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DEFINITIONS
Trial Review
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Trial registered on ANZCTR
Registration number
ACTRN12618001480279
Ethics application status
Approved
Date submitted
7/08/2018
Date registered
4/09/2018
Date last updated
1/10/2019
Date data sharing statement initially provided
1/10/2019
Type of registration
Prospectively registered
Titles & IDs
Public title
Comparing alternating oxaliplatin and irinotecan chemotherapy versus standard of care for metastatic colorectal cancer.
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Scientific title
Alternating oxaliplatin and irinotecan doublet schedules versus continuous doublet chemotherapy in previously untreated metastatic colorectal cancer: A Treatment of Recurrent and Advanced Colorectal Cancer registry-based prospective randomised trial
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Secondary ID [1]
295444
0
Nil known
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Universal Trial Number (UTN)
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Trial acronym
ALT-TRACC
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Metastatic Colorectal Cancer
309125
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Condition category
Condition code
Cancer
308000
308000
0
0
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Bowel - Back passage (rectum) or large bowel (colon)
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Alternating oxaliplatin and irinotecan doublet treatment schedules.
Arm A: Clinician’s choice doublet chemotherapy (standard chemotherapy)
Arm B: Alternating schedule of 2 cycles of oxaliplatin doublet chemotherapy and 2 cycles of irinotecan doublet chemotherapy, i.e. mFOLFOX6-FOLFIRI or CAPOX-CAPIRI
In both arms, initial combination chemotherapy will be given for 4-6 months as per standard of care, followed by maintenance fluoropyrimidine chemotherapy until disease progression, unmanageable toxicity or patient or treating clinician’s request. Biologic therapy (bevacizumab or an EGFR inhibitor) will be given according to clinician’s choice; however, as per guidelines, EGFRI use will be restricted to patients with left-sided RAS wild-type tumours.
1) Intervention drug - Doublet chemotherapy (mFOLFOX6, FOLFIRI, CAPOIX or CAPIRI)
mFOLFOX6
Frequency: every 2 weeks
Oxaliplatin 85 mg/m2 IV day 1
Leucovorin 50 mg IV day 1
Fluorouracil (5FU) 400 mg/m2 IV day 1
Fluorouracil (5FU) infusion 2,400 mg/m2 over 46 hours day 1-2
FOLFIRI
Frequency: every 2 weeks
Irinotecan 180 mg/m2 IV day 1 (150 mg/m2 if > 70 y.o.)
Leucovorin 50 mg IV day 1
Fluorouracil (5FU) 400 mg/m2 IV day 1
Fluorouracil (5FU) infusion 2,400 mg/m2 over 46 hours day 1-2
CAPOX
Frequency: every 3 weeks
Oxaliplatin 130 mg/m2 IV day 1
Capecitabine 850-1000 mg/m2 orally BD days 1-14
CAPIRI
Frequency: every 3 weeks
Irinotecan 240 mg/m2 IV day 1
Capecitabine 850-1000 mg/m2 orally BD days 1-14
New drug schedules have been created for the hospital staff to keep track of the alternating cycles.
Whether a participant receives mFOLFOX6-FOLFIRI or CAPOX-CAPIRI is decided by the treating practitioner, based on their usual treatment practice.
When a patient is on the interventional treatment e.g. CAPOX-CAPIRI, the different treatments are staggered every 3 weeks. For FOLFOX-FOLFIRI, the the different treatments are staggered every 2 weeks.
2) This is an open-label, prospective, multi-centre registry-based study evaluating the impact of delivering all active cytotoxic agents during initial systemic therapy on outcomes in treatment-naïve mCRC. Participants will be randomised in a 1:1 ratio to one of two treatment arms and followed according to standard protocols, with treatment, toxicity and outcome data captured in the TRACC registry.
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Intervention code [1]
302051
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Treatment: Drugs
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Comparator / control treatment
Standard treatment group (standard continuous doublet chemotherapy)
Doublet chemotherapy (mFOLFOX6 or FOLFIRI or CAPOX or CAPIRI)
mFOLFOX6
Frequency: every 2 weeks
Oxaliplatin 85 mg/m2 IV day 1
Leucovorin 50 mg IV day 1
Fluorouracil (5FU) 400 mg/m2 IV day 1
Fluorouracil (5FU) infusion 2,400 mg/m2 over 46 hours day 1-2
FOLFIRI
Frequency: every 2 weeks
Irinotecan 180 mg/m2 IV day 1 (150 mg/m2 if > 70 y.o.)
