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VISTA

VISTA: Vaccination with ITOP1 in resectable oesophageal adenocarcinoma – Safety, Tolerability and Anti-Tumour activity

VISTA trial logo

Full Title

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

Chief investigator: Prof Mark Middleton

Sponsor: University of Oxford

Study Status

In set-up

Contact Us

VISTA Trial Office:  OCTO-VISTA@oncology.ox.ac.uk

Target Population

Patients with resectable oesophageal adenocarcinoma (OAC) recommended for neoadjuvant chemotherapy. Additionally, the VISTA trial focuses on target populations with specific HLA type for each Phase as described below:

Phase I Safety Lead-in: HLA A*02:01

Phase II Randomised trial: At least one or more of HLA A*02:01, HLA B*07:02 or HLA B*40:01

(Detailed eligibility criteria mentioned below)

Recruitment

Recruitment Target:  60 in total (8 participants in Phase I and 52 participants in Phase II)

Recruitment Duration: 24 months

Trial Duration:  Participants will be followed up for 2 years from when they receive their first dose of ITOP1/Placebo (with possibility to extend with the optional survival follow-up period)

Participating Sites

The VISTA trial will be opening to recruitment at the following sites:

Churchill Hospital, Oxford

University Hospital Southampton

Leeds Teaching Hospital

 

Lay Summary

Unfortunately, it is very common for patients with oesophageal cancer for their cancer to return at a later date. The VISTA trial aims at reducing this risk for those patients with oesophageal cancer who have received an initial course of chemotherapy and then had their main tumour removed by surgery.

VISTA will investigate a new cancer vaccine called ITOP1, which uses virus-based technology. A cancer vaccine is similar to those given for seasonal flu and is made up of dead/weakened germs to train the immune system to protect against future infection. ITOP1 aims to help the immune system ‘mop up’ any cancer cells still in the body after treatment and prevent them from developing into new cancers.

ITOP1 has not been used on patients before, and VISTA is designed to look at its safety, any side effects the vaccine may cause, and early signs of the vaccine’s potential to prevent cancer from coming back.

The current UK standard of care for newly diagnosed treatment of oesophageal cancer is based on a course of chemotherapy given before the primary tumour is removed by surgery, followed by further chemotherapy once the patient has fully recovered from surgery.

The first (prime) injection of the ITOP1 dose will be given 4 weeks after the first course of chemotherapy and before the surgery. A second (boost) dose injection would be given before the second course of chemotherapy. This ensures that it would not harm the standard of care that the patients can expect to receive. The aim of ITOP1 is that once the main tumour is removed, the body's immune response will be triggered by the vaccine and prevent the cancer from returning or spreading, which is the cause of the majority of oesophageal cancer deaths.

The trial will be conducted in two phases and a total of 60 participants will be enrolled. In Phase I, 8 patients will receive the ITOP1 vaccine, and a safety review will be conducted before moving to Phase II. In Phase II, 52 patients will be randomly assigned to receive either the ITOP1 vaccine or a placebo (sterile normal saline).

Trial Schema

VISTA Schema

Trial Design

The VISTA trial is a double-blinded, randomised Phase I/IIa trial for patients with resectable oesophageal adenocarcinoma (OAC) recommended for neoadjuvant chemotherapy. Patients are first screened for HLA types, with only those matching at least one of the specific HLA types would be eligible for the trial.

In the Phase I safety lead-in, the vaccine ITOP1 A/B is administered to the first 8 participants in staggered doses, with the safety assessed by a Data & Safety Monitoring Committee (DSMC). The trial will progress to Phase II unless specific adverse event criteria are met during Phase I, which could result in a safety review.

 

In Phase II 52 participants will randomly be assigned to receive either ITOP1 or placebo (3:1 ratio). All participants randomised to ITOP1 will receive ITOP1A/B and/or ITOP1C/D and/or ITOP1E/F.  ITOP1 is administered in a prime and boost regimen after neoadjuvant chemotherapy and before adjuvant FLOT chemotherapy.

Doses of ITOP1 depend on the individual participant’s HLA type, ranging from 2.0 x 1010 to a maximum of 6.0 x 1010 viral particles per participant. After 4 cycles of neoadjuvant chemotherapy, participants will receive the first dose of ITOP1 and undergo surgery, followed by a post-surgery recovery period of 8-12 weeks. The boost dose of ITOP1 treatment will be administered 2 weeks prior to the planned initiation of the adjuvant cycles of FLOT. The trial will also monitor for new autoimmune conditions over a 2-year follow-up period. In Phase II, participants will continue treatment and be monitored with imaging and tumour sampling, with an optional long-term follow-up extending up to 3 years after the final visit.

Objectives

Primary Objective:

  • Characterisation of the safety and tolerability of ITOP1

Secondary Objectives:

  • Immunogenicity of ITOP1
  • Preliminary clinical efficacy of ITOP1

Exploratory Objectives:

  • Determine prevalence of target epitopes in participant samples
  • Assess anti-drug antibodies dynamics
  • Evaluate changes in ctDNA levels in response to treatment
  • Detection of epitope-specific T cells
  • Characterisation of RNA expression of tumour infiltrating T Cells
  • Impact of gut microbiome on clinical outcomes/response to treatment

Participant Eligibility

Pre-trial screening

Patients will be eligible for screening for HLA-type testing provided that:

  1. They give written informed consent to pre-screening
  2. The Investigator anticipates that they may satisfy the eligibility criteria for entry into the main trial (Phase I or Phase II as  applicable at time of screening) detailed below (NB formal screening for the trial should not be performed until the HLA pre-trial screening result is known).
Following pre-trial screening, patients will be consented for either Phase I Safety Lead-in or Phase II of the VISTA trial.

