Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000079549
Ethics application status
Approved
Date submitted
11/10/2023
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): Pharmacogenomics primary study and discovery program
Scientific title
PhaRmacogEnomiC medIcines optimiSatIon for peOple with caNcer – a multicentre teletrial enabled Interrupted Time Series trial (PRECISION-ITS): Medication safety outcomes in the Pharmacogenomics primary study and discovery program
Secondary ID [1] 310692 0
MRFMMIP000011
Universal Trial Number (UTN)
Trial acronym
PRECISION-ITS
Linked study record
Linked to the following substudies:
1. PRECISION-ITS: Pharmacogenomics Education & Implementation Program for Pharmacists
2. PRECISION-ITS: A nested cohort substudy evaluating the safety & efficacy of 5-Fluorouracil Therapeutic Drug Monitoring in patients

Health condition
Health condition(s) or problem(s) studied:
Cancer and other malignant neoplasms 331658 0
Condition category
Condition code
Cancer 328376 328376 0 0
Any cancer
Public Health 329046 329046 0 0
Health service research

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pharmacogenomics (PGx) primary study:
The intervention group will be participants recruited in Time Series 2. The intervention in Time Series 2 is expanded PGx prescribing (including, but not limited to DPYD & UGT1A1) according to Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, Royal Dutch Pharmacogenetics Working Group (DPWG) guidelines, or other clinical evidence (i.e. evidence from Time Series 1 or from systemic literature that has sufficient evidence to support PGx prescribing). CPIC guidelines for specific medicines can be accessed via: https://cpicpgx.org/guidelines/. DPWG guidelines for specific medicines can be accessed via: https://www.pharmgkb.org/guidelineAnnotations. Any PGx dosing recommendations used in Time Series 2 will be endorsed by the trial steering committee and approved by the human ethics human and research committee (HREC). PGx-expanded prescribing will be limited to medications commonly used in the treatment or supportive care of cancer (referred to as 'Included Medicines'). Time Series 2 will open 3-4 months after Time Series 1 accrual is completed.

One DNA sample will be collected (via buccal/blood swab) for standard pharmacogenomics panel testing (NATA-approved test) from all patients in both time series. Results will be reported by the testing laboratory to the pharmacogenomics pharmacist. Broad panel PGx results (including, but not limited to DPYD & UGT1A1) will be shared with the patient/treating clinician and reported by the PGx pharmacist in the patient’s medical record in real-time (within 30 days before commencement of systemic anticancer therapy). PGx dosing recommendations will be provided as a recommendation only. It will remain the responsibility and choice of the treating clinician to implement/not implement dosing recommendations based on broad panel genotyping results, and to manage all aspects of cancer treatment.

All patients will be followed up 5 times for symptom burden and toxicity within 12 weeks after commencement of systemic anticancer therapy. At each follow up visit, the pharmacogenomics pharmacist will conduct symptom/toxicity assessments, medication reconciliation and provide advice on symptom/toxicity management. Hospitalizations (including any admissions in between trial visits), serious adverse events, and their associations with toxicity or inefficacy from an 'Included Medicine' will be assessed throughout the whole 12-week primary follow up period.

PGx Discovery Program:
A discovery program consisting of optional pharmacokinetic (PK)/pharmacodynamic (PD) substudies, a PGx global screening array (Illumina array) and optional whole exome sequencing (WES) will run concurrently alongside the primary PGx trial.

The same DNA sample taken for the standard PGx panel in the primary PGx study will also be analysed via the Illumina array for all patients. Gene test results from the Illumina array will be used to evaluate novel genomic predictors of medicines toxicity beyond the standard PGx panel, and to prospectively validate the impact of unproven PGx variants that have been associated with severe medicines toxicities in the literature. Patients who experience grade 3 or higher adverse medicine events and who do not have actionable PGx variants from the standard PGx panel, will also be given the option to provide an additional DNA sample (via buccal/blood swab) for WES. WES will be conducted to identify novel PGx variants associated with medicines toxicity beyond the standard PGx panel. Results from the Illumina array and WES will not be shared with patients or treating clinicians since they do not have actionable medication prescribing recommendations and will not impact clinical care.

