Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000491662
Ethics application status
Approved
Date submitted
19/04/2023
Date registered
12/05/2023
Date last updated
4/08/2023
Date data sharing statement initially provided
12/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Single Centre, Open Label, Single Dose, Pharmacokinetic Study of Erwinaze in Healthy Adult Volunteers
Scientific title
A Phase 1, Single Centre, Open Label, Single Dose, Pharmacokinetic Study of Erwinaze in Healthy Adult Volunteers
Secondary ID [1] 309477 0
ERW-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Lymphoblastic Leukemia 329743 0
Condition category
Condition code
Cancer 326641 326641 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a study of pharmacokinetics, safety, tolerability and pharmacodynamics of a single dose of Erwinaze in healthy participants. At least 6 and up to 12 participants will receive 25,000 IU/m2 of Erwinaze.
Eligibility will be assessed during a screening period of up to 28 days prior to dosing. For the treatment period, subjects will be admitted to the clinical research unit (CRU) one day prior to the dosing (Day -1). Dosing of eligible participants will occur on the morning of dosing (Day 1).
On Day 1, all subjects will receive the calculated intramuscular dose of Erwinaze administered by a study nurse or doctor qualified to administer Intramuscular injections. Participants will be discharged from the clinic on Day 5 after all required study procedures are completed and if deemed medically fit. Subjects will return to the clinic on Day 8 (± 1 day), Day 15 (± 2 days) and Day 30 (± 2 days) for follow up visits. Additional follow-up visits may occur at discretion of the Principal Investigator.
Intervention code [1] 325903 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334506 0
To characterise the serum pharmacokinetic (PK) profile following a single intramuscular (IM) dose of Erwinaze in healthy adult participants based on serum asparaginase activity levels (SAA) including AUC0-t, AUC0-8, AUC0-x, Cmax, tmax, t½, CL/F, Vz/F.
Timepoint [1] 334506 0
Development of a population PK model using PK data following a single IM dose of Erwinaze in healthy adult participants. PK samples will be collected at 20 timepoints from pre-dose through Day 30 as follows: Day 1: Pre-dose, 30 minutes; 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 18 hours post dose. Day 2: 24 and 36 hours post dose Day 3: 48 hours post dose Day 4: 72 hours post dose Day 5: 96 hours post dose Day 8 post dose Day 15 post dose Day 30 post dose
Secondary outcome [1] 420928 0
To evaluate the safety and tolerability of Erwinaze when administered as a single IM dose to healthy adult participants.

Safety and tolerability of Erwinaze will be assessed by the incidence, nature, causal relationship to Erwinaze, and severity of all adverse events (AEs), AEs of special interest (AESIs), and serious adverse events (SAEs) during the study period.
• Safety during the study period will also be assessed based on:
• Clinical laboratory safety analyses (haematology, coagulation, clinical chemistry, and urinalysis)
• Vital signs
- respiratory rate is measured by sight by the study nurse
- heart rate is measured by both the ECG and vital sign machines i.e., electronic BP machine.
- Systolic and Diastolic blood pressure is measured using an electronic BP machine.
- Tympanic Temperature is measured using a tympanic thermometer
• 12-lead-electrocardiogram (ECG)
• Physical examination
• Local tolerability/injection site reactions
Timepoint [1] 420928 0
Adverse event data will be collected from the time of consent until the last study visit (Day 30 post dose)
Safety assessments will include the following:

- Laboratory Tests (biochemistry, haematology, urinalysis, coagulation):
Baseline
Day 2
Day 5
Day 8
Day 15
Day 30

- Ammonia Blood Testing:
Day 2

- Vital signs:
Baseline
Day 1 (pre-dose, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours post dose),
Day 2: 24 hours post dose
Day 3: 48 hours post dose
Day 4: 72 hours post dose
Day 5: 96 hours post dose
Day 8
Day 15
Day 30

