Clinical trial NCT01726452: NEOadjuvant Trial in Adenocarcinoma of the oEsophagus and oesophagoGastric Junction International Study (Neo-AEGIS)
Official title: Neo-AEGIS (NEOadjuvant Trial in Adenocarcinoma of the oEsophagus and oesophagoGastric Junction International Study): Randomised Clinical Trial of Neoadjuvant and Adjuvant Chemotherapy (Modified MAGIC or FLOT Regimen) vs. Neoadjuvant Chemoradiation (CROSS Protocol) in Adenocarcinoma of the Oesophagus and Oesophago-gastric Junction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Adenocarcinoma of the Oesophagus
Adenocarcinoma of the Oesophago-gastric Junction
Oesophageal Tumours
Junctional Tumours
Oesophageal Cancer
Lead sponsor: Cancer Trials Ireland
Sponsor class: NETWORK
Collaborators: name: Southampton Clinical Trials Unit
name: Region H Rigshospitalet
name: Centre Hospitalier Régional, Universitaire de Lille
First posted: 2012-11-15
Enrollment: 377
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicentre phase III open-labelled, randomised controlled trial. Eligible patients will be randomised in a 1:1 fashion between neoadjuvant and adjuvant chemotherapy (Investigator's choice modified MAGIC (ECF/ECX or EOF/EOX) or FLOT regimen) and surgery or Arm B (CROSS protocol: chemotherapy with radiation therapy and surgery as per multimodal protocol).

Primary Objective:

To evaluate one, two and three year survival of patients treated with resection plus neoadjuvant and adjuvant chemotherapy versus resection plus neoadjuvant chemo radiotherapy.

Secondary Objective(s):

To evaluate the effect of both neoadjuvant regimens on clinical and pathological response rate (in particular relief of dysphagia, improvement in health related quality of life (HRQL), endoscopic regression, and CT-PET evidence of tumour response), tumour regression grade, node-positivity, post-operative pathology, disease-free survival, time to treatment failure, toxicity, post-operative complications and Health Related Quality of Life (HRQL).

Exploratory Objective(s):

Translational Research: The collection of blood and tissue samples for storage in the bio bank for future research.

Detailed description: Indication:

Patients with cT2-3 N0-1 M0 adenocarcinoma of the oesophagus or junction, based on clinical, CT-PET, and EUS staging, will be randomised to the modified MAGIC (ECF/ECX or EOF/EOX) or FLOT regimen and chemotherapy regimen versus the CROSS neoadjuvant chemo radiation protocol prior to surgery. Patients will be randomised to either Arm A (modified MAGIC or FLOT chemotherapy only and surgery) or Arm B (CROSS protocol: chemotherapy with radiation therapy and surgery as per multimodal protocol).

Eligible patients will be randomised in a 1:1 fashion between the modified MAGIC or FLOT regimen or the CROSS protocol.

Exploratory Study- Translational Research :

The collection of blood and tissue samples for storage in the bio bank for future research.

Patients enrolled in this trial at the St James's' Hospital site, will be invited to consent to having some of their tissue and blood taken for use in future research studies. Following consent from the patient, tissue biopsy of tumour and/or normal oesophageal tissue will be obtained for research at the same time as that biopsied for histological diagnosis. In addition, tumour and/or normal tissue will also be obtained following surgical resection. Patient blood samples will also be obtained, both before and during treatment. The identification of both tumour and circulating biomarkers will increase knowledge of the molecular mechanism(s) underlying treatment response in oesophageal cancer and may facilitate the identification of biomarkers predicting patient response to treatment.

Eligibility criteria: Inclusion Criteria:

1. Histologically verified adenocarcinoma of the oesophagus or oesophago-gastric junction based on endoscopy (OGD)
2. CT-18FDG-PET performed in all patients for disease staging.
3. EUS in all patients unless luminal obstruction precludes sensitivity of the test.
4. Staging laparoscopy performed at the investigator's discretion for locally advanced AEG II and AEG III tumours .
5. Pre-treatment stage cT2-3, N0-3, M0.
6. Maximum tumour length should be no more than 8cm (equal to 8 cm is acceptable)
7. Male/female patients aged ≥18 years
8. ECOG Performance Status 0, 1 or 2 (Appendix F).
9. ASA I-II (Appendix F).
10. Adequate cardiac function. For all patients, an ejection fraction of \> 50% is required. If patients have a known cardiac history (e.g. known ischemic disease, cardiomyopathy) an ejection fraction \> 50% and cardiac clearance by a consultant cardiologist for major surgery and cancer therapies is required.
11. Adequate respiratory function. Patients should have pulmonary function tests completed with a minimum FEV1 ≥ 1.5L. CPEX acceptable
12. 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).
13. Adequate renal function: glomerular filtration rate \>60ml/minute calculated using the Cockcroft-Gault Formula (Appendix O).
14. Adequate liver function: serum bilirubin \<1.5x ULN; AST \<2.5x ULN and ALP \<3x ULN (ULN as per institutional standard).
15. Written informed consent must be obtained from the patient before any study-trial specific procedures are performed.
16. Women of child-bearing potential and male subjects must agree to use an effective barrier method of contraception for up to 6 months following discontinuation of therapy. Effective contraception is defined as any medically recommended (or combination of methods) as per standard of care.
17. Women of childbearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to treatment.

