Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001047785
Ethics application status
Approved
Date submitted
14/07/2022
Date registered
28/07/2022
Date last updated
2/03/2023
Date data sharing statement initially provided
28/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Australian Comprehensive Molecular Evaluation of Advanced Biliary Cancer Trial (ACME ABC)
Scientific title
Feasibility and role for comprehensive molecular evaluation for Advanced Biliary Cancer (ABC) in Australia.
Secondary ID [1] 307570 0
Nil known
Universal Trial Number (UTN)
Trial acronym
ACME ABC Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Biliary cancer / Cholangiocarcinoma 327022 0
Condition category
Condition code
Oral and Gastrointestinal 324196 324196 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with suspected diagnosis of ABC who have a good performance status are candidates for entry into this trial. If participants are later found to have a benign condition, they will be excluded from the assessment of primary and relevant secondary outcomes.

Potential participants will have been identified at and reviewed at multi-disciplinary team meeting (MDT) and are not suitable for surgical resection as the tumour is locally advanced, metastatic or recurrent.

Participants will provide informed consent for additional biopsies to be taken at the initial or subsequent endoscopic interventions (endoscopic ultrasound with fine needle biopsy or direct cholangioscopy with biopsies) for the routine diagnosis and management of cholangiocarcinoma. No additional procedures will be organised for research biopsies but if a patient requires a replacement stent or repeat procedure for their diagnosis, then that would be the opportunity for the additional biopsies for the genomic profiling to be obtained. These biopsies from EUS or direct cholangioscopy will be obtained by a highly skilled interventional endoscopist (typically a gastroenterologist or a hepatopancreaticobiliary surgeon). The extra biopsies typically may add 2-5 minutes to the procedure and blood samples will be obtained by the anaesthetist via the existing cannula or additional venepuncture whilst the patient has the endoscopic procedure.

DNA and RNA will be extracted from these additional biopsies using a standardised protocol (from Qiagen) and then quantified. If the quality of the genomic material is sufficient, then it will progress to have whole genome sequencing (WGS) completed through the Victorian Comprehensive Cancer Centre run by Professor Sean Grimmond.

Peripheral blood taken at the time of the endoscopic procedure will be stored for future circulating tumour DNA analysis and possible comprehensive molecular profiling.

After molecular profiling of biopsies has been completed and the results will be reviewed in the forum of a MTB. If a patient is potentially suitable or eligible for potential participation in therapeutic trials, then they may be referred to MoST (ACTRN12616000908437)
Intervention code [1] 324026 0
Diagnosis / Prognosis
Comparator / control treatment
Prospective cohort study. There will be no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332009 0
To determine the proportion of patients with advanced biliary cancer (ABC) that can have comprehensive molecular profiling of the tumour using a fresh-frozen endoscopic fine needle biopsy (EUS-FNB).
Timepoint [1] 332009 0
It is anticipated that the target number of participants (50-75) will be reached within 12 months post enrolment commencement. The proportion of patients with Advanced Biliary Cancer (ABC) will then be able to be completed once recruitment target number has been achieved - this is anticipated to be 12 months from the start of enrolment. Analysis of the results of the sequencing for each patient will completed in a timely fashion.
Primary outcome [2] 332030 0
To determine the proportion of patients with advanced biliary cancer (ABC) that can have comprehensive molecular profiling of the tumour using direct cholangioscopic biopsies
Timepoint [2] 332030 0
At conclusion of the trial (anticipated to be 12 months post enrolment commencement), the proportion of patients with Advanced Biliary Cancer (ABC) will be able to be calculated once target recruitment for the study is completed.
Secondary outcome [1] 411891 0
Proportion of patients with a molecular characterisation of ABC that can have treatment recommendations made on the basis of comprehensive molecular profiling (CMP) from EUS-FNB and direct cholangioscopic biopsies. The decision as to which type of biopsy for the patient is most appropriate either EUS-FNB or direct cholangioscopic biopsy will vary from patient to patient.

The proportion of patients that can have treatment recommendations made on the basis of CMP of EUS-FNB and direct cholangioscopic biopsies will be analysed together as a composite outcome.

Those enrolled in the trial will have informed consent included in their medical records and data will be collected and stored in a secure de-identified form. The outcomes of the CMP of the participants sample will be evaluated in a formal capacity in a molecular tumour board meeting (MTB) coordinated through Monash Health.
Timepoint [1] 411891 0
Timepoint: 18 months from the commencement of the trial
Secondary outcome [2] 411941 0
Proportion of patients with a targetable phenotype that have targeted treatment . There will be a standardised manual entry into the patient's medical record detailing the outcome of the CMP results and MTB meeting as well as correspondence to the patient's referring doctor.
Timepoint [2] 411941 0
The proportion of participants who receive targeted treatment will be assessed 18 months post-enrolment commencement..
Secondary outcome [3] 411942 0
The time taken between enrolment in the study and MTB assessment will be calculated by audit of the study database and data linkage to medical records. This will help inform the assessment of the feasibility of CMP in ABC.
Timepoint [3] 411942 0
The goal is for the time taken between enrolment and MTB assessment to be less than 3 months. This will be assessed at completion of recruitment of study participants.
Secondary outcome [4] 411943 0
Assessment of overall survival of patients who receive targeted therapy using data linkage to medical records.
Timepoint [4] 411943 0
Annual follow-up with the MoST study if referred for clinical trial/therapy for 3 years from enrolment in the MoST trial (ACTRN12616000908437)
Secondary outcome [5] 412211 0
The sensitivity and specificity of a molecular diagnosis of ABC using whole genome sequencing to detect the presence of one or more mutations that have previously been described in cholangiocarcinoma, for example in The Cancer Genome Atlas (TCGA). The whole genome sequencing will be completed on the tissue biopsies and blood samples and the proportion of patients with one or more mutations will be calculated. A two by two table and other statistical analyses will be calculated with input from a statistician.
Timepoint [5] 412211 0
Calculation will be completed within 6 months of target number of study participants being reached.
Secondary outcome [6] 412212 0
Sensitivity and specificity of a molecular diagnosis of ABC using a NanoString signature previously validated in pancreatic cancer. Irrespective of the source of the genomic material, the quality and quantity of DNA will be determined on a NanoDrop Spectrophotometer (Thermo Fisher Scientific, Waltham, MA). Qualitative analysis of extracted supernatant DNA will be performed using Agilent High Sensitivity D1000 ScreenTape on the Agilent 2200 TapeStation system (Agilent, Santa Clara, CA) according to manufacturer’s instructions. RNA will be quantified and assessed for fragmentation using a NanoDrop and Qubit Fluorometer (Life Technologies), and the Aligent Bioanalyzer (Aligent Technologies).
The quantity and quality of DNA and RNA recovered from each source/technique will be reported as part of this study
Timepoint [6] 412212 0
Completed within 6 months of target recruitment population being reached
Secondary outcome [7] 412213 0
Assessment of peripheral blood as a potential source of comprehensive molecular profiling in ABC. CMP on the peripheral blood will be compared with the tissue samples and CMP for the respective patient and evaluated using statistical analysis .
Timepoint [7] 412213 0
Completed within 6 months of target recruitment population being reached
Secondary outcome [8] 412214 0
Telephone interview asking about disease progress and diagnosis. Standardised questions will be asked to each participant and documented n the medical records of the patient.
Timepoint [8] 412214 0
Participants will be contacted within 6 months post-enrolment

Eligibility
Key inclusion criteria
1. Males or females with suspected advanced biliary tract cancer as determined by MDT review that is either:
a. Locally advanced
b. Metastatic
c. Recurrent
2. Study participants either:
a. Are scheduled for an endoscopic procedure for the purposes of tissue diagnosis or biliary stenting
b. Have previously consented to biobanking of endoscopic biopsy material
3. Study participants must be 18 years of age or older at time of screening
4. ECOG Performance Status 0-2
5. Suitability for chemotherapy
6. Able to give signed informed consent
7. Life expectancy of at least 3 months from the time of screening as judged by screening investigator
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients considered to have operable or potentially operable biliary cancer (BC)
2. Patients with hepatocellular cancer or liver metastatic disease in which the primary malignancy is not BC.
3. Evidence of systemic disease (cardiovascular, respiratory, renal, hepatic, etc.) that would preclude chemotherapy.
4. Serious medical or psychiatric conditions that might compromise protocol-based management as judged by investigator

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised 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)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Prospective multi-centre cohort study - patients with advanced biliary cancer meeting the inclusion criteria will be offered entry into the trial
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
This is a prospective cohort study to investigate feasibility of minimally invasive biopsy material to provide sufficient DNA/RNA to allow for comprehensive molecular phenotyping of advanced biliary cancer.

The co-primary endpoints of the study are to determine the proportion of patients with ABC that can have successful molecular analysis using either fresh frozen EUS-FNA or cholangioscopic biopsy material. We postulate that a significant proportion of patients who can have successful molecular phenotyping using fresh frozen could also have CMP from supernatant (cell free) biopsy material. The former may be more effective in enabling CMP but the latter has the benefit of posing no additional risk to the patient and may be more widely applicable as it does not required immediate storage on an additional biopsy.

We expect that with 50 (ideally 75-100) matched patients should be sufficient to establish the proportion of patients who can comprehensive molecular profiling with an additional biopsy and with cell free DNA/RNA obtained from routine diagnostic biopsies (“the supernatant”). Given that the expect incidence of targetable mutations in ABD is 30-40%, We have with a reasonable level of confidence that 50 patients will be sufficient to confirm this

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/08/2022
Actual
23/02/2023
Date of last participant enrolment
Anticipated
1/10/2024
Actual
Date of last data collection
Anticipated
1/10/2026
Actual
Sample size
Target
50
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 22821 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 22822 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [3] 22823 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [4] 22824 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 22825 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 22826 0
Royal Perth Hospital - Perth
Recruitment hospital [7] 22827 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [8] 22828 0
Launceston General Hospital - Launceston
Recruitment postcode(s) [1] 38110 0
3168 - Clayton
Recruitment postcode(s) [2] 38111 0
3065 - Fitzroy
Recruitment postcode(s) [3] 38112 0
2050 - Camperdown
Recruitment postcode(s) [4] 38113 0
2031 - Randwick
Recruitment postcode(s) [5] 38114 0
5000 - Adelaide
Recruitment postcode(s) [6] 38115 0
6000 - Perth
Recruitment postcode(s) [7] 38116 0
4029 - Herston
Recruitment postcode(s) [8] 38117 0
7250 - Launceston

Funding & Sponsors
Funding source category [1] 311843 0
Other Collaborative groups
Name [1] 311843 0
Australasian Gastro-Intestinal Cancer Trials Group (AGITG)
Country [1] 311843 0
Australia
Funding source category [2] 311845 0
Hospital
Name [2] 311845 0
Monash Health
Country [2] 311845 0
Australia
Funding source category [3] 311846 0
University
Name [3] 311846 0
Monash University
Country [3] 311846 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Cancer Trials Group (AGITG)
Address
Locked Bag 77 Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 313319 0
None
Name [1] 313319 0
Address [1] 313319 0
Country [1] 313319 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311286 0
Monash Health HREC
Ethics committee address [1] 311286 0
Ethics committee country [1] 311286 0
Australia
Date submitted for ethics approval [1] 311286 0
24/05/2022
Approval date [1] 311286 0
19/08/2022
Ethics approval number [1] 311286 0

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

Contacts
Principal investigator
Name 120574 0
Dr Daniel Croagh
Address 120574 0
HPB Surgeon
Lecturer in Surgery
Monash Medical Centre, Monash
Department of Surgery
Monash Gastrointestinal Specialists
Monash House
Suite 9
271 Clayton Rd
Clayton Vic 3168
Country 120574 0
Australia
Phone 120574 0
+61 0428 121 121
Fax 120574 0
+61 3 9543 3805
Email 120574 0
[email protected]
Contact person for public queries
Name 120575 0
Kathryn Goss
Address 120575 0
Clinical Research and Data Coordinator / Endoscopy & Upper Gastrointestinal Surgery
246 Clayton Road, Clayton 3168 Victoria
Country 120575 0
Australia
Phone 120575 0
+61 3 9543 5311
Fax 120575 0
+61 3 95433805
Email 120575 0
[email protected]
Contact person for scientific queries
Name 120576 0
Daniel Croagh
Address 120576 0
Monash Health / Monash University
HPB Surgeon
Lecturer in Surgery
Monash Medical Centre, Monash
Department of Surgery

Monash Gastrointestinal Specialists
Monash House
Suite 9
271 Clayton Rd
Clayton Vic 3168
Country 120576 0
Australia
Phone 120576 0
+61 0428121121
Fax 120576 0
+61 3 9543 3805
Email 120576 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Basic demographics and outcome data will be shared/available for relevant involved parties
The sequencing is being performed by a collaborator (VCCC)
When will data be available (start and end dates)?
Most of the data will be stored in a secure RedCap database. There will be ongoing collection of such data from the time the trial start till it concludes with subsequent data analysis to continue after completion of the trial. Relevant data that can impact on patient care will be provided to the relevant parties involved in care and subsequent treatment trial groups.

Start date: 15/8/2022 - date of trial for when the 1st participant will be recruited.
Finish date: 1/9/2026 years from start of trial (allows 3 year follow-up)
Available to whom?
Relevant data that can impact on patient care will be provided to the referring clinician/surgeon and disclosed to the patient/family members if a relevant finding is discovered or it impacts of treatment options/outcomes.
Available for what types of analyses?
The outcomes of the genomic sequencing will be reviewed in a molecular tumour board meeting (MTB) that reviews the Pierian Diagnostic reports generated from the sequencing.
How or where can data be obtained?
Access will be subject to approval by the principal investigator ([email protected])


What supporting documents are/will be available?




Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.