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Trial registered on ANZCTR


Registration number
ACTRN12610000647033
Ethics application status
Approved
Date submitted
18/03/2010
Date registered
9/08/2010
Date last updated
21/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
ATTACHE: A Trial in the Timing of Surgery and Adjuvant Chemotherapy for Hepatic Metastases from Colorectal Cancer.
Scientific title
ATTACHE: A Trial in the Timing of Surgery and Adjuvant Chemotherapy for Hepatic Metastases from Colorectal Cancer. A phase III, multi-centre, randomised trial comparing perioperative morbidity between those given chemotherapy prior to and post surgical resection versus those given chemotherapy post surgical resection.
Secondary ID [1] 1527 0
nil
Universal Trial Number (UTN)
Trial acronym
ATTACHE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
colorectal cancer 256862 0
Condition category
Condition code
Cancer 257011 257011 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Chemoptherapy agents used in this trial will be mFOLFOX6, XELOX or FOLFIRI. mFOLFOX6 is the combination of Oxaliplatin, Leucovorin and Fluorouracil as set out below. XELOX is the combination of Oxaliplatin and Capecitabine set out below. FOLFIRI is the combination of Irinotecan, Leucovorin and Fluorouracil as set out below. There are two different treatment options mFOLFOX6 or XELOX which will be determined by the treating investigator prior to randomisaiotn. Patients are not permitted to change treatments during the trial. Preoperatively: mFOLFOX6 Every 2 weeks for 6 cycles: Oxaliplatin 85mg/m2 by intravenous infusion over 2 hours on day 1. Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on days 1 and 2 Fluorouracil 400mg/m2 by intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2) equivalent to 1200mg/m2/day.
OR
XELOX Every 3 weeks for 4 cycles: Oxaliplatin 130mg/m2 by intravenous infusion over 2 hours on day 1 Capecitabine 1000mg/m2 oral tablet twice daily on days 1-14.

Followed by Surgery: Surgical resection of liver metastases will be carried out, at the earliest 4 weeks and at the latest 8 weeks after completion of cycle 6 mFOLFOX6 or cycle 4 XELOX. Patients must have recovered from side effects and liver function must be adequate for liver surgery as per local hospital guidelines.
Post-operatively: Chemotherapy should not be administered until at least 4 weeks after surgery. This must not be started after surgery unless the liver, renal and haematological functions are within the same limits determined for the introduction of pre-operative chemotherapy. In the event of a surgical complication a delay of up to 12 weeks is acceptable before the patient is deemed to be off study.
mFOLFOX6 Every 2 weeks for 6 cycles: Oxaliplatin 85mg/m2 by intravenous infusion over 2 hours on day 1. Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on day 1 Fluorouracil 400mg/m2 by intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2) equivalent to 1200mg/m2/day. OR

XELOX Every 3 weeks for 4 cycles: Oxaliplatin 130mg/m2 by intravenous infusion over 2 hours on day 1 Capecitabine 1000mg/m2 oral tablets twice daily on days 1-14. Patients who have previously received Oxaliplatin as part of their adjuvant treatment will be permitted to receive FOLFIRI, instead of FOLFOX6/XELOX, as per their allocation to either ARM. FOLFIRI will be: every 2 weeks for 12 cycles: Irinotecan 180mg/m2 by intravenous infusion over 90 minutes on day 1 Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on day 1 Fluorouracil 400mg/m2 intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2 equivalent to 1200mg/m2/day).
Intervention code [1] 256165 0
Treatment: Drugs
Comparator / control treatment
Chemoptherapy agents used in this trial will be mFOLFOX6, XELOX or FOLFIRI. mFOLFOX6 is the combination of Oxaliplatin, Leucovorin and Fluorouracil as set out below. XELOX is the combination of Oxaliplatin and Capecitabine set out below. FOLFIRI is the combination of Irinotecan, Leucovorin and Fluorouracil as set out below. Patients randomised to Arm A will have surgical resection of liver metastases followed by chemotherapy. Post surgical chemotherapy should not be administered until at least 4 weeks after surgery. Chemotherapy must not be started after surgery unless the liver, renal and haematological funcions are within the same limits determined for the introduction of pre-operative chemotherapy in Arm B. In the event of a surgical complication preventing the introduction of post-operative chemotherapy a delay of not more than 12 weeks is acceptable. If recovery is delayed 12 weeks or more then the patient would be deemed off study and will be treated at the discretion of the clinicians. There are two different treatment options mFOLFOX6 or XELOX which will be determined by the treating investigator prior to randomisaiotn. Patients are not permitted to change treatments during the trial.
Post operative chemotherapy will be either - mFOLFOX6 Every 2 weeks for 12 cycles: Oxaliplatin 85mg/m2 by intravenous infusion over 2 hours on day 1. Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on day 1 Fluorouracil 400mg/m2 by intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2) equivalent to 1200mg/m2/day. OR

