Healthy Male Volunteers
Secondary ID [1] 298673 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal cancer 314410 0
Non-small cell lung cancer 314445 0
Cervical (cervix) cancer 314446 0
Ovarian or primary peritoneal cancer 314447 0
Renal cancer 314448 0
Glioblastoma 314485 0
Breast Cancer 314486 0
Condition category
Condition code
Cancer 312783 312783 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 312818 312818 0 0
Lung - Non small cell
Cancer 312819 312819 0 0
Cervical (cervix)
Cancer 312820 312820 0 0
Ovarian and primary peritoneal
Cancer 312821 312821 0 0
Kidney
Cancer 312822 312822 0 0
Brain
Cancer 312823 312823 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: 25 mg/mL BP01 (bevacizumab biosimilar) administered as single intravenous infusion of 1 mg/kg over a period of approximately 90 minutes.
Intervention code [1] 314943 0
Treatment: Drugs
Comparator / control treatment
Arm 2: 25 mg/mL US-licensed Avastin (US-licensed bevacizumab) administered as single intravenous infusion of 1 mg/kg over a period of approximately 90 minutes
Arm 3: 25 mg/mL EU-licensed (EU-licensed bevacizumab) administered as single intravenous infusion of 1 mg/kg over a period of approximately 90 minutes
Control group
Active

Outcomes
Primary outcome [1] 320645 0
To determine the pharmacokinetic profile of BP01 following a single intravenous administration of 1 mg/kg in healthy male subjects. PK parameters determined are to include AUC(0-inf), AUC(0-t), C(max), residual area, T(max), T(1/2 el), K(el), Cl and V(d).
Timepoint [1] 320645 0
Blood PK samples will be collected for analysis during the treatment period at: pre-infusion (0 hour), prior to end of infusion (within 5 minutes before end of infusion), and at 2, 4, 6, 9, 12, 24, 48 (Day 3), 72 (Day 4), 168 (Day 8), 336 (Day 15), 504 (Day 22), 1008 (Day 43), 1512 (Day 64), and 2016 hours (Day 85).
Primary outcome [2] 320646 0
To determine the pharmacokinetic profile of US-licensed Avastin following a single intravenous administration of 1 mg/kg in healthy male subjects. PK parameters determined are to include AUC(0-inf), AUC(0-t), C(max), residual area, T(max), T(1/2 el), K(el), Cl and V(d).
Timepoint [2] 320646 0
Blood PK samples will be collected for analysis during the treatment period at: pre-infusion (0 hour), prior to end of infusion (within 5 minutes before end of infusion), and at 2, 4, 6, 9, 12, 24, 48 (Day 3), 72 (Day 4), 168 (Day 8), 336 (Day 15), 504 (Day 22), 1008 (Day 43), 1512 (Day 64), and 2016 hours (Day 85).
Primary outcome [3] 320647 0
To determine the pharmacokinetic profile of EU-licensed Avastin following a single intravenous administration of 1 mg/kg in healthy male subjects. PK parameters determined are to include AUC(0-inf), AUC(0-t), C(max), residual area, T(max), T(1/2 el), K(el), Cl and V(d).
Timepoint [3] 320647 0
Blood PK samples will be collected for analysis during the treatment period at: pre-infusion (0 hour), prior to end of infusion (within 5 minutes before end of infusion), and at 2, 4, 6, 9, 12, 24, 48 (Day 3), 72 (Day 4), 168 (Day 8), 336 (Day 15), 504 (Day 22), 1008 (Day 43), 1512 (Day 64), and 2016 hours (Day 85).
Secondary outcome [1] 372316 0
To assess the safety and tolerability after a single intravenous infusion of BP01 is administered to healthy male subjects. Safety and tolerability will be assessed by observation of the incidence, severity, causality and seriousness of adverse events (the most common adverse events are asthenia, pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliate dermatitis, and proteinuria); vital signs (blood pressure, heart rate, and tympanic temperature); laboratory tests (drug and alcohol screening, hematology and coagulation, and biochemistry); infusion site evaluation; and medical surveillance by clinical site staff.
Timepoint [1] 372316 0
Safety and tolerability information will be recorded from the first date of admission to the study unit for a period of 85 days following study drug administration.
