| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with histologically verfied lower oesophageal, Siewert Type I, II or III oesophagogastric junction or gastric adenocarcinoma.
Type III or gastric tumours should be stage 1b (T1N1, T2a/bN0), II,III or stage IV (T4 N1orN2 M0).
Lower oesophageal, Type I and II tumours should be stage II to stage IVa (T1N1, T2N1, T3N0-1, but not T2N0). T4 tumours are eligible if they involve the crura or invade the mediatinal pleural only.
The tumour should be operable |
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| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the stomach, 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017758 |
| E.1.2 | Term | Gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
| To assess safety and overall survival of patients by adding the monoclonal antibody bevacizumab to Epirubicin, Cisplatin, Capecitabine (ECX) chemotherapy administered peri-operatively in patients with operable oesophagogastric adenocarcinoma and (in selected centres) a feasibility study evaluating the safety and feasibility of adding lapatinib, a small molecule tyrosine kinase inhibitor of HER-2 and epidermal growth factor receptor to peri-operative ECX chemotherapy in patients with HER-2 positive tumours. |
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| E.2.2 | Secondary objectives of the trial |
Bevacizumab comparison: To assess the feasibility of the trial in terms of patient's acceptance of the trial and how many patients are able to complete the treatment.
The trial will also assess:
Treatment-related morbidity
Response rates to pre-operative treatment
Surgical resection rates
Disease free Survival
Quality of Life
Cost-effectiveness
Lapatinib feasibility study:
Feasibility in terms of HER-2 testing within an acceptable time frame and assessment of HER-2 positivity rate in the study population. |
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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 |
All sub-studies are detailed within the ST03 trial protocol:
Quality of Life study
Trans-ST03: Tissue and Blood Collection for Translational Research
MRI Sub-study: High resolution MR imaging as a predictive biomarker for determining
resectability in oesophageal and oesophagogastric cancer.
18F-FDG PET/CT Sub-study: A multicentre trial to evaluate the role of 18F-FDG PET/CT as a surrogate biomarker for prediction of treatment response and prognosis, following the first course of neoadjuvant chemotherapy in resectable oesophageal adenocarcinoma.
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| E.3 | Principal inclusion criteria |
1. a) Siewert type III OGJ or Gastric Adenocarcinomas (using gastric cancer staging system)
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.
b) Lower Oesophageal or Siewert type I/II OGJ Adenocarcinomas (using oesophageal cancer staging system)
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.
2. 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.
3. WHO performance status of 0 or 1.
4. Adequate respiratory function: FEV1 greater than 1.5 litres (mandatory for all lower oesophageal and junctional tumours only)
5. Adequate cardiac ejection fraction greater than or equal to 50% for ECHO or greater than or equal to LLN for MUGA, BP less than or equal to 140/90mmHg.
6. Adequate bone marrow, Liver and renal function
7. 24 hr Urine collection for protein uria < 1g
8. Adequate coagulation profile
9. Patient fit to receive protocol treatment
10. Patients aged over 18 years
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| E.4 | Principal exclusion criteria |
1. Cereborvascular disease
2. Cardiovascular Diseses including:
-myocardial Infarction (less than 1 year prior to randomisation)
- uncontrolled hypertension (BP>140/90mmHg)
- angina requiring nitrate therapy within 1 year prior to randomisation
- New York Heart Association Grade II or greater
- Serious cardiac arrhythmia requiring medication
3. Major Surgery/Trauma or biopsy within 28 days prior to randomisation
4. Serious non-healing wound, ulcer or bone fracture
5. Evidence of bleeding diathesis or coagulopathy
6. Recent history of any gastric inflammatory condition
7. Patient's with severe tinnitus
8. Patient's who have received chemotherapy or radiotherapy treatment previously
9. Lack of physical intergrity of the upper GI tract.
10. Positive serology for HIV, Hep C or active Hep B.
11. Patients who have previously received anthracycline treatment
12. known peripheral neuropathy (grade 1 and greater).
13. DPD deficiency
14. Allergy to chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any exicpients of bevacizumab formulation, platinum compounds or to any other components of the study drugs.
15. Patients with oesophageal or gastric stent (metal or biodegradable) in situ.
16. Patients with a history of interstitial lung disease or radiological evidence of lung fibrosis. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Bevacizumab comparison:
Primary endpoint in stage 1 (Phase II) is safety of the investigational arm in particular the rates of :
•gastric perforations at the site of the primary tumour
•cardiovascular complications, specifically congestive (ie symptomatic) cardiac failure, myocardial infarction and symptomatic (ie requiring treatment) arrhythmias.
•Perforations elsewhere in the intestine
•wound-healing related events
•gastrointestinal bleeding.
Primary endpoint stage 2 (phase III) is overall survival.
Lapatinib feasibility study:
The primary end point for the feasibility study will be the establishment of a recommended dose (capecitabine and lapatinib) for a potential subsequent phase III trial. The recommended dose must have an estimated grade 3/4 diarrhoea rate of no more than 20%.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Bevacizumab comparison:
Phase II completed recruitment in April 2010 and the results have already been evaluated.
The primary analysis of stage 2 (phase III) will take place when 420 deaths have been reported.
Lapatinib feasibility study:
A provisional decision about the recommended capecitabine and lapatinib doses for phase III will be made when the 20th lapatinib arm patient has completed their pre-operative treatment. The primary analysis of the feasibility study will take place once 20 patients have completed treatment with lapatinib. |
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| E.5.2 | Secondary end point(s) |
Bevacizumab comparison:
Secondary endpoint in stage 1 (Phase II) is feasibility in terms of:
1. patients acceptance of the randomisation as reflected in the rate of accural
2. the proportion of patients that are able to complete treatment.
Secondary endpoints stage 2 (phase III) are:
1. response rates to pre-operative treatment
2. surgical complete resection rates
3. treatment-related morbidity
4. disease-free survival
5. quality of life
6. cost-effectiveness
Lapatinib feasibility study:
Secondary endpoints are:
1. HER-2 testing within an acceptable timeframe
2. assessment of HER-2 positivity rate in the study population
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bevacizumab comparison:
Phase II completed recruitment in April 2010 and the results have already been evaluated.
The secondary analysis of stage 2 (phase III) will take place once the primary analysis is completed.
Lapatinib feasibility study:
Feasibility of HER-2 testing will be assessed when 60 patients have been tested, we require the proportion of results provided within 10 working days to be 90%. (First 10 patients used as a run-in, the next 50 patients used to assess feasibility). If less than 90% are turned around in 10 days we would not consider this acceptable and would implement changes and review across the next 50 patients.
HER-2 positivity rate will be assessed after 200 patients are tested assuming 20% HER-2 positivity, more patients may be required if rate lower.
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| 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 | Yes |
| 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 | Yes |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Against standard ECX chemotherapy |
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| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 108 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 109 |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| The end of the trial is defined as 12 weeks after the date of the last treatment visit for the last patient undergoing protocol treatment. This is followed by the non-interventional phase of long term follow-up, which will continue for a minimum of 5 years, after entry of the last patient until death. |
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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 | 6 |
| 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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