XELOX Every 3 weeks for 8 cycles: Oxaliplatin 130mg/m2 by intravenous infusion over 2 hours on day 1 Capecitabine 1000mg/m2 an oral tablet, twice daily on days 1-14 Patients who have previously received Oxaliplatin as part of their adjuvant treatment will be permitted to receive FOLFIRI instead of FOLFOX6/XELOX, as per their allocation to either ARM.
FOLFIRI will be: every 2 weeks for 12 cycles: Irinotecan 180mg/m2 by intravenous infusion over 90 minutes on day 1 Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on day 1 Fluorouracil 400mg/m2 intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2 equivalent to 1200mg/m2/day)
Control group
Active

Outcomes
Primary outcome [1] 257906 0
Determine the differences in peri-operative morbidity between groups?
Tools and tests used to gather this information will include, post operative follow up and reports of serious complications, blood tests, physical exams, World Health Organisation (WHO) performance status, urinanalysis, Carcinoembryonic Antigen tumour marker, (CEA), toxicity, adverse events Computed Tomography Scan (CT scan) of chest, abdomen and pelvis.
Timepoint [1] 257906 0
These assessments will be made pre and post surgery. Post surgery CT scans of chest, abdomen and pelvis to be performed within 30 days of surgery.
Secondary outcome [1] 263371 0
Determine the tolerability of chemotherapy received in pre-and post-operative chemotherapy regimens.

Assessment tools to be used include physical examination, weight, Body Surface Area (BSA) and vital signs, WHO performance status, blood and urinalalysis and collection of adverse events and toxicity indicators.
Timepoint [1] 263371 0
These assessments will be made befoer the commencement of each chemotherapy cycle (within 3 days of Day 1 of next cycle).

Every three months CT scans of chest, abdomen and pelvis will conducted, CEA, Alkaline phosphatase, total bilirubin, serum glutamate oxaloacetate transaminase (aspartate aminotransferase, SGOT), serum glutamate pyruvate transaminase (alanine aminotransferase, SGPT), serun creatinine: 3 months, 6 months.

After completion of study treatment, subjects will be followed every 3 months for the first 2 years and every 6 months therafter up to 5 years. Evaluations will include Physical exam, weight, BSA, vital signs, CT scans of chest, abdo and pelivs, CEA and toxicity and adverse event assessment.

A safety visit will be perofmed 30 days after the last study drug administration to include Physical exam, weight, BSA, vital signs, WHO performance status, toxicity and adverse event assessment.
Secondary outcome [2] 263424 0
Compare surgical mortality.

Death will be recorded in the patient notes and the Case Report Form and will be reported as a Serious Adverse Event.
Timepoint [2] 263424 0
Within 30 days after surgery.
Secondary outcome [3] 263425 0
Determine treatment related toxicity. Tools used to gather this information for assessment will include, blood tests, physical examination, WHO performance status, BSA, toxicity and adverse event reports.
Timepoint [3] 263425 0
Wihtin 30 days before commencement of each cycle of chemotherapy, before and after surgery, at end of treatment and 30 days after last study drug administration.
Secondary outcome [4] 263426 0
Determine the response rate (RR) to pre-operative chemotherapy.