- ECG:
Baseline
Day 1 (pre-dose, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours post dose),
Day 2: 24 hours post dose
Day 3: 48 hours post dose
Day 4: 72 hours post dose
Day 5: 96 hours post dose
Day 8
Day 15
Day 30
- Physical Exam:
Baseline,
Day 1 (pre and post dose)
Day 2
Day 3
Day 4
Day 5
Day 8
Day 15
Day 30

- Local Tolerability/Injection Site Reaction Assessment:
Day 1: pre-dose, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours post dose
Day 2: 24- and 36-hours post dose
Day 3: 48 hours post dose
Day 4: 72 hours post dose
Day 5: 96 hours post dose
Day 8
Day 15
Day 30
Secondary outcome [2] 420929 0
To investigate the presence of antibodies that bind to Erwinaze (immunogenicity) in serum, and if detected, to initiate the characterisation of these anti- Erwinaze antibodies (anti-drug antibodies;
ADA). Both measures will be assessed as a composite secondary outcome.
Timepoint [2] 420929 0
Samples will be analysed for the presence of anti-Erwinaze antibodies. ADA samples must be collected
pre-dose
Day 8,
Day 15 and
Day 30.
Additional samples for ADA assessment in serum may be collected in participants with serious clinically relevant signs per PI discretion on:
Day 2
Day 3
Day 4
Day 5
Secondary outcome [3] 420930 0
To characterise the PK profile following a single IM dose of Erwinaze in healthy adult participants based on SAA including AUC0-t, AUC0-8, AUC0-x, Cmax, tmax, t½, CL/F, Vz/F.
Timepoint [3] 420930 0
Development of a population PK model following single dose IM administration.
PK samples will be collected at 20 timepoints from pre-dose through Day 30 as follows:
Day 1: Pre-dose, 30 minutes; 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 18 hours post dose.
Day 2: 24 and 36 hours post dose
Day 3: 48 hours post dose
Day 4: 72 hours post dose
Day 5: 96 hours post dose
Day 8 post dose
Day 15 post dose
Day 30 post dose
Secondary outcome [4] 420931 0
EXPLORATORY OUTCOME: To characterise the serum PK profile following a single IM dose of Erwinaze in healthy adult participants based on serum asparaginase concentration (SAC).
Timepoint [4] 420931 0
Determination of SAC and derived Serum PK parameters from a non-compartmental PK analysis following single dose IM administration:
PK samples will be collected at 20 timepoints from pre-dose through Day 30 as follows:
Day 1: Pre-dose, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 18 hours post dose.
Day 2: 24 and 36 hours post dose
Day 3: 48 hours post dose
Day 4: 72 hours post dose
Day 5: 96 hours post dose
Day 8 post dose
Day 15 post dose
Day 30 post dose
Secondary outcome [5] 420932 0
EXPLORATORY OUTCOME: To explore the pharmacodynamic (PD) profile of Erwinaze by measuring levels of specific amino acids in plasma.
Timepoint [5] 420932 0
EXPLORATORY TIMEPOINT: ADA samples will be collected to determine L-asparagine and L-glutamine levels in plasma. PD samples will be collected at 8 timepoints from pre-dose through Day 30 as follows:
Pre, dose
Day 2: 24 post dose
Day 3: 48 hours post dose
Day 4: 72 hours post dose
Day 5: 96 hours post dose
Day 8 post dose
Day 15 post dose
Day 30 post dose

