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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01726452
Recruitment Status : Active, not recruiting
First Posted : November 15, 2012
Last Update Posted : January 6, 2021
Sponsor:
Collaborators:
Southampton Clinical Trials Unit
Region H Rigshospitalet
Centre Hospitalier Régional, Universitaire de Lille
Information provided by (Responsible Party):
Cancer Trials Ireland

Tracking Information
First Submitted Date  ICMJE November 6, 2012
First Posted Date  ICMJE November 15, 2012
Last Update Posted Date January 6, 2021
Study Start Date  ICMJE August 2012
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 9, 2012)
Overall survival [ Time Frame: At end of trial- up to 3 years in follow up ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NEOadjuvant Trial in Adenocarcinoma of the oEsophagus and oesophagoGastric Junction International Study (Neo-AEGIS)
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adenocarcinoma of the Oesophagus
  • Adenocarcinoma of the Oesophago-gastric Junction
  • Oesophageal Tumours
  • Junctional Tumours
  • Oesophageal Cancer
Intervention  ICMJE
  • Drug: Epirubicin
    50mg/m2 on Day 1 of each cycle only (i.e. every 21 days)
  • Drug: 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.
  • Drug: 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.
  • Drug: Carboplatin
    Dose determined as per calculation, infused on Days 1, 8, 15, 22 and 29
  • Drug: Docetaxel
    Docetaxel, 50 mg/m², day 1 of each cycle (i.e. every 14 days)
  • Drug: Oxaliplatin
    85 mg/m², day 1 of each cycle (i.e. every 14 days)
  • Drug: Leucovorin
    200 mg/m², day 1 of each cycle (i.e. every 14 days).
  • Drug: 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
Study Arms  ICMJE
  • Experimental: A (Modified MAGIC) OR Arm A: FLOT

    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.

    Interventions:
    • Drug: Epirubicin
    • Drug: Cisplatin / Oxaliplatin
    • Drug: 5 Flourouracil/ Capecitabine
    • Drug: Docetaxel
    • Drug: Oxaliplatin
    • Drug: Leucovorin
    • Drug: 5-Fluorouracil
  • Experimental: B (CROSS)
    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.
    Interventions:
    • Radiation: (41.4 Gy/23 fractions)
    • Drug: Paclitaxel
    • Drug: Carboplatin
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 5, 2021)
377
Original Estimated Enrollment  ICMJE
 (submitted: November 9, 2012)
366
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   France,   Ireland,   Sweden,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01726452
Other Study ID Numbers  ICMJE CTRIAL-IE (ICORG) 10-14
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Cancer Trials Ireland
Study Sponsor  ICMJE Cancer Trials Ireland
Collaborators  ICMJE
  • Southampton Clinical Trials Unit
  • Region H Rigshospitalet
  • Centre Hospitalier Régional, Universitaire de Lille
Investigators  ICMJE
Principal Investigator: John V. Reynolds, Professor Trinity Centre, St. James's Hospital, Dublin 8, Ireland
PRS Account Cancer Trials Ireland
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP