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

NCT01726452 | Completed Phase 3

• 1 other identifier: CTRIAL-IE (ICORG) 10-14
• Study Type: interventional
• Target: 377
• Locations: 5 countries
• Sites: 29

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.

Conditions

Adenocarcinoma of the Oesophagus; Adenocarcinoma of the Oesophago-gastric Junction; Oesophageal Tumours; Junctional Tumours; Oesophageal Cancer

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

A (Modified MAGIC) OR Arm A: FLOT

EXPERIMENTAL

Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks.

Drug: Epirubicin; Drug: Cisplatin / Oxaliplatin; Drug: 5 Flourouracil/ Capecitabine; Drug: Docetaxel; Drug: Oxaliplatin; Drug: Leucovorin; Drug: 5-Fluorouracil

B (CROSS)

EXPERIMENTAL

Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.

Radiation: (41.4 Gy/23 fractions); Drug: Paclitaxel; Drug: Carboplatin

Interventions

Epirubicin DRUG

50mg/m2 on Day 1 of each cycle only (i.e. every 21 days)

A (Modified MAGIC) OR Arm A: FLOT

Cisplatin / Oxaliplatin DRUG

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.

A (Modified MAGIC) OR Arm A: FLOT

5 Flourouracil/ Capecitabine DRUG

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.

A (Modified MAGIC) OR Arm A: FLOT

(41.4 Gy/23 fractions) RADIATION

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

B (CROSS)

Paclitaxel DRUG

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.

B (CROSS)

Carboplatin DRUG

Dose determined as per calculation, infused on Days 1, 8, 15, 22 and 29

B (CROSS)

Docetaxel DRUG

Docetaxel, 50 mg/m², day 1 of each cycle (i.e. every 14 days)

A (Modified MAGIC) OR Arm A: FLOT

Oxaliplatin DRUG

85 mg/m², day 1 of each cycle (i.e. every 14 days)

A (Modified MAGIC) OR Arm A: FLOT

Leucovorin DRUG

200 mg/m², day 1 of each cycle (i.e. every 14 days).

A (Modified MAGIC) OR Arm A: FLOT

5-Fluorouracil DRUG

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

A (Modified MAGIC) OR Arm A: FLOT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically verified adenocarcinoma of the oesophagus or oesophago-gastric junction based on endoscopy (OGD)
• CT-18FDG-PET performed in all patients for disease staging.
• EUS in all patients unless luminal obstruction precludes sensitivity of the test.
• Staging laparoscopy performed at the investigator's discretion for locally advanced AEG II and AEG III tumours .
• Pre-treatment stage cT2-3, N0-3, M0.
• Maximum tumour length should be no more than 8cm (equal to 8 cm is acceptable)
• Male/female patients aged ≥18 years
• ECOG Performance Status 0, 1 or 2 (Appendix F).
• ASA I-II (Appendix F).
• 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.
• Adequate respiratory function. Patients should have pulmonary function tests completed with a minimum FEV1 ≥ 1.5L. CPEX acceptable
• 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).
• Adequate renal function: glomerular filtration rate \>60ml/minute calculated using the Cockcroft-Gault Formula (Appendix O).
• Adequate liver function: serum bilirubin \<1.5x ULN; AST \<2.5x ULN and ALP \<3x ULN (ULN as per institutional standard).
• Written informed consent must be obtained from the patient before any study-trial specific procedures are performed.

You may not qualify if:

• Tumours of squamous histology.
• Patients with advanced inoperable or metastatic oesophageal, junctional or gastric adenocarcinoma.
• 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.
• Any prior chemotherapy for gastrointestinal cancer.
• Prior abdominal or thoracic, chest wall or breast radiotherapy.
• Patients who are unfit for surgery or cancer treatments based on cardiac disease.
• Patients with acute systemic infections.
• Patients who are receiving treatment with sorivudine or its chemical related analogues, such as brivudine which is contraindicated with capecitabine and 5-fluorouracil administration.
• Clinical COPD with significant obstructive airways disease classified by FEV1 \< 1.5 L or PaO2 less than 9kPa on room air
• Known peripheral neuropathy \>Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
• Known positive tests for human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B infection.
• 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)
• 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
• Women who are pregnant or breastfeeding.
• Psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• Cancer Trials Ireland: lead
• Southampton Clinical Trials Unit: collaborator
• Rigshospitalet, Denmark: collaborator
• Centre Hospitalier Régional, Universitaire de Lille: collaborator

Study Sites (29)

Rigshospitalet

Blegdamsvej 9, 2100 København Ø, Denmark

Location

Centre Hospitalier Régional, Universitaire de Lille 2 Avenue Oscar Lambret, 59000

