A phase I/IIa, double-blinded, randomised controlled trial to assess the safety, tolerability, and early signs of anti-tumour activity of ITOP1 – a prime/boost viral vector vaccine targeting tumour specific antigens in subjects with surgically resectable oesophageal adenocarcinoma (VISTA)

Research summary

VISTA is a multicentre,double-blinded,randomised Phase I/IIa trial. Patients diagnosed with resectable OAC and recommended to have neoadjuvant chemotherapy will be offered entry into the trial. The Phase I Safety Lead-in will treat 8x participants with ITOP1 A/B,and Phase II will randomise 52x participants (3:1) to receive either ITOP1 or placebo (sterile 0.9% normal saline). Patients will initially be asked to consent to undergo a pre-screening test to determine their HLA type. Only patients that match to at least one of the HLA types expressed in ITOP1 can mount an immune response to the vaccine,so trial entry will be limited to those with relevant HLA types (expected to be ~60% of patients). Those that have the relevant HLA type will then be invited to consent to take part in either the Phase I Safety Lead in or Phase II trial (according to the phase of the trial underway at the time of consent). Trial IMP treatment will be given in a prime/boost regimen following neoadjuvant and before adjuvant FLOT (fluorouracil,leucovorin,oxaliplatin,and docetaxel) chemotherapy,in oesophageal cancer patients eligible for surgery. Phase I Safety Lead-in trial IMP treatment will be ITOP1,and for Phase II,participants will be randomly allocated either ITOP1 or placebo (sterile normal saline (0.9%)). ITOP1 will be administered as between 1 and 3 individual IMPs HLA matched to the individual participant and each delivering 2.0 x 1010 viral particles (vp). The number of IMPs that each participant receives will be dependent on their HLA match to the vaccines. The maximum dose of Ad5 vector for any single participant (6.0 x 1010 vp delivered in a prime/boost regimen) has been safely used in patients with other solid malignancies,in both neoadjuvant and advanced tumour settings,where it has been demonstrated to be safe and immunogenic (i.e. biologically active). Following 4 initial cycles of neoadjuvant FLOT chemotherapy all participants will receive their first intravenous (iv) dose of trial IMP treatment 4 weeks after the last cycle of chemotherapy starts. Participants will then proceed to definitive surgical resection followed by a post-surgical recovery period (typically 8-12 weeks). The iv boost dose(s) of trial IMP treatment will be administered 2 weeks prior to the planned initiation of the adjuvant cycles of FLOT. To minimise any initial safety risk in the trial,a safety lead-in phase will be conducted in the first eight participants (Phase I Safety Lead-in),with staggered dosing of participants of their prime dose by at least 1 week between participants one and two,and by at least 24 hours in participants two to eight. A Data & Safety Monitoring Committee (DSMC),operating according to a DSMC Charter,will perform a comprehensive safety evaluation 28 days after the last participant in Phase I Safety Lead-in has received their prime dose. The trial will proceed to Phase II provided the following criteria are not met during the Phase I Safety Lead-in safety assessment window,with regards to Treatment-Related Adverse Events (TRAE) deemed related/likely related to ITOP1 administration (i.e. not inclusive of AEs related to NIMP administration,standard-of-care treatment,or surgical procedure(s)):  Any NCI CTCAE (Version 5.0) Grade ≥3 ITOP1-related adverse event that does not resolve to Grade 2 (or baseline,if pre-existing) within 28 days  ITOP1-related adverse events in two or more participants resulting in the cancellation of,or delay by ≥28 days,of planned surgical resection Likewise,if either of the above criteria are met prior to this scheduled DSMC review,recruitment will be paused until a review by the DSMC is conducted and recommendation made to continue,amend,or terminate the trial. Adverse Events of Special Interest (AESIs) will include the onset of new autoimmune conditions during the active follow-up period (i.e. 2 years). Additional AESIs may be added in subsequent amendments based on emergent safety data. The DSMC will also meet to review all Phase I patients after they have received their boost dose. In the Phase II part of the trial,a further 52 eligible participants will be randomly assigned (in a 3:1 ratio) to receive either ITOP1 or placebo (sterile 0.9% normal saline). All participants randomised to ITOP1 will receive ITOP1A/B and/or ITOP1C/D and/or ITOP1E/F. Depending on HLA genotype,between 2×1010 vp and 6×1010 vp will therefore be administered per vaccination dose. Translational sampling and computed tomography (CT) scans will be conducted during the trial. Tumour sampling will be performed at the time of surgical resection.

Principal Investigator

Dr Elizabeth Smyth

Contact us

Email: orh-tr.earlyphasenurses@nhs.net

IRAS number

1008088