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Trial registered on ANZCTR


Registration number
ACTRN12620000777998
Ethics application status
Approved
Date submitted
30/04/2020
Date registered
30/07/2020
Date last updated
30/07/2020
Date data sharing statement initially provided
30/07/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A First-in-Human Study to Evaluate the Administration of ReoCure alone and in combination with Keytruda (Pembrolizumab) in Patients with Advanced Malignant Solid Tumours
Scientific title
A First-in-Human Dose Escalation and Expansion Study to Evaluate Intratumoral Administration of ReoCure as Monotherapy and in Combination with Keytruda (Pembrolizumab) in Patients with Advanced Malignant Solid Tumours
Secondary ID [1] 301046 0
VCT-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Malignant Solid Tumours 317096 0
Condition category
Condition code
Cancer 315262 315262 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This research study involves a test drug called ReoCure alone or in combination with another drug called Keytruda® (pembrolizumab). ReoCure is a live Reovirus, commonly isolated from human digestive and respiratory tracts and has not been associated with symptoms or causing clinical disease. ReoCure which is under development by ViroCure, Inc. is a genetically unmanipulated naturally occurring, non-mutated strain of virus that preferentially infects and kills cancer cells, and hence being classified as oncolytic virus. As the infected cancer cells are destroyed by ReoCure (Reovirus that is able to kill cancer cells), they release new virus particles or virions to help destroy the remaining tumour.
The aim of this study is to assess the safety and find the correct dose of ReoCure alone and in combination with Pembrolizumab to patients with advanced malignant solid tumours. The study also aims to provide information on how the body handles ReoCure i.e. how it absorbs, distributes and eliminates ReoCure. Another aim of this study is to learn if ReoCure in combination with Pembrolizumab can help to control cancer better.
The study is divided in two parts, Phase 1a and Phase 1b. In Phase 1a - Dose Escalation, participants will receive either ReoCure alone or ReoCure in a combination with Pembrolizumab. Part 1a will take place in 2 parts: Part A ReoCure Monotherapy Dose Escalation and Part B ReoCure Combination therapy Dose Escalation. Phase 1b is the Dose Expansion part of the study.

Phase 1a Dose Escalation;
Part A (ReoCure Monotherapy Dose Escalation): There will be up to 3 cohorts (Cohorts 1, 2 and 3), with a minimum of 3 and a maximum of 18 participants until the recommended dose is determined or until the last dose level. If there are no changes seen in the participant's tumour after week 6, they may be eligible to receive Pembrolizumab (200mg once in every 3 weeks) alone or in combination with ReoCure at the same dose level as per the Cohort the participant is in. If the highest tolerable dose is not identified during the course of Part A study, the highest dose level (last dose level) will be the recommended dose of ReoCure monotherapy.
In Part A (ReoCure Monotherapy Dose Escalation), following dose levels are planned. The planned dose levels are as below:
• Cohort 1: 1.0×10^8 PFU ReoCure, 1 injection/cycle
• Cohort 2: 1.0×10^9 PFU ReoCure, 1 injection/cycle
• Cohort 3: 1.0×10^10 PFU ReoCure, 1 injection/cycle
Dose escalation will continue from the initial dose group (Cohort 1) within the range of 3 dose groups (Cohort 1-3) until the MTDReoCure is identified or until the last dose level.
The highest dose level at which MTDReoCure is not identified in Part A will be the RP2D of ReoCure monotherapy (RP2DReoCure).
After the tumour evaluation at week 6, patients in part A, who do not show any tumour response and patients who display a tumour progression (complete response [CR], partial response [PR] or stable disease [SD]), may receive 200 mg once every 3 weeks (Q3W) of Keytruda (Pembrolizumab) alone or in combination with ReoCure (at the dose level of relevant cohort) in subsequent cycles. This decision will be based upon mutual consultation between Investigator, Sponsor’s CMO and medical monitor, and will be taken based on the Investigator’s evaluation of clinical risks/benefits for the patient, on a case by case basis, and in the interest of the patient.

The duration of part A for each cohort is as follows: Minimum 21 days based on safety data and maximum number of cycles is based on response and safety outcome as per study stopping rules. This means patients who continue to derive the benefit from therapy can receive any amount of additional cycles with IP.