PK/PD assessments for specific medicines of interest will be used to assess the correlation between PK and genotype-predicted phenotypes of pharmacogenes, and the association between phenotypes, medicines exposure and medicines response. These substudies will be available in both Time Series 1 and 2; with an aim to generate PGx dosing algorithms for specific medicines of interest in Time Series 2. Patients will be eligible to participate in these optional PK/PD substudies if they are having treatment with a medicine of interest at the time of PK sampling and are receiving anticancer treatment at the primary site (Peter MacCallum Cancer Centre). Patients may consent to multiple PK substudies if they are being treated with multiple medicines of interest. Irinotecan PKs will only be available to 5-FU TDM participants, Sacituzumab govitecan PKs will only be available to patients not participating in 5-FU TDM.

Medicines of interest include: Sacituzumab govitecan, Irinotecan, Netupitant/Palonosetron (oral), Morphine (oral controlled release), Oxycodone (oral controlled release), Fentanyl (slow-release patch) and Esomeprazole (oral). PK/PD results will not be reported to patients or treating clinicians since the reliability of these results for medication management is unclear and will not impact clinical care.

The number of blood samples and participant activities required will vary according to the medicine of interest:
- Irinotecan PKs: 1 peripheral blood sample taken on Day 1 and Day 2 of a single chemotherapy cycle. If the patient is participating in 5-Fluorouracil therapeutic drug monitoring (TDM) at the time of PK sampling, an additional sample is not required since the same sample used for TDM will also be used for irinotecan PK.
- Sacituzumab govitecan PKs: 1 peripheral blood sample taken on Day 1, Day 2 and Day 8 of a single chemotherapy cycle
- Netupitant/Palonosetron PKs: 2 peripheral blood samples taken on Day 1 of a single chemotherapy cycle, and option for patients to provide additional peripheral blood samples on Day 2 and Day 3.
- Esomeprazole PKs: 3 peripheral blood samples taken on a single day between Week 4-9.
- Morphine or Oxycodone PK/PDs: 6 peripheral blood samples and 3 finger prick blood samples (via volumetric absorptive microsampling device) taken on a single day between Week 5-9. Patients will be asked to complete an opioid diary in the week preceding PK testing.
- Fentanyl PK/PDs: 2 peripheral blood samples and 1 finger prick blood sample (via volumetric absorptive microsampling device) taken on a single day between Week 5-9. Patients will be asked to complete an opioid diary in the week preceding PK testing.
Intervention code [1] 327119 0
Early detection / Screening
Intervention code [2] 327120 0
Treatment: Drugs
Intervention code [3] 327121 0
Treatment: Other
Comparator / control treatment
PGx primary study:
The 'control' group will be participants recruited in Time Series 1. Enrolment to Time Series 1 will occur over 10-12 months, followed by Time Series 2 (which will open 3-4 months after Time Series 1 accrual is completed). Time Series 1 is an observation time series with standard of care pharmacogenomic testing and prescribing. Standard of care testing and prescribing is described under this protocol as limited pharmacogenomic testing and decision support (DPYD for fluoropyrimidines and UGT1A1 for irinotecan). Clinician decision support will be according to Peter Mac institutional guidelines, which align with CPIC recommendations for DPYD and DPWG recommendations for UGT1A1. Dosing recommendations will be provided as a recommendation only. It will remain the responsibility and choice of the treating clinician to implement/not implement dosing recommendations, and to manage all aspects of cancer treatment.

