| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non operable oesophageal cancer patients |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10030151 |
| E.1.2 | Term | Oesophageal cancer |
| 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 |
There are two principal research questions within this trial. Firstly, is it effective and safe to treat oesophageal cancer patients presenting with either adenocarcinoma, undifferentiated or squamous cell carcinoma, with an elevated dose of radiotherapy? Secondly, would patients that do not respond to initial chemotherapy treatment with the standard regiment (capecitabine and cisplatin) benefit from switching to a different chemotherapy regiment (carboplatin and paclitaxel)?
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| E.2.2 | Secondary objectives of the trial |
The secondary research questions will be;
1. Do participants receiving high dose radiotherapy live longer without the disease?
2. Do participants that do not respond to early chemotherapy treatment live longer without their disease if they switch to a different chemotherapy regimen?
3. Is it safe to deliver high dose radiotherapy in this patient group? We will assess this by carefully monitoring any side-effects that the patients have and grading them according to a very specific set of toxicity criteria.
4. Do patients receiving high dose radiotherapy have a reduced quality of life? It is expected that although a high dose of radiography may lead to better disease control, increased toxicity and side effects (and poorer quality of HRQL) maybe experienced during treatment. We will answer this question by looking at questionnaires (EORTC QLQ-C30 and EORTC QLQ-OES18) completed by trial participants.
5. Has the trial protocol been followed in this trial? The study aims to look a |
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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 patients will be asked to take part in the optional translational sub-study called T-SCOPE2. This will collect blood and biopsy samples for future translational research.
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| E.3 | Principal inclusion criteria |
1.17 years of age or older.
2.Have been selected to receive potentially curative definitive chemoradiotherapy by a specialist Upper GI MDT.
3.Histologically confirmed adenocarcinoma, undifferentiated cancer or squamous cell carcinoma.
4.Tumours of the cervical, thoracic oesophagus, or gastro-oesophageal junction (GOJ) with proximal extent of disease no more proximal than 15cm aboral and distal extent of primary tumour no more than 2 cm beyond the GOJ.
5. Tumours staged with spiral CT scan, PET-CT with/without endoscopic ultrasound (EUS), to be T1-4, N-/+ (provided total tumour length including nodes is ≤10). To be eligible for PET randomisation, the PET-CT must be within 4 weeks of start date of treatment.
6. Total contiguous disease length ≤10cm defined by CT, EUS and/or PET. This includes ≤8cm primary tumour plus nodes within 2cm.
7. WHO performance status 0 or 1.
8. Adequate haematological, renal, respiratory, cardiac and hepatic function, and are fit to receive all protocol treatment.
9. Patients with reproductive potential (male or female), who are sexually active during the duration of the trial, should be prepared to use a highly effective method of contraception preferably with low user dependency for at least six months after the last dose of chemoradiotherapy.
10. Patients who have provided written informed consent prior to randomisation.
Additional inclusion criteria for patient eligibility for PET randomisation:
11.Baseline SUVmax ≥ 5.
12.PET scan 14 days after start of chemo (-2/+3 days from this date is acceptable)
13.Not responding to early cis/cape chemotherapy (<35% reduction in SUVmax)
14.For diabetics, fasting Blood glucose ≤12 mmol/L.
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| E.4 | Principal exclusion criteria |
1. Patients who have had previous treatment for invasive oesophageal carcinoma or gastro-oesophageal junction carcinoma
2. Patients with metastatic disease
3. Patients with other active malignancy or past malignancy in remission for less than 3 years except patients that have been curatively treated from the following conditions; basal cell carcinoma, Carcinoma-in-situ breast and carcinoma-in-situ cervix
4. Patients with >2cm mucosal extension of tumour into the stomach or where the superior extent is proximal to 15 cm ab oral.
5. Patients with unstable angina or uncontrolled hypertension or cardiac failure or other clinically significant cardiac disease.
6. Patients who need continued treatment with a contraindicated concomitant medication or therapy.
7. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
8. Patients with hearing impairment or sensory-motor neuropathy of WHO grade ≥2.
9. Known hypersensitivity to IMPs.
10. Women who are pregnant or breastfeeding..
11. Oesophageal stent (Patients requiring a PEG/RIG/feeding jejunostomy for nutritional purposes are eligible).
12. Any other situation, which in the opinion of the local PI, makes the patient an unsuitable candidate for this trial (eg with profusely bleeding tumours where the PI has concerns about randomisation to paclitaxel/carboplatin arm where there is risk of aggravation of bleeding due to higher risk of thrombocytopenia)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There are two principal research questions within this trial. Firstly, is it effective to treat oesophageal cancer patients presenting with either adenocarcinoma, undifferentiated or squamous cell carcinoma, with an elevated dose of radiotherapy?
