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 MedDRA version: 18.0 Level: PT C
Conditions
Sponsors
Medical Research Council Clinical Trials Unit
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 500
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Secondary Objective: 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.;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%. ;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. ;Main Objective: To assess safety and overall | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 ;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. | — |
Countries
Germany, United Kingdom
Contacts
Public ContactST03 Trial Manager
Medical Research Council Clinical Trials Unit
Outcome results
None listed