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Trial registered on ANZCTR


Registration number
ACTRN12620000008921
Ethics application status
Approved
Date submitted
25/11/2019
Date registered
8/01/2020
Date last updated
19/05/2020
Date data sharing statement initially provided
8/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I study of increasing doses of T3011 in patients with advanced cancer
Scientific title
A Phase I, Open-Label, Multiple Ascending Dose Study of the Safety and Tolerability of T3011 in advanced Cutaneous or Subcutaneous Malignancies
Secondary ID [1] 299887 0
Theravir Protocol Number: CTIV1708
Universal Trial Number (UTN)
U1111-1244-4129
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Any malignancy with cutaneous and/or subcutaneous tumours 315322 0
Condition category
Condition code
Cancer 313629 313629 0 0
Other cancer types
Cancer 313630 313630 0 0
Malignant melanoma
Cancer 313631 313631 0 0
Non melanoma skin cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention = Investigational Product = T3011, a genetically modified oncolytic virus.

Participants will receive T3011 at the assigned dose level by intratumoural injection commencing on W1D1, and approximately every 14 days thereafter (ie: W3D1, W5D1 etc) for up to 2 years (unless disease progression, unacceptable toxicity, death or withdrawal of consent).

Part 1 – Dose Escalation
The starting dose of T3011 is 1.0 × 10^6 PFU/mL with the volume injected intratumourally based on tumour size, but not exceeding a total of 4 mls for each visit for all tumours combined.

The study uses a 3+3 dose escalation design to evaluate escalating doses of T3011 monotherapy. Three additional doses are planned to be tested (1.0 × 10^7, 5.0 × 10^7, and 1 × 10^8 PFU/ml). At any dose level, if no dose-limiting toxicity (DLT) occurs among the first 3 participants, then escalation to the next dose level may proceed if approved by the Safety Review committee (SRC). If 1 DLT occurs in the first 1 to 3 participants, the dose level will expand to a maximum of 6 participants. If no DLT occurs among the additional participants, then escalation to the next dose level may proceed if approved by the SRC. The non-tolerated dose (NTD) is the dose level at which 2 or more participants experience a DLT during the DLT evaluation period. The maximum tolerated dose (MTD) will be defined as the dose level immediately below the NTD. At least 6 participants will be treated at the MTD before expansion to Part 2 (Dose Expansion) with additional participants treated with a dose selected by the SRC.
Intervention code [1] 316157 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322058 0
Safety and tolerability of escalating doses of T3011 through incidence of DLTs; assessed by blood and urine tests, clinical examination and participant self reported events
Timepoint [1] 322058 0
Evaluation period for assessment of DLTs is for 4 week from start of Treatment Day 1 to just prior to dosing on Week 5

Blood test samples, Clinical examination and Patient self-reported event assessments occur on Day 1, Day 2, then weekly until Week 5.
Urine test samples occur on Day 1 , Weeks 3 and 5.
Primary outcome [2] 322059 0
To evaluate the safety and tolerability of T3011 dose(s) - Incidence of TEAEs and clinical laboratory abnormalities; assessed by blood and urine tests, clinical examination and participant self reported events

Possible adverse events include cold sores, viral infection with effects ranging from flu-like symptoms to more severe reactions, infection of cornea of the eye (foreign body sensation or light sensitivity), allergic reaction (itching, hives to more severe difficulty breathing), infection of the brain (high fevers, confusion, loss of consciousness, neurologic difficulties, seizures)
Timepoint [2] 322059 0
Start of treatment through to 30+/- 5 days after last treatment.

Blood test samples, Clinical examination and Patient self-reported event assessments occur on Day 1, Day 2, then weekly until Week 11 and then every 4 weeks until last dose of treatment and then 30+/- 5 days after last treatment.

Urine test samples occur on Day 1 , Weeks 3,, 5, 7, 9, 11 and then every 4 weeks until last dose of treatment and then 30 +/- 5 days until last treatment.
Secondary outcome [1] 377174 0
Pharmacokinetics
Measured by biodistribution of viral DNA at different sites
(eg: serum, saliva, urine and injection site dressing viral DNA).
(Note: these are not standard PK measures but are appropriate to the product and in accordance with regulatory authority requirement)
Timepoint [1] 377174 0
At least weekly for 4 weeks from commencement of treatment, then every 2 weeks until Week 9 and then every 4 weeks (Week 13 onwards) until approximately 24 months

