ANZCTR - Registration

Please note the ANZCTR will be unattended from Friday 20 December 2024 for the holidays. The Registry will re-open on Tuesday 7 January 2025. Submissions and updates will not be processed during that time.

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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]

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

Condition category

Condition code

Oral and Gastrointestinal

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]

Diagnosis / Prognosis

Comparator / control treatment

Prospective cohort study. There will be no control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

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]

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]

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]

Timepoint: 18 months from the commencement of the trial

Secondary outcome [2]

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]

The proportion of participants who receive targeted treatment will be assessed 18 months post-enrolment commencement..

Secondary outcome [3]

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]

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]

Assessment of overall survival of patients who receive targeted therapy using data linkage to medical records.

Timepoint [4]

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]

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]

Calculation will be completed within 6 months of target number of study participants being reached.

Secondary outcome [6]

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]

Completed within 6 months of target recruitment population being reached

Secondary outcome [7]

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]

Completed within 6 months of target recruitment population being reached

Secondary outcome [8]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [2]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [3]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [4]

Prince of Wales Hospital - Randwick

Recruitment hospital [5]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [6]

Royal Perth Hospital - Perth

Recruitment hospital [7]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [8]

Launceston General Hospital - Launceston

Recruitment postcode(s) [1]

3168 - Clayton

Recruitment postcode(s) [2]

3065 - Fitzroy

Recruitment postcode(s) [3]

2050 - Camperdown

Recruitment postcode(s) [4]

2031 - Randwick

Recruitment postcode(s) [5]

5000 - Adelaide

Recruitment postcode(s) [6]

6000 - Perth

Recruitment postcode(s) [7]

4029 - Herston

Recruitment postcode(s) [8]

7250 - Launceston

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Australasian Gastro-Intestinal Cancer Trials Group (AGITG)

Address [1]

Locked Bag 77 Camperdown NSW 1450.

Country [1]

Australia

Funding source category [2]

Hospital

Name [2]

Monash Health

Address [2]

246 Clayton Road Clayton Victoria 3149

Country [2]

Australia

Funding source category [3]

University

Name [3]

Monash University

Address [3]

Wellington Road, Clayton Victoria 3149

Country [3]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health HREC

Ethics committee address [1]

246 Clayton Road, Clayton Victoria 3149

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/05/2022

Approval date [1]

19/08/2022

Ethics approval number [1]

Summary

Brief summary

Biliary Cancer (BC) or Cholangiocarcinoma remains a rare but important cause of cancer related mortality worldwide. Although surgical resection can be curative, most patients present with advanced disease not suitable for surgery. Current chemotherapy has improved median survival to 1-2 years for these patients.

The aim of this study is to examine the feasibility and benefit or role for integrating comprehensive molecular profiling (CMP) of advanced biliary cancer (ABC) using tissue collected during routine diagnostic tests or procedures.

Who is it for?
You may be eligible to join this study if you are aged 18 years or older, have suspected advanced biliary tract cancer, and are either scheduled for an endoscopy procedure or have pre-existing "biobanked" (stored) endoscopic biopsy tissue.

Study Details:
All participants will have been reviewed in a multi-disciplinary meeting and deemed suitable for inclusion in the trial. Those enrolled will be asked to provide a sample of their pre-existing or upcoming cancer biopsy tissue. The tissue will be collected at the time of the routine endoscopic procedure, or from the existing tissue sample stored at the hospital. Then, 6 months after providing the tissue sample, participants will be called by a member of the study team for telephone interview asking about disease progress and diagnosis. Additionally, information related to advanced biliary cancer diagnosis will be directly collected from medical records for the 12 month period after providing the tissue sample.

It is hoped this research will show that comprehensive molecular profiling (CMP) on samples obtained /biopsies from routine diagnostic tests is able to perform comprehensive molecular profiling of advanced biliary tract cancer, and improve the detail on the profile and accuracy of cancer diagnosis.

Trial website

Not yet established.

Trial related presentations / publications

Public notes

The trial will be open to any patients who meet the inclusion criteria. Patients can be referred from outside of the main selected involved centres.

Related publications:

Aguirre AJ, N. J. (2018). Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov, 8(9):1096–1111.

Aung KL, F. S. (2018). Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. Clin Cancer Res, 24(6):1344–1354. doi:10.1158/1078-0432.
Australian Government Cancer. (2019). Pancreatic Cancer. Retrieved from Pancreatic cancer in Australia statistics: https://pancreatic-cancer.canceraustralia.gov.au/statistics

Berry W, A. E. (2017). Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity in KRAS wild-type tumors. Int J Cancer, 140(10):2331–2343.

Biankin AV, H. T. (2011). Somatic variation and cancer: therapies lost in the mix. Hum Gene, 130(1):79–91.

Cao, J., Hu, J., Liu, S., Meric-Bernstam, F., Abdel-Wahab, R., Xu, J., . . . al., e. (2020). Intrahepatic Cholangiocarcinoma: Genomic Heterogeneity Between Eastern andWestern Patients. JCO Precis. Oncol., 557–569.

Chantrill LA, N. A. (2015). Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) Trial. Clin Cancer Res, 21(9):2029–2037.

Churi, C., Shroff, R., Wang, Y., Rashid, A., Kang, H., Weatherly, J., . . . al., e. (2014). Mutation profiling in cholangiocarcinoma: Prognostic and therapeutic implications. PLoS ONE , 9, e115383.

Eisenhauer E A et al. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer, 228-247.

Fisher KE, Z. L. (2016). Clinical Validation and Implementation of a Targeted Next-Generation Sequencing Assay to Detect Somatic Variants in Non-Small Cell Lung, Melanoma, and Gastrointestinal Malignancies. J Mol Diagn, 18(2):299–315.

Fuccio L, H. C. (2013). The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest Endosc, 78(4):596–608.

Golan T, H. P. (2019). Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med, 381(4):317–327.

Golan T, K. Z. (2014). Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer, 111(6):1132–1138.

Jennings LJ, A. M. (2017). Guidelines for Validation of Next-Generation Sequencing-Based Oncology Panels: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn, 19(3):341–365.

Lim SM, Y. J. (2017). Rare Incidence of ROS1 Rearrangement in Cholangiocarcinoma. Cancer Res Treat., 185-192.

Lordick, F; Goldstein, D; Chantrill, L A et al. (2017). Current challenges in optimizing systemic therapy for patients with pancreatic cancer: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty. Expert Review of Anticancer therapy , 951-964.

Moore DA, K. M. (2019). Prospective analysis of 895 patients on a UK Genomics Review Board. ESMO Open, 4(2):e000469.

Ogura T, Y. K. (2013). Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol, 48(5):640–646.

Perez EA, R. E. (2011). Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol, 29(25):3366–3373.

Rahman, S. H., Urquhart, R., & Molnari, M. (2017). Neoadjuvant therapy for resectable pancreatic cancer. World Journal of Gastrointestinal Oncology, 457-465.

Singhi AD, G. B. (2019). Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers. Gastroenterology, 156(8):2242–2253.e4.

van de Haar J, H. L. (2019). Advancing molecular tumour boards: highly needed to maximise the impact of precision medicine. ESMO Open, 4(2):e000516.

Witkiewicz AK, M. E. (2015). Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun, 6:6744.

Wolpin BM, R. C. (2014). Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nature Genetics, 46(9):994–1000.

Contacts

Principal investigator

Name

Dr Daniel Croagh

Address

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

Australia

Phone

+61 0428 121 121

Fax

+61 3 9543 3805

daniel.croagh@monashhealth.org

Contact person for public queries

Name

Kathryn Goss

Address

Clinical Research and Data Coordinator / Endoscopy & Upper Gastrointestinal Surgery
246 Clayton Road, Clayton 3168 Victoria

Country

Australia

Phone

+61 3 9543 5311

Fax

+61 3 95433805

kathryn.goss@monashhealth.org

Contact person for scientific queries

Name

Daniel Croagh

Address

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

Australia

Phone

+61 0428121121

Fax

+61 3 9543 3805

daniel.croagh@monashhealth.org

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 (daniel.croagh@monashhealth.org)

What supporting documents are/will be available?

Doc. No.	Type	Other Details	Attachment
16621	Study protocol	ACME ABC Study Protocol submitted the HREC for rev... [More Details]	384379-(Uploaded-14-07-2022-17-12-26)-Study-related document.pdf
16622	Informed consent form	For ACME ABC trial	384379-(Uploaded-15-07-2022-22-26-14)-Study-related document.docx
16623	Ethical approval	Completed documentation attached	384379-(Uploaded-01-03-2023-15-55-53)-Study-related document.pdf

Results publications and other study-related documents

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