Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000251820
Ethics application status
Approved
Date submitted
30/11/2020
Date registered
8/03/2021
Date last updated
24/03/2024
Date data sharing statement initially provided
8/03/2021
Date results information initially provided
20/03/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Pharmacogenomics guided dosing for fluoropyrimidine and irinotecan chemotherapies for patients with cancer (PACIFIC-PGx)
Scientific title
A multisite prospective study to implement and evaluate the feasibility of a Pharmacogenetics Screening Program for 5-fluorouracil, capecitabine and irinotecan chemotherapies in patients with cancer.
Secondary ID [1] 302901 0
None
Universal Trial Number (UTN)
U1111-1262-0278
Trial acronym
PACIFIC-PGx
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastrointestinal cancers 320220 0
Breast cancer 320221 0
Head and neck cancer 320222 0
Gynaecological cancers 320223 0
Urogenital cancers 320224 0
Condition category
Condition code
Cancer 317854 317854 0 0
Oesophageal (gullet)
Cancer 318426 318426 0 0
Breast
Cancer 318427 318427 0 0
Biliary tree (gall bladder and bile duct)
Cancer 318428 318428 0 0
Bladder
Cancer 318429 318429 0 0
Bowel - Anal
Cancer 318430 318430 0 0
Cervical (cervix)
Cancer 318431 318431 0 0
Head and neck
Cancer 318433 318433 0 0
Pancreatic
Cancer 318434 318434 0 0
Stomach

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention comprises of single time-point pharmacogenetics screening for:
1. DPYD gene test for patients newly commencing on 5-fluorouracil and capecitabine chemotherapy
2. UGT1A1*28 gene test for patients newly commencing on irinotecan chemotherapy

Genetic samples will be collected via blood draw or cheek swab. Interventions will be delivered by a pharmacogenetics pharmacist on referral from the treating medical oncologist. Screening occurs at single time point prior to commencement of 5-fluorouracil, capecitabine or irinotecan. Patients will be followed to cycle 3 of chemotherapy for adverse event, toxicity and health resource utilisation data, and to 12 months after commencement of chemotherapy for response and survival outcomes. All chemotherapy treatments will be administered (dose, route, frequency) according to standard guidelines at the treating institution. Treating clinicians will be provided chemotherapy dosing recommendations based on genetic screening according to protocol specified adjustments based on CPIC/DPWG guidelines, however it is it is the responsibility and choice of the treating clinician to implement/not implement dosing recommendations and to manage all aspects of cancer treatment. Decision to implement/ not implement will be recorded as part of trial outcomes.
The study includes 3 main timepoints:
1. TimePoint 1: Baseline visit - Referral details to Pharmacogenetic (PG) screening clinic, consent to PG program testing for DPYD gene +/- UGT1A1 gene testing +/- research sample collection
Demographics and clinical characteristics (medical, disease and treatment history)
Eastern Cooperative Oncology Group (ECOG) performance status
DNA sample (blood or cheek swab)
EQ-5D-5L questionnaire for health economic study (QALY) and EORTC QLQ-C30 (version 3) questionnaire will be collected.

TimePoint 2: Sample Collection - DNA sample (blood or cheek swab)
PG Program sample for DPYD gene +/- UGT1A1 gene testing +/- research sample collection). Note: Patients already completed SOC PG Screening Program (since December 2019) or will be enrolled in the Program will only have research sample taken if have provided consent. Research sample collection for new patients will be collected at a suitable time.

TimePoint 3: Follow-up visits which includes follow-up 1 to follow-up 6 as explained below:
Follow-up 1 (Pre C1D1 of chemotherapy): Pharmacogenetics Program Pharmacist discusses DPYD gene test results 7 to 10 days after collection of sample with the treating oncologist via email and/or phone call for dose adjustment recommendations and patient. Dose recommendation will be recommended according to the Clinical Pharmacogenetics Implementation Consortium (CPIC) updated guidelines 2018 for DPYD gene test, they have recommended if patients are poor metabolisers to avoid fluoropyrimidines. If patients are DPYD intermediate metabolisers - the CPIC recommendation is for a 50% dose reduction on the intended starting dose of fluoropyrimidine and for dose increases to be made from cycle 3 onwards, depending on tolerability of the first 2 cycles. For UGT1A1*28, dose adjustment will be recommended according to Dutch Pharmacogenetics Working Group (DPWG) 2018 updated guidelines they have precisely stated initial dose reduction of irinotecan by 30% in homozygous (*28/*28) poor metabolizer patients, and the dose can be increased, guided by the neutrophil count.