The frequency of ReoCure Administration: 1 cycle (C) consists of 21 days. Day (D) 22 of each cycle is D1 of the following cycle. Cohort 1, Cohort 2 and Cohort 3 of dose escalation phase: Intratumoral administration on Day (D) 1 of Cycle 1. The Investigator will determine whether a patient will continue treatment with the IP in the next cycle considering the tumour response and clinical condition of the patient after Cycle 1.
In the dose escalation cohort, a patient who experiences a DLT during the DLT observation period (Cycle 1, 3 weeks after first dose of IP) will temporarily discontinue the IP until recovery of the DLT. However, after resolution of the DLT, treatment may be resumed at the discretion of the Investigator with allowance of up to 2 weeks of delay in the next cycle. Dosing in Cycle 2 and Beyond: Patients with no clinical deterioration after Cycle 1 (21 days) will be allowed to be treated with subsequent cycles of ReoCure (and combination drug Keytruda [Pembrolizumab] where applicable) until any stopping rules are met.

ReoCure will be Intratumoral administration and pembrolizumab will be intravenous as per approved prescribing information

Part B (ReoCure Combination Therapy Dose Escalation):This part will test 2 dose levels of ReoCure in combination with a fixed dose of Pembrolizumab (200mg every 3 weeks) in 2 cohorts. There will be up to 2 cohorts (Cohorts 4 and 5) with a minimum of 2 and maximum of 12 participants, until the recommended dose is determined or until the last dose level. If the highest tolerable dose is not identified during the course of Part B study, the highest dose level (last dose level) will be the recommended dose of ReoCure combination therapy

2 dose levels are planned for 1a Part B on following lines
Here IP will be given in combination with fixed dose (200 mg Q3W) of Keytruda (Pembrolizumab).
Up to 2 cohorts (Cohorts 4 and 5) consisting of 1-6 patients per cohort will be recruited sequentially at 2 dose levels of ReoCure:
• at one dose level below maximum tolerated dose (MTD)ReoCure or at the Part A Cohort 2 dose (if MTDReoCure has not been determined) and
• at MTD ReoCure or at the Part A Cohort 3 dose (if MTD ReoCure has not been determined).

In phase 1a Part B;
• ReoCure will be given on Day (D) 1 of Cycle 1 .
• Fixed dose (200 mg Q3W every 3 weeks) of combination drug Keytruda (Pembrolizumab) will be provided on D8.
• Same dose will be administered for Cycle 2 and beyond.
ReoCure will be Intratumoral administration and pembrolizumab will be intravenous as per approved prescribing information
IP as monotherapy and in combination with Pembrolizumab will be administered in hospital setting.

Phase 1b Dose Expansion: This part will include a minimum of 10 and maximum of 15 participants (Cohort 6), to further test the safety of ReoCure in combination with a fixed dose of pembrolizumab (200 mg once in every 3 weeks) treated with the recommended dose selected from the Dose Escalation part of the study.

The MTD (or RP2D) will be assessed by dose limiting toxicity (DLT) evaluation in Phase 1a. MTD ReoCure is defined as the highest dose level of ReoCure alone at which less than or equal to 33% of patients.

Patients with no clinical deterioration after Cycle 1 (21 days) will be allowed to be treated with subsequent cycles of ReoCure alone or in combination with a a fixed dose of pembrolizumab (200mg once in every 3 weeks( until any stopping rules are met. This will occur at the Investigator’s discretion and with patient’s agreement. The selected dose and timing will be as per the most recently completed treatment period in which patients were enrolled - Since Intra-participant dose escalation is not allowed in any cohort. This is with reference to dosing patients in subsequent cycles of ReoCure with no clinical deterioration after Cycle 1 (21 days). The dose and timing in subsequent cycles will be based on previous cycles.
The decision to continue with dosing will be determined by the SRC after review of safety data.
An SRC comprising relevant site Investigator(s), the medical monitor and a Sponsor representative will oversee safety, cohort evaluation and dose escalation for the study. The SRC will be responsible for the safety of patients, and decisions relating to dose escalation and dose-expansion for the study.

