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Trial registered on ANZCTR


Registration number
ACTRN12621001198819
Ethics application status
Approved
Date submitted
6/07/2021
Date registered
8/09/2021
Date last updated
8/09/2021
Date data sharing statement initially provided
8/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised Phase II Trial to Evaluate the Strategy of Integrating Local Ablative Therapy with First-Line Systemic Treatment for Unresectable Oligometastatic Colorectal Cancer (RESOLUTE)
Scientific title
Randomised Phase II Trial to Evaluate Progression-Free Survival in Integrating Local Ablative Therapy with First-Line Systemic Treatment for Unresectable Oligometastatic Colorectal Cancer
Secondary ID [1] 304686 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
metastatic colorectal cancer 322669 0
Condition category
Condition code
Cancer 320283 320283 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 320284 320284 0 0
Bowel - Small bowel (duodenum and ileum)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Local ablative therapy: a maximum of three LAT modalities can be administered for each participant, with a maximum of 2 modalities per organ, provided all LAT can be delivered within 12 weeks and participant can safely resume systemic treatment within 16 weeks from randomisation. LAT modalities allowed include surgical resection, stereotactic radiotherapy (SRT), laparoscopic or percutaneous thermal ablation [radiofrequency ablation (RFA) or microwave ablation (MWA)]. The LAT modalities will be delivered by specialists in the field (surgeons, radiation oncologists and/or interventional radiologists). The precise mode of delivery and number of times the LAT modality is delivered is case-dependent and is determined at a multi-disciplinary meeting (MDM).

Resuming previous standard of care first-line systemic treatment: after completing LAT, participant is to resume a further two to three months of first-line systemic treatment to a total of 6 months (including the initial 3-4 months of treatment). For patients receiving a doublet or triplet regimen, treatment may be de-escalated to maintenance fluoropyrimidine +/- biologics or anti-EGFR monotherapy at any point after trial entry at clinician discretion. The treating clinician may choose to discontinue systemic treatment following LAT for patients who have experienced prior intolerable toxicity.

Local guidelines will be implemented to ensure intervention fidelity. Case report forms (CRF) specific to each LAT modality will capture specific mode of delivery, organ being treated and number of times the intervention is delivered over a period of time.
Intervention code [1] 321063 0
Treatment: Other
Comparator / control treatment
The first-line systemic treatment will be standard of care as determined by the treating clinician. The following standard chemotherapy regimens are allowed: single agent fluoropyrimidine, CAPOX, FOLFOX, FOLFIRI, CAPIRI or FOLFOXIRI. Treatment with a biologic is allowed including bevacizumab or an anti-EGFR antibody (cetuximab or panitumumab). For patients receiving a doublet or triplet regimen, treatment may be de-escalated to maintenance fluoropyrimidine +/- biologics or anti-EGFR monotherapy at any point after trial entry at clinician discretion.
Control group
Active

Outcomes
Primary outcome [1] 328137 0
Efficacy of metastasis-directed local ablative therapies (LAT) following initial standard first-line systemic treatment vs continued first-line systemic treatment alone, as measured by Progression-Free Survival (PFS)
Timepoint [1] 328137 0
PFS rate (by Investigator) at 12 months from randomisation
Secondary outcome [1] 397787 0
Efficacy of LAT following initial standard first-line systemic treatment, compared to continued first-line systemic treatment alone, as measured by Overall Survival (OS)
Timepoint [1] 397787 0
At 12 months from randomisation and at study completion.
Secondary outcome [2] 397788 0
Efficacy of LAT following initial standard first-line systemic treatment, compared to continued first-line systemic treatment alone, as per imaging (RECIST) criteria.
Timepoint [2] 397788 0
At 12 months from randomisation and at study completion.
Secondary outcome [3] 397790 0
Systemic treatment-free interval between the two treatment groups.
Patient medical records will be used to determine systemic treatment-free interval, which is defined as the total time period where systemic treatment is not being regularly administered from randomisation until the initiation of 2nd line systemic treatment.
Timepoint [3] 397790 0
At study completion.
Secondary outcome [4] 397791 0
Rate of high-grade (Grades 3-5 according to CTCAE v5) toxicities between the two treatment groups.
Timepoint [4] 397791 0
At study completion
Secondary outcome [5] 397925 0
Quality of life measures between the two treatment groups using patient questionnaires (EORTC QLQ-C30 and QLQ-CR29, LAT-specific PRO-CTCAE).

