The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12624000078550
Ethics application status
Approved
Date submitted
21/11/2023
Date registered
30/01/2024
Date last updated
30/01/2024
Date data sharing statement initially provided
30/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
PhaRmacogEnomiC medIcines optimiSatIon for peOple with caNcer – a multicentre teletrial enabled Interrupted Time Series trial (PRECISION-ITS): A nested cohort substudy evaluating the safety & efficacy of 5-Fluorouracil Therapeutic Drug Monitoring in patients with metastatic/unresectable colorectal cancer.
Scientific title
PhaRmacogEnomiC medIcines optimiSatIon for peOple with caNcer – a multicentre teletrial enabled Interrupted Time Series trial (PRECISION-ITS): A nested cohort substudy evaluating the safety & efficacy of 5-Fluorouracil Therapeutic Drug Monitoring in patients with metastatic/unresectable colorectal cancer.
Secondary ID [1] 310978 0
MRFMMIP000011
Universal Trial Number (UTN)
Trial acronym
PRECISION-ITS
Linked study record
Linked to the primary trial:
1. PhaRmacogEnomiC medIcines optimiSatIon for peOple with caNcer – a multicentre teletrial enabledInterrupted Time Series trial (PRECISION-ITS): Medication safety outcomes in the Pharmacogenomics primary study and discovery program

Health condition
Health condition(s) or problem(s) studied:
Metastatic or unresectable colorectal cancer 332063 0
Condition category
Condition code
Cancer 328791 328791 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Public Health 329059 329059 0 0
Health service research

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is combined TDM and PGx-guided 5-FU prescribing.

5-FU TDM results, including recommended dose adjustments based on exposure levels (AUC), will be provided to the treating clinician based on the International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5-Fluorouracil Therapy. It is the decision of the clinician to implement/not implement dose changes after considering both exposure levels and other clinical factors such as observed toxicities and treatment intent/patient goals of care. TDM will commence from the patient’s first chemotherapy cycle and will be repeated at consecutive chemotherapy cycles of 5-FU until the target AUC is reached (20-30mg – h/L). Dosing recommendations will be based on single timepoint blood sample collection 18-40hours after commencement of infusional 5-FU. At trial commencement this will be based on peripheral blood sample results, with the aim for within trial validation and conversion to finger prick blood sampling. The first set of samples (consisting of 2 finger prick blood samples) will be self-collected by participants 3-17 hours after commencement of infusional 5-FU. The second set of samples (consisting of 1 peripheral + 2 finger prick blood samples) will be collected by qualified site staff 18-40 hours after commencement of infusional 5-FU to ensure viable samples are consistently collected and to allow for feasibility assessments of patient self-testing. Patients will receive a TDM self-testing kit (designed specifically for this substudy) and education from the pharmacogenomics pharmacist on how to use the kit. Finger prick blood samples will be collected with a Volumetric Absorptive Microsampling (VAMS) device and dried plasma separation card.

Participants recruited in this substudy will also participate in the PRECISION-ITS primary PGx trial and undergo PGx testing/prescribing/clinical follow up (as per the primary PGx trial), but will have additional trial visits due to TDM. Participants enrolled in Time Series 1 and 2 in the primary PGx trial will be able to participate in this substudy if they are receiving infusional 5-FU for metastatic/unresectable colorectal cancer. In the primary PGx trial, Time Series 2 will commence 3-4 months after accrual to Time Series 1 is completed.
Intervention code [1] 327409 0
Early detection / Screening
Intervention code [2] 327410 0
Treatment: Other
Intervention code [3] 327411 0
Behaviour
Comparator / control treatment
There will be 2 historic comparator/control treatments, which reflect standard care practices for 5-FU prescribing:

1. Control 1 = BSA/PGx-guided prescribing for 5-FU without TDM. Patients within this control group would have received this intervention for various 5-FU-based chemotherapy regimens with or without radiotherapy between 7 Jan 2021 and 25 Feb 2022 in the PACIFIC-PGx trial (ACTRN12621000251820), or for fluoropyrimidine-based anticancer therapy with or without radiotherapy/other chemotherapeutic agents between 30 April 2015 and 21 Dec 2017 in the trial conducted by Henricks et al (NCT02324452).

2. Control 2 = BSA-guided prescribing for 5-FU without TDM and without PGx for various 5-FU-based chemotherapy regimens with or without radiotherapy/other chemotherapeutic agents, from previously published, prospective clinical trials with no limitation relating to year of treatment. Trials included will be dependent on availability of required datapoints.
Control group
Historical

Outcomes
Primary outcome [1] 336599 0
Overall Response Rates (ORR) to cancer treatment in patients with metastatic/unresectable colorectal cancer receiving infusional 5-FU.
Timepoint [1] 336599 0
12 weeks after commencement of systemic anticancer treatment.
Secondary outcome [1] 428925 0
5-FU therapeutic drug levels within target range (AUC equal to 20-30mg - h/L).
Timepoint [1] 428925 0
First 5-FU chemotherapy cycle (nil TDM), and last cycle of 5-FU utilising TDM.
Secondary outcome [2] 428928 0
Adverse events (clinician reported)
Timepoint [2] 428928 0
12 weeks after commencement of systemic anticancer treatment
Secondary outcome [3] 428932 0
Adverse medicines events (patient reported)
Timepoint [3] 428932 0
12 weeks after commencement of systemic anticancer treatment
Secondary outcome [4] 428933 0
Feasibility of patients to administer at-home TDM self-testing (finger prick blood samples)
Timepoint [4] 428933 0
Last cycle of 5-FU utilising TDM among consecutively recruited patients undergoing both peripheral blood sampling and at home finger-prick sampling.
Secondary outcome [5] 428934 0
Feasibility of TDM testing
Timepoint [5] 428934 0
12 weeks after commencement of systemic anticancer treatment
Secondary outcome [6] 428937 0
Acceptability of TDM testing
Timepoint [6] 428937 0
12 weeks after commencement of systemic anticancer therapy
Secondary outcome [7] 428938 0
Feasibility of 5-FU TDM-optimised prescribing
Timepoint [7] 428938 0
12 weeks after commencement of systemic anticancer treatment
Secondary outcome [8] 428941 0
Acceptability of TDM dose recommendations (including uptake/timeliness)
Timepoint [8] 428941 0
12 weeks after commencement of systemic anticancer therapy .
Secondary outcome [9] 428942 0
Acceptability of pharmacist education for 'at home' 5-FU TDM testing (finger prick blood samples).
Timepoint [9] 428942 0
12 weeks after commencement of systemic anticancer therapy.
Secondary outcome [10] 428943 0
Validation of 5-FU dosing algorithms for finger prick blood samples.
Timepoint [10] 428943 0
Last cycle of 5-FU utilising TDM for the ~50th consecutively recruited patient.
Secondary outcome [11] 429970 0
ORR at 12 months
Timepoint [11] 429970 0
12 months after commencement of systemic anticancer therapy
Secondary outcome [12] 429972 0
Overall survival (OS) rate at 12 months.
Timepoint [12] 429972 0
12 months after commencement of systemic anticancer therapy
Secondary outcome [13] 429973 0
OS at 12 months
Timepoint [13] 429973 0
12 months after commencement of systemic anticancer therapy
Secondary outcome [14] 429974 0
Progression free survival (PFS) at 12 months
Timepoint [14] 429974 0
12 months after commencement of systemic anticancer therapy
Secondary outcome [15] 430142 0
Disease Control Rate (DCR) at 12 months
Timepoint [15] 430142 0
12 months after commencement of systemic anticancer therapy
Secondary outcome [16] 430143 0
Duration Overall Response (DOR) at 12 months
Timepoint [16] 430143 0
12 months after commencement of systemic anticancer therapy
Secondary outcome [17] 430144 0
Duration Disease Control (DDC) at 12 months
Timepoint [17] 430144 0
12 months after commencement of systemic anticancer therapy

Eligibility
Key inclusion criteria
Inclusion Criteria:
1. Aged 18 years or older
2. Metastatic or unresectable colorectal cancer commencing first-line 5-FU based systemic anticancer therapy or 5-FU based systemic anticancer therapy with first exposure to irinotecan (utilised first or subsequent line); prior treatment for early stage disease permitted.
3. Diagnostic work-up and treatment planned to be undertaken at participating trial site.
4. Patient has capacity to provide consent using the ethics approved PICF, and has provided written informed consent.
5. Patient and/or carer can complete patient surveys
6. Study enrolment limit has not been reached
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
1. Commenced systemic anticancer therapy.
2. Referral to participating trial site for second opinion only, with no intent for treatment at the participating site.
3. Patients receiving a pharmacogenomics drug of interest (Appendix 1) as an investigational medicinal product in another interventional clinical drug trial that prohibits concurrent enrolment (as part of eligibility or PI’s discretion), or that represents an unreasonable burden of patient participation at the discretion of the patient or investigator.
4. Diagnosis of neuroendocrine cancer (due to differences in treatment pathways and routine follow-up schedules).
5. Patient is receiving HIPEC (due to differences in treatment pathways and routine follow-up schedules).
6. Does not meet inclusion criteria

Study design
Purpose of the study
Treatment
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
Other
Other design features
Interrupted time series trial where participants in Time Series 1 and 2 of the 5-FU TDM substudy will receive study intervention of combined TDM/PGx 5-FU prescribing, and be compared to historical cohorts from previous trials with standard care 5-FU prescribing practices.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The 5-FU TDM nested cohort study is powered to demonstrate a difference in overall response rate (ORR) (primary endpoint) and 5-FU drug concentration within target therapeutic range (secondary endpoint),among individuals treated with infusional 5-FU with or without radiotherapy and other systemic agents for unresectable or metastatic colorectal cancer with TDM-augmented pharmacogenomics prescribing (PRECISION-ITS Time Series 1 & 2) versus 1) pharmacogenomics and body surface area prescribing(historic cohort 1) and 2) body surface area prescribing without pharmacogenomics or TDM (historic cohort 2).

The Pharmacogenomics + TDM prescribing arm (intervention) will come from the PRECISION ITS trial (both time series). The Pharmacogenomics + BSA prescribing arm (control 1) will come from pooled historic cohorts (prospective studies). The BSA prescribing arm (control 2) will come from pooled historic cohorts (prospective studies dependent on availability of required data-points and representation of final included regimens).

A sample size of 400 patients (200 PGx and 200 PGx + TDM) will provide 80% power to detect a minimum 15% absolute increase in the primary endpoint of ORR (two-sided a equal to 5%, 50%, 65%), allowing for 10% drop-out. Calculation is based on 50% ORR without TDM as the lowest likely ORR in our real-world unresectable or metastatic colorectal cancer cohort, based on published literature requiring the largest sample size. Allowing this sample size will provide sufficient power (80%) for an ORR between 50-70%. The target 15% absolute increase in ORR was selected as a clinically meaningly difference and is based on minimum observed improvements from previous 5-FU TDM studies.

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)
VIC
Recruitment hospital [1] 25854 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 25855 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [3] 25856 0
Border Medical Oncology - Albury
Recruitment hospital [4] 25857 0
Goulburn Valley Health - Shepparton campus - Shepparton
Recruitment hospital [5] 25858 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [6] 25859 0
South West Healthcare - Warrnambool - Warrnambool
Recruitment hospital [7] 25860 0
Mildura Base Hospital - Mildura
Recruitment hospital [8] 25861 0
Latrobe Regional Hospital - Traralgon
Recruitment postcode(s) [1] 41681 0
3000 - Melbourne
Recruitment postcode(s) [2] 41682 0
3550 - Bendigo
Recruitment postcode(s) [3] 41683 0
2640 - Albury
Recruitment postcode(s) [4] 41684 0
3630 - Shepparton
Recruitment postcode(s) [5] 41685 0
3220 - Geelong
Recruitment postcode(s) [6] 41686 0
3280 - Warrnambool
Recruitment postcode(s) [7] 41687 0
3500 - Mildura
Recruitment postcode(s) [8] 41688 0
3844 - Traralgon

Funding & Sponsors
Funding source category [1] 315237 0
Hospital
Name [1] 315237 0
Peter MacCallum Cancer Centre
Country [1] 315237 0
Australia
Funding source category [2] 315241 0
Government body
Name [2] 315241 0
Department of Health and Aged care (Medical research future fund)
Country [2] 315241 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan St Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 317269 0
None
Name [1] 317269 0
Address [1] 317269 0
Country [1] 317269 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314161 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 314161 0
Ethics committee country [1] 314161 0
Australia
Date submitted for ethics approval [1] 314161 0
12/09/2023
Approval date [1] 314161 0
30/10/2023
Ethics approval number [1] 314161 0
HREC/101174/PMCC (23/149)

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

Contacts
Principal investigator
Name 130634 0
Dr Marliese Alexander
Address 130634 0
Peter MacCallum Cancer Centre - Pharmacy Department, 305 Grattan St, Melbourne VIC 3000
Country 130634 0
Australia
Phone 130634 0
+61385596137
Fax 130634 0
Email 130634 0
Contact person for public queries
Name 130635 0
Vivian Shen
Address 130635 0
Peter MacCallum Cancer Centre - Pharmacy Department, 305 Grattan St, Melbourne VIC 3000
Country 130635 0
Australia
Phone 130635 0
+61385595628
Fax 130635 0
Email 130635 0
Contact person for scientific queries
Name 130636 0
Vivian Shen
Address 130636 0
Peter MacCallum Cancer Centre - Pharmacy Department, 305 Grattan St, Melbourne VIC 3000
Country 130636 0
Australia
Phone 130636 0
+61385595628
Fax 130636 0
Email 130636 0

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Shared data will be limited to the data within the trial dataset approved by the PRECISION-ITS steering committee and sponsor.
When will data be available (start and end dates)?
Data will be available 2 years after publication of primary results.
Available to whom?
Researchers whose proposed use of the data has been approved.
Available for what types of analyses?
Meta analyses
How or where can data be obtained?
By request to the CPI ([email protected]) or co-principal investigator ([email protected]) and signed data access agreement.


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.