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Trial registered on ANZCTR


Registration number
ACTRN12620000244909
Ethics application status
Approved
Date submitted
10/12/2019
Date registered
26/02/2020
Date last updated
26/02/2020
Date data sharing statement initially provided
26/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A first-in-human study of VG161 in participants with advanced malignant tumours that have not responded to conventional therapies.
Scientific title
A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Biologic Effect of VG161 in Subjects with Advanced Malignant Solid Tumors that are Refractory to Conventional Therapies
Secondary ID [1] 299819 0
VG161-A101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced malignant solid tumors 315196 0
Condition category
Condition code
Cancer 313510 313510 0 0
Other cancer types
Cancer 313998 313998 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
VG161 will be intratumorally injected in to the injectable lesion(s) including visible, palpable, or detectable cutaneous or subcutaneous lesion(s). VG161 is a recombinant oncolytic Herpes Simplex Virus (HSV)-1 expressing human-Interleukin-12/Interleukin-15RA/Programmed death ligand-1 block peptide (IL12/15/PDL1B) . While oncolytic virus replicate in tumour cells and destroy the tumour, the payloads expressed by the virus can synergistically stimulate anticancer immunity. Increasing doses will be evaluated in a sequential fashion such that a higher dose will be administered only after the safety and tolerability of the preceding dose have been determined. Three dose levels at both Part A and B include Level 1: 5.0×10^7 PFU, Level 2: 1.0×10^8 PFU and Level 3: 2.0×10^8 PFU. VG161 is injected intratumorally into cutaneous, subcutaneous, and/or nodal lesions that are visible or palpable.
For Part A, the Dose Limiting Toxicities (DLT) observation period for a subject is 21-day following VG161 treatment at each given dose during accelerated titration design and standard 3+3 titration design if triggered. The 21-day DLT observation period is defined to determine the given dose is safe/tolerable before the higher dose can be administered. Please refer to the details of accelerated titration design and standard titration design (if triggered) for Part A study as follows. One subject will be enrolled at dose level 1 initially. If there are no dose limiting toxicities (DLTs), the next subject will be enrolled at dose level 2. If there are no DLTs, a third subject will be enrolled at dose level 3. Every subject’s DLTs will be assessed during the first 21 days following VG161 treatment. If one (1) DLT is observed, or three (3) moderate toxicities (defined per National Cancer Institute (NCI)-CTC AE Version 5.0 and assessed by the Investigator as either possibly, probably, or definitely related to the study drug) happen at any dose level, the cohort will be expanded per the 3+3 design at the current dose level. This expanded cohort of three (3) will consist of two (2) new subjects at the current dose level. If two (2) out of these three (3) subjects experience a DLT, dose escalation is stopped. The standard titration design (3+3) will be implemented for all further dose levels. During this phase, the subjects will be enrolled in a cohort of three (3) subjects per dose level and treated. First subject will be dosed and observed for 48 hours and then subsequent 2 subjects will be dosed. This staggered enrolment and dosing will be followed at each dose level where standard 3+3 design is being followed. During accelerated titration phase, after completion of DLT observation period (21 days) at a given dose, a subject who does not experience a decrease in tumour volume or DLT can escalate to the next dose level based on the decision from PI, monitor and sponsor. Part A data will also be reviewed by SRC.
Part A: Only 1 Dose will be administered to the participants, i.e. VG161 will be administered as a single dose on Day 1 only. The first participant receives a single dose 5.0×10^7 PFU, the second participant receives a single dose 1.0×10^8 PFU, the third participant receives a single dose 2.0×10^8 PFU. Part A will test up to 3 increasing dose levels of single dose VG161. Dose levels will not increase until the lower dose is determined to be safe. Participants from Part A will be able to take part in Part B, if eligibility criteria is met.
In Part B, The participants will receive the escalating ‘once daily’ doses of VG161 on Days 1 through 5 at the first cycle and for Cycle 2 and beyond, If a subject has no observed DLT at the completion of Cycle 1, the subject will continue the same dose of VG161 for 5 days (the same dose level of Cycle 1). Cycle 2 (and each subsequent cycle) will consist of 5 days of dosing (the same dose level of Cycle 1) and 23 days of observation. Additional cycles of treatment will be available to all Part B subjects until there is evidence of disease progression, removal from active treatment due to toxicity, or withdrawal of consent. No maximum cycle number is defined.
There is no washout period, Subjects from Part A will be eligible for Part B if they meet the inclusion and exclusion criteria. A new informed consent form (ICF) must be signed for Screening for Part B, therefore 21 days from completion of Part A dosing, the participants if eligible may be dosed in Part B.