One DNA sample will be collected (via buccal/blood swab) for standard pharmacogenomics panel testing (NATA-approved test) from all patients in both time series. Unlike Time Series 2, only DPYD & UGT1A1 genotype results and associated PGx dosing recommendations will be shared with the patient/treating clinician and reported by the PGx pharmacist in the patient’s medical record in real-time (within 30 days before commencement of systemic anticancer therapy). PGx dosing recommendations will be provided as a recommendation only. It will remain the responsibility and choice of the treating clinician to implement/not implement dosing recommendations based on genotype results, and to manage all aspects of cancer treatment. Genotype results other than DPYD & UGT1A1 will be reported to patients/treating clinicians at or after the end of the 12-week primary follow up period.

Like Time Series 2, all patients will be followed up 5 times for symptom burden and toxicity within 12 weeks after commencement of systemic anticancer therapy. At each follow up visit, the pharmacogenomics pharmacist will conduct symptom/toxicity assessments, medication reconciliation and provide advice on symptom/toxicity management. Hospitalizations (including any admissions in between trial visits), serious adverse events, and their associations with toxicity or inefficacy from an 'Included Medicine' will be assessed throughout the whole 12-week primary follow up period.

PGx discovery program:
This program will also be available to patients in the control group. The same DNA sample taken for the standard PGx panel in the primary PGx study will also be analysed via the Illumina array for all patients. Gene test results from the Illumina array will be used to evaluate novel genomic predictors of medicines toxicity beyond the standard PGx panel, and to prospectively validate the impact of unproven PGx variants that have been associated with severe medicines toxicities in the literature. Patients who experience grade 3 or higher adverse medicine events and who do not have actionable PGx variants from the standard PGx panel, will also be given the option to provide an additional DNA sample (via buccal/blood swab) for WES. WES will be conducted to identify novel PGx variants associated with medicines toxicity beyond the standard PGx panel. Results from the Illumina array and WES will not be shared with patients or treating clinicians since they do not have actionable medication prescribing recommendations and will not impact clinical care.

PK/PD assessments for specific medicines of interest will be used to assess the correlation between PK and genotype-predicted phenotypes of pharmacogenes, and the association between phenotypes, medicines exposure and medicines response. These substudies will be available in both Time Series 1 and 2; with an aim to generate PGx dosing algorithms for specific medicines of interest in Time Series 2. Patients will be eligible to participate in these optional PK/PD substudies if they are having treatment with a medicine of interest at the time of PK sampling and are receiving anticancer treatment at the primary site (Peter MacCallum Cancer Centre). Patients may consent to multiple PK substudies if they are being treated with multiple medicines of interest. Irinotecan PKs will only be available to 5-FU TDM participants, Sacituzumab govitecan PKs will only be available to patients not participating in 5-FU TDM.

Medicines of interest include: Sacituzumab govitecan, Irinotecan, Netupitant/Palonosetron (oral), Morphine (oral controlled release), Oxycodone (oral controlled release), Fentanyl (slow-release patch) and Esomeprazole (oral). PK/PD results will not be reported to patients or treating clinicians since the reliability of these results for medication management is unclear and will not impact clinical care.

The number of blood samples and participant activities required will vary according to the medicine of interest:
- Irinotecan PKs: 1 peripheral blood sample taken on Day 1 and Day 2 of a single chemotherapy cycle. If the patient is participating in 5-Fluorouracil therapeutic drug monitoring (TDM) at the time of PK sampling, an additional sample is not required since the same sample used for TDM will also be used for irinotecan PK.
- Sacituzumab govitecan PKs: 1 peripheral blood sample taken on Day 1, Day 2 and Day 8 of a single chemotherapy cycle
- Netupitant/Palonosetron PKs: 2 peripheral blood samples taken on Day 1 of a single chemotherapy cycle, and option for patients to provide additional peripheral blood samples on Day 2 and Day 3.
- Esomeprazole PKs: 3 peripheral blood samples taken on a single day between Week 4-9.
- Morphine or Oxycodone PK/PDs: 6 peripheral blood samples and 3 finger prick blood samples (via volumetric absorptive microsampling device) taken on a single day between Week 5-9. Patients will be asked to complete an opioid diary in the week preceding PK testing.
- Fentanyl PK/PDs: 2 peripheral blood samples and 1 finger prick blood sample (via volumetric absorptive microsampling device) taken on a single day between Week 5-9. Patients will be asked to complete an opioid diary in the week preceding PK testing.
Control group
Active