Eligibility
Key inclusion criteria
1. The participant must be in good general health, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, safety laboratory tests and cardiac monitoring at screening and before administration of Erwinaze.
2. The participant must weigh more or equal to 50.0 kg and less or equal to 120.0 kg and have a body surface area less or equal to 2.0 m2 at screening and on Day -1.
3. The participant must have clinical laboratory values within the limit of normal as specified by the testing laboratory at Screening and Day -1, unless deemed not clinically significant by the PI or if specified by protocol restrictions.
4. The participant must have normal vital signs after more or equal to 5 minutes resting supine:
a. More than 90.0 mmHg and less than 140.0 mmHg systolic blood pressure
b. More than 50.0 mmHg and less than 95.0 mmHg diastolic blood pressure
c. more than 45.0 bpm and less than 100.0 bpm heart rate
d. Body temperature more or equal to 35.5 and less than 37.5°C.
5. The participant must have a standard 12-lead electrocardiogram (ECG) parameters after more or equal to 5 minutes resting in supine position with PR more or equal to 120.0 ms and less or equal to 220.0 ms, QRS less than 120.0 ms, QTcF less or equal to 450.0 ms for males and less or equal to 470.0 ms for females, and otherwise normal ECG, unless deemed not clinically significant by the PI. Eligibility should be assessed based on average of triplicate assessments.
6. The participant must have a negative urine drug screen and alcohol breath test at screening and at time of admission to the CRU (on Day -1). A positive drug or alcohol screen test result may be verified by re-testing (up to 1 false positive result permitted) and may be followed up at the discretion of the PI.
7. The participant must have the ability and willingness to attend the necessary visits to the CRU.
8. The participant must sign a written informed consent prior to undergoing any of the study-specific procedures, including screening procedures.
9. Females must not be pregnant nor lactating, and either surgically sterile since at least 90 days prior to screening (eg, tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or, if women of childbearing potential (WOCBP) engaged in a sexual relationship with a fertile male partner, use highly effective double barrier contraceptive method as assessed by the PI (condom AND a vaginal ring or a non-hormonal intrauterine device [IUD]) from screening until study completion, for at least 90 days after the administration of study drug, or be post-menopausal for more or equal to 12 months. Post-menopausal status will be confirmed through testing of follicle-stimulating hormone (FSH) per testing laboratory standards at screening for amenorrheic female participants. Females who are abstinent from heterosexual intercourse as part of their usual lifestyle and are not planning to conceive will be eligible for participation and are not required to use contraception.
10. WOCBP must have a negative pregnancy test at screening and admission and be willing to have additional pregnancy tests as required throughout the study.
11. Males must be surgically sterile (participants provide confirmation of the lack of viable sperm prior to screening), abstinent, or if engaged in a sexual relationship with a WOCBP, the participant and his partner must use an acceptable, highly effective, double barrier contraceptive method as assessed by the PI from screening until study completion, including the follow-up period, for at least 90 days after the administration of study drug. Acceptable methods of contraception include the use of condoms in combination with the use of an effective contraceptive for the female partner (WOCBP). Male participants whose female partner is post-menopausal, and participants who are abstinent from heterosexual intercourse as part of their usual lifestyle will be eligible and are not required to use contraception.
12. Male participants must agree to refrain from donating sperm from screening until study completion, including the follow-up period, for at least 90 days after the last dose of study drug.
13. The participant must be either non-smoker (have last smoked more than 30 days prior to screening and no longer smoking, or have never smoked), or smoke no more than the equivalent of 5 cigarettes per day since at least 30 days prior to screening. If user of other nicotine products (ie, spray, patch, e-cigarette) no more than the equivalent of 5 cigarettes per day since at least 30 days prior to screening is allowed. The participant must agree to abstain from smoking while in the CRU.
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Participant with medical history of or a positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), hepatitis B core antigen (HbcAg) or hepatitis C virus (HCV) antibodies at screening.
2. The participant has previously been exposed to treatment with any form of L-asparaginase.
3. The participant has a current and/or past history of pancreatitis or hepatitis.
4. The participant has a current and/or past history of haemorrhagic or severe thrombotic events.