Additional cycles of treatment will be available to all participants (Part A and Part B) until there is evidence of disease progression, removal from active treatment due to toxicity, or withdrawal of consent. If the enestic lesion disappears other lesions are allowed to be injected at the Investigator’s discretion after discussion with the CRO Medical Monitor or Sponsor.
Intervention code [1] 316075 0
Treatment: Drugs
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322004 0
Part A: To assess the safety and tolerability of VG161 after a single intratumoral dose.
Timepoint [1] 322004 0
This is a composite primary outcome. Safety and Tolerability are monitored throughout the study.
During Part A, Physical examination, Weight, Vital signs (blood pressure, heart rate, body temperature), 12-lead electrocardiogram (ECG) monitoring is done in the screening visit, Day 1, Day 7, Day 21 or Early termination visit. 12 lead ECG will be obtained twice during first 24 hours post-dose on Day 1 of every Cycle.
Blood and urine sampling for hematology and clinical chemistry will be performed on Days 1, 3, 7, 21 or Early termination visit.
Primary outcome [2] 322005 0
Part B: To assess the safety and tolerability of VG161 after multiple intratumoral dose and define the maximum tolerate dose.
Timepoint [2] 322005 0
This is a composite primary outcome. Safety and Tolerability are monitored throughout the study.
During Part B, Physical examination, Weight, Vital signs (blood pressure, heart rate, body temperature), 12-lead electrocardiogram (ECG) monitoring is done on following visits: screening, Day 1, 2, 3, 4, 5, 6, 7, 15, 21 and 28 or Early termination visit of each Cycle. 12 lead ECG will be obtained twice during first 24 hours post-dose on Day 1 of every Cycle
Blood and urine sampling for hematology and clinical chemistry will be performed on following visits: Day 1, 2, 3, 4, 5, 6, 7, 15, 21 and 28 or Early termination visit of each Cycle.
Secondary outcome [1] 376982 0
Part A: To characterize the PK profile of VG161 as assessed by plasma, urine, oral mucosa, injection site and tissue concentrations of VG161 DNA copy number after intratumoral injection of a single dose of virus.
Pharmacokinetic parameters will be derived for each subject from the plasma VG161 viral DNA concentration-time data using standard non-compartmental methods. Virus DNA copy number of VG161 in plasma will be analyzed to determine the following PK parameters: Cmax, Tmax, AUCT, AUC0-inf, t1/2, CL, Css.
Timepoint [1] 376982 0
Plasma concentrations of VG161 DNA will be collected at the following timepoints: up to 7 days post dose, tissue concentration of VG161 DNA up to 15 days post dose and concentrations of VG161 DNA in urine, oral mucosa and injection site up to 21 days post dose :
- Blood, urine, oral mucosa, injection site and tissue samples will be collected to measure the level of VG161 DNA copy number following VG161 single dose
Secondary outcome [2] 376983 0
Part B: To characterize the PK profile of VG161 as assessed by plasma, urine, oral mucosa, injection site and tissue concentrations of VG161 DNA copy number after multiple doses.
Pharmacokinetic parameters will be derived for each subject from the plasma VG161 viral DNA concentration-time data using standard non-compartmental methods. Virus DNA copy number of VG161 in plasma will be analyzed to determine the following PK parameters: Cmax, Tmax, AUCT, AUC0-inf, t1/2, CL, Css.
Timepoint [2] 376983 0
Plasma concentrations of VG161 will be collected at the following timepoints: up to Day 28, tissue concentration of VG161 up to Day 15 and concentrations of VG161 DNA in urine, oral mucosa and injection site up to 28 days post dose.
Blood and tissue samples will be collected to measure the level of VG161 DNA copy number following VG161 multiple dose