Follow-up 2 (C1D3-C1D7 of chemotherapy): the pharmacogenetics program pharmacist will follow up patients via telehealth or phone call (or in person if they are attending an appointment at primary site) 3 to 7 days post 5-FU or capecitabine Cycle 1 commencement, and coument toxicity data according to according to CTCAE v5.0 and check on adherence to capecitabine tablets. Assist and counsel patients on how to manage side effects and escalate to medical oncologist as required.
EQ-5D-5L questionnaire for health economic study (QALY), EORTC QLQ-C30 (version 3) questionnaire and Clinician and patient survey will be collected. Survey/ questionnaires to be completed at suitable time for patients/clinicians.

Follow-up 3 and 4 (Pre C2D1 of chemotherapy and Pre-C3D1): medical oncologist will document adverse effects according to CTCAE v5.0 prior to Cycle 2 and prior to Cycle 3 in patient medical record.
EQ-5D-5L questionnaire for health economic study (QALY) will be collected preC2 and pre-C3
EORTC QLQ-C30 (version 3) questionnaire will be collected at pre-C3

Follow-up 5 and 6 (at month 6) and (at month 12) : Treatment data, response and status will only be collected from the primary site.

The health economic data will be collected upto pre-C3 and patients who cease drug prior to pre C3D1 review will be followed for adverse events and cost data collection until equivalent pre C3D1 review date had they continued on the same treatment regimen. Toxicity data will be collected as per above specified timepoints and cancer and cancer treatment information will be collected during the study.
Intervention code [1] 319421 0
Early detection / Screening
Comparator / control treatment
None. Single arm design was chosen as a randomised trial comparing pharmacogenetic screening to no pharmacogenetic screening was deemed unethical. Historical control group with no pharmacogenetic screening to be utilised for economic analyses.
Control group
Historical

Outcomes
Primary outcome [1] 325859 0
Operational feasibility: proportion of patients with pre-emptive pharmacogenetic screening among all patients newly treated with 5-fluorouracil, capecitabine and/or irinotecan chemotherapies).
Timepoint [1] 325859 0
12-months
Secondary outcome [1] 389357 0
Operational feasibility: proportion of patients enrolled for pharmacogenetic screening program for whom gene test results were analysed and reported prior to cycle 1 of fluoropyrimidine and irinotecan chemotherapies, overall and by treatment site.
This outcome will be assessed using treatment site records.
Timepoint [1] 389357 0
12-months
Secondary outcome [2] 389358 0
Operational feasibility: proportion of patients enrolled for pharmacogenetic screening program for whom cheek swab samples give inconclusive assay results requiring subsequent blood sampling.
This outcome will be assessed using laboratory data.
Timepoint [2] 389358 0
12-months
Secondary outcome [3] 389360 0
Operational feasibility: proportion of patients enrolled for pharmacogenetic screening program harbouring one of the five established DPYD gene variants requiring fluoropyrimidine dose adjustment.
This outcome will be assessed using laboratory data and treatment site records.
Timepoint [3] 389360 0
12-months
Secondary outcome [4] 389362 0
Operational feasibility: proportion of patients enrolled for pharmacogenetic screening program harbouring homozygous UGT1A1*28 requiring irinotecan dose adjustment.
This outcome will be assessed using laboratory data and treatment site records.
Timepoint [4] 389362 0
12-months
Secondary outcome [5] 391359 0
Operational feasibility: average time from sample collection to referring clinician being informed of the gene test results.
This outcome will be assessed using treatment site records
Timepoint [5] 391359 0
12-months
Secondary outcome [6] 391360 0
Operational feasibility: proportion of clinicians who make the recommended dose changes as per CPIC and DPWG guidelines.
This outcome will be assessed using treatment site records
Timepoint [6] 391360 0
12-months
Secondary outcome [7] 391361 0
Operational feasibility: proportion of patients with subsequent up-titration of dose following initial dose reduction.
This outcome will be assessed using treatment site records
Timepoint [7] 391361 0
12-months
Secondary outcome [8] 391362 0
Operational feasibility: end-user acceptance of the Pharmacogenetics Screening Program (clinician/patient survey).
Clinician/patient survey is designed specifically for this study.
Timepoint [8] 391362 0
12-months
Secondary outcome [9] 391363 0
Operational feasibility: cost for the fluoropyrimidine treatment and management of patients enrolled in the Pharmacogenetics Screening Program compared to non-screening strategies in historical controls.
This outcome will be assessed by the following:
1. To conduct cost-effectiveness analysis (CEA) to determine if the PG Screening Program is cost-effective compared to no screening program in terms of adverse events saved from a health care payer perspective.
2. To conduct a cost-utility analysis (CUA) to determine if the PG Screening Program is cost-effective compared to no screening program in terms of quality-adjusted life years (QALYs) saved from a health care payer perspective.
3. Health service utilisation and treatment data collection will inform cost and probability parameters for the health economic model. Cost parameters will include overall PG Screening Program running costs, and direct overall average medical costs including fluoropyrimidine drug therapy (start dates and stop dates, hospitalization for drug administration (chemotherapy day unit), doctor consultation (outpatients), emergency department and hospitalisation for adverse events (inpatient ward, intensive care unit, emergency department). Costs for other than fluoropyrimidine anticancer drugs will not be included in the analysis. Collection of all health service utilisation and treatment data will continue until pre C3D1 review of fluoropyrimidine drug therapy
4. The EQ-5D-5L version 3.0 (EuroQol 2019) questionnaire, will be used to capture utilities across the study and derive QALYs and will be used to as part of health economic assessment.
Timepoint [9] 391363 0
12-months
Secondary outcome [10] 391364 0
Safety: Quality of life and patient reported symptom burden (assessed by EORTC QLQ-C30 version 3)
Timepoint [10] 391364 0
12-months
Secondary outcome [11] 391365 0
Safety: Type, grade and relationship to treatment of adverse events according to CTCAE v5.0, by cycle.
Timepoint [11] 391365 0
Prior to cycle 3 of fluoropyrimidine or irinotecan chemotherapy
Secondary outcome [12] 391368 0
Safety: number and type of unplanned hospital admissions per patient with/without any of the five established DPYD gene variants and UGTA1A.
This outcome will be determined from hospital records
Timepoint [12] 391368 0
Prior to cycle 3 of fluoropyrimidine or irinotecan chemotherapy
Secondary outcome [13] 391370 0
Research feasibility: proportion of patients who consent for additional genetic research sample collection for future evaluation of genomic predictors of toxicity beyond the existing five gene variants
Timepoint [13] 391370 0
Prior to cycle 3 of fluoropyrimidine or irinotecan chemotherapy
Secondary outcome [14] 391372 0
Exploratory outcome: overall response (OR) and disease control rate defined as clinician reported best response to cancer therapy [response categories defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD)].
Timepoint [14] 391372 0
12-months
Secondary outcome [15] 391373 0
Exploratory outcome: progression free survival, defined as the time from cancer treatment initiation to the earliest of date of disease progression or death.
Timepoint [15] 391373 0
12-months
Secondary outcome [16] 391374 0
Exploratory outcome: 12-month survival rate, defined as number of patients alive divided by number of consented patients at 12-month follow-up, overall and by cancer type/stage
Timepoint [16] 391374 0
12-months

