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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.
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
Secondary ID [1] 295444 0
Nil known
Universal Trial Number (UTN)
Trial acronym
ALT-TRACC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Colorectal Cancer 309125 0
Condition category
Condition code
Cancer 308000 308000 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 302051 0
Treatment: Drugs
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
Control group
Active

Outcomes
Primary outcome [1] 306977 0
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.
Timepoint [1] 306977 0
Eligible participants will be recruited over 1.5 years. All participants will be followed until death or study completion.
Secondary outcome [1] 350304 0
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
Timepoint [1] 350304 0
• After completion of first line chemotherapy (8-12 cycles)
• Chemotherapy approximately completed 6 months from treatment start data
Secondary outcome [2] 350305 0
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
Timepoint [2] 350305 0
• After completion of first line chemotherapy (8-12 cycles)
• Chemotherapy approximately completed 6 months from treatment start data
Secondary outcome [3] 350306 0
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
Timepoint [3] 350306 0
• 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.
Secondary outcome [4] 351065 0
To determine the efficacy and toxicity of alternating oxaliplatin and irinotecan doublet schedules vs. continuous doublet chemotherapy, including:
• Overall survival
Timepoint [4] 351065 0
• 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.
Secondary outcome [5] 351067 0
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
Timepoint [5] 351067 0
• 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.
Secondary outcome [6] 351068 0
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
Timepoint [6] 351068 0
• 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
Secondary outcome [7] 351069 0
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
Timepoint [7] 351069 0
• At the completion of first line chemotherapy (8-12 cycles)
• Chemotherapy approximately completed 6 months from treatment start data

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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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

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)
Central randomisation by computer (using RedCap database)
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
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/efficacy
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.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
6/09/2018
Actual
6/09/2018
Date of last participant enrolment
Anticipated
31/12/2019
Actual
Date of last data collection
Anticipated
31/08/2022
Actual
Sample size
Target
140
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11573 0
Western Hospital - Footscray - Footscray
Recruitment hospital [2] 11574 0
Sunshine Hospital - St Albans
Recruitment hospital [3] 11575 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 11576 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 11577 0
The Northern Hospital - Epping
Recruitment hospital [6] 11578 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [7] 11579 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [8] 14921 0
Southwest Health Care - Warrnambool - Warrnambool
Recruitment hospital [9] 14922 0
Latrobe Regional Hospital - Traralgon
Recruitment postcode(s) [1] 23617 0
3011 - Footscray
Recruitment postcode(s) [2] 23618 0
3021 - St Albans
Recruitment postcode(s) [3] 23619 0
3000 - Melbourne
Recruitment postcode(s) [4] 23620 0
3128 - Box Hill
Recruitment postcode(s) [5] 23621 0
3076 - Epping
Recruitment postcode(s) [6] 23622 0
3065 - Fitzroy
Recruitment postcode(s) [7] 23623 0
3084 - Heidelberg
Recruitment postcode(s) [8] 28190 0
3280 - Warrnambool
Recruitment postcode(s) [9] 28191 0
3844 - Traralgon

Funding & Sponsors
Funding source category [1] 300034 0
Other
Name [1] 300034 0
Victorian Comprehensive Cancer Centre
Country [1] 300034 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Walter and Eliza Hall Institute of Medical Research
Address
1G Royal Parade
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 299422 0
None
Name [1] 299422 0
Address [1] 299422 0
Country [1] 299422 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300884 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 300884 0
Ethics committee country [1] 300884 0
Australia
Date submitted for ethics approval [1] 300884 0
15/03/2018
Approval date [1] 300884 0
18/04/2018
Ethics approval number [1] 300884 0
2017.355

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

Contacts
Principal investigator
Name 85150 0
Dr Hui-li Wong
Address 85150 0
Gibbs Lab, Systems Biology and Personalised Medicine Division
The Walter & Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052
Country 85150 0
Australia
Phone 85150 0
+61 3 9345 2189
Fax 85150 0
Email 85150 0
HuiLi.Wong@mh.org.au
Contact person for public queries
Name 85151 0
Hui-li Wong
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
Country 85151 0
Australia
Phone 85151 0
+61 3 9345 2189
Fax 85151 0
Email 85151 0
HuiLi.Wong@mh.org.au
Contact person for scientific queries
Name 85152 0
Hui-li Wong
Address 85152 0
Gibbs Lab, Systems Biology and Personalised Medicine Division
The Walter & Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052
Country 85152 0
Australia
Phone 85152 0
+61 3 9345 2189
Fax 85152 0
Email 85152 0
HuiLi.Wong@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only aggregated data will be available


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
4753Study protocol  Michael.Harold@mh.org.au
4754Ethical approval  Michael.Harold@mh.org.au
4755Informed consent form  Michael.Harold@mh.org.au
4756Statistical analysis plan  Michael.Harold@mh.org.au


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseBeyond standard data collection - the promise and potential of BRAIN (Brain tumour Registry Australia INnovation and translation registry).2022https://dx.doi.org/10.1186/s12885-022-09700-3
N.B. These documents automatically identified may not have been verified by the study sponsor.