Exclusion Criteria:

1. Tumours of squamous histology.
2. Patients with advanced inoperable or metastatic oesophageal, junctional or gastric adenocarcinoma.
3. Disease length (total length of tumour plus node) greater than 10cm (up to 10 cm will be allowed) -as measured by any modality or, if appropriate, combination of modalities-, unless in the opinion of the investigator in discussion with national RT lead, it is felt that OAR constraints are likely to be achievable.
4. Any prior chemotherapy for gastrointestinal cancer.
5. Prior abdominal or thoracic, chest wall or breast radiotherapy.
6. Patients who are unfit for surgery or cancer treatments based on cardiac disease.
7. Patients with acute systemic infections.
8. Patients who are receiving treatment with sorivudine or its chemical related analogues, such as brivudine which is contraindicated with capecitabine and 5-fluorouracil administration.
9. Clinical COPD with significant obstructive airways disease classified by FEV1 \< 1.5 L or PaO2 less than 9kPa on room air
10. Known peripheral neuropathy \>Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
11. Known positive tests for human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B infection.
12. Any other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix)
13. Participation in other clinical trials of investigational or marketed agents for the treatment of oesophageal cancer or other diseases within 30 days from registration. UK sites please refer to Group Specific Appendix
14. Women who are pregnant or breastfeeding.
15. Psychiatric illness/social situations that would limit compliance with study requirements.

Primary outcomes:
measure: Overall survival
timeFrame: At end of trial- up to 3 years in follow up
Secondary outcomes:
Other outcomes:
Locations:
city: Blegdamsvej 9
country: Denmark
facility: Rigshospitalet
city: Lille
country: France
facility: Centre Hospitalier Régional, Universitaire de Lille 2 Avenue Oscar Lambret, 59000
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Dublin
country: Ireland
facility: SLRON- St Luke's Radiation Oncology Network
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Stockholm
country: Sweden
facility: Karolinska Institutet and Karolinska University Hospital
city: The Royal Bournemouth And Christchurch Hospitals NHS Foundation
country: United Kingdom
facility: The Royal Bournemouth Hospital
state: Bournemouth
city: Addenbrooke's Hospital, Box 279(s4), Cambridge Biomedical Camp
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Cambridge
city: Velindre NHS Trust, Velindre Road, Whitchurch
country: United Kingdom
facility: Velindre Cancer Centre
state: Cardiff
city: Clifford Bridge Road, Walsgrave
country: United Kingdom
facility: University Hospitals Coventry & Warwickshire
state: Coventry
city: Cottingham
country: United Kingdom
facility: Hull and East Yorkshire Hospitals NHS Trust, Castle Hill Hospital,
state: East Riding Of Yorkshire
city: Southwick Hill Road, Cosham
country: United Kingdom
facility: Portsmouth Hospitals NHS Trust
state: Hampshire
city: E & N Hertfordshire NHS Trust, Rickmansworth Road, Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre
state: Middlesex
city: Nottingham University Hospitals NHS Trust, Hucknall Road
country: United Kingdom
facility: Nottingham City Hospital
state: Nottingham
city: Headington
country: United Kingdom
facility: Oxford University Hospital NHS Trust Churchill Hospital
state: Oxfordshire
city: Southampton General Hospital, Division A Cancer Care, Mp307, T
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
state: Southampton
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: Surrey
city: Worcestershire Oncology Centre, Charles Hastings Way
country: United Kingdom
facility: Worcestershire Royal Hospital
state: Worcester
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust, Northern Ireland Cancer Centre, Belfast CityHospital
city: Birkenhead, Wirral
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Derriford Hospital, Derriford Road, Crownhill, Plymouth
country: United Kingdom
facility: University Hospital Plymouth NHS Trust
city: Edinburgh
country: United Kingdom
facility: NHS Lothian, Edinburgh Cancer Centre,
city: Glasgow, 1056 Great Western Road
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust St Mary's Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospital NHS Foundation TrustFreeman Hospital, Freeman Road, High Heaton
city: Sharoe Garoo Lane, Fulwood, Preston
country: United Kingdom
facility: Royal Preston Hospital
Study officials:
affiliation: Trinity Centre, St. James's Hospital, Dublin 8, Ireland
name: John V. Reynolds, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reynolds JV, Preston SR, O'Neill B, Baeksgaard L, Griffin SM, Mariette C, Cuffe S, Cunningham M, Crosby T, Parker I, Hofland K, Hanna G, Svendsen LB, Donohoe CL, Muldoon C, O'Toole D, Johnson C, Ravi N, Jones G, Corkhill AK, Illsley M, Mellor J, Lee K, Dib M, Marchesin V, Cunnane M, Scott K, Lawner P, Warren S, O'Reilly S, O'Dowd G, Leonard G, Hennessy B, Dermott RM. ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS). BMC Cancer. 2017 Jun 3;17(1):401. doi: 10.1186/s12885-017-3386-2.