Leucovorin 50 mg IV day 1
Fluorouracil (5FU) 400 mg/m2 IV day 1
Fluorouracil (5FU) infusion 2,400 mg/m2 over 46 hours day 1-2
CAPOX
Frequency: every 3 weeks
Oxaliplatin 130 mg/m2 IV day 1
Capecitabine 850-1000 mg/m2 orally BD days 1-14
CAPIRI
Frequency: every 3 weeks
Irinotecan 240 mg/m2 IV day 1
Capecitabine 850-1000 mg/m2 orally BD days 1-14
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Control group
Active
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Outcomes
Primary outcome [1]
306977
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To examine the feasibility of a multi-centre prospective registry-based randomised clinical trial evaluating alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy during initial treatment of metastatic colorectal cancer.
The primary feasibility endpoint will be evaluated by recruitment rate, defined as the proportion of eligible mCRC patients who enrol onto this study.
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Assessment method [1]
306977
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Timepoint [1]
306977
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Eligible participants will be recruited over 1.5 years. All participants will be followed until death or study completion.
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Secondary outcome [1]
350304
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To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Overall response rate on first line chemotherapy
• Assessed from medical records and data collection tool
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Assessment method [1]
350304
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Timepoint [1]
350304
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• After completion of first line chemotherapy (8-12 cycles)
• Chemotherapy approximately completed 6 months from treatment start data
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Secondary outcome [2]
350305
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To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Disease control rate on first line chemotherapy
• Assessed from medical records and data collection tool
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Assessment method [2]
350305
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Timepoint [2]
350305
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• After completion of first line chemotherapy (8-12 cycles)
• Chemotherapy approximately completed 6 months from treatment start data
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Secondary outcome [3]
350306
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To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Time to progression on first line chemotherapy
• Assessed from medical records and data collection tool
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Assessment method [3]
350306
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Timepoint [3]
350306
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• Measured from the date of first chemotherapy dose to the date of first documented disease progression or death from any cause, whichever is the earlier event.
• The study will be considered closed after the last patient enrolled has dies or had 2.5 years of follow-up, whichever occurs earlier. it is anticipated that this study will run for approximately 4 years.
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Secondary outcome [4]
351065
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To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Overall survival
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Assessment method [4]
351065
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Timepoint [4]
351065
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• Measured from the date of first chemotherapy dose to the date of death from any cause
• The study will be considered closed after the last patient enrolled has dies or had 2.5 years of follow-up, whichever occurs earlier. it is anticipated that this study will run for approximately 4 years.
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Secondary outcome [5]
351067
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To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Metastatic disease resection rate
• Assessed from medical records and data collection tool
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Assessment method [5]
351067
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Timepoint [5]
351067
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• The proportion of patients who undergo resection of metastatic disease at any time during the course of their disease.
• The study will be considered closed after the last patient enrolled has dies or had 2.5 years of follow-up, whichever occurs earlier. it is anticipated that this study will run for approximately 4 years.
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Secondary outcome [6]
351068
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To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Overall incidence of adverse events during first line chemotherapy
• Assessed from medical records and data collection tool
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Assessment method [6]
351068
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Timepoint [6]
351068
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• Proportion of patients who experience a serious adverse event at any time during first line chemotherapy.
• Chemotherapy approximately completed 6 months from treatment start data
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Secondary outcome [7]
351069
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To examine overall treatment delivery among patients receiving alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Proportion of patients who receive all cytotoxics (5FU, oxaliplatin and irinotecan) over the course of their disease
• Assessed from medical records and data collection tool
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Assessment method [7]
351069
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Timepoint [7]
351069
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• At the completion of first line chemotherapy (8-12 cycles)
• Chemotherapy approximately completed 6 months from treatment start data
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Eligibility
Key inclusion criteria
Inclusion Criteria
1. Signed informed consent obtained prior to any study specific procedures and willingness to comply with study requirements
2. Age greater than or equal to 18 years
3. Histologically confirmed, metastatic colorectal adenocarcinoma treated with less than or equal to 2 cycles of doublet chemotherapy
4. ECOG performance status of 0-2
5. Life expectancy of greater than or equal to 3 months
6. Adequate major organ function to receive doublet chemotherapy as judged by the treating clinician
7. No contraindication to any of the 3 cytotoxic agents (5FU, oxaliplatin and irinotecan)
8. Recent imaging of chest, abdomen and pelvis. It is recommended that this should be within 4 weeks of first chemotherapy dose (no more than 8 weeks).