5. The participant has hyperammonemia at screening.
6. The participant is immunocompromised as a result of conditions and/or treatments.
7. The participant has an absolute neutrophil count less than 1500/microliter at screening or on Day -1.
8. The participant is unsuitable for the intramuscular (IM) injection of Erwinaze and the evaluation of its safety and tolerability (eg, the presence of tattoos or scarring) at either the right or the left ventrogluteal site, as defined by the PI (or qualified designee).
9. The participant has any underlying physical or psychological medical condition that, in the opinion of the PI, would make it unlikely for them to complete the study.
10. The participant has evidence and/or history of blood clotting abnormalities and/or coagulopathies.
11. The participant has evidence or history of any current chronic medical condition (eg, hypertension, elevated cholesterol/triglycerides, asthma, or diabetes).
12. The participant uses or is planning to use any analgesic (with the exception of paracetamol/acetaminophen up to 3000 mg per day), antibiotic, antifungals, acetylsalicylic acid (aspirin), systemic steroids, and/or any nonsteroidal anti-inflammatory drugs (NSAIDs) within 28 days prior to the initial study drug administration and/or any other prescription or over the counter (OTC) medicines (with the exception of oral contraceptives) within 7 days prior to the initial study drug administration, unless in the opinion of the PI, local medical monitor (MM) and sponsor representative (must be a physician) the medication will not interfere with the study procedures or compromise participant safety.
13. The participant uses or is planning to use hormone replacement therapy (HRT) medications within 30 days following Erwinaze administration, and/or has used HRT within 30 days or 5 half-lives prior to Erwinaze administration, whichever is greater.
14. The participant has aspartate aminotransferase (AST) and/or alanine transaminase (ALT) levels that are more or equal to 1.25 times above the upper limit of normal (ULN) at screening or on Day -1.
15. The participant has an estimated glomerular filtration rate (GFR, calculated with the CKI-EPI) less or equal to 90.0 mL/min at screening or on Day -1. The participant has amylase levels and/or lipase levels that are above the ULN at screening or on Day -1.
16. The participant has any of the standard coagulation blood parameters at screening and on Day -1 that are out of normal range, and/or the participant has protein C activity, protein S activity, and/or anti-thrombin III levels that are out of normal range at screening.
17. The participant has fasting glucose levels outside of the normal range, per testing laboratory standards at screening or on Day -1.
18. The participant has a total bilirubin above the ULN at screening or on Day -1. Participants with Gilbert’s syndrome are excluded from this study.
19. The participant has a history of or current alcoholism or drug abuse within the 1 year prior to the initial study drug administration. Alcohol abuse is defined as more than10 standard drinks per week.
20. The participant has donated whole blood (more than 499 mL), has had a significant blood loss (more than 499 mL) within 30 days prior to the initial study drug administration, or has donated plasma within 2 weeks prior to the initial study drug administration.
21. The participant has been dosed in a clinical study within 30 days before the initial administration of the study drug; used any experimental therapy within 30 days or 5 half-lives prior to the initial administration of the study drug, whichever is greater; or used any biologic therapy within 12 weeks or 5 half-lives prior to the initial administration of the study drug, whichever is greater.
22. The participant has had any clinically significant surgery within the 3 months prior to the initial study drug administration that is determined by the PI to have a potential impact on study participation.
23. The participant has an active infection (diagnosed or suspected), and/or history of recurrent infection (local or systemic) within 30 days prior to the initial study drug administration.
24. The participant has any acute and clinically relevant illness within 30 days prior to the initial study drug administration.
25. The participant has any known history of severe allergic, anaphylactic, or other hypersensitivity reactions to the study drug or its excipients, or a history of drug or other allergies including severe allergic reactions that in the opinion of the PI, contraindicates their participation in the study.
26. The participant has been judged by the PI to be unfit to participate for any other reason.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
The number of participants (at least 6 and up to 12) in this study was selected based on practical considerations and is consistent with standard practice for Phase 1 studies of this nature. The sample size is deemed sufficient to evaluate the PK as well as the safety, tolerability, and immunogenicity of a single Erwinaze dose to be administered in this study.
No inferential analyses are planned.

