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Trial registered on ANZCTR


Registration number
ACTRN12609000665235
Ethics application status
Approved
Date submitted
31/07/2009
Date registered
5/08/2009
Date last updated
4/07/2019
Date data sharing statement initially provided
4/07/2019
Date results information initially provided
4/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Randomised Phase II Trial of Pre-operative cisplatin, 5 fluorouracil and docetaxel ± Radiotherapy based on poor early response to standard chemotherapy for resectable adenocarcinoma of the oesophagus and/or OG Junction.
Scientific title
A Randomised Phase II Trial of Pre-operative cisplatin, 5 fluorouracil and docetaxel +/- Radiotherapy based on poor early response to standard chemotherapy for resectable adenocarcinoma of the oesophagus and/or Oesphago-gastric Junction.
Secondary ID [1] 273423 0
NIL
Universal Trial Number (UTN)
Trial acronym
DOCTOR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Adenocarcinoma of the Oesophagus and/or OG Junction 243415 0
Condition category
Condition code
Cancer 239717 239717 0 0
Oesophageal (gullet)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Randomised study of patients that have not shown early response to standard chemotherapy. All participants receive the standard treatment of a 21 day cycle of Cisplatin 80mg/m2 (intravenously infused over 2 hours) Day 1 and 5-Fluorouracil 1000 mg/m2 (continuous infusion) Days 1-4. All participants are restaged at day 15 with Positron Emission Tomography (PET). If significant response then standard treatment is repeated over another 21 day cycle. However if no significant response, subjects will be randomised to receive either 2 x 21 day cycles of Cisplatin 60mg/m2 (intravenously infused over 2 hours) on day 22 & day 50, Docetaxel 35mg/m2 (intravenously infused over 1 hour) on Day 22, 29, 36, 50 ,57 & 64 & 5-Fluorouracil 150mg/m2 continuous intravenous infusion for 6 weeks starting Day 22 OR Cisplatin 60mg/m2 (intravenously infused over 2 hours) on day 22 & day 50, Docetaxel 35mg/m2 (intravenously infused over 1 hour) on Day 22, 29, 36, 50 ,57 & 64 & 5-Fluorouracil 150mg/m2 continuous intravenous infusion for 6 weeks starting Day 22 plus radiation 45Gy/25Fr starting Day 22. Radiation will be administered once daily, Monday to Friday on 25 occasions. All participants will have surgery in an attempt for complete resection, 4 - 8 weeks after completion of neoadjuvant therapy. The operation should aim to remove the tumour in total, with an adequate margin in each direction. This may be done as a subtotal esophagectomy with proximal gastric resection and a right intrathoracic oesophago-gastrostomy (Ivor–Lewis procedure), a subtotal oesophagectomy with proximal gastric resection and a cervical oesophago-gastrostomy (McKeon procedure). This is a complicated surgery often taking more than 6 hours.
Intervention code [1] 237051 0
Treatment: Drugs
Comparator / control treatment
Standard treatment of Cisplatin 80mg/m2 Day 1(intravenously infused over 2 hours) & 5-Fluorouracil 1000 mg/m2 Days 1-4 continous intravenous infusion for first 21 day cycle then if significant response on PET restaging at day 15. Cisplatin & 5-Fluorouracil repeated.

All participants will have surgery in an attempt for complete resection, 4 - 8 weeks after completion of neoadjuvant therapy.
Control group
Active

Outcomes
Primary outcome [1] 240484 0
To evaluate the histological response to the neoadjuvant therapy regime
Timepoint [1] 240484 0
Tumour samples will be taken at baseline and at surgery (after neoadjuvant therapy). After 23 patients have completed neoadujvant treatment and no histological responses have been observed then consideration will be given to stopping that particular arm.
Secondary outcome [1] 257022 0
To evaluate the early PET response to the induction neoadjuvant therapy regimen
Timepoint [1] 257022 0
Pet scans will be done at baseline and then day 15.
Secondary outcome [2] 257023 0
To evaluate the toxicity of Docetaxel in combination therapy for oesophageal cancer. This will be done be review of clinical data such as physical exams and blood analysis.
Timepoint [2] 257023 0
Toxicity will be assessed weekly whilst participants are receiving docetaxel. Toxicity will be assessed pre-surgery, 6 weeks post surgery, 12 weeks post surgery, every 3 months for 2 years, then every 6 months out to 5 yrs
Secondary outcome [3] 257024 0
To evaluate the overall survival in the three treatment arms
Timepoint [3] 257024 0
After follow up completed for enrolled patients. Patients will followed up until 5 years post surgery.
Secondary outcome [4] 257025 0
To evaluate the disease-free survival in the three treatment arms.
Timepoint [4] 257025 0
After follow up completed for enrolled patients. Patients will followed up until 5 years post surgery.
Secondary outcome [5] 257026 0
To evaluate the tumour down-staging in the three treatment arms.

Participants will be restaged post completion of neoadjuvant therapy with endoscopy, computed tomography scan and comparison of pre and post neoadjuvant tumour samples
Timepoint [5] 257026 0
Studies to be done on tissue samples banked at baseline and pre-surgery. Surgery will be done 4-8 weeeks after completion of neoadjuvant therapy. To ensure participants have recovered.
Secondary outcome [6] 257027 0
To assess the effect of the treatment regimen on quality of life in each of the treatment arms. To be assessed by quality of life forms.
Timepoint [6] 257027 0
Quality of life forms done at baseline, pre-surgery and at various timepoints though-out the 5 year follow up period. Surgery will be done 4-8 weeeks after completion of neoadjuvant therapy. To ensure participants have recovered.

Eligibility
Key inclusion criteria
1. Histologically proven invasive adenocarcinoma of the oesophagus or gastroesophageal junction.

2. Tumour thought to be T2 or greater or T1 tumours that are poorly differentiated or thought to be node-positive.

3. Technically resectable disease, as assessed in consultation with the intended surgeon.

4. Tumour is sufficiently F-18 fluorodeoxyglucose (FGD) avid on the initial staging PET scan to provide sufficient contrast between tumour and the surrounding normal tissues so that a response to the neoadjuvant therapy may be assessed.

5. Written informed consent of the patient according to local ethics committee guidelines.

6. Medically fit for surgical resection, defined as having adequate cardiopulmonary function and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Evidence of extrathoracic or extragastric spread apart from perigastric or mediastinal nodes, which are resectable. (Supraclavicular nodes renders the patient ineligible) 2. Tumour is located in the cervical oesophagus requiring pharyngolaryngectomy. 3. Tumour is predominantly within the stomach ie. most of the tumour is not involving the oesophagus or gastroesophageal junction. 4. Evidence of tracheo- or broncho oesophageal fistula. 5. Adequate haematological function. 6. Adequate renal function 7. Adequate liver function 8. Previous radiation therapy to the chest, previous chemotherapy within the last 5 years. 9. Previous malignancy for the previous 5 years apart from non metastatic Squamous Cell Carcinoma of the skin, Basal Cell Carcinoma or carcinoma in situ of the cervix. 10. Pregnant, lactating or inadequate contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The study population will consist of patients with localised, resectable adenocarcinoma of the oesophagus or gastroesophageal junction. Patients that show less than a 35% reduction from the baseline PET scan standard uptake value (SUV) on a PET scan performed 15 days after the commencement of the first cycle of cisplatin/5-FU chemotherapy will be randomised between chemotherapy (cisplatin/5-FU with the addition of docetaxel) followed by surgery or chemotherapy (cisplatin/5-FU with the addition of docetaxel) and radiation followed by surgery. Patients are allocated treatment via telephone randomisation with the NHMRC clinical trials centre.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment will be allocated using the minimization method, patients will be stratified using the following factors: Site of disease: OG Junction or Oesophogus and insitution.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,NSW,VIC,SA,WA

Funding & Sponsors
Funding source category [1] 237424 0
Government body
Name [1] 237424 0
NHMRC
Address [1] 237424 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 237424 0
Australia
Primary sponsor type
Other Collaborative groups
Name
AGITG
Address
NHMRC Clinical Trials Centre, THE UNIVERSITY OF SYDNEY
The Lifehouse Building, Level 6, 119-143 Missenden Road Camperdown, NSW, 2050