Secondly, would patients that do not respond to initial standard chemotherapy treatment (capecitabine and cisplatin) benefit from switching to a different chemotherapy regiment (carboplatin and paclitaxel)?
This will be assessed by looking at the proportion of patients that do not show any evidence of remaining tumour on the 24 week CT scan and endoscopic assessment between a) the 50/60Gy radiotherapy arms,
b) the two different chemotherapy arms (standard chemo of capecitabine+cisplatin vs alternative regimen of paclitaxel+carboplatin) within the PET non-responders group. The PET non-responders group refer to the group of patients that do not show a response to early standard chemotherapy treatment as determined by the 14 day PET scan.
Based on the outcome of the phase II data, the 50/60Gy radiotherapy arms will progress into a phase III study. This part of the study will compare the overall survival of patients receiving 50 and 60Gy of radiotherapy.
As a lower percentage of patients with adenocarcinoma are expected to be recruited into the trial in comparison to patients having squamous cell carcinoma, the phase III part of the trial will recruit patients with squamous cell carcinoma only.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Both research questions will be assessed by looking at the 24 week treatment failure free survival and overall survival which will be assessed at each visit. |
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| E.5.2 | Secondary end point(s) |
1. Do participants receiving high dose radiotherapy live longer without the disease (progression free survival (PFS) rate)? PFS will be assessed during the follow-up visits. Suspected disease progression will be confirmed by CT/endoscopic assessment. This information will be collected on the trial CRFs.
2. Do participants that do not respond to early chemotherapy treatment live longer without their disease if they switch to a different chemotherapy regimen? PFS will be assessed during the follow-up visits. Suspected disease progression will be confirmed by CT/endoscopic assessment. This information will be collected on the trial CRFs.
3. Is it safe to deliver high dose radiotherapy in this patient group? We will assess this by carefully monitoring any side-effects that the patients have and grading them according to a very specific set of toxicity criteria; the NCI Common Terminology Criteria for Adverse Events. Patients receiving the higher dose of radiotherapy will have additional assessments after radiotherapy to monitor toxicities. The toxicity profile between the two different chemotherapy regiments received by the PET non-responders will also be compared.
4. Do patients receiving high dose radiotherapy have a reduced quality of life? It is expected that although a high dose of radiography may lead to better disease control, increased toxicity and side effects (and poorer quality of HRQL) maybe experienced during treatment. We will answer this question by looking at questionnaires (EORTC QLQ-C30 and EORTC QLQ-OES18) completed throughout the trial by trial participants.
5. Has the trial protocol been followed in this trial? The study aims to look at how well the patient has followed the protocol (treatment compliance). This will be assessed across all trial arms by looking at protocol deviations noted by the site and those raised by QC checks.
6. Is it cost effective to treat patient with high dose radiotherapy relative to the health benefits (if any)? Is it cost effective to switch to a non-standard chemotherapy regimen in patients who do not respond to standard chemotherapy (as defined by the day 14 PET scan)? We will answer this question by looking at questionnaires (EQ-5D and health utilisation log) completed by trial participants.
7. Can we use blood and tissue samples to tailor patient treatment and predict patient outcomes in future? Samples will be collected from consenting patients and will used to answer these research questions as part of the T-SCOPE2 sub study.
8. Do patients with different types of oesophageal cancers (adenocarcinoma and squamous cell carcinoma) respond differently to a) an increase in radiotherapy dose and b) a change in chemotherapy regimen? This will be assessed towards the end of the trial.
9. Can a special CT scan (4D CT) be used to help account for breathing movement during radiotherapy? This will only been done at certain sites.
10. We would like to know more about the patients’ experienced of being on the different trial arms and how they felt about the trial. A proportion of patients will be invited to take part in interviews as part of the optional embedded qualitative study described in more detail in section A11.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival and progression free survival: this will be assessed at each visit. Patients will be flagged using HSCIC.
Safety: SAEs and toxicities will be presented to the IDMC for a recommendation as to whether or not to continue the trial after 40 patients have completed trial treatment. Toxicity will be measured using the CTCAE V4 at baseline, after each treatment cycle, and follow up visits. Patients in the dose escalation arm will have additional assessments post RT to monitor toxicities.
Quality of Life assessment will be captured through the EORTC QLQ-C30 and EORTC QLQ-OES18 questionnaires administered at baseline, at the end of treatment, and at 6, 12 and 24 months.
Health economic data will be collected using EQ-5D plus data on health resource usage. |
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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 | Yes |
| 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 | 8 |
| 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 | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
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The end of the trial is defined as the date of final data capture for the last patient that completes 2 years of follow up. However, patients recruited at the beginning of the trial we will be following up for 5 years whilst the trial is in the 5/6 year recruitment phase.
The end of the trial is defined as the date that the last patient complet |
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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 | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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