Eligibility
Key inclusion criteria
A subject will be eligible for study participation if all the following criteria are met:
1. Signed written informed consent.
2. Males or females aged greater than or equal to 18 years.
3. Performance status: Eastern Cooperative Oncology Group (ECOG) 0 or 1.
4. Subject with late stage carcinoma which is refractory/relapsed after and/or intolerant of standard therapies or for which no standard therapy exists.
5. At least 1 injectable cutaneous or subcutaneous lesion greater than or equal to 20 mm in longest diameter and/or nodal lesions that are visible or palpable deemed injectable as per Principal Investigator’s (PIs) discretion.
6. Seropositive for Herpes Simplex Virus (HSV)
7. Had an interval of greater than or equal to 2 weeks since exposure to systemic chemotherapy, an interval of greater than or equal to 6 weeks since exposure to nitrosourea, and an interval of greater than or equal to 4 weeks since exposure to radiotherapy.
Subjects must either
a. Have failed the standard treatment (due to either disease progression or intolerable toxicity), or
b. Have a specific condition for which the standard of care had not been established, or
c. Have received at least two (2) prior therapy regimens other than surgery and must have fully recovered from the acute treatment related toxicities of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
8. Life expectancy of at least 3 months.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A subject will be ineligible for study participation if any of the following criteria are met:
1. Participation in any previous immunotherapy trial within one month prior to entry to this trial or any trial of any other investigational agent within the last 4 weeks prior to entry to this trial.
2. Tumors to be injected lying in mucosal regions or close to an airway, major blood vessel or spinal cord that, in the opinion of the Investigators, could cause occlusion or compression in the case of tumor swelling or erosion into a major vessel in the case of necrosis.
3. Subjects with any primary CNS malignancy including glioma and current, active, progressing CNS malignancy, including carcinomatosis meningitis are excluded. Subjects with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period and off steroids (for at least 2 weeks prior to first dose of IP).
4. Major surgery within 14 days prior to enrolment.
5. Intercurrent serious infections within the 28 days prior to enrolment.
6. Life-threatening illness unrelated to cancer.
7. Active Herpes labialis infection.
8. Treatment with antiviral agents within 14 days prior to enrolment.
9. Uncontrolled congestive cardiac failure.
10. Clinically active autoimmune disease.
11. Known to test positive for human immunodeficiency virus (HIV), hepatitis B or C virus, or syphilis.
12. Subjects on systemic anticoagulants are excluded from this study.
13. Subjects with prior radiation therapy to the tumor lesion to be injected are excluded from the study, unless there is evidence of tumor progression in the most recent imaging, following completion of radiotherapy.
14. Subjects with active or documented history of autoimmune disease within 2 years prior to screening.
15. Subjects with history of primary immune deficiency
16. Subjects with history of organ transplant that requires use of immunosuppressive medications
17. Use of any live vaccines within 4 weeks of study treatment