The Stopping Rules are defined as per below:
The decision to continue with dosing will be determined by the SRC after review of safety data.
Administration of study drug in a dose cohort may be paused, and additional patients will not receive study drug, until a consultation has taken place between the Investigator, the medical monitor, and the ViroCure representative under the following circumstances:
• 2 or more patients experience a DLT at dose level 1 (1.0x10^8 PFU, 1 injection/cycle) in Phase 1a Part A;
• 2 or more patients experience a Grade 3 or higher clinical abnormality (except fever) (as defined in the NCI-CTCAE version 5.0) that is considered to be possibly or probably related to study drug;
• Any patient experiences an SAE that is considered to be possibly or probably related to study drug;
• Any patient experiences a Grade 3 or higher laboratory abnormality (as defined in the NCI-CTCAE version 5.0) that is considered to be possibly or probably related to study drug.
• An AE or group of AEs that singularly or in aggregate suggests to the Investigator or Sponsor that the study drug is poorly tolerated and further treatment per protocol may not be safe.

There is no maximum period specified for participants are followed for the purposes of this study. For cycle 2 onwards Patients with no clinical deterioration after Cycle 1 (21 days) will be allowed to be treated with subsequent cycles of ReoCure until any stopping rules are met. This will occur at the Investigator’s discretion and with patient’s agreement.

Intervention code [1] 317389 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 323542 0
Dose Escalation Phase: To determine the overall safety & Tolerability profile of ReoCure when administered intratumorally in hepatic and subcutaneous lesions as monotherapy and in combination with Keytruda (Pembrolizumab)
Timepoint [1] 323542 0
Assessed through the dose escalation phase of intratumoral administration of 3 dose levels, 1 injection/cycle.
Safety will be assessed as follows:
- Incidence, severity and causality of adverse events (AEs) and serious adverse events (SAEs) - Assessed at every visit from Baseline (Cycle 1 Day 1) to the Safety Follow up visit.
- Vital sign changes from baseline (pulse rate, SBP/DBP, RR and tympanic BT) – Assessed at every visit from screening to End of Treatment
- Haematology and chemistry parameter changes from baseline and presence of any abnormally high or low results. – Assessed every week starting from Baseline (Cycle 1 Day 1) to End of Treatment
- Physical examination – Performed during screening, Day 1 of each cycle and End of Treatment visit.
- 12- lead electrocardiogram (ECG) changes from baseline - Performed during screening, Day 1 of each cycle and End of Treatment visit.
• Tolerability will be assessed as:
- Permanent discontinuation/dose de-escalation due to adverse drug reaction (ADR) – ADR is assessed at every visit from Baseline (Cycle 1 Day 1) to the Safety Follow up visit.
Primary outcome [2] 323543 0
Dose-Expansion Phase: To further evaluate the safety profile of ReoCure at the MTD (or RP2D) when administered intratumorally in hepatic and subcutaneous lesions in combination with Keytruda (Pembrolizumab)
Timepoint [2] 323543 0
Assessed through the dose expansion phase of intratumoral administration of the dose level (RP2D) determined in Dose Escalation phase.
• The MTD (or RP2D) will be assessed by dose limiting toxicity (DLT) evaluation. DLT observation period is Cycle 1, 3 weeks after first dose of IP)
• Three 12-lead ECGs will be performed at Screening, CnD1 and EOS visits, at least 5 minutes apart and after at least a 10-minute rest.
• For tumour evaluation, CT or MRI scans will be conducted at Screening and every 6 weeks (± 7 days) from baseline (C1D1) (on a calendar day basis).
• Blood sampling for tumour marker evaluation will be conducted at baseline (C1D1) and CnD1 of each cycle (before treatment with the IP).
• Tumour biopsy (optional): Tumour biopsy may be conducted at Screening and/or on Day 1(only patients who consent to tumour biopsy). Tumour biopsy may also be performed at the time of disease progression. Tumour biopsy may be omitted at Screening if there are stored samples before Screening, and the stored tumour samples may be used.
• Blood sampling for immunological response evaluation will be conducted. It will be conducted at baseline (C1D1) and every 3 weeks from baseline before treatment with the IP.
Primary outcome [3] 323904 0
Dose Escalation Phase: To determine MTD (or RP2D) of ReoCure when administered intratumorally in hepatic and subcutaneous lesions as monotherapy and in combination with Keytruda (Pembrolizumab)
Timepoint [3] 323904 0
The MTD (or RP2D) will be assessed by dose limiting toxicity (DLT) evaluation in Phase 1a. DLT observation period is Cycle 1, 3 weeks after first dose of IP)
• Three 12-lead ECGs will be performed at Screening, CnD1 and EOS visits, at least 5 minutes apart and after at least a 10-minute rest.
• For tumour evaluation, CT or MRI scans will be conducted at Screening and every 6 weeks (± 7 days) from baseline (C1D1) (on a calendar day basis).
• Blood sampling for tumour marker evaluation will be conducted at baseline (C1D1) and CnD1 of each cycle (before treatment with the IP).
• Tumour biopsy (optional): Tumour biopsy may be conducted at Screening and/or on Day 1 (only patients who consent to tumour biopsy). Tumour biopsy may also be performed at the time of disease progression.
• Blood sampling for immunological response evaluation will be conducted. It will be conducted at baseline (C1D1) and every 3 weeks from baseline before treatment with the IP.
Secondary outcome [1] 382189 0
Dose Escalation Phase: To evaluate the PK profile (viral shedding) and the immunological response (neutralizing anti-Reovirus antibody) of ReoCure when administered intratumorally in hepatic and subcutaneous lesions as a monotherapy and in combination with Keytruda (Pembrolizumab). In oncolytic virus therapy like ReoCure, traditional parameters like e.g. AUC, Cmax, etc. do not apply. Key PK parameter is Biodistribution which will be assessed as per timepoints below;
Timepoint [1] 382189 0
• PK sampling will be conducted according to the following schedule. On D1 and D2 of each cycle, PK sampling will be done before treatment and after treatment.
• Blood sampling: D1 (pre-injection), D2 (24 hours post D1 injection), and D15 (anytime between 07h00 and 12h00) in Cycle 1 and Cycle 2; and D1 (pre-injection) and D2 (24 hours post D1 injection) from Cycle 3 onwards.
• Sputum, urine and faeces sampling: D1 (pre-injection), D2 (24 hours post D1 injection ± 5 min) and D15 (anytime between 07h00 and 12h00) in Cycle 1 and Cycle 2; and D1 (pre-injection) and D2 (24 hours post D1 injection ± 5 min) from Cycle 3 onwards.

