| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer of the stomach is the 6th most common cancer in the UK, causing over 5000 deaths each year. All treatments aimed at cure involve surgery, but when it is used alone only around 20% of patients are alive after 5 years. The MRC ST02 trial (also known as MAGIC) has shown that progression free and overall survival are significantly improved by the administration of peri-operative chemotherapy with ECF (epirubicin, cisplatin and 5-fluorouracil (5-FU)). |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the stomach, or cancer at the junction of the stomach and oesophagus (the tube that connects your mouth and stomach), or in the oesophagus itself. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007284 |
| E.1.2 | Term | Carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the ST03 trial are
- to assess the safety and efficacy of adding the monoclonal antibody bevacizumab to ECX chemotherapy administered peri-operatively in patients with operable adenocarcinoma of the stomach and gastro-oesophageal junction.
- to assess the safety of adding the small molecule tyrosine kinase inhibitor, lapatinib, to ECX chemotherapy administered peri-operatively in patients with HER-2 positive operable oesophagogastric adenocarcinoma. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. MRI-Substudy
The MRI sub-study is an observational study designed to assess the potential benefit of MRI in the selection of patients for surgery based on the ability of MRI to predict patients who are likely to have a positive circumferential resection margin (CRM).
The study will use T2 weighted high resolution MRI as a predictive biomarker for resectability in patients with oesophageal and oesophagogastric junction cancer recruited into the ST03 clinical trial. The MR imaging data will be collected prospectively but not used to inform patient management. In this way the MRI prediction of resectability can be validated against the surgical and histological findings and the integrity of the chemotherapy trial is maintained.
2. 18F-FDG PET/CT Sub-Study
The objective of the trial is to evaluate the role of FDG-PET/CT after 1 cycle of neoadjuvant chemotherapy, for the early prediction of non-response to neoadjuvant chemotherapy in patients with potentially resectable adenocarcinoma of the OGJ or lower oesophagus, specifically answering the following questions:
• Does early response (defined as >20% reduction in metabolic activity) on FDG-PET after 1 cycle predict a better prognosis (and does the lack of response predict a poor prognosis) with respect to:
o progression-free survival
o overall survival
o pathological response (Mandard grade)
o clinical response (RECIST, Ro resection rate)
• Can response be quantitatively assessed with FDG-PET ie do the 4 response categories (see appendix 2) divide the PET positive group into distinct prognostic groups? |
|
| E.3 | Principal inclusion criteria |
Patients with histologically verified lower oesophageal, Siewert Type I, II or III oesophagogastric junction (OGJ) adenocarcinoma or gastric adenocarcinoma, who have not received any treatment for their cancer.
Tumours should be Stage Ib (T1 N1, T2a/b N0), II, III or stage IV (T4 N1 or N2) with no evidence of distant metastases (M0) where the surgeon believes that an R0 resection can be achieved by excision of a contiguous structure. Patients with linitis plastica should not be randomised.
Tumours should be Stage II to Stage IVa (T1 N1, T2 N1, T3 N0-1, but not T2N0). T4 (N0 or N1) tumours are also eligible providing that they involve only the crura OR invade only the mediastinal pleura, where the surgeon believes that an R0 resection can be achieved by excision of a contiguous structure.
Patients with nodal disease affecting the origin of the left gastric and splenic artery or coeliac axis (hitherto staged as M1a) are also eligible.
All patients should have a CT of chest and abdomen (pelvis is optional) prior to study entry. Patients with gastric and Siewert type II and III OGJ adenocarcinomas should also have a laparoscopy prior to study entry. Endoscopic ultrasound (EUS) should be performed for all lower oesophageal and OGJ adenocarcinomas and according to local practice for other tumours.
The following assessments should normally be performed within 6 weeks prior to randomisation. If assessments are > 6 weeks or results are borderline please contact the ST03 Trial manager who will refer your query to the Chief Investigator.
- WHO performance status 0 or 1
- Adequate respiratory function: FEV1 > 1.5 litres (mandatory for patients with lower oesophageal and OGJ tumours only)
- Adequate cardiac ejection fraction (as determined by ECHO or MUGA scan) > 50% or > your centres LLN for MUGA and BP <140/90mmHg.
The following assessments should normally be performed within 1 week prior to randomisation and be as defined. If assessments are > 1 week or results are borderline please contact the ST03 Trial manager who will refer your query to the Chief Investigator.
- Adequate bone marrow function
• Absolute neutrophil count (ANC) >1.5x109/l
• White blood cell count > 3x109/l
• Platelets > 100x109/l
• Haemoglobin (Hb) > 9g/dl (can be post-transfusion)
- Adequate renal function: glomerular filtration rate (GFR) >60ml/min calculated or measured. If the calculated GFR is <60ml/min then a measured GFR is required (see appendix I). The measured GFR should always take precedence over the calculated
GFR.