Patients will be eligible for Phase I Safety Lead-in or Phase II screening provided that the following criteria are met in addition to the inclusion and exclusion criteria:


Eligibility criteria for entry into the Phase I Safety Lead-in:

  1. They give written informed consent to Phase I Safety Lead-in
  2. They have the relevant HLA type for the Phase I Safety Lead-in treatment: HLA A*02:01

Eligibility criteria for entry into the Phase II screening:

  1. They give written informed consent to Phase II
  2. They have the relevant HLA type for the Phase II trial IMP treatment: At least one or more of HLA A*02:01, B*07:02 or B*40:01 

Phase I Safety Lead-in & Phase II

Inclusion criteria:

  1. Histological diagnosis of oesophageal or gastroesophageal junctional (types 1, 2 or 3) adenocarcinoma, deemed suitable for surgery with curative intent
  2. Deemed suitable for oesophagectomy with curative intent by the relevant multidisciplinary team
  3. Planned neoadjuvant and adjuvant treatment with FLOT chemotherapy
  4. ECOG performance status of 0 or 1
  5. Written informed consent obtained for Phase I Safety Lead-in /Phase II (as applicable).
  6. Age ≥ 18 years.
  7. Willing and able to comply with the protocol for the duration of the trial including undergoing treatment, scheduled visits, examinations, biopsies and follow up.
  8. Adequate normal organ and marrow function as defined below.
Laboratory parameters for vital functions should be in the normal range. Laboratory abnormalities that are not clinically significant are generally permitted, except for the following laboratory parameters, which must be within the ranges specified, regardless of clinical significance:

Lab Test

Value required

Haemoglobin (Hb)

≥ 90 g/L

Neutrophil count

≥ 1.5 x 109/L

Platelet count

≥ 100 x 109/L

Serum creatinine, or Creatinine Clearance

≤ 1.5x Institutional Upper Limit of Normal (ULN), or ≥ 40 mL/min (by Cockcroft-Gault formula)

 

Aspartate transferase (AST) or Alanine aminotransferase (ALT)

AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal

Alkaline phosphatase

≤ 2.5 x ULN

Serum bilirubin

≤ 1.5 x institutional ULN. This will not apply to subjects with documented Gilbert’s syndrome as evidenced by persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology, who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN

Exclusion criteria:

A patient will not be eligible for the trial if any of the following apply:

  1. Prior treatment in another clinical trial with an investigational product within 4 weeks prior to Day 1 of the trial; any respective adverse events must have resolved to Grade 1 or lower to be eligible.
  2. Any contraindications to the FLOT chemotherapy or planned surgery
  3. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with coeliac disease, vitiligo or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
  4. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
  5. History of allogeneic organ transplant
  6. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s Correction
  7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, known immunodeficiency or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with trial requirements or compromise the ability of the subject to give written informed consent
  8. Known history of previous clinical diagnosis of tuberculosis
  9. History of severe allergic reactions to any unknown allergens or any components of the trial drugs.
  10. Known dihydropyrimidine dehydrogenase (DPD) deficiency
  11. Peripheral sensory neuropathy with functional impairment.
  12. History of sarcoidosis/sarcoidosis syndrome.
  13. Major surgical procedure (as defined by the Investigator) within 30 days prior to Day 1 or still recovering from prior surgery.
  14. SARS-CoV2 vaccine (mRNA, subunit /viral vector or other) within 6 weeks of administration of first dose of trial drug(s); or any live attenuated vaccine within 28 days of first dose of trial drug(s).
  15. Women who are breast feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG)).
  16. Patients of reproductive potential who are not willing to use adequate contraceptive measures for the duration of the trial and for 6 months after last dose of trial IMP (both male and female patients). Male participants must use condoms for the duration of the trial and for 6 months after last dose of trial IMP.
  17. Patients unable to commit to avoiding contact with young children or the severely immunocompromised for 5 days after each IMP dose*
  18. Any condition that, in the clinical judgment of the treating physician, is likely to interfere with evaluation of trial treatment, interpretation of subject safety or trial results, prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk.

*Defined as follows:

‘Young Children’ are individuals aged 0 to 12 years’ old whom do not otherwise meet the criteria for ‘severely

immunocompromised’

‘Severely immunocompromised’ are those who meet any of the following criteria:

- Active haematological malignancy (excluding Monoclonal gammopathy of undetermined significance

- (MGUS), or those in currently receiving treatment for a haematological malignancy and/or those within oneyear of bone marrow or stem cell transplant

- Solid organ transplant(s) requiring immunosuppression

- Advanced or untreated HIV/AIDs

- Congenital or primary immunodeficiencies

- Immunosuppressive therapy (equivalent to ≥20 mg/day of prednisone for ≥2 weeks)

- End-stage Renal Disease

- Other condition(s) which, in the opinion of the Principal Investigator, would put close contacts of participants receiving ITOP1 at unreasonable risk should ITOP1 result in clinically significant viral shedding in the 5 days following dosing

Site investigators should discuss with the Chief Investigator any potential patients whose eligibility is affected by this exclusion criterion

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