PK of ReoCure will be assessed through following: - Viral shedding in urine, serum, saliva, and stool
Secondary outcome [2] 382190 0
Dose-Expansion Phase: To evaluate the immunological response (neutralizing anti-Reovirus antibody) of ReoCure when administered intratumorally in hepatic and subcutaneous lesions in combination with Keytruda (Pembrolizumab) in patients with advanced malignant solid tumours that have hepatic and/or subcutaneous metastases.
Timepoint [2] 382190 0
The presence and titre of neutralizing anti-ReoCure antibody in serum at baseline (C1D1) and at all post baseline time points until the end of administration of the IP.
Blood sampling for immunological tests will be conducted at baseline (C1D1) and every 3 weeks from baseline before treatment with the IP.

• Immunological response evaluation:
- Presence of Neutralizing anti-Reovirus antibody
Secondary outcome [3] 382191 0
Dose-Expansion Phase: To evaluate the efficacy of ReoCure when administered intratumorally in hepatic and subcutaneous lesions in combination with Keytruda (Pembrolizumab)
Efficacy of ReoCure and Keytruda (Pembrolizumab) combination therapy is evaluated through composite measurement of tumor markers and immune related markers in the blood at the following timepoints;
Timepoint [3] 382191 0
Efficacy of ReoCure and Keytruda (Pembrolizumab) combination therapy is evaluated through measurement of tumor markers and immune related markers in the blood at the following timepoints: Blood samples will be collected at Baseline (Cycle 1 Day 1), Day 1 of each cycle (before study drug administration) for measurement of tumor markers and immune related markers in the blood and CT/MRI scans will be performed at Screening and every 6 weeks (± 7 days) from baseline (Cycle 1 Day 1) on a calendar day basis.

• Blood sampling for tumour marker evaluation will be conducted at baseline (C1D1) and CnD1 of each cycle (before treatment with the IP).
• Tumour biopsy (optional): Tumour biopsy may be conducted at Screening and/or on Day 1(only patients who consent to tumour biopsy). Tumour biopsy may also be performed at the time of disease progression. Tumour biopsy may be omitted at Screening if there are stored samples before Screening, and the stored tumour samples may be used.
• Blood sampling for immunological response evaluation will be conducted. It will be conducted at baseline (C1D1) and every 3 weeks from baseline before treatment with the IP.

