Study of Chemoradiotherapy in Oesophageal Cancer Including PET Response and Dose Escalation

Study Overview
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Brief Summary
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Research has shown that increasing the dose of radiotherapy improves outcomes in patients with lung and head and neck cancers. This study aims to see whether this is also the case for patients with tumour of the oesophagus. This trial will compare the effects of the standard dose of radiotherapy to a higher dose whilst closely monitoring the side effects. A comparison will also be made regarding the effects of the standard drugs used in chemotherapy (cisplatin and capecitabine) with an alternative combination (carboplatin and paclitaxel) in patients that do not show a response to chemotherapy with standard drugs early on in treatment. All patients will receive 6 weeks of chemotherapy and 5 weeks of chemoradiotherapy. How the study will be conducted: Prior to the commencement of treatment each patient will have a special scan called a PET scan. Patients will receive a second PET scan two weeks after the start of standard chemotherapy. The changes between the two scans will then be used to allocate treatment into the different arms of the study. All study subjects will be randomised to receive either the standard radiotherapy dose or the high radiotherapy dose. The participants that do not respond to the first cycle of standard chemotherapy will be eligible to take part in the aspect of the trial looking at an alternative chemotherapy regimen. Patients will be randomised as follows; On the basis of the second PET scan, patients who are not responding to standard chemotherapy will be allocated by a computer to one of the four groups detailed below: Standard chemotherapy and standard dose of radiotherapy Standard chemotherapy and higher dose of radiotherapy Alternative chemotherapy and standard dose of radiotherapy Alternative chemotherapy and higher dose of radiotherapy Patients who are responding to standard chemotherapy (or where the response is unknown or those who were not eligible for PET scan portion of the study) will be allocated by a computer to one of two groups detailed below: Standard chemotherapy and standard dose of radiotherapy Standard chemotherapy and higher dose of radiotherapy The arms within each of the groups above (responders and non-responders) will be equal in size and patients will be allocated randomly by a computer. This study will also compare the way that this treatment affects the two different cell types found in oesophageal tumours. The effects of the different treatment, together with the costs of the different treatment and the effects on quality of life will be analysed to see which is more effective for each of the different groups.

Official Title
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SCOPE2 - A Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients With Oesophageal Cancer Treated With Definitive Chemo-radiation With an Embedded Phase II Trial for Patients With a Poor Early Response Using Positron Emission Tomography (PET)

Conditions
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Oesophageal Cancer

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Cisplatin
* Drug: Capecitabine
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Main inclusion criteria: 17 years of age or older. Have been selected to receive potentially curative definitive chemoradiotherapy by a specialist Upper GI MDT. Histologically confirmed adenocarcinoma, undifferentiated cancer or squamous cell carcinoma. Tumours of the cervical, thoracic oesophagus, or gastro-oesophageal junction (GOJ) with proximal extent of disease no more proximal than 15cm ab oral and distal extent of primary tumour no more than 2 cm beyond the GOJ. Tumours staged with endoscopic ultrasound*, CT and PET-CT to be T1-4 and N+/- (provided total tumour length including nodes is ≤10). Total contiguous disease length ≤10cm defined by CT, EUS and/or PET. The primary tumour should also be ≤8cm. WHO performance status 0 or 1. Adequate cardiovascular function for safe delivery of chemo-radiation in the opinion of the principal investigator. Where there is clinical concern patients should have an adequate cardiac ejection fraction ≥ 40% as determined by MUGA scan or ECHO (within 4 weeks prior to enrolment). Adequate respiratory function for safe delivery of chemo-radiation in the opinion of the Principal Investigator. Where there is clinical concern FEV1 ≥ 1 litre as determined by spirometry (within 4 weeks prior to enrolment). Patients with clinically significant hearing impairment (hearing loss with hearing aid, or hearing loss where intervention indicated, or limiting daily activities or tinnitus limiting daily activities or sensory-motor neuropathy are eligible, however, cisplatin will be replaced by carboplatin (AUC 5) Adequate haematological, hepatic and renal function Patients agree to use effective forms of contraception during the trial (if applicable to patient). Patients who have provided written informed consent prior to enrolment. Additional inclusion criteria for patient eligibility for PET randomisation (cisplatin/capecitabine vs carboplatin/paclitaxel) as assessed at local centre: Baseline SUVmax ≥ 5. PET scan 14 days after start of chemo (-2/+3 days from this date is acceptable) Not responding to early cis/cape chemotherapy (this is defined as patients having a <35% reduction in SUVmax) 18. To be eligible for PET randomisation, the baseline PET-CT must have been within 4 weeks prior to start date of treatment. Patients that are eligible for the trial but are ineligible for PET randomisation will be randomised to receive 50/60Gy radiotherapy plus cisplatin and capecitabine. * Patients where the EUS scope is unable to pass are eligible. Main exclusion criteria: Patients who have had previous treatment for invasive oesophageal carcinoma or gastro-oesophageal junction carcinoma (not including PDT or laser therapy for high grade dysplasia/carcinoma in-situ). Patients with metastatic disease i.e. M1a or M1b according to UICC TNM version 7. Patients with other active malignancy or past malignancy in remission for less than 3 years are not eligible for the trial. However, patients with the following conditions which have been curatively treated will NOT be excluded: basal cell carcinoma, carcinoma-in-situ breast and carcinoma-in-situ cervix. Patients with >2cm mucosal extension of tumour into the stomach or where the superior extent is proximal to 15 cm ab oral. Patients with unstable angina or uncontrolled hypertension or cardiac failure or other clinically significant cardiac disease. Patients who need continued treatment with a contraindicated concomitant medication or therapy. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. 9. Patients with serious infections 10. Known hypersensitivity to IMPs. 11. Women who are pregnant or breastfeeding. 12. Oesophageal stent (patients requiring a PEG/RIG/feeding jejunostomy for nutritional purposes are eligible). 13. Any other situation, which in the opinion of the local PI, makes the patient an unsuitable candidate for this trial.