Outcomes
Primary outcome [1] 336239 0
Patient-reported (PRO-CTCAE) adverse medicines events associated with actionable medicine-gene interactions (Pharmacogenomics primary study).
Timepoint [1] 336239 0
12 weeks after commencement of systemic anticancer treatment
Primary outcome [2] 336583 0
Clinician-reported (CTCAE) adverse medicines events associated with actionable medicine-gene interactions (Pharmacogenomics primary study).
Timepoint [2] 336583 0
12 weeks after commencement of systemic anticancer treatment
Secondary outcome [1] 427494 0
Secondary outcome (Pharmacogenomics primary study): the prevalence of patient utilisation of Included Medicines.
Timepoint [1] 427494 0
12 weeks after commencement of systemic anticancer treatment.
Secondary outcome [2] 427495 0
Secondary outcome (Pharmacogenomics primary study - Time Series 1): the prevalence of actionable medicine-gene interactions for Included Medicines.
Timepoint [2] 427495 0
12 weeks after commencement of systemic anticancer treatment.
Secondary outcome [3] 427496 0
Secondary outcome (Pharmacogenomics primary study): the incidence of medication management interventions (dose adjustments and discontinuation due to toxicity/lack of efficacy) for included medicines.
Timepoint [3] 427496 0
12 weeks after commencement of systemic anticancer treatment.
Secondary outcome [4] 427497 0
Secondary outcome (Pharmacogenomics primary study): the incidence of hospitalisation (toxicity or symptom burden due to lack of efficacy) due to adverse medicines related events caused by included medicines.
Timepoint [4] 427497 0
12 weeks after commencement of systemic anticancer treatment
Secondary outcome [5] 427498 0
Secondary outcome (Pharmacogenomics primary study): the feasibility (including uptake/timeliness of testing) in relation to pharmacogenomics testing and prescribing by patients and health professionals participating in the PRECISION-ITS study.
Timepoint [5] 427498 0
Timeliness/Availability: baseline (at or up to 30 days before commencement of systemic anticancer treatment).
Uptake: 12 weeks after commencement of systemic anticancer therapy.
Secondary outcome [6] 427501 0
Secondary outcome (Pharmacogenomics primary study - Time Series 2): cost effectiveness of pharmacogenomics-optimised prescribing versus standard of care prescribing.
Timepoint [6] 427501 0
Baseline (Week 0), Week 1 (3-7 days after commencement of systemic therapy), Week 4, Week 8, Week 12 and Week 52,
Secondary outcome [7] 427502 0
Secondary outcome (Pharmacogenomics primary study - Time Series 2): Scalability of the pharmacogenomics program.
Timepoint [7] 427502 0
First assessment will occur at the end of Time Series 1.
Second assessment to occur end of Time Series 2.
Third assessment to occur at the end of the trial.
Secondary outcome [8] 427503 0
Secondary outcome (Pharmacogenomics primary study - Time Series 2): Pain control among patients receiving combined modality chemo-radiotherapy for head and neck or gastrointestinal cancers.
Timepoint [8] 427503 0
Baseline (Week 0), Week 1 (3-7 days after commencement of systemic therapy), Week 4, Week 5 (if patient is having chemoradiotherapy), Week 6 (if patient is having chemoradiotherapy), Week 7 (if patient is having chemoradiotherapy), Week 8, and Week 12,
Secondary outcome [9] 427504 0
Secondary outcome (Pharmacogenomics primary study - Time Series 2): Prescriber uptake of pharmacogenomics-guided dosing recommendations.
Timepoint [9] 427504 0
12 weeks are commencement of systemic anticancer therapy.
Secondary outcome [10] 427505 0
Secondary outcome (Pharmacogenomics primary study - Time Series 2): Reasons why prescribers do not implement pharmacogenomics-guided dosing recommendations.
Timepoint [10] 427505 0
12 weeks are commencement of systemic anticancer therapy.
Secondary outcome [11] 427701 0
Secondary outcome (discovery program substudy): Correlation of pharmacokinetic and genotype predicted phenotypes of pharmacogenes for specific medicines of interest.
Timepoint [11] 427701 0
Irinotecan, Sacituzumab govitecan & Netupitant/Palonosetron: 12 weeks after commencement of systemic anticancer therapy.
Morphine, oxycodone & fentanyl: 5-9 weeks after commencement of systemic anticancer therapy.
Esomeprazole: 4-9 weeks after commencement of systemic anticancer therapy.
Secondary outcome [12] 427704 0
Secondary outcome (discovery program substudy): Identification of novel genomic predictors of toxicity using the illumina global screening array and whole exome sequencing.
Timepoint [12] 427704 0
12 weeks after commencement of systemic anticancer therapy
Secondary outcome [13] 427705 0
Secondary outcome (Discovery program substudy): Validation of unproven pharmacogenomic variants associated with severe toxicities.
Timepoint [13] 427705 0
12 weeks after commencement of systemic anticancer therapy
Secondary outcome [14] 428894 0
Secondary outcome (Pharmacogenomics primary study): the prevalence of clinician prescribing of Included Medicines.
Timepoint [14] 428894 0
12 weeks after commencement of systemic anticancer therapy
Secondary outcome [15] 428895 0
Secondary outcome (Pharmacogenomics primary study): the acceptability of pharmacogenomics testing by patients and health professionals participating in the PRECISION-ITS study.
Timepoint [15] 428895 0
Uptake of PGx testing/Reasons for not consenting/timeliness/availability (points #1 to #5): Baseline (at or up to 30 days before commencement of systemic anticancer therapy).
Uptake of PGx dosing recommendations/acceptability (points #6 to #7): 12 weeks after commencement of systemic anticancer therapy
Secondary outcome [16] 429131 0
Secondary outcome (Pharmacogenomics primary study): the acceptability of pharmacogenomics-optimised prescribing by patients and health professionals participating in the PRECISION-ITS study.
Timepoint [16] 429131 0
12 weeks after commencement of systemic anticancer therapy.
Secondary outcome [17] 429987 0
PK of controlled release oral morphine
Timepoint [17] 429987 0
PK sampling to occur on any one day between Week 5 and 9. Sample 1 to be taken 2-4 hours post morning dose; Sample 2 to be taken 4-6 hours post morning dose; Sample 3 to be taken 6-8 hours post morning dose.
Secondary outcome [18] 429988 0
PK of controlled release oral oxycodone
Timepoint [18] 429988 0
PK sampling to occur on any one day between Week 5 and 9. Sample 1 to be taken 2-4 hours post morning dose; Sample 2 to be taken 4-6 hours post morning dose; Sample 3 to be taken 6-8 hours post morning dose.
Secondary outcome [19] 429989 0
PK of controlled release fentanyl patch
Timepoint [19] 429989 0
PK sampling to occur on any one day between Week 5 and 9. Sample to be taken at least 48 hours after last patch change.
Secondary outcome [20] 429990 0
PK of oral esomeprazole
Timepoint [20] 429990 0
PK sampling day to occur on any one day between Week 4 and 9. Sample 1 to be taken 2-4 hours post morning dose; Sample 2 to be taken 4-6 hours post morning dose; Sample 3 to be taken 6-8 hours post morning dose.
Secondary outcome [21] 429991 0
PK of Netupitant/Palonosetron
Timepoint [21] 429991 0
PK sampling day to occur at a single chemotherapy cycle (any cycle) when Netupitant/Palonosetron is administered as a pre-medication. Sample 1 to be taken 30-60mins post dose; Sample 2 to be taken 2-6 hours post dose; Sample 3 to be taken 18-40 hours post dose; Sample 4 to be taken 42-53 hours post dose.
Secondary outcome [22] 429992 0
PK of Sacituzumab govitecan
Timepoint [22] 429992 0
PK sampling day to occur at a single chemotherapy cycle (any cycle). Sample 1 to be taken 0-1 hour after end of Day 1 infusion; Sample 2 to be taken 16-28 hours after end of Day 1 infusion; Sample 3 to be taken any time before Day 8 infusion.
Secondary outcome [23] 429993 0
PK of Irinotecan
Timepoint [23] 429993 0
PK sampling day to occur at a single chemotherapy cycle (any cycle). Sample 1 to be taken 0-6 hours after end of infusion; Sample 2 to be taken 18-40 hours after end of infusion.

Eligibility
Key inclusion criteria
Inclusion Criteria for Patients not receiving 5-FU therapeutic drug monitoring (TDM):
1. Aged 18 years or older
2. Meets at least one criterion related to cancer diagnosis and treamtent:
2.1 UGI/LGI cancer commencing first-line systemic anticancer therapy with first exposure to 5-FU or , capecitabine, or systemic anticancer treatment with first exposure to irinotecan (utilised first or subsequent line) for any stage disease with curative or palliative intent (concurrent radiotherapy and other anticancer therapies permitted).
2.2 Breast cancer commencing any CDK4/6 inhibitor, capecitabine, or Sacituzumab govitecan in any line of therapy for any stage disease, with curative or palliative intent (concurrent hormone therapies and other anticancer therapies permitted).
2.3 Head and neck cancer commencing curative intent chemo-radiotherapy with high dose cisplatin (70mg/m2 or higher planned dose), with or without immunotherapy.
2.4 HL commencing treatment with ABVD-like or escalated BEACOPP-like pathways.
2.5 NHL commencing treatment with HyperCVAD, CODOX-M, or treatment containing high-dose methotrexate
2.6 CUP receiving treatment for presumed diagnosis of an included cancer and meeting treatment requirements specified for included cancers (2.1 to 2.5)
3. Diagnostic workup and treatment plan 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