Timepoints the participants will be followed up for purposes of this study are;
• Patients will have the End of Treatment Visit after permanent discontinuation of the IP (+7 days).
Secondary outcome [4] 383269 0
Dose-Expansion Phase: To evaluate the antitumoral activity of ReoCure when administered intratumorally in hepatic and subcutaneous lesions in combination with Keytruda (Pembrolizumab)
The antitumoral activity of ReoCure and Keytruda (Pembrolizumab) combination therapy is evaluated through composite measurement of tumor markers and immune related markers in the blood at the following timepoints;
Timepoint [4] 383269 0
• Blood sampling for tumour marker evaluation will be conducted at baseline (C1D1) and CnD1 of each cycle (before treatment with the IP).
• Tumour biopsy (optional): Tumour biopsy may be conducted at Screening and/or on Day 1(only patients who consent to tumour biopsy). Tumour biopsy may also be performed at the time of disease progression. Tumour biopsy may be omitted at Screening if there are stored samples before Screening, and the stored tumour samples may be used.
• Blood sampling for immunological response evaluation will be conducted. It will be conducted at baseline (C1D1) and every 3 weeks from baseline before treatment with the IP.

Timepoints the participants will be followed up for purposes of this study are;
• Patients will have the End of Treatment Visit after permanent discontinuation of the IP (+7 days).

