Version 3.0 dated 21 Oct 2014 Patient Population • To allow for patients to be included in Phase Ia and for the first three Phase Ib to reflect usual Phase I population criteria e.g. patients who exhausted all other treatment options, with no measurable disease acceptance of other malignancies in the 3 years prior to study entry • To accept prior weekly paclitaxel monotherapy if there had been a 6 months between last weekly paclitaxel administration and first administration enadenotucirev • To better define the exclusion criterion relating to intestinal subocclusion • To allow nonsymptomatic central nervous system metastasis • To remove the time window between last administration of prior systemic treatment for cancer and the first dose of study treatment as long had recovered from side effects to NCI CTCAE Grade 1 or less • To not restrict the choice of IP catheter • To allow for the IP catheter to be removed at any time post last administration study treatment according to the Investigator’s clinical judgement Study Design To extend the screening period to 21 days and mandate for the screening eligibility procedures to be completed before insertion of the catheter

Version 4.0 dated 23 Mar 2015 Patient Population To refine the eligibility criteria relating to tolerance of administration procedures for enadenotucirev, to only select patients likely to tolerate the procedures Safety To allow for no or partial drainage of ascites prior to enadenotucirev administration in patients who had not tolerated the procedure during prior enadenotucirev administration or who were unlikely to further tolerate it

Version 5.0 dated 25 Jan 2016 Patient Population To remove the eligibility criterion excluding patients who had received a weekly regimen of paclitaxel in the previous 6 months

Version 6.0 dated 01 Nov 2016 Patient Population: The requirement for having historical biopsy samples was removed from a specific inclusion criterion and included as a study requirement Safety: • The use of acetaminophen/paracetamol and ibuprofen was amended to be administered according to the Investigator’s normal prescribing practices and their discretion • The DLT definition was amended to specify that the causality of an adverse event must be considered at least possibly attributed to enadenotucirev (whether it is given as a monotherapy or in combination with paclitaxel), in order to be considered a DLT Study Design: To add an IV dosing arm to the study to evaluate the safety and tolerability, PFS, anti-tumour activity, immune responses and exploratory objectives in patients with platinum-resistant ovarian cancer receiving IV enadenotucirev in combination with paclitaxel. Since the initiation of the study investigating the IP dosing route, two other clinical studies had investigated the IV administration of enadenotucirev (Study ColoAd1-1001 and ColoAd1-1002). The safety and tolerability profile had been outlined for a range of doses, dosing schedules and dosing regimens of enadenotucirev administered IV to more than 70 patients with a variety of epithelial derived cancers. A dose level of enadenotucirev for IV administration was identified to take forward in development that had both an acceptable tolerability profile and demonstrated delivery to an epithelial derived tumour type (colon cancer). The objective of this study changed to investigate administration of enadenotucirev by IP injection alongside IV infusion, the latter providing a potentially more convenient and acceptable route of administration in these patients.

Version 7.0 dated 04 Apr 2017 Study Design • An exploratory objective of Phase I of this study was added to measure a panel of cytokines in peripheral blood samples to explore the safety, the mechanism of action and the activity of enadenotucirev • The cytokine sampling for Phase Ib IV administration was amended to be taken at pre-dose and 6 hours post-dose and 12 hours post-dose. This was to be consistent with another active study with IV enadenotucirev administration (ColoAd1-1003)

Version 8.0 dated 14 Dec 2017 Safety: Procedures were implemented as part of an urgent safety measure to increase monitoring of kidney function. This was in response to a Grade 4 SAE of acute renal injury in a single patient with Stage IV colon cancer in Study ColoAd1-1003 with enadenotucirev and nivolumab combination therapy. The event was assessed to be related to enadenotucirev. For the two ongoing patients in the Dose Expansion Phase (both had completed Cycle 1 and were due to enter Cycle 2 at the time of this amendment): • To make all safety laboratory tests mandatory (when previously optional based upon clinical judgement) • To add urinalysis assessments at the following timepoints: Day 37, Day 44 and to correct an inconsistency and include urinalysis on Day 51 • To specify that any proteinuria detected on urinalysis must have been confirmed by repeat testing. If the patient presented any indication of decreased renal function on clinical assessment, then the Sponsor must have been contacted and a renal consultation arranged immediately.

Version 9.0 05 Feb 2018 Safety Following the implementation of an urgent safety measure to increase monitoring of kidney function in Version 8.0 of the protocol, in response to a treatment-related SAE of Grade 4 acute renal injury in a single patient with Stage IV colon cancer in a separate study with enadenotucirev and nivolumab combination therapy (Study ColoAd1-1003). Although this patient met the eligibility criteria for study entry (with adequate renal function) he had a past history of methotrexate-related renal injury and chronic kidney disease that was not declared at study entry. In the overall context of three patients out of around 100 treated with enadenotucirev presenting with significant renal injury and in the context of risk:benefit of treatment, measures were implemented in ongoing studies to exclude those potentially at higher risk of renal injury (e.g. those with past history of renal disease, reduced renal function or proteinuria), monitoring patients more closely (at least weekly urinalysis assessment with appropriate confirmation of dipstick results with spot albumin creatinine ratios and 24-hour urinary protein if necessary) in turn with a view to early specialist intervention for investigation and treatment if decline in renal function should be detected. In addition, prophylactic hydrocortisone therapy was to be given with each administration of enadenotucirev to minimise any potential for renal damage as a result of cytokine-release mediated vascular leak syndrome.

Version 10.0 14 Dec 2018 Safety: The status, findings and recommendations following investigation into the renal injury signal were updated, including the risk: benefit assessment

Version 11.0 08 Apr 2019 Safety: • This protocol amendment comprised an urgent safety measure to exclude all patients from this study who had suspected, or evidence of, pulmonary lymphangitic carcinomatosis. This urgent safety measure followed an SAE of Grade 4 hypoxia in a patient treated with enadenotucirev at a dose of 1 x 1012 vp on Day 1 followed by 3 x 1012 vp on Days 3 and 5 in Study ColoAd1-1003. This patient was noted to have pre-existing pulmonary lymphangitic carcinomatosis. The cause of the profound hypoxia in this case was thought to be due to viral replication in tumour cells that had diffusely infiltrated the pulmonary lymphangitic channels with associated inflammation leading to impairment of diffusion capacity. This patient was treated with the antiviral medication cidofovir with some clinical improvement. • When treatment with cidofovir should be considered was outlined. Patient Population: An exclusion criterion was added ‘Clinically or radiologically suspected, or evidence of, lymphangitic carcinomatosis