Evaluation of the efficacy of chemotherapy on hepatic metastases is done by CT scans according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria V1.1, all patients on ARM B ( those receiving chemotherapy both pre and post surgery) will be assessed for best overall response to chemotherapy prior to surgery.
Timepoint [4] 263426 0
After the 3rd cycle and 6th cycle of chemotherapy in the study group receiving chemotherapy both pre and post-operatively. (Arm B only)
Secondary outcome [5] 263427 0
Determine progression free survival (PFS) for each treatment arm.


assessment of this will include blood analysis, CT of chest, abdomen and pelvis, chest xray.
Timepoint [5] 263427 0
Within 14 days before randomisation, every 3 months on treatment, before and after surgery, every 3 months for 2 years after treatment completion and every 6 months therafter for up to 5 years.
Secondary outcome [6] 263428 0
Detemine the overall survival (OS) for each treatment arm.

Overall survival is defined as the time interval between date of randomisation and the date of death. This will be assessed by completion and submission of case report forms or other notification by the treating site.
Timepoint [6] 263428 0
From the date of randomisation up to 5 years after treatment completion
Secondary outcome [7] 263429 0
Determine the effects of treatment on the quality of life (QoL)

Assessment tools to be used are the the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 plus QLQ-LMC21) and the Functional Assessment of Cancer Therapy (FACT) modules Functional Assessment of Cancer Therapy - General(FACT-G core ) and Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep)
Timepoint [7] 263429 0
At baseline, after 3/6/9/12 cycles of FOLFOX6 or 2/4/6/8/ cycles of XELOX, one month post- surgery and 7/12/18/24/30/36/months post-completion of therapy

Eligibility
Key inclusion criteria
* 18 years of age or older
* Patients must have histological or
cytological confirmation of a diagnosis of
colorectal adenocarcinoma.
* Patients with colorectal liver metastasis
which in the opinion of the liver surgeon
can be completely removed achieving a
microscopic margin of >1mm
* patients with metachronous metastases
may be included only if the oncologist
feels there is an indication for
chemotherapy
* Positron Emission Tomography (PET) scan within 4 weeks
prior to randomisation demonstrating:
# Hepatic metastasis; and
# No evidence of extrahepatic disease
* World health Organisation (WHO) performance status
less than or equal to 2
* Fit for chemotherapy and surgery
Absolute neutrophil count > 1.5x10-9 per
litre, platelet count >100x10-9 per litre,
creatinine <2 x upper limit of normal.
* Adequate renal function, with calculated
creatinine clearance >/= 30ml/min
(Cockroft and Gault;) For patients with
creatinine clearance </= 50ml.min
starting dose of capecitabine may not be
greater than 2000mg/m2/d
* Adequate hepatic function with serum
total bilirubin <1.5 x upper limit of
normal range
* Written consent for main study
participation, including tissue banking.