Lille, France

Location

Cork University Hospital

Cork, Ireland

Location

Beaumont Hospital

Dublin, Ireland

Location

SLRON- St Luke's Radiation Oncology Network

Dublin, Ireland

Location

St. James's Hospital

Dublin, Ireland

Location

University Hospital Galway

Galway, Ireland

Location

Karolinska Institutet and Karolinska University Hospital

Stockholm, Sweden

Location

The Royal Bournemouth Hospital

The Royal Bournemouth and Christchurch Hospitals NHS Foundation, Bournemouth, BH7 7DW, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust

Addenbrooke's Hospital, Box 279(s4), Cambridge Biomedical Camp, Cambridge, CB2 0QQ, United Kingdom

Location

Velindre Cancer Centre

Velindre NHS Trust, Velindre Road, Whitchurch, Cardiff, CF14 2TL, United Kingdom

Location

University Hospitals Coventry & Warwickshire

Clifford Bridge Road, Walsgrave, Coventry, CV2 2DX, United Kingdom

Location

Hull and East Yorkshire Hospitals NHS Trust, Castle Hill Hospital,

Cottingham, East Riding Of Yorkshire, HU16 5JQ, United Kingdom

Location

Portsmouth Hospitals NHS Trust

Southwick Hill Road, Cosham, Hampshire, PO6 3LY, United Kingdom

Location

Mount Vernon Cancer Centre

E & N Hertfordshire NHS Trust, Rickmansworth Road, Northwood, Middlesex, HA6 2RN, United Kingdom

Location

Nottingham City Hospital

Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham, HG5 1PB, United Kingdom

Location

Oxford University Hospital NHS Trust Churchill Hospital

Headington, Oxfordshire, OX3 7LE, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton General Hospital, Division A Cancer Care, Mp307, T, Southampton, SO16 6YD, United Kingdom

Location

Royal Surrey County Hospital

Guildford, Surrey, GU2 7XX, United Kingdom

Location

Worcestershire Royal Hospital

Worcestershire Oncology Centre, Charles Hastings Way, Worcester, WR5 1DD, United Kingdom

Location

Belfast Health and Social Care Trust, Northern Ireland Cancer Centre, Belfast CityHospital

Belfast, BT9 7AB, United Kingdom

Location

The Clatterbridge Cancer Centre NHS Foundation Trust

Birkenhead, Wirral, CH63 4JY, United Kingdom

Location

University Hospitals Bristol NHS Foundation Trust

Bristol, BS2 8ED, United Kingdom

Location

University Hospital Plymouth NHS Trust

Derriford Hospital, Derriford Road, Crownhill, Plymouth, PL6 8DH, United Kingdom

Location

NHS Lothian, Edinburgh Cancer Centre,

Edinburgh, EH4 2XU, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, 1056 Great Western Road, G12 0YN, United Kingdom

Location

Imperial College Healthcare NHS Trust St Mary's Hospital

London, W2 1NY, United Kingdom

Location

The Newcastle upon Tyne Hospital NHS Foundation TrustFreeman Hospital, Freeman Road, High Heaton

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Royal Preston Hospital

Sharoe Garoo Lane, Fulwood, Preston, PR2, United Kingdom

Location

Related Publications (2)

• Reynolds JV, Preston SR, O'Neill B, Lowery MA, Baeksgaard L, Crosby T, Cunningham M, Cuffe S, Griffiths GO, Parker I, Risumlund SL, Roy R, Falk S, Hanna GB, Bartlett FR, Alvarez-Iglesias A, Achiam MP, Nilsson M, Piessen G, Ravi N, O'Toole D, Johnston C, McDermott RS, Turkington RC, Wahed S, Sothi S, Ford H, Wadley MS, Power D; Neo-AEGIS Investigators and Trial Group. Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol. 2023 Nov;8(11):1015-1027. doi: 10.1016/S2468-1253(23)00243-1. Epub 2023 Sep 18.

  PMID: 37734399 DERIVED

• 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.

  PMID: 28578652 DERIVED

MeSH Terms

Conditions

Esophageal Neoplasms

Interventions

Epirubicin; Cisplatin; Oxaliplatin; Capecitabine; Paclitaxel; Carboplatin; Docetaxel; Leucovorin; Fluorouracil

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Study Officials

• John V. Reynolds, Professor

  Trinity Centre, St. James's Hospital, Dublin 8, Ireland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2012
• First Posted: November 15, 2012
• Study Start: January 24, 2013
• Primary Completion: August 4, 2022
• Study Completion: August 4, 2022
• Last Updated: September 30, 2022

Record last verified: 2022-09

Locations

IE (5); GB (21); FR (1); SE (1); DK (1)