Country
Australia
Secondary sponsor category [1] 236918 0
None
Name [1] 236918 0
Address [1] 236918 0
Country [1] 236918 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 239554 0
Princess Alexandra Hospital
Ethics committee address [1] 239554 0
Ipswich Road, Woolloongabba, Qld 4102
Ethics committee country [1] 239554 0
Australia
Date submitted for ethics approval [1] 239554 0
Approval date [1] 239554 0
09/12/2008
Ethics approval number [1] 239554 0
2008/148
Ethics committee name [2] 239555 0
Greenslopes Private Hospital
Ethics committee address [2] 239555 0
Newdegate Street
Greenslopes Qld 4120
Ethics committee country [2] 239555 0
Australia
Date submitted for ethics approval [2] 239555 0
Approval date [2] 239555 0
09/06/2009
Ethics approval number [2] 239555 0
09/23
Ethics committee name [3] 286200 0
Cancer Institute NSW
Ethics committee address [3] 286200 0
Level 9, 8 Central Avenue, Australian Technology Park, Eveleigh, NSW 2015
Ethics committee country [3] 286200 0
Australia
Date submitted for ethics approval [3] 286200 0
Approval date [3] 286200 0
28/09/2011
Ethics approval number [3] 286200 0
2011C/06/162
Ethics committee name [4] 295661 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [4] 295661 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [4] 295661 0
Australia
Date submitted for ethics approval [4] 295661 0
10/07/2013
Approval date [4] 295661 0
12/07/2013
Ethics approval number [4] 295661 0
X13-0175 and HREC/13/RPAH/261

Summary
Brief summary
This study compares the effectiveness of pre-operative treatment with cisplatin, 5 fluorouracil and docetaxel with or without radiotherapy in treating people who have shown a poor early response to standard chemotherapy for adenocarcinoma of the oesophagus and/or gastroesophageal junction.

Who is it for?
You can join this study if you have localised adenocarcinoma of the oesophagus or gastroesophageal junction which is due to be treated by surgery.

Trial details:
After the first cycle of standard cisplatin/5-FU chemotherapy all patients will have a PET scan. Patients who have a poor response on the PET scan, will be randomly divided into two groups. One group will receive chemotherapy (cisplatin/5-FU with the addition of docetaxel) followed by surgery, and the other will receive chemotherapy (cisplatin/5-FU with the addition of docetaxel) and radiation followed by surgery. In both groups, the chemotherapy is given intravenously. In the group receiving radiation treatment, this will overlap with the chemotherapy treatment. The study aims to evaluate the response to the different therapy regimens, by comparing pathology samples, looking at the response on PET scans, toxicity, survival rates and quality of life.
Trial website
Trial related presentations / publications
Barbour A. et al. (2016) An AGITG trial – A randomised phase II study of pre-operative cisplatin, fluorouracil and DOCetaxel +/-radioTherapy based on poOR early response to cisplatin and fluorouracil for resectable esophageal adenocarcinoma. Ann Oncol 27(6): 2016 ESMO Congress. Abstract 610O. Presented October 8, 2016.
Public notes

Contacts
Principal investigator
Name 29992 0
A/Prof Andrew Barbour c/- DOCTOR Trial Coordinator
Address 29992 0
NHMRC Clinical Trials Centre, University of Sydney, Locked bag 77, Camperdown, NSW, 1450
Country 29992 0
Australia
Phone 29992 0
+61 2 9562 5000
Fax 29992 0
Email 29992 0
doctor@ctc.usyd.edu.au
Contact person for public queries
Name 13239 0
Ms DOCTOR Trial Coordinator
Address 13239 0
NHMRC Clinical Trials Centre, University of Sydney, Locked bag 77, Camperdown, NSW, 1450
Country 13239 0
Australia
Phone 13239 0
02 9562 5000
Fax 13239 0
Email 13239 0
doctor@ctc.usyd.edu.au
Contact person for scientific queries
Name 4167 0
A/Prof Andrew Barbour c/- DOCTOR Trial Coordinator
Address 4167 0
NHMRC Clinical Trials Centre, University of Sydney, Locked bag 77, Camperdown, NSW, 1450
Country 4167 0
Australia
Phone 4167 0
+61 2 9562 5000
Fax 4167 0
Email 4167 0
doctor@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary