PhaRmacogEnomiC medIcines optimiSatIon for peOple with caNcer – a multicentre teletrial enabled Interrupted Time Series trial (PRECISION-ITS): Pharmacogenomics primary study and discovery program

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.