Eligibility
Key inclusion criteria
1. See Age criteria
2. Histologically confirmed diagnosis of cutaneous and subcutaneous advanced malignancy.
3. Measurable disease per RECIST version 1.1.
4. Must have at least 1 tumour lesion with a longest dimension of greater than or equal to 10 mm (greater than or equal to 15 mm for the short axis for malignant lymph node lesions) that can be easily palpated or detected by ultrasound to facilitate IT injection of T3011 (ie, tumour in skin, muscle, subcutaneous tissue, or accessible lymph node).
5. Disease progression after standard-of-care (SOC) therapy or in the opinion of the Investigator unlikely to benefit from SOC therapy.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Life expectancy > 12 weeks.
8. Adequate bone marrow function defined by ANC of greater than or equal to 1.5 × 10^9/L, platelet count of greater than or equal to 100.0 × 10^9/L, and hemoglobin of greater than or equal to 90 g/L (with or without transfusion).
9. Adequate hepatic function defined as serum total bilirubin < 2.5 × ULN, AST/ALT of less than or equal to 2.5 × ULN (or less than or equal to 5 × ULN in participants with liver metastases).
10. Adequate renal function defined as creatinine clearance > 50 mL/min as determined by the Cockcroft-Gault equation.
11. Female participants must be surgically sterile (or have a monogamous partner who is surgically sterile), or be least 2 years postmenopausal, or commit to using 2 acceptable forms of birth control (defined as the use of an intrauterine device, a barrier method with spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration of the study and for 6 months following the last dose of study treatment. Male participants must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 6 months following the last dose of study treatment.
12. Women of childbearing potential (WCBP) must have a negative serum pregnancy test at Screening within 7 days of dosing with T3011.
13. Last dose of previous anticancer therapy greater than or equal to 28 days, radiotherapy > 21 days (concurrent targeted palliative radiotherapy is allowed to non-injected lesions during T3011 treatment), or surgical intervention > 21 days prior to the first dose of T3011.
14. Resolution of all prior anticancer therapy toxicities (except for alopecia) to less than or equal to Grade 1.
Note: patients previously treated with immunotherapy who have endocrinopathies may enrol if on adequate replacement therapy.
15. Willingness to provide pre- and post-treatment fresh tumour biopsy specimens.
16. Capable of understanding and complying with protocol requirements.
17. Signed and dated institutional review board/independent ethics committee-approved informed consent form before any protocol-directed screening procedures are performed.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients are to be excluded from the study if they meet any of the following criteria:
1. Have only tumours with severe fibrosis and therefore not injectable.
2. Patients with injectable tumours impinging upon major airways or blood vessels.
3. Prior treatment with another oncolytic virus or cellular therapy.
4. Requires continued concurrent therapy with any drug active against HSV (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir).
5. Systemic therapy with immunosuppressive agents within 28 days before the start of T3011 treatment; topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement for patients with adrenal insufficiency are allowed.
6. Live vaccines within 4 weeks of initiation of study treatment.
7. Primary or acquired immunodeficient states (leukaemia, lymphoma, human immunodeficiency virus (HIV)/AIDS).
8. Pregnant or lactating.
9. Prior organ transplantation.
10. Active hepatitis B virus, hepatitis C virus, and HIV infection or a positive serological test at Screening within 7 days of dosing with T3011.
11. Active autoimmune disease or medical conditions requiring chronic steroid
(ie, > 10 mg/day prednisone or equivalent) or immunosuppressive therapy; patients with a prior history of autoimmune disease may be eligible following discussion with and written approval from the Medical Monitor.
12. History of or current central nervous system metastases (brain imaging [eg, by CT scan, PET scan, MRI scan, etc., per site standards] completed within 3 months of Screening [required for all participants]).
13. History of seizure disorders within 6 months of Screening.
14. Active oral herpes lesion at Screening.
15. Baseline pulse oximetry < 92% on room air.
16. Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.
17. Congestive heart failure (> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest), or clinically significant cardiac arrhythmias.
18. History of allergic reactions attributed to compounds of similar biological composition .
19. Other systemic conditions or organ abnormalities that, in the opinion of the Investigator, may interfere with the conduct and/or interpretation of the current study.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable as non-randomised study
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
2 Part study with Part 1 being a dose escalation ( 3+3 dose escalation design to evaluate escalating doses of T3011 monotherapy without intraparticipant dose escalation) and Part 2 additional participants treatment with dose selected based on Part 1
Phase
Not Applicable
Type of endpoint(s)
Safety
Statistical methods / analysis
Sample Size Determination
No formal hypothesis testing is planned. The number of participants in each period of the study is based on safety and tolerability. Part 1 (Dose Escalation) will enrol approximately up to 24 participants using a 3+3 dose escalation design without intraparticipant dose escalation. Part 2 (Dose Expansion) will enrol approximately up to 30 participants to be apportioned among disease-specific cohorts.

