NEOadjuvant Trial in Adenocarcinoma of the oEsophagus and oesophagoGastric Junction International Study (Neo-AEGIS)

Oesophageal Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01726452
• Other study ID #: CTRIAL-IE (ICORG) 10-14
• Status: Completed
• Phase: Phase 3
• Start date: January 24, 2013
• Est. completion date: August 4, 2022

Study information

• Verified date: September 2022
• Source: Cancer Trials Ireland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 377
• Est. completion date: August 4, 2022
• Est. primary completion date: August 4, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma of the Oesophago-gastric Junction
• Adenocarcinoma of the Oesophagus
• Esophageal Neoplasms
• Junctional Tumours
• Oesophageal Cancer
• Oesophageal Tumours

Intervention

Drug:
• Epirubicin
50mg/m2 on Day 1 of each cycle only (i.e. every 21 days)
• Cisplatin / Oxaliplatin
Cisplatin, 60mg/m2 on day 1 of each cycle only (i.e. every 21 days). OR Oxaliplatin,130 mg/m2 on Day 1 of each cycle (i.e. every 21 days) The choice between administering Cisplatin or Oxaliplatin is at the discretion of the investigator.
• 5 Flourouracil/ Capecitabine
5-Flourouracil 200 mg/m2/day every day for 21 days OR Capecitabine 625 mg/m2 twice daily orally). The choice between administering 5 Flourouracil or Capecitabine is at the discretion of the investigator.

Radiation:
• (41.4 Gy/23 fractions)
Patient will receive 4.5 weeks of radiation therapy (41.4 Gy/23 fractions).

Drug:
• Paclitaxel
50mg/ m2 Paclitaxel dose administered on Days 1, 8, 15,22 and 29. Dexamethasone, Chlorphenamine and Ranitidine dose given per local standard practice. NACL infusion per local standard practice. Ondansetron dose given per local standard practice on Days 1, 8, 15, 22 and 29.
• Carboplatin
Dose determined as per calculation, infused on Days 1, 8, 15, 22 and 29
• Docetaxel
Docetaxel, 50 mg/m², day 1 of each cycle (i.e. every 14 days)
• Oxaliplatin
85 mg/m², day 1 of each cycle (i.e. every 14 days)
• Leucovorin
200 mg/m², day 1 of each cycle (i.e. every 14 days).
• 5-Fluorouracil
2600 mg/m² Day 1 of each cycle (i.e. every 14 days) Dexamethasone or equivalent, 8mg, twice daily, Day before, day of and day after OR administered as per standard practice

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Blegdamsvej 9
France	Centre Hospitalier Régional, Universitaire de Lille 2 Avenue Oscar Lambret, 59000	Lille
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital	Dublin
Ireland	SLRON- St Luke's Radiation Oncology Network	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	University Hospital Galway	Galway
Sweden	Karolinska Institutet and Karolinska University Hospital	Stockholm
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Addenbrooke's Hospital, Box 279(s4), Cambridge Biomedical Camp	Cambridge
United Kingdom	Belfast Health and Social Care Trust, Northern Ireland Cancer Centre, Belfast CityHospital	Belfast
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Birkenhead, Wirral
United Kingdom	University Hospitals Bristol NHS Foundation Trust	Bristol
United Kingdom	University Hospitals Coventry & Warwickshire	Clifford Bridge Road, Walsgrave	Coventry
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust, Castle Hill Hospital,	Cottingham	East Riding Of Yorkshire
United Kingdom	University Hospital Plymouth NHS Trust	Derriford Hospital, Derriford Road, Crownhill, Plymouth
United Kingdom	Mount Vernon Cancer Centre	E & N Hertfordshire NHS Trust, Rickmansworth Road, Northwood	Middlesex
United Kingdom	NHS Lothian, Edinburgh Cancer Centre,	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow, 1056 Great Western Road
United Kingdom	Royal Surrey County Hospital	Guildford	Surrey
United Kingdom	Oxford University Hospital NHS Trust Churchill Hospital	Headington	Oxfordshire
United Kingdom	Imperial College Healthcare NHS Trust St Mary's Hospital	London
United Kingdom	The Newcastle upon Tyne Hospital NHS Foundation TrustFreeman Hospital, Freeman Road, High Heaton	Newcastle upon Tyne
United Kingdom	Nottingham City Hospital	Nottingham University Hospitals NHS Trust, Hucknall Road	Nottingham
United Kingdom	Royal Preston Hospital	Sharoe Garoo Lane, Fulwood, Preston
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton General Hospital, Division A Cancer Care, Mp307, T	Southampton
United Kingdom	Portsmouth Hospitals NHS Trust	Southwick Hill Road, Cosham	Hampshire
United Kingdom	The Royal Bournemouth Hospital	The Royal Bournemouth And Christchurch Hospitals NHS Foundation	Bournemouth
United Kingdom	Velindre Cancer Centre	Velindre NHS Trust, Velindre Road, Whitchurch	Cardiff
United Kingdom	Worcestershire Royal Hospital	Worcestershire Oncology Centre, Charles Hastings Way	Worcester

Sponsors (4)

Lead Sponsor	Collaborator
Cancer Trials Ireland	Centre Hospitalier Régional, Universitaire de Lille, Region H Rigshospitalet, Southampton Clinical Trials Unit

Countries where clinical trial is conducted

Denmark,  France,  Ireland,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Overall survival will be calculated from the date of randomisation and an event registered on the date of death from any cause. Patients lost to follow up, or those with no death recorded on the day the database is frozen, will be censored on the date of last follow up.	At end of trial- up to 3 years in follow up