Eligibility
Key inclusion criteria
A patient will be eligible for study participation if all the following criteria are met:
1. Willing to sign ICF on a voluntary basis and to voluntarily participate in the study, after being fully informed of and completely understanding this study, prior to any Screening procedure being undertaken.
2. Males and females, of any race, aged greater than or equal to 18 years at time of signing the ICF.
3. Patients with histologically or cytologically confirmed advanced/late stage solid tumours:
• of any type, for patients in Phase1a Part A:
• classified as melanoma, gastric adenocarcinoma or gastro-oesophageal junction adenocarcinoma or gastrointestinal stromal tumours or solid tumours of colon or lung, for participants in Phase 1a Part B and in Phase 1b, with hepatic and/or subcutaneous metastases, who failed to respond to existing standard chemotherapies or have refused standard treatment or have condition for which no standard therapy exists.
Patients must have at least one of the below lesions that are accessible (palpable or can be visualized by ultrasound) and amenable to multiple intratumoral injections of ReoCure:
a. Measurable Hepatic lesion as per RECIST 1.1
b. Measurable Subcutaneous lesion as per RECIST 1.1.
4. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
5. Patients must have a life expectancy of greater than or equal to 12 weeks.
6. Patients who have adequate haematologic, renal, and hepatic functions as confirmed by the following criteria;
a. ANC greater than or equal to 1,500/µL
b. Platelet greater than or equal to 100,000/µL
c. Hb greater than or equal to 9.0 mg/dL
d. Serum creatinine less than or equal to 1.5 × ULN or eGFR greater than or equal to 45 mL/min/1.73 m2, for patients with creatinine levels above institutional normal
e. Total bilirubin: less than or equal to 1.5 × ULN
f. AST and ALT: less than or equal to 5 × ULN
g. Prothrombin time and aPTT must be normal or in case of borderline elevation must be deemed clinically not significant as ascertained by the Investigator
h. Non-clinically-significant hypoalbuminemia as ascertained by the Investigator is acceptable, provided that there is no:
• Ascites
• Hepatic encephalopathy
7. Patients must have had an interval of greater than or equal to 21 days since exposure to cytotoxic drugs, greater than or equal to 28 days or greater than or equal to 5 half-lives whichever is shorter since exposure to targeted agents (small molecule inhibitors), greater than or equal to 28 days since biological therapy (immunotherapy), hormone therapy and gene therapy, or greater than or equal to 14 days since radiotherapy, at baseline:
a. Patients must have fully recovered to NCI-CTCAE Grade 1 or better from AEs due to all previous cancer therapeutics prior to entering this study.
Note: Patients with less than or equal to Grade 2 neuropathy or less than or equal to Grade 2 alopecia or Grade 2 AEs that qualify as Grade 2 due to replacement hormonal or steroid therapy may qualify for the study with approval by Sponsor/ medical monitor.
b. If a patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to enrolment.
c. Patients must have received their last dose of known myelosuppressive anti-cancer chemotherapy at least 3 weeks prior to administration of first dose of IP or at least 6 weeks if nitrosourea.
d. For radiation therapy (especially involving brain tumour):
i. Craniospinal irradiation (greater than 24 Gy) or TBI greater than 3 months prior to Screening
ii. Focal irradiation to symptomatic metastatic sites greater than 2 weeks prior to Screening, if patients have recovered from any AE related to the procedure
iii. Local palliative external beam radiation therapy (XRT) (small port) greater than or equal to 2 weeks, if patients have recovered from any AE related to the procedure
iv. If prior total body irradiation (TBI), craniospinal XRT or if greater than or equal to 50% radiation of pelvis greater than or equal to 6 months must have elapsed
v. If other substantial bone marrow (BM) radiation greater than or equal to 6 weeks must have elapsed.
8. Patients with dermatoses without active infection will be allowed based on case by case prior discussion with study medical monitor, Investigator and Sponsor’s CMO.
9. Male patients must abstain from heterosexual activities or agree to use a condom through 90 days after final dose of study drug. Women of childbearing potential must be willing to abstain from heterosexual activities or agree to use highly effective, double-barrier contraception during the study and for 90 days following the final dose of ReoCure, to avoid pregnancy. Double-barrier contraception is defined as a condom AND one other form of the following:
a. Birth control pills (The Pill)
b. Depot or injectable birth control
c. Intrauterine Device
d. Birth control patch (e.g. Ortho Evra)
e. NuvaRing®
f. Documented evidence of surgical sterilization at least 6 months prior to the Screening Visit, i.e., tubal ligation or hysterectomy for women or vasectomy for men.
Male patients must not donate sperm for at least 24 weeks post-dose of the last study treatment. Male partners of female patients and female partners of male patients must also use contraception as listed above, if they are of childbearing potential.
Female patients of childbearing potential must have a negative serum pregnancy test at Screening and on Day 1.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
A patient will be ineligible for study participation if any of the following criteria are met:
1. Patients with severe hypersensitivity or a history of any hypersensitivity to the similar drug class of the study drugs (IP and Pembrolizumab).
2. Patients with tumour lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, unless there is demonstrated progression in the lesion as per the Investigator’s assessment.
3. Patients with tumour lesions with macroscopic intravascular tumour invasion (e.g. liver lesions with tumour infiltration into the main portal vein, hepatic vein or vena cava).
4. Patients with any of the following medical histories or surgery/procedure histories:
a. Major surgery requiring general anaesthesia or a respiratory assistance device within 4 weeks prior to baseline (within 2 weeks for video-assisted thoracoscopic surgery or open-and-closed surgery)
b. Severe cardiovascular disease within 24 weeks prior to baseline