Statistical methods will be primarily descriptive in nature. No hypothesis will be formally tested. Categorical variables will be summarised using numbers and percentages. Continuous variables will be summarised by total number (n), mean, standard deviation, median, and range (minimum and maximum). The dose escalation period and the dose expansion period will be analysed separately. Within each study period, the analyses will be conducted by dose group. Across different study periods, participants on the same dose level may be pooled together if specified.


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)
SA,VIC
Recruitment postcode(s) [1] 29341 0
3199 - Frankston
Recruitment postcode(s) [2] 30306 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 304344 0
Commercial sector/Industry
Name [1] 304344 0
Theravir Pty Ltd
Address [1] 304344 0
Level 13, Citigroup Tower, 2 Park Street, Sydney NSW 2000
Country [1] 304344 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Theravir Pty Ltd
Address
Level 13, Citigroup Tower, 2 Park Street, Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 304595 0
Commercial sector/Industry
Name [1] 304595 0
Immvira Pharma Co. Ltd
Address [1] 304595 0
Unit 402, 4/F Fairmont HSE
No.8 Cotton Tree Drive Admiralty,
Hong Kong
Country [1] 304595 0
China

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304796 0
Alfred Hospital Ethics Committee EC00315
Ethics committee address [1] 304796 0
Alfred Health
Commercial Rd
Melbourne Vic 3004
Ethics committee country [1] 304796 0
Australia
Date submitted for ethics approval [1] 304796 0
11/11/2019
Approval date [1] 304796 0
20/03/2020
Ethics approval number [1] 304796 0
HREC/59150/Alfred-2020
Ethics committee name [2] 305375 0
Bellberry Human Research Ethics Committee EC00430
Ethics committee address [2] 305375 0
123 Glen Osmond Rd
Eastwood
South Australia 5063
Ethics committee country [2] 305375 0
Australia
Date submitted for ethics approval [2] 305375 0
02/12/2019
Approval date [2] 305375 0
06/02/2020
Ethics approval number [2] 305375 0
2019-12-1082

Summary
Brief summary
The purpose of this study is to assess the safety of a genetically modified virus, called T3011 in advanced cancer

Who is it for?
You may be eligible for this study if you are aged 18 or over and have advanced cancer presenting with a skin or subcutaneous (under the skin) malignancy.

Study details
All participants in this study will have injections into their tumour(s). These injections will contain the genetically modified virus T3011, which is oncolytic – this means it bursts open cancer cells. The dose administered will increase for each new cohort until the maximum tolerated dose is identified. Participants will have the injection every 2 weeks for up to 2 years, depending on how well the treatment is tolerated. As part of the study, participants will provide saliva, blood and urine samples.

It is hoped this research will provide some safety data for T3011 and identify the appropriate dose of T3011 for bigger clinical trials.
Trial website
Trial related presentations / publications
Public notes
All Site locations not yet confirmed - will be listed as approved.

Contacts
Principal investigator
Name 98234 0
A/Prof Andrew Haydon
Address 98234 0
Medical Oncology
Alfred Hospital
55 Commercial Rd
Melbourne VIC 3004
Country 98234 0
Australia
Phone 98234 0
+61 3 9076 3129
Fax 98234 0
Email 98234 0
a.haydon@alfred.org.au
Contact person for public queries
Name 98235 0
A/Prof Andrew Haydon
Address 98235 0
Medical Oncology
Alfred Hospital
55 Commercial Rd
Melbourne VIC 3004
Country 98235 0
Australia
Phone 98235 0
+61 3 9076 3129
Fax 98235 0
Email 98235 0
a.haydon@alfred.org.au
Contact person for scientific queries
Name 98236 0
Dr Dongyao Ni
Address 98236 0
Theravir Pty Ltd
A Subsidiary fully owned by Immvira Pharma Co. Ltd
Level 13
Citigroup Tower
2 Park Street
Sydney NSW 2000
Country 98236 0
Australia
Phone 98236 0
+61 403 151 568
Fax 98236 0
Email 98236 0
dongyao.ni@immvira-theravir.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