- Adequate liver function
• serum billirubin V1.5x ULN
• ALT/AST V2.5x ULN
• ALP V3x ULN
- Absence of proteinuria at baseline, defined as <2+ of protein on urine dipstick, <1g of protein/24 hr by a 24-hour urine collection or spot morning urine proteincreatinine ratio (UPCR) of <1.
- Adequate Coagulation profile:
• International normalised ratio (INR) < 1.5
• Activated ProThrombin Time (APTT) < 1.5xULN
- Patients on oral anticoagulation are advised to change to low molecular weight heparin prior to randomisation, to be eligible.
- Patients with high frequency hearing loss are eligible for ST03. They should be treated with cisplatin but changed to carboplatin if there is any evidence of deterioration
- Patient is fit to receive all protocol treatment
- Completion of baseline quality of life questionnaire
- Women of childbearing potential should have a negative pregnancy test within 7 days prior to commencing treatment, or have had amenorrhea for more than 2 years. Fertile men and women must agree to take adequate contraceptive precautions.
- Male/female patients aged >18 years
- Written informed consent obtained before randomisation
|
|
| E.4 | Principal exclusion criteria |
Cerebrovascular disease (including transient ischaemic attacks (TIA) and strokes) within 1 year before trial entry
Cardiovascular diseases as follows:
- Myocardial infarction (V 1 year prior to randomisation)
- Uncontrolled hypertension (defined as BP W140/90mmHg) while receiving chronic medication Patients with a BP W140/90mmHg prior to randomisation should be commenced on an ACE inhibitor or other antihypertensive agent then BP re-checked a few days later, if BP is controlled to <140/90mmHg then the patient may be entered into the trial.
- Angina requiring nitrate therapy within 1 year prior to randomization
- New York Heart Association (NYHA) Grade II or greater congestive heart failure
- Serious cardiac arrhythmia requiring medication (for example, ventricular tachycardia, supraventricular tachycardia or atrial fibrillation with a resting heart rate >110bpm)
- Major surgery, major trauma or open biopsy within 28 days prior to study entry (not including staging laparoscopy)
- Serious non-healing wound, ulcer or bone fracture
- Evidence of bleeding diathesis or coagulopathy
- Recent history of any active gastrointestinal inflammatory condition such as peptic ulcer disease, diverticulitis or inflammatory bowel disease. If patients have a known diagnosis of any of the above, evidence of disease control is required by negative endoscopy within the past 28 days.
- Patients with mild/intermittent tinnitus can be randomised to ST03 but patients with more severe tinnitus should not be randomised.
- Patients who have received chemotherapy or radiotherapy for a previous malignancy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint sECX+/-B comparison
Stage 1 assessed the safety of the investigational arm B (sECX+B) compared with the control arm A (sECX). This was monitored by assessing the number of:
• Perforations at the site of the primary tumour and elsewhere in the gastrointestinal tract
• Wound-healing related events
• Gastrointestinal bleeding events
• Cardiovascular events
This stage was completed in April 2010. The IDMC reviewed the data in June 2011 and agreed the trial should continue and that the additional monitoring of LVEF could be discontinued
Stage 2 will assess whether the addition of bevacizumab to standard treatment results in improved overall survival (OS)
Primary Endpoint sECX Vs mECX+L comparison
The primary outcome measure for the feasibility study is the safety of the addition of lapatinib to mECX chemotherapy.
Formal safety reviews will occur after 10 and 20 patients have completed one cycle of mECX+lapatinib. Additionally, a further safety review will be conducted once 10 patients have completed 1 cycle of maintenance lapatinib. We intend to publish the results of the safety of the addition of lapatinib to mECX chemotherapy once the recommended dose is established.
Toxicity will continue to be monitored throughout post-op treatment and dose reductions will be made accordingly on an individual basis. The primary endpoint will be the establishment of a recommended dose for expanded recruitment at all ST03 centres. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1: during adiministration of chemotherapy before and after surgery
Stage2: during follow up |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints sECX +/- B comparison
Stage 1 assessed the feasibility of the trial in terms of:
• Patient’s acceptance of the trial
• How many patients are able to complete the treatment
Stage 2 will assess:
• Treatment-related morbidity
• Response rates to pre-operative treatment
• Surgical resection rates
• Disease free survival
• Quality of life
• Cost-effectiveness
Secondary Endpoints sECX Vs mECX+L comparison
1. The aim would be for >90% of samples to have a HER-2 result within 10 working days. This target is ambitious, and given that this is a neoadjuvant study with patients undergoing a series of investigations prior to commencing neoadjuvant chemotherapy it is unlikely to delay treatment if the HER-2 testing takes longer. Results now available from the FOCUS-3 study suggest 15 working days may be a more realistic target. The key measure will be to assess feasibility and to ensure that HER-2 testing does not delay treatment.
2. To determine the proportion of samples that are HER-2 positive. Feasibility of a
national HER-2 trial will depend on the HER-2 positivity rate. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage 1: during chemotherapy
Stage 2: during treatment and follow up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 107 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 12 weeks after the date of the last treatment visit for the last patient undergoing protocol treatment |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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