A first-in-human study of VG161 in participants with advanced malignant tumours that have not responded to conventional therapies.

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 on Day 1 and observed for one week 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). 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.