Proof-of-concept Study of Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma (iMYC)

This is an open-label, single-arm phase II study. Patients will receive standard dose single-agent ibrutinib delivered orally at a dose of 560mg once daily continuously on a 4 weekly cycle until disease progression or unacceptable toxicity occurs.

Single arm, open label means that both researchers and participants know the treatment which is being administered, and all participants in the trial will receive the study drug ibrutinib.

A Phase 2 study was chosen as more information about the efficacy and toxicity of this drug in this specific group of patients is needed prior to considering a larger phase 3 study.

Eligible patients are those with advanced unresectable or metastatic oesophagogastric adenocarcinoma or squamous cell carcinoma who have been treated with at least 1 prior chemotherapy for advanced or metastatic disease. In the case of HER2 positive tumours, previous treatment with chemotherapy with or without a HER2 targeted agent is allowed.

There will be a two step enrollment process:

1. Enrollment for prescreening to establish cMYC and HER2 status (which may occur during 1st line treatment or after progression on 1st line treatment)

2. Enrollment for randomisation and treatment The patient will first be given the prescreening participant information sheet (PIS) and informed consent form (ICF) that has been approved by the Ethics Committee. They will have the study explained to them and be given the opportunity to ask questions. If they agree to take part, they will be asked to sign the approved consent form, and they will keep a copy of the signed consent form.

   Prescreening If a participant agrees to take part in the prescreening for the study a previously obtained sample of their cancer (usually a diagnostic biopsy) will be taken out of storage and sent to the trial laboratory where the tissue will be tested for both cMYC and HER2 amplification. If there is no archival tumour sample available or if the existing tumour sample is of insufficient quality, the patient will be given the option to consent to a pre-screening biopsy to obtain a fresh sample.

   A blood test will be taken for plasma DNA analysis including circulating tumour cell number, c-MYC copy number variation (by digital droplet PCR) and blood-borne biomarkers. It can take up to 4 weeks to get these results which is why we will try to pre-screen patients to avoid delays in treatment. When the patient's disease progresses on 1st line treatment and if they are a suitable candidate for second line treatment their team will confirm if there are spaces available on study according to the the patients cMYC and HER2 status.

   If there are spaces available they will be given the main study PIS and ICF that has been approved by the Ethics Committee. They will have the study explained to them and be given the opportunity to ask questions. If they agree to take part, they will be asked to sign the approved consent form, and they will keep a copy of the signed consent form

   Screening

   If a participant agrees to take part in the main study, assessments will be made to make sure that he/she is eligible for the study. Some of these assessments may already have been done as part of the participant's standard of care, in which case, the results of those tests may be used. The assessments that will be done are described below:

   Disease status Tumour sample details, c-MYC and HER2 status if re-tested Medical/surgical history Pregnancy testing for female patients World Health Organisation (ECOG) performance status Physical examination to assess all conditions that are current and ongoing. Vital signs: height, weight, pulse, systolic blood pressure and diastolic blood pressure ECG Tumour biopsy* Tumour assessments (RECIST v1.1), consisting of either staging CT or MRI imaging FDG-PET scan* Concomitant medication. Adverse events Blood tests for clinical biochemistry and haematology Urinalysis Blood tests for DNA analysis including Circulating Tumor Cell (CTC) number, c-MYC copy number variation (by digital droplet PCR) and bloodborne biomarker analysis*

   *These procedures will only be carried out once all other criteria for trial entry are met.

   If the results of screening tests confirm that the patient can take part in the study they will be asked to return to the clinic to see their doctor for assessments as detailed below during the study treatment period.

   Study treatment period During the treatment period the patient will be seen regularly in clinic.The treatment is oral capsules given once per day every day in cycles lasting 28 days. Patients will be seen on day 1, 8 and 15 of the first cycle of treatment and then on day 1 of every cycle (every four weeks) for the remainder of the study duration. When they stop being treated within the study they will have a 30 day follow up visit and then be followed up every 8 weeks, although this contact can be over the telephone.

   Before each treatment cycle, the patient will be examined and have safety blood tests to make sure that it is safe to proceed with treatment as mentioned below. Patients will have different procedures done at different times during the study treatment period including:

   Measurement of resting blood pressure and pulse rate before every treatment (at all study visits).

   Physical examination at the beginning of each cycle (every four weeks). Documentation of any changes in the medication taken and whether the patient has had any problems or discomfort since the last visit (at all study visits).

   An ECG at baseline and on completion of study, and at any further timepoint if clinically indicated Blood samples to check haematology and clinical chemistry results (every 4 weeks or if clinically indicated) Blood samples for plasma DNA analysis including CTC number, c-MYC copy number variation (by ddPCR) and bloodborne biomarker analysis. These will be taken on cycle 1 day 15, cycle 3 day 1 and then every 8 weeks (alternate cycles).

   Blood samples to assess pharmacokinetics of ibrutinib on cycle 1 day 8 (predose, 2 hours, 6 hours post dose) and one further sample on cycle 1 day 15.

   Assessment of the status of disease using CT or MRI imaging at week 8 and then every 8 weeks.

   Assessment with PET CT scan at baseline, day 14 and week 8 to correlate with tumour response and genetic changes seen Health related quality of life questionaires for the patient to fill out at the beginning of each cycle (every 4 weeks)

   As mentioned above, a biopsy at the time of screening is mandatory for entry into the trial. As part of the trial further optional biopsies will be offered to the patient:

   at day 14 (in all patients on ibrutinib) at week 8 (on those patients responding to ibrutinib) on discontinuation of study treatment (on those patients who have progressed on ibrutinib)

   Treatment discontinuation visit:

   When the patient withdraws from the study or treatment is permanently discontinued, they will need to attend the clinic for a visit and the following assessments will be carried out:

   Changes in the medication taken and any problems or discomfort since their last visit will be documented.

   If the patient has a side effect at their final study visit or withdrawal visit then the study doctor may wish to contact them and ask about it, until it has completely resolved. The study sponsor may also ask the study doctor for this information.

   When the patient has completed the study, the doctor will then decide whether they require further treatment outside the study. They will continue to be followed up within the study every 8 weeks to document what other cancer treatment they may or may not be taking and to document overall survival. This contact may be in clinic if they are attending the hospital or can be by telephone if they are not.

   Timeline for Final Report The study is planned to recruit over 24 months with a further 12 months of follow up with final report planned for within 12 months of the last patient's last visit.