Secondary outcome [2] 372317 0
To compare immunogenicity after a single intravenous infusion of BP01, US-licensed Avastin or EU-licensed Avastin is administered to healthy male subjects. Immunogenicity will be assessed using an ELISA assay to test blood samples for anti-drug antibodies, with further assessment for neutralizing antibodies in samples with positive readings.
Timepoint [2] 372317 0
Blood samples will be drawn for anti-drug antibody and neutralizing antibody detection at: pre-infusion (0 hour), Day 22, Day 64, and Day 85 following study drug administration.

Eligibility
Key inclusion criteria
1) Male, non-smoker, greater than or equal to 18 and less than or equal to 55 years of age, with BMI greater than or equal to 18.5 and less than or equal to 30.0 kg/m^2 and body weight greater than or equal to 50.0 kg and less than or equal to 100 kg.
2) Healthy as defined by:
a) the absence of clinically significant illness within 4 weeks prior to dosing and surgery requiring general anesthesia within 6 months prior to dosing. Inclusion pre-dosing is at the discretion of the Investigator.
b) the absence of clinically significant history of neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
c) hemoglobin greater than or equal to 12.8 g/dL and hematocrit greater than or equal to 0.37 L/L, and all other laboratory parameters within the normal range of the local biomedical laboratory or outside the normal range but assessed as not clinically significant by the Investigator, at screening and on Day -1.
3) Male subjects who are not vasectomized for at least 6 months, and who are sexually active with a non-sterile female partner (sterile female partners include post-menopausal females and surgically sterile females) must be willing to use one of the following acceptable contraceptive method from dosing until at least 90 days after study drug administration:
a) simultaneous use of a male condom and, for the female partner, hormonal contraceptives (used since at least 4 weeks) or intra-uterine contraceptive device (placed since at least 4 weeks);
b) simultaneous use of a male condom and, for the female partner, a diaphragm.
4) Male subjects with a pregnant partner, including subjects who have had a vasectomy must agree to use a condom throughout the study and for 90 days after study drug administration.
5) Male subjects must be willing not to donate sperm until 90 days following study drug administration.
6) Capable of consent.
7) Willing and able to comply with the requirements of the protocol and be available for the planned duration of the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) Any clinically significant abnormality at physical examination at screening or on Day -1.
2) Positive test for hepatitis B, hepatitis C, or HIV at screening.
3) Positive urine drug screen, alcohol test or cotinine test at screening or on Day -1.
4) History of allergic reactions to bevacizumab, CHO cell products, other recombinant human or humanized antibodies, other related drugs, or to any excipients of the drug products.
5) History of anaphylaxis, angioedema, hypertensive crisis or infusion-related reactions following i.v. administration of a drug.
6) Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.
7) Clinically significant ECG abnormalities (e.g., QTcF greater than 450 ms) or vital sign abnormalities (sustained systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 45 or over 100 bpm) at screening.
8) History of significant alcohol abuse within one year prior to screening or regular use of alcohol within 6 months prior to the screening visit (more than 21 units of alcohol per week [1 unit is equal to 150 mL of wine, 360 mL of beer, or 45 mL of 40 percent alcohol]).
9) History of significant drug abuse within one year prior to screening or use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening.
10) Previous exposure to bevacizumab or biphosphonates for a medical condition or in the context of another clinical trial.
11) Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to dosing or administration of a biological product in the context of a clinical research study within 90 days prior to dosing.
12) Use of medication other than topical products without significant systemic absorption:
a) prescription medication within 14 days prior to dosing;
b) over-the-counter products and herbal remedies, such as St. John’s wort, homeopathic and traditional medicines, within 7 days prior to dosing, with the exception of the occasional use of acetaminophen (up to 4 g daily). Vitamins, minerals and nutritional supplements may be taken at the discretion of the Investigator;
c) a depot injection or an implant of any drug within 3 months prior to dosing.
d) use of immunosuppressive drug within 6 weeks prior to dosing.
13) Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding volume drawn at screening) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 days prior to dosing.
14) Administration of immunoglobulin or blood products within 6 weeks prior to dosing.
15) History of gastrointestinal perforation or bleeding, gall bladder perforation, intra-abdominal abscess, internal fistula, hemorrhage, frequent epistaxis, clinically significant history of hemoptysis or evidence of bleeding diathesis or coagulopathy.
16) Clinically significant history of arterial or venous thromboembolic events or clinically significant peripheral vascular disease.