*There must be an estimated pre-operative margin of 5mm or greater. No restrictions are placed on the number of tumours.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Extrahepatic disease, including the presence of lymph node metastases or wound implantation metastasis * Patients with liver metastasis that cannot, in the opinion of the liver surgeon be resected. * Prior chemotherapy for metastatic disease. Adjuvant chemotherapy with 5-FU or FOLFOX is allowed providing it was given in association with complete resection of prirmary colon or rectal cancer, and treatment was completed at least 12 months prior * Patients in whom the surgical treatment plan includes radiofrequency ablation, synchronous resection of primary and metastatic disease, staged resection of hepatic metastases, pre-operative portal vein embolisation, tumour involving all three major hepatic veins or bilateral liver inflow involvement or any other where there is a possibility of the need for a vascular resection to achieve tumour clearance. * Previous treatment with an anti- Vascular Endothial Growth Factor (VEGF) anitbody. * WHO perfomance status >2 * Any other malignancy, other than adequately treated in situ carcinoma of the cervix or non-melanoma skin cancer (unles there has been a disease free interval of at 10 years). * Peripheral neuropathy common Terminology Criteria (CTC )> grade 1 as per version 4.0 of Common Terminology Criteria for Adverse Events (CTCAE). Patients with grade >1 neuropathy are still eligible if they are planned to receive FOLFIRI. * Uncontrolled congestive heart failure, angina, hypertension or arrhythmia. * History of Transient Ischaemic Attack (TIA) or Cerebroascular Accident (CVA) within 180 days prior to randomization; * Known bleeding diathesis or coagulopathy; * Requirement for therapeutic anticoagulation * Administration of another investigational drug within 30 days prior to randomisation. * Significant neurological or psychiatric disorders * Active infection * Serious or non-healing wound, skin ulcers or bone fracture * Active inflammatory bowel disease or history of bowel perforation <180 days of randomization * Gastro-intestinal ulceration determined by endoscopy to be active <180 days of randomization * Pregancy or lactation. Adequate contraception is required in pre-menopausal female patients. * Inability to comply with treatment schedule * Unable to give informed consent * Patients known to have Gilbert’s syndrome; and * Patients who will be required to receive the FOLFIRI chemotherapy section and are known to be homozygous for the UGT1A1 28 allele.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Upon confirmation of eligibility, patients will be stratified according to surgeon, their WHO performance status (0-1 or 2), planned chemotherapy schedule (FOLFOX6 or XELOX or FOLFIRI), and disease extent (1-4 or >4 metastases), and randomised to one of the two treatments arms in a 1:1 ratio using the minimisation method.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
19/10/2011
Actual
19/10/2011
Date of last participant enrolment
Anticipated
Actual
28/05/2013
Date of last data collection
Anticipated
Actual
1/02/2016
Sample size
Target
200
Accrual to date
Final
8
Recruitment in Australia
Recruitment state(s)
VIC,QLD,SA,WA,TAS
Recruitment outside Australia
Country [1] 2504 0
New Zealand
State/province [1] 2504 0

Funding & Sponsors
Funding source category [1] 256561 0
Government body
Name [1] 256561 0
Cancer Australia
Country [1] 256561 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-intestinal Trials Group
Address
Locked Bag 77
Camperdown
NSW 1450
Country
Australia
Secondary sponsor category [1] 255856 0
None
Name [1] 255856 0
Address [1] 255856 0
Country [1] 255856 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258598 0
Cancer Institute NSW Clinical Research Ethics Committee
Ethics committee address [1] 258598 0
Ethics committee country [1] 258598 0
Australia
Date submitted for ethics approval [1] 258598 0
08/03/2010
Approval date [1] 258598 0
27/07/2010
Ethics approval number [1] 258598 0
2010C/04/128

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30866 0
Prof Jonathan Fawcett
Address 30866 0
Queensland Liver Transplant Unit
Princess Alexandra Hospital
Ipswich Road
Woolloongabba QLD 4102
Country 30866 0
Australia
Phone 30866 0
+61 7 3240 5309
Fax 30866 0
Email 30866 0
[email protected]
Contact person for public queries
Name 14113 0
ATTACHE Trial Coordinator
Address 14113 0
NHMRC Cinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 14113 0
Australia
Phone 14113 0
+61 2 9562 5000
Fax 14113 0
+61 2 9562 5094
Email 14113 0
[email protected]
Contact person for scientific queries
Name 5041 0
ATTACHE Trial Coordinator
Address 5041 0
NHMRC Cinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 5041 0
Australia
Phone 5041 0
+61 2 9562 5000
Fax 5041 0
+61 29562 5094
Email 5041 0
[email protected]

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No Supporting Document Provided



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