Patients with metastatic/unresectable colorectal cancer receiving 5-FU TDM will also be included in the primary PGx study.

Inclusion Criteria for patients participating in 5-FU TDM:
1. Aged 18 years or older
2. Metastatic or unresectable colorectal cancer commencing first-line 5-FU based systemic anticancertherapy 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 writteninformed 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 for Patients not receiving 5-FU TDM:
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 PGx drug of interest (Appendix 1) as an investigational medicinal product in another interventional clinical drug trial that prohibits concurrent enrolment (as part of eligibility criteria or at 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. Patients receiving HIPEC (due to differences in treatment pathways and routine follow-up schedules).
6. Does not meet inclusion criteria

The same exclusion criteria apply for patients receiving 5-FU TDM.

Exclusion Criteria for patients receiving 5-FU TDM:
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 diff erences in treatment pathways and routine follow-upschedules).
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.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
ITS trial - pharmacogenomics primary study:
The PRECISION-ITS trial is powered to demonstrate a difference in adverse medicines events (AME) with Pharmacogenomic versus Standard of Care prescribing (Time Series 2 vs Time Series 1), among the subgroup of patients with actionable pharmacogenomics, defined as at least one actionable medicine:gene interaction for an included medicine. A sample size of 1470 patients (735 per Time Series) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of AME (two-sided a equal to 5%, 80% v 61%), allowing for 10% drop-out.

Calculation is based on a required minimum of 100 patients per group with actionable pharmacogenomics (+10 per group allowing 10% dropout). The target relative risk reduction reflects that achieved in the PREPARE international pharmacogenomics trial, which corresponds to a clinically meaningful ~20% absolute risk reduction. Based on interim data from the single centre study preceding this protocol (HREC/86638/PMCC), the frequency of actionable pharmacogenomics related to cancer/supportive care medications will be approximately 15% (110/735 patients enrolled per group).