c. Severe cerebrovascular disease within 24 weeks prior to baseline
d. Pulmonary thromboembolism, deep vein thrombosis (DVT) or other clinically significantly severe lung disease within 24 weeks prior to baseline
e. History of organ transplant that requires use of immunosuppressive medications
5. Patients who have any of the following concomitant diseases at baseline:
a. History of malignancies other than melanoma, gastric adenocarcinoma or gastro-oesophageal junction adenocarcinoma or gastrointestinal stromal tumours or solid tumours of colon or lung within 5 years
b. Clinically significant symptom or uncontrolled central nervous system or brain metastases. Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system-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).
c. History or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy or evidence of clinically significant immunosuppression. Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
d. Class III or IV heart failure by New York Heart Association classification
e. Uncontrolled hypertension (SBP/ DBP greater than 160/100 mmHg)
f. Active hepatitis B and hepatitis C virus infection
g. Known infection with human immunodeficiency virus
h. History of primary immune deficiency
i. Other active viral infections
j. Thromboembolic disease or bleeding diatheses
k. Severe infection or other uncontrolled active infectious disease requiring antibiotics or antiviral agents that would interfere with the evaluation of safety and efficacy in the judgment of the Investigator.
6. Patients who have received any of the following medications:
a. Administration of granulocyte colony-stimulating factor or platelet transfusion within 2 weeks prior to baseline for correction of ANC or platelet count
b. Patients with therapeutic doses of anticoagulants, should be excluded from most deep lesion biopsies and injections. However, for deep injections in patients receiving a preventive dose of LMW heparin it is recommended that their LMW heparin treatment is stopped 24 hours before the intratumoral injection and resumed 24 hours after the injection.
c. Patients with current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:
i. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra-articular injection)
ii. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. Inhaled or topical steroids, and adrenal replacement steroid doses less than or equal to 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Inhaled or topical steroids, and adrenal replacement steroid doses less than or equal to 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
iii. Steroids as premedication for hypersensitivity reactions (e.g. computerized tomography [CT] scan premedication)
iv. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
v. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
7. Patients who have received other IP or investigational device within 4 weeks prior to baseline.
8. Patients with any prior Grade 3 or higher immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved Grade >1 irAE (as per NCI-CTCAE version 5.0)
9. Patients with any Grade greater than 1 toxicity (as per NCI-CTCAE version 5.0) related to prior anti-cancer therapy, except those that are deemed not clinically significant by the Investigator in discussion with the study medical monitor, sponsor’s CMO.
10. Patients who, in the opinion of the Investigator, are unsuitable or unable to participate in the 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)
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
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
27/08/2020
Actual
Date of last participant enrolment
Anticipated
16/03/2021
Actual
Date of last data collection
Anticipated
31/08/2021
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 16520 0
Sydney Southwest Private Hospital - Liverpool
Recruitment hospital [2] 16521 0
Westmead Hospital - Westmead
Recruitment hospital [3] 16522 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 30076 0
2170 - Liverpool
Recruitment postcode(s) [2] 30077 0
2145 - Westmead
Recruitment postcode(s) [3] 30078 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 305488 0
Commercial sector/Industry
Name [1] 305488 0
ViroCure, Inc.
Country [1] 305488 0
Korea, Republic Of
Primary sponsor type
Commercial sector/Industry
Name
ViroCure, Inc.
Address
ViroCure, Inc.
#503 AceTwinTower1cha Gurodigital complex (#501, 504)
(Or: 212-1 Guro-dong, Guro-gu), Gurodong
Seoul, Republic of Korea. 08381
Country
Korea, Republic Of
Secondary sponsor category [1] 305886 0
None
Name [1] 305886 0
NA
Address [1] 305886 0
NA
Country [1] 305886 0
Other collaborator category [1] 281292 0
Commercial sector/Industry
Name [1] 281292 0
Novotech (Australia) Pty Limited
Address [1] 281292 0
Level 3, 235 Pyrmont Street, Pyrmont NSW 2009
Country [1] 281292 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305801 0
Bellberry Limited HREC
Ethics committee address [1] 305801 0
Ethics committee country [1] 305801 0
Australia
Date submitted for ethics approval [1] 305801 0
19/02/2020
Approval date [1] 305801 0
16/04/2020
Ethics approval number [1] 305801 0
Ethics committee name [2] 305838 0
Alfred Health HREC
Ethics committee address [2] 305838 0
Ethics committee country [2] 305838 0
Australia
Date submitted for ethics approval [2] 305838 0
23/04/2020
Approval date [2] 305838 0
Ethics approval number [2] 305838 0

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

Contacts
Principal investigator
Name 101642 0
Dr Adam Cooper
Address 101642 0
Liverpool Hospital 40 Bigge St, Liverpool NSW 2170
Country 101642 0
Australia
Phone 101642 0
+61 2 8738 9744
Fax 101642 0
Email 101642 0
Adam.Cooper@health.nsw.gov.au
Contact person for public queries
Name 101643 0
Juhan Yoon
Address 101643 0
#503 AceTwinTower1cha Gurodigital complex (#501, 504) (Or: 212-1 Guro-dong, Guro-gu)
Gurodong, Seoul, Republic of Korea. 08381
Country 101643 0
Korea, Republic Of
Phone 101643 0
+82 2 861 0317
Fax 101643 0
Email 101643 0
Juhan@virocure.net
Contact person for scientific queries
Name 101644 0
Juhan Yoon
Address 101644 0
#503 AceTwinTower1cha Gurodigital complex (#501, 504) (Or: 212-1 Guro-dong, Guro-gu)
Gurodong, Seoul, Republic of Korea. 08381
Country 101644 0
Korea, Republic Of
Phone 101644 0
+82 2 861 0317
Fax 101644 0
Email 101644 0
Juhan@virocure.net

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.