17) Current or past history of hypertension.
18) History or presence of any clinically significant nervous system disease including, but not restricted to any stroke, transient ischemic attack, seizures, migraine headaches or migrainous aura (scotoma with zig-zag lines or blinking lights).
19) Presence of serious, non-healing wound, or recent wound for which the healing process is not completed or surgical wound 28 days or less before dosing.
20) Elective surgery or invasive dental procedure planned over the course of the study.
21) Body temperature > 38.0ºC prior to dosing on Day 1.
22) Evidence of chronic or significant active infection, as judged by the Investigator, prior to dosing on Day 1.
23) Live virus vaccination within 3 months prior to dosing on Day 1 or live virus vaccine planned over the course of the study.
24) Family history of coagulopathy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Designated Pharmacy personnel at the clinical site not directly involved with the clinical aspects of the trial will prepare and dispense the study medication and will be aware of the randomization code. All study treatments will have the same visual appearance in order to avoid compromising the study blinding.
In the event of an emergency for an individual subject, the Investigator may break the blind for that subject. An envelope for each subject containing their treatment assignment will be made available from the pharmacy personnel.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be stratified according to the subject's weight. The following weight strata will be used: less than or equal to 77 kg or greater than 77 kg. For each body weight strata, block randomization will be used to randomize subjects equally to each of the 3 treatment arms.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-equivalence
Statistical methods / analysis
Statistical Analysis will be performed using SAS v9.3 (SAS Institute, Cary, USA). Statistical analysis will be performed between BP01 and US-licensed Avastin (to evaluate similarity between test compound and US reference), BP01 and EU-licensed Avastin (to evaluate similarity between test compound and EU reference), and US-licensed Avastin and EU-licensed Avastin (to evaluate similarity between US and EU references).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/09/2019
Actual
17/10/2019
Date of last participant enrolment
Anticipated
Actual
11/12/2019
Date of last data collection
Anticipated
Actual
6/03/2020
Sample size
Target
111
Accrual to date
Final
111
Recruitment outside Australia
Country [1] 21675 0
New Zealand
State/province [1] 21675 0

Funding & Sponsors
Funding source category [1] 303213 0
Commercial sector/Industry
Name [1] 303213 0
Aurobindo Pharma Ltd.
Country [1] 303213 0
India
Primary sponsor type
Commercial sector/Industry
Name
Syneos Health New Zealand Limited
Address
Unit G1, 14-22 Triton Drive, Rosedale, Auckland 0632
Country
New Zealand
Secondary sponsor category [1] 303226 0
Commercial sector/Industry
Name [1] 303226 0
Aurobindo Pharma Ltd.
Address [1] 303226 0
Biological R&D Center
Survey No. 77 & 78, Indrakaran (V),
Sangareddy (M), Medak Dist-502320
Telgana
Country [1] 303226 0
India

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303770 0
HDEC - Health and Disability Ethics Committees
Ethics committee address [1] 303770 0
Ethics committee country [1] 303770 0
New Zealand
Date submitted for ethics approval [1] 303770 0
04/07/2019
Approval date [1] 303770 0
22/08/2019
Ethics approval number [1] 303770 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 94738 0
Dr Christian Schwabe
Address 94738 0
Auckland Clinical Studies
3 Ferncroft Street, Grafton
Ground Floor, ACS House
Auckland 1010
Country 94738 0
New Zealand
Phone 94738 0
+64 9 3737474
Fax 94738 0
Email 94738 0
[email protected]
Contact person for public queries
Name 94739 0
Shuruthi Balachandran
Address 94739 0
Auckland Clinical Studies
3 Ferncroft Street, Grafton
Ground Floor, ACS House
Auckland 1010
Country 94739 0
New Zealand
Phone 94739 0
+64 9373 7474
Fax 94739 0
+64 9373 3479
Email 94739 0
[email protected]
Contact person for scientific queries
Name 94740 0
Janaki Raghu Ram P 
Address 94740 0
Aurobindo Pharma Ltd (Biologics Division) 
Unit XVII, Sy No 77&78, Indrakaran (V), Kandi (M) 
Sangareddy District Hyderabad 502320 
Country 94740 0
India
Phone 94740 0
+91 8 4552 5522
Fax 94740 0
Email 94740 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As this is a Phase 1 study, only aggregate data may be posted/published.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.