This study does not include formal hypothesis testing, and In general, descriptive statistics (mean, standard deviation [SD], median, minimum, and maximum) will be calculated for summaries of continuous data, and frequency counts and percentages (where appropriate) will be calculated for summaries of discrete/ categorical data.

The following analysis sets are defined for the study:
Safety set: includes all participants who receive any amount of the study drug Erwinaze. The Safety set will be used to summarise safety, tolerability, and immunogenicity data.

PK set: includes all participants who receive any amount of Erwinaze with sufficient Erwinaze concentration-time data to determine at least one main PK parameter. The PK set will be used to summarise all PK concentrations and parameters data.
Participant inclusion into each analysis set will be determined after database lock for the final analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/09/2023
Actual
Date of last participant enrolment
Anticipated
31/07/2023
Actual
Date of last data collection
Anticipated
29/08/2023
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 24552 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 40146 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 313674 0
Commercial sector/Industry
Name [1] 313674 0
Porton Biopharma Limited
Country [1] 313674 0
United Kingdom
Primary sponsor type
Commercial sector/Industry
Name
Porton Biopharma Limited
Address
Manor Farm Road,
Porton Down, Salisbury,
Wiltshire, SP4 0JG,
Country
United Kingdom
Secondary sponsor category [1] 315474 0
Commercial sector/Industry
Name [1] 315474 0
Beyond Drug Development Pty Ltd
Address [1] 315474 0
17 Brereton St
South Brisbane QLD 4101
Country [1] 315474 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312839 0
Bellberry Limited
Ethics committee address [1] 312839 0
123 Glen Osmond Road Eastwood Adelaide
South Australia 5063
Ethics committee country [1] 312839 0
Australia
Date submitted for ethics approval [1] 312839 0
05/04/2023
Approval date [1] 312839 0
03/07/2023
Ethics approval number [1] 312839 0

Summary
Brief summary
This study will assess the safety and tolerability of a single dose of Erwinaze, and how this drug acts in the body in healthy volunteers. Erwinaze is indicated for use in patients with acute lymphoblastic leukemia (blood cancer), but a trial of the drug in healthy volunteers is needed to obtain additional information to potentially make Erwinase available in more countries.

Who is it for?
You may be eligible for this study if you are aged 18 to 40 years and are in good general health without a clinically significant medical history. People who have been diagnosed with cancer will not be eligible for this study.

Study details
All participants who choose to enrol in this study will be screened for eligibility within the 28 days prior to being admitted to a clinical research unit for up to 5 days. Eligibility will be confirmed within the 24 hours prior to participants receiving a single intramuscular (injected) dose of Erwinaze. Participants will then be asked to provide a series of blood and urine samples to assess the effect of the drug on their body. After 5 days, participants will be discharged home and will be asked to attend two further study visits to provide blood samples.

It is hoped this research will determine whether Erwinaze can be safely administered without causing severe reactions. Once the safety and tolerability of Erwinaze has been determined, further studies to assess the effect of Erwinaze in people with leukemia may proceed.
Trial website
Trial related presentations / publications
Public notes
Inclusion Criteria related to COVID-19:
The participant must agree to adhere to the current clinical site, state and national advice regarding lifestyle exposure to coronavirus disease of 2019 (COVID-19) during the study.
Exclusion Criteria related to COVID-19
The participant has received a COVID-19 and/or influenza vaccination within 14 days, and/or any other vaccination within 28 days of the anticipated dosing with Erwinaze and/or are expected to be vaccinated within 2 weeks postdosing.

Contacts
Principal investigator
Name 126098 0
Dr Michele DeSciscio
Address 126098 0
CMAX Clinical Research
Ground Floor, 21-24 North Terrace
Adelaide, South Australia 5000
Country 126098 0
Australia
Phone 126098 0
+61 422447902
Fax 126098 0
Email 126098 0
Michele.DeSciscio@sa.gov.au
Contact person for public queries
Name 126099 0
Dr Michele DeSciscio
Address 126099 0
CMAX Clinical Research
Ground Floor, 21-24 North Terrace
Adelaide, South Australia 5000
Country 126099 0
Australia
Phone 126099 0
+61 422447902
Fax 126099 0
Email 126099 0
Michele.DeSciscio@sa.gov.au
Contact person for scientific queries
Name 126100 0
Dr Michele DeSciscio
Address 126100 0
CMAX Clinical Research
Ground Floor, 21-24 North Terrace
Adelaide, South Australia 5000
Country 126100 0
Australia
Phone 126100 0
+61 422447902
Fax 126100 0
Email 126100 0
Michele.DeSciscio@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.