PK/PD studies in PGx discovery program:
Dosing algorithms for supportive care medicines of interest (netupitant/palonosetron, esomeprazole, morphine, oxycodone and fentanyl) will be generated based on the relationship between genotype, measured phenotype, and observed clinical outcomes (efficacy/toxic effects) – algorithms will be described using descriptive statistics.

Associations between phenotypes and 1) medicines PK at steady state (area under the curve (AUC); 2) maximum concentration (Cmax); 3) medicines consumption (opioids only); and 4) clinical outcomes (efficacy and toxicity – PRO-CTCAE, CTCAE, Pain Assessments) will be reported by drug. For opiates, medicines consumption will be assessed by opiate dosing diary completed by participants in the 7 days leading up to pharmacokinetic blood testing.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/02/2024
Actual
Date of last participant enrolment
Anticipated
29/03/2026
Actual
Date of last data collection
Anticipated
31/08/2027
Actual
Sample size
Target
1470
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 25664 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 25665 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [3] 25666 0
Border Medical Oncology - Albury
Recruitment hospital [4] 25667 0
Goulburn Valley Health - Shepparton campus - Shepparton
Recruitment hospital [5] 25668 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [6] 25669 0
South West Healthcare - Warrnambool - Warrnambool
Recruitment hospital [7] 25670 0
Mildura Base Hospital - Mildura
Recruitment hospital [8] 25671 0
Latrobe Regional Hospital - Traralgon
Recruitment postcode(s) [1] 41487 0
3000 - Melbourne
Recruitment postcode(s) [2] 41488 0
3550 - Bendigo
Recruitment postcode(s) [3] 41489 0
2640 - Albury
Recruitment postcode(s) [4] 41490 0
3630 - Shepparton
Recruitment postcode(s) [5] 41491 0
3220 - Geelong
Recruitment postcode(s) [6] 41492 0
3280 - Warrnambool
Recruitment postcode(s) [7] 41493 0
3500 - Mildura
Recruitment postcode(s) [8] 41494 0
3844 - Traralgon

Funding & Sponsors
Funding source category [1] 314909 0
Hospital
Name [1] 314909 0
Peter MacCallum Cancer Centre
Country [1] 314909 0
Australia
Funding source category [2] 314946 0
Government body
Name [2] 314946 0
Department of Health and Aged care (Medical research future fund)
Country [2] 314946 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan St Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 317011 0
None
Name [1] 317011 0
Address [1] 317011 0
Country [1] 317011 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313902 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 313902 0
Ethics committee country [1] 313902 0
Australia
Date submitted for ethics approval [1] 313902 0
12/09/2023
Approval date [1] 313902 0
30/10/2023
Ethics approval number [1] 313902 0
HREC/101174/PMCC (23/149)

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

Contacts
Principal investigator
Name 129730 0
Dr Marliese Alexander
Address 129730 0
Peter MacCallum Cancer Centre - Pharmacy Department, 305 Grattan St, Melbourne VIC 3000
Country 129730 0
Australia
Phone 129730 0
+61385596137
Fax 129730 0
Email 129730 0
[email protected]
Contact person for public queries
Name 129731 0
Vivian Shen
Address 129731 0
Peter MacCallum Cancer Centre - Pharmacy Department, 305 Grattan St, Melbourne VIC 3000
Country 129731 0
Australia
Phone 129731 0
+61385595628
Fax 129731 0
Email 129731 0
[email protected]
Contact person for scientific queries
Name 129732 0
Vivian Shen
Address 129732 0
Peter MacCallum Cancer Centre - Pharmacy Department, 305 Grattan St, Melbourne VIC 3000
Country 129732 0
Australia
Phone 129732 0
+61385595628
Fax 129732 0
Email 129732 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?
Shared data will be limited to the data within the trial dataset approved by the PRECISION-ITS steering committee and sponsor. Services Australia data (PBS/MBS data) and CVDL data linkage data (hospitalisations) will not be shared.
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
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