This will be assessed as a composite outcome
Timepoint [5] 397925 0
At study completion

Eligibility
Key inclusion criteria
Inclusion:
-Metastatic colorectal adenocarcinoma that is not amenable to potentially curative surgery.
-Primary tumour must be controlled if the primary is intact, with no evidence of progression at primary site prior to study entry
-Imaging demonstrating ongoing treatment benefit (partial response or stable disease as per RECIST criteria) after 3-4 months of standard first-line systemic treatment.
-3 to 10 metastatic lesions detected on CT +/- FDG-PET scan prior to first line systemic treatment AND on screening FDG-PET and CT scans:
o maximum of 3 lesions per organ except for the liver.
o maximum of 3 involved organs including a lymph node station.
o only one lymph node station involvement is allowed.
-All lesions can be safely treated by LAT as determined by multidisciplinary team meeting.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion:
-Concurrent or previous other malignancy within 2 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen’s disease or prostate cancer with a Gleason score =6.
-Presence of brain, peritoneal, omental or ovarian metastases
-Malignant pleural effusion or ascites.

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 phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Once eligibility has been confirmed against key source documents, patients will be centrally randomised using the method of minimisation stratified by:
- number of metastatic lesions (less than or equal to 5 vs greater than 5),
- synchronous vs metachronous disease,
- primary tumour site (right vs left),
- participating primary sites and
- chemotherapy regimen (single agent vs doublet vs triplet regimens).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Sample Size
This study was designed to assess whether immediate LAT after first-line induction systemic treatment for oligometastatic CRC could reduce disease progression compared with continuing on systemic treatment only. The primary outcome is the proportion of patients in each arm with disease progression or death at 12 months. 12-month PFS from randomisation (after 3-4 months of first-line induction systemic treatment) corresponds to 15 months from the initiation of first-line treatment. Based on recently completed first-line clinical trials of doublet chemotherapy + biologics treatment, 15-month PFS (from initiation of first-line therapy) is estimated to be 24% in the control group with a median PFS of 10 months. Using a randomised phase II screening design with a recommended 2-sided a of 0.2, a sample size of 71 with a randomisation ratio of 1:2 will provide 80% power to detect a difference in 12-month event-free rate of 50% in the LAT group compared

Statistical analysis
All analyses will include all patients who are randomised.
Descriptive statistics of baseline characteristics of all treated patients will be reported. Continuous variables will be described as mean, standard deviation, median, interquartile range, minimum and maximum, and qualitative variables will be described as counts and percentages. Unless stated otherwise, the calculation of proportions will not include the missing category in the denominator. No imputation for missing value is intended and all confidence intervals provided will be 95% two-sided, unless stated otherwise.
Time to progression of treated lesions, time to development of new metastatic lesions, time to initiation of 2nd line systemic treatment, PFS and OS curves will be described using Kaplan-Meier methods. The curves will be presented with 95% confidence intervals. Estimates at key time point (e.g. 12 months) and median times will also be provided with respective 95% confidence interval. An event history plot will also be provided. The cut-off date for primary analysis will be when the final patient enrolled have been followed for 12 months from randomisation unless progression or death has occurred prior.
Safety will be assessed using CTCAE v5.0. The number of patients who suffer from grade 3 or higher toxicities (for each toxicity type and overall) will be provided at landmark timepoints.
QoL analyses and translational research endpoints will be reported using descriptive statistics.


Recruitment
Recruitment status
Not yet recruiting
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)
NSW,VIC
Recruitment hospital [1] 19917 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 19918 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [3] 19922 0
The Northern Hospital - Epping
Recruitment hospital [4] 19923 0
Border Medical Oncology - Albury
Recruitment hospital [5] 19924 0
Frankston Hospital - Frankston
Recruitment hospital [6] 19925 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [7] 19926 0
Goulburn Valley Health - Shepparton campus - Shepparton
Recruitment hospital [8] 19929 0
Epworth Eastern Hospital - Box Hill
Recruitment hospital [9] 19930 0
Sunshine Hospital - St Albans
Recruitment hospital [10] 20321 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 35063 0
2640 - Albury
Recruitment postcode(s) [2] 34618 0
3000 - Melbourne
Recruitment postcode(s) [3] 34632 0
3021 - St Albans
Recruitment postcode(s) [4] 34619 0
3065 - Fitzroy
Recruitment postcode(s) [5] 34623 0
3076 - Epping
Recruitment postcode(s) [6] 35064 0
3084 - Heidelberg
Recruitment postcode(s) [7] 34622 0
3128 - Box Hill
Recruitment postcode(s) [8] 34625 0
3199 - Frankston
Recruitment postcode(s) [9] 34626 0
3550 - Bendigo
Recruitment postcode(s) [10] 34627 0
3630 - Shepparton

Funding & Sponsors
Funding source category [1] 309057 0
Charities/Societies/Foundations
Name [1] 309057 0
Cancer Council Victoria
Address [1] 309057 0
615 St Kilda Road,
Melbourne, VIC, 3004, Australia
Country [1] 309057 0
Australia
Funding source category [2] 309069 0
Other Collaborative groups
Name [2] 309069 0
The Australasian Gastro-Intestinal Cancer Trials Group
Address [2] 309069 0
GI Cancer Institute @Lifehouse
Level 6, 119-143 Missenden Rd
Camperdown, NSW, 2050, Australia
Country [2] 309069 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Cancer Council Victoria
Address
615 St Kilda Road,
Melbourne, VIC, 3004, Australia
Country
Australia
Secondary sponsor category [1] 309998 0
Charities/Societies/Foundations
Name [1] 309998 0
The Australasian Gastro-Intestinal Cancer Trials Group
Address [1] 309998 0
GI Cancer Institute @Lifehouse
Level 6, 119-143 Missenden Rd
Camperdown, NSW, 2050, Australia
Country [1] 309998 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308933 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 308933 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 308933 0
Australia
Date submitted for ethics approval [1] 308933 0
31/03/2021
Approval date [1] 308933 0
01/07/2021
Ethics approval number [1] 308933 0

Summary
Brief summary
This study aims to assess the clinical benefit of local ablative therapy (LAT) following initial standard first-line systemic treatment, compared to continued standard first-line systemic treatment for metastatic colorectal cancer.

Who is it for?
You may be eligible for this trial if you are aged 18 years or over, have metastatic colorectal adenocarcinoma, have between 3-10 lesions, and are receiving first-line systemic treatment.

Study details
Participants will be randomly allocated to either a LAT arm, who will receive metastasis-directed LAT such as radiotherapy or thermal ablation following initial standard first-line systemic treatment, or a control arm who will receive continued first-line systemic treatment alone. Those receiving LAT will return to systemic treatment 16 weeks post-randomisation. Information on progression-free survival and treatment outcomes will be collected.

Data from this study will inform investigators of the potential benefit of local ablative therapy in the therapeutic setting for metastatic colorectal cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112382 0
A/Prof Jeanne Tie
Address 112382 0
Personalised Oncology Division
Walter and Eliza Hall Institute of Medical Research
1G Royal Parade Parkville Victoria 3052 Australia
Country 112382 0
Australia
Phone 112382 0
+61 3 9345 2707
Fax 112382 0
+61 3 9498 2010
Email 112382 0
jeanne.tie@petermac.org
Contact person for public queries
Name 112383 0
A/Prof Jeanne Tie
Address 112383 0
Personalised Oncology Division
Walter and Eliza Hall Institute of Medical Research
1G Royal Parade Parkville Victoria 3052 Australia
Country 112383 0
Australia
Phone 112383 0
+61 3 9345 2707
Fax 112383 0
+61 3 9498 2010
Email 112383 0
jeanne.tie@petermac.org
Contact person for scientific queries
Name 112384 0
A/Prof Jeanne Tie
Address 112384 0
Personalised Oncology Division
Walter and Eliza Hall Institute of Medical Research
1G Royal Parade Parkville Victoria 3052 Australia
Country 112384 0
Australia
Phone 112384 0
+61 3 9345 2707
Fax 112384 0
+61 3 9498 2010
Email 112384 0
jeanne.tie@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Due to limited resources, unfortunately, individual participant data will not be available.
What supporting documents are/will be available?
No other documents available
Summary results
No Results