Please note: Every patient enrolled in the study is then entered in the TRACC Registry to enable the data collection for the study.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion Criteria
1. Previous chemotherapy and/or biologic therapy for CRC, except for adjuvant treatment if completed more than 6 months earlier
2. Not suitable for doublet chemotherapy
3. Significant concomitant medical condition which the treating clinician believes precludes the patient from enrolling in the study
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer (using RedCap database)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
The participants are stratified by:
Primary tumour location
Treatment intent
Study centre
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
Safety/efficacy
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Statistical methods / analysis
Sample Size Considerations and Primary Outcome Analysis
The primary aim of this study is to determine the feasibility of conducting a multi-centre prospective registry-based randomised clinical trial evaluating treatment sequencing in metastatic colorectal cancer (mCRC). Considering the low participation rate in clinical trials, consistently reported to be <5%, 53 feasibility will primarily be assessed by recruitment rate. We aim to enrol at least one in three (33%) potentially eligible mCRC patients registered in the TRACC registry to ALT-TRACC. If the study proves to be feasible, consideration will be given to expanding the study to new sites as a randomised phase III trial with a primary endpoint of overall survival.
The participants are registered on to the TRACC registry because they have metastatic colorectal cancer. A participant can be eligible for the study without necessarily being on the registry. However, once they are identified as being mCRC they are captured on the registry.
Based on a review of TRACC data, approximately 200 new mCRC cases are recorded each year across the 3 participating centres. Of these, 75% (N=150) do not have immediately resectable metastatic disease and would be considered for upfront chemotherapy, where two thirds (N=100) receive combination chemotherapy and might be considered to be potentially eligible for this study.
A Simon’s two-stage optimal design was used to enable an interim analysis to identify lower than expected recruitment (set at <20%), in order to define factors that impact recruitment to registry-based randomised controlled trials, and to identify opportunities to boost study recruitment. Recruitment rate will be initially assessed after 50 consecutive TRACC patients who meet eligibility criteria for ALT-TRACC are registered. If fewer than 11 patients have enrolled in ALT-TRACC, a review of reasons for non-enrolment will be undertaken, including procedures for identifying, tracking and consenting patients at participating sites. Ultimately, 140 consecutive TRACC patients who meet eligibility criteria for this study are required to reject a recruitment rate of 20% in favour of the target recruitment rate of 33%, with over 90% power and type I two-sided error rate of 0.05.
Secondary Outcome Analyses
Several secondary outcome analyses will be performed comparing the alternating oxaliplatin and irinotecan doublet schedules and continuous doublet chemotherapy arms. These will be exploratory in nature, and will be performed by comparing proportions using Chi-squared statistics, or the Kaplan-Meier method with the log-rank test to compare survival analyses. Efficacy analyses will be performed on the intention-to-treat (ITT) and per-protocol populations, stratified by primary tumour location, RAS mutation status, BRAF mutation status and choice of biologic therapy. Time-to-event analyses will be adjusted for prognostic factors using proportional hazards regression methods, with results expressed as the estimated hazard ratio with the corresponding 95% confidence interval. In order to ensure accurate overall survival analysis, linkage with the Victorian Cancer Registry and National Death Index for date and cause of death will be undertaken.
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Recruitment
Recruitment status
Recruiting
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Date of first participant enrolment
Anticipated
6/09/2018
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Actual
6/09/2018
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Date of last participant enrolment
Anticipated
31/12/2019
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Actual
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Date of last data collection
Anticipated
31/08/2022
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Actual
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Sample size
Target
140
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Accrual to date
12
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Final
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
11573
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Western Hospital - Footscray - Footscray
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Recruitment hospital [2]
11574
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Sunshine Hospital - St Albans
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Recruitment hospital [3]
11575
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Peter MacCallum Cancer Centre - Melbourne
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Recruitment hospital [4]
11576
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Box Hill Hospital - Box Hill
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Recruitment hospital [5]
11577
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The Northern Hospital - Epping
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Recruitment hospital [6]
11578
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St Vincent's Hospital (Melbourne) Ltd - Fitzroy
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Recruitment hospital [7]
11579
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Austin Health - Austin Hospital - Heidelberg
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Recruitment hospital [8]
14921
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Southwest Health Care - Warrnambool - Warrnambool
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Recruitment hospital [9]
14922
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Latrobe Regional Hospital - Traralgon
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Recruitment postcode(s) [1]
23617
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3011 - Footscray
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Recruitment postcode(s) [2]
23618
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3021 - St Albans
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Recruitment postcode(s) [3]
23619
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3000 - Melbourne
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Recruitment postcode(s) [4]
23620
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3128 - Box Hill
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Recruitment postcode(s) [5]
23621
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3076 - Epping
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Recruitment postcode(s) [6]
23622
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3065 - Fitzroy
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Recruitment postcode(s) [7]
23623
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3084 - Heidelberg
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Recruitment postcode(s) [8]
28190
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3280 - Warrnambool
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Recruitment postcode(s) [9]
28191
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3844 - Traralgon
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Funding & Sponsors
Funding source category [1]
300034
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Other
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Name [1]
300034
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Victorian Comprehensive Cancer Centre
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Address [1]
300034
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305 Grattan Street, Melbourne VIC 3000
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Country [1]
300034
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Australia
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Primary sponsor type
Other Collaborative groups
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Name
The Walter and Eliza Hall Institute of Medical Research
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Address
1G Royal Parade
Parkville VIC 3052
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Country
Australia
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Secondary sponsor category [1]
299422
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None
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Name [1]
299422
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Address [1]
299422
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Country [1]
299422
0
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
300884
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Melbourne Health Human Research Ethics Committee
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Ethics committee address [1]
300884
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Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
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Ethics committee country [1]
300884
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Australia
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Date submitted for ethics approval [1]
300884
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15/03/2018
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Approval date [1]
300884
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18/04/2018
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Ethics approval number [1]
300884
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2017.355
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Summary
Brief summary
The purpose of this study is to assess the effect of delivering all anti-cancer medications during initial systemic therapy on outcomes in those undergoing treatment for metastatic colorectal cancer.
Who is it for?
You may be eligible for this study if you are an adult who has been diagnosed with metastatic colorectal cancer.
Study details
Participants will be randomly allocated to receive one of two treatments:
1. Alternating schedule of 2 cycles of oxaliplatin based chemotherapy and 2 cycles of irinotecan based chemotherapy
2. Clinician’s choice of chemotherapy.
Participants will receive combination chemotherapy for 4-6 months followed by a maintenance period where participants will continue to receive 'maintenance' chemotherapy until disease progression, toxicity or patient/treating clinician request.
It is hoped that combining the two effective chemotherapy drugs in first line treatment, but in an alternating pattern, will be beneficial to the patient's outcome and that this alternating use of them will reduce the higher toxicity that occurs when these drugs are used together.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
85150
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Dr Hui-li Wong
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Address
85150
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Gibbs Lab, Systems Biology and Personalised Medicine Division
The Walter & Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052
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Country
85150
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Australia
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Phone
85150
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+61 3 9345 2189
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Fax
85150
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Email
85150
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[email protected]
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Contact person for public queries
Name
85151
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Dr Hui-li Wong
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Address
85151
0
Gibbs Lab, Systems Biology and Personalised Medicine Division
The Walter & Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052
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Country
85151
0
Australia
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Phone
85151
0
+61 3 9345 2189
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Fax
85151
0
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Email
85151
0
[email protected]
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Contact person for scientific queries
Name
85152
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Dr Hui-li Wong
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Address
85152
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Gibbs Lab, Systems Biology and Personalised Medicine Division
The Walter & Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052
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Country
85152
0
Australia
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Phone
85152
0
+61 3 9345 2189
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Fax
85152
0
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Email
85152
0
[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Only aggregated data will be available
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What supporting documents are/will be available?
No Supporting Document Provided
Doc. No.
Type
Citation
Link
Email
Other Details
Attachment
4753
Study protocol
[email protected]
4754
Ethical approval
[email protected]
4755
Informed consent form
[email protected]
4756
Statistical analysis plan
[email protected]
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Beyond standard data collection - the promise and potential of BRAIN (Brain tumour Registry Australia INnovation and translation registry).
2022
https://dx.doi.org/10.1186/s12885-022-09700-3
N.B. These documents automatically identified may not have been verified by the study sponsor.
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