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
Other
Other design features
Other design features: The study consists of 2 parts; Part A: Single ascending Dose and Part B: Multiple Ascending Dose
Part A: During this phase, one participant will be enrolled at dose level 1 (5.0×10^7 PFU) initially. If there are no DLTs or Grade >3 toxicity, the next participant will be enrolled at dose level 2 (1.0×10^8 PFU). If there are no DLTs, a third participant will be enrolled at dose level 3 (2.0×10^8 PFU). If one (1) DLT is observed, or three (3) moderate toxicities happen at any dose level, the cohort will be expanded per the 3+3 design at the current dose level. This expanded cohort of 3 will consist of two (2) new participants at the current dose level. If two (2) out of these three (3) participants experience a DLT, dose escalation is stopped. If one of the three new participants experience a DLT, the cohort will be expanded to six (6) participants. The standard titration design (3+3) will be implemented for all subsequent dose levels in Part A.
After review of the Part A data by the SRC, and if acceptable, Part B of this study will proceed.
Part B: A minimum of 3 and maximum of 6 participants will be enrolled per dose level. The trial design is a standard 3+3 Phase 1 trial. This part of the study involves administration of escalating multiple doses of VG161 to participants with advanced malignant solid tumors that are refractory to conventional therapies. There will be no intra-participant dose escalation. Participant accrual to subsequent cohorts will not begin until all participants in the prior cohort have completed one full cycle of dosing.
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 15883 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 15884 0
St Vincent's Private Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 29340 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 304279 0
Commercial sector/Industry
Name [1] 304279 0
Virogin Biotech Australia Pty. Ltd.
Address [1] 304279 0
58 Gipps St, Collingwood VIC 3066, Australia
Country [1] 304279 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Virogin Biotech Australia Pty. Ltd.
Address
58 Gipps St, Collingwood VIC 3066, Australia
Country
Australia
Secondary sponsor category [1] 304554 0
None
Name [1] 304554 0
Address [1] 304554 0
Country [1] 304554 0
Other collaborator category [1] 281047 0
Commercial sector/Industry
Name [1] 281047 0
Novotech (Australia) Pty Limited
Address [1] 281047 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 281047 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304737 0
Bellberry Limited HREC
Ethics committee address [1] 304737 0
123 Glen Osmond Rd, Eastwood SA 5063, Australia
Ethics committee country [1] 304737 0
Australia
Date submitted for ethics approval [1] 304737 0
05/11/2019
Approval date [1] 304737 0
11/12/2019
Ethics approval number [1] 304737 0
2019/ETH13393

Summary
Brief summary
This study aims to evaluate the Safety, Tolerability of VG161 in the treatment of people with advanced malignant tumours that have not responded to conventional therapies.

Who is it for?
You may be eligible to join this study if you are aged 18 years or older and have late stage carcinoma which is refractory/relapsed and/or intolerant of standard therapies or for which no standard therapy exists. Eligible participants must have at least 1 injectable cutaneous or subcutaneous lesion greater than or equal to 20 mm in longest diameter.

Study details:
Part A of this study involves up to 3 increasing dose levels of VG161. The treatment will be given as a single dose, and the dose level will not be increased until the lower dose has been determined to be safe.
Part B will test up to 3 increasing dose levels of VG161 given as multiple doses. Treatment will be given in cycles of 28 days, with VG161 given once daily on days 1-5, followed by a 23- day observation period each cycle. Participants from Part A will be able to take part in Part B only if eligibility criteria are still met.
The study will also involve taking a variety of biological samples including, blood, urine, and tissue. The samples will be used to assess your eligibility to participate in the study, your safety profile during study participation, and to evaluate how the study drug is metabolised in the body.
It is hoped that this study can provide greater insight to novel treatments that may stimulate anticancer immunity and help fight cancer. Furthermore it is hoped this treatment can improve control of disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98034 0
Dr Amy Prawira
Address 98034 0
The Kinghorn Cancer Centre/St Vincent’s Hospital Sydney, 390 Victoria Street, Darlinghurst NSW 2010
Country 98034 0
Australia
Phone 98034 0
+61 02 9355 5655
Fax 98034 0
Email 98034 0
amy.prawira@svha.org.au
Contact person for public queries
Name 98035 0
Ms Lauren Armstrong
Address 98035 0
The Kinghorn Cancer Centre, Level 6, 370 Victoria Street, Darlinghurst, NSW 2010
Country 98035 0
Australia
Phone 98035 0
+61 2 9355 5783
Fax 98035 0
Email 98035 0
Lauren.Armstrong@svha.org.au
Contact person for scientific queries
Name 98036 0
Dr Ramandeep Sharma
Address 98036 0
Novotech (Australia) Pty Limited
Level 2, 15-31 Pelham Street Carlton VIC 3053 Australia

Country 98036 0
Australia
Phone 98036 0
+61 3 9341 1992
Fax 98036 0
Email 98036 0
Ramandeep.Sharma@novotech-cro.com

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 other documents available
Summary results
No Results