Ages Eligible for Study
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Minimum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (carboplatin/paclitaxel+standard RT dose)<br>Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: carboplatin AUC 5 on D1 and paclitaxel 175mg/m2 on D1 Week 7-11: Weekly carboplatin AUC 2 and paclitaxel 50mg/m2 concomitant with radiotherapy (50Gy/25 fractions) | Drug: Carboplatin<br>* For more information please see the arm descriptions section.<br>Drug: Paclitaxel<br>* For more information please see the arm descriptions section.<br>Drug: Cisplatin<br>* For more information please see the arm descriptions section.<br>Drug: Capecitabine<br>* For more information please see the arm descriptions section.<br>Radiation: Radiotherapy<br>* For more information please see the arm descriptions section.<br>|
| Experimental: Arm 2 (cisplatin/capecitabine+standard RT dose)<br>Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 3: Week 7-9: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 4: Week 10-11: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-14 Cycles 3 and 4 are given concomitantly with radiotherapy (50Gy/25 fractions). Capecitabine stops on last day of RT. | Drug: Cisplatin<br>* For more information please see the arm descriptions section.<br>Drug: Capecitabine<br>* For more information please see the arm descriptions section.<br>Radiation: Radiotherapy<br>* For more information please see the arm descriptions section.<br>|
| Experimental: Arm 3 (carboplatin/paclitaxel+high RT dose)<br>Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: carboplatin AUC 5 on D1 and paclitaxel 175mg/m2 on D1 Week 7-11: Weekly carboplatin AUC 2 and paclitaxel 50mg/m2 concomitant with radiotherapy (60Gy/25 fractions) | Drug: Carboplatin<br>* For more information please see the arm descriptions section.<br>Drug: Paclitaxel<br>* For more information please see the arm descriptions section.<br>Drug: Cisplatin<br>* For more information please see the arm descriptions section.<br>Drug: Capecitabine<br>* For more information please see the arm descriptions section.<br>Radiation: Radiotherapy<br>* For more information please see the arm descriptions section.<br>|
| Experimental: Arm 4 (Cisplatin+Capecitabine+high RT dose)<br>Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 3: Week 7-9: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 4: Week 10-11: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-14 Cycles 3 and 4 are given concomitantly with radiotherapy (60Gy/25 fractions). Capecitabine stops on last day of RT. | Drug: Cisplatin<br>* For more information please see the arm descriptions section.<br>Drug: Capecitabine<br>* For more information please see the arm descriptions section.<br>Radiation: Radiotherapy<br>* For more information please see the arm descriptions section.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoint phase II in squamous cell carcinoma comparing standard dose radiotherapy to high dose radiotherapy | 24 week treatment failure free survival (TFFS). | 24 weeks | 
| Primary endpoint phase III in squamous cell carcinoma: Overall survival (OS) comparing standard dose radiotherapy to high dose radiotherapy | Overall survival (OS) | 24 weeks | 
| Primary endpoint in squamous cell carcinoma when switching chemotherapy | 24 week treatment failure free survival (TFFS). | 24 weeks | 
| Primary endpoint phase in adenocarcinoma phase II comparing standard dose radiotherapy to high dose radiotherapy | 24 week treatment failure free survival (TFFS). | 24 weeks | 
| Primary endpoint in adenocarcinoma when switching chemotherapy | 24 week treatment failure free survival (TFFS). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival assessed at each visit. Additionally patients will be flagged with the HSCIC to reduce loss to follow up. | 5 years follow up | 
| Progression free survival | Progression free survival (PFS), additionally patients will be flagged with the HSCIC to reduce loss to follow up. | 5 years | 
| Quality of Life | Quality of Life (QoL): EORTC QLQ-C30 and EORTC QLQ-OES18 questionnaires | Baseline, week 7, end of treatment, 6, 12 and 24 months | 
| Toxicity | CTCAE v4.03 at baseline, after each treatment cycle, and follow up visits. Patients in the dose escalation arm will have additional assessment and 6 and 9 weeks post RT to monitor toxicities. | After each treatment cycle and at follow up visits | 
| Health economics | Health economic data will be collected using health resource utilisation log plus data on health resource usage | Baseline, end of treatment, 6, 12 and 24 months |