Eligibility
Key inclusion criteria
1. Aged 18 years or older
2. First time exposure to fluoropyrimidine and/or irinotecan chemotherapy for cancer treatment (any line of treatment, any cancer diagnosis, any stage of disease).
3. Previously enrolled patients in the Peter Mac Pharmacogenetics Screening Program, for purpose of consenting for collection and storage of research samples for future genomic testing.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients that have had prior exposure to fluoropyrimidine and irinotecan, other than those previously enrolled in the Peter Mac Pharmacogenetics Screening program who are included only for research sample collection.
2. Patients with known DPD deficiency or Gilberts’ syndrome
3. Patients undergoing cytoreduction surgeries and HIPEC planned to receive HIPEC, single dose 5-fluorouracil

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
As this is a feasibility study, there is no formal sample size calculation. A pragmatic sample size including patients enrolled within 12-months is estimated at 630.

Descriptive statistics of patient demographics, disease characteristics, gene test results, feasibility, health resource utilisation, and program interventions (dose modifications/supportive medications post chemotherapy cycle) will be summarised. Continuous variables will be described as mean, standard deviation, interquartile range, medians, and ranges; qualitative variables will be described as counts and percentages. Unless stated otherwise, the calculation of proportions will not include the missing category. The proportion of patients with and without pharmacogenetic guided dose reduction, and 12 months survival rate will be presented with 95% confidence interval. The 12 months survival rate will be analysed for patients at primary site only; this based on pragmatic decision given secondary outcome.

Safety will be assessed using CTCAE v5.0 and maximum toxicity grade per patient of each adverse event will be derived and presented in table format. Type, grade and timing of treatment-related adverse events for all patients and for patients with and without any of the five established DPYD gene variants and UGT1A1. .A number of patients who suffer from grade 3 or higher toxicities related to study treatment will be provided by patients with/without any of the five established DPYD gene variants. All AEs will be described overall and separately by cycle. PFS and 12 months survival curves will be compared using the Kaplan-Meier methods, Cox proportional hazard models will be used to assess the impact of potential prognostic factors including (age, sex, ECOG PS, cancer diagnosis, stage of disease and cancer treatment) on PFS and 12 months survival rate. The curves will be presented with 95% confidence intervals. A cut-off date for follow-up will be determined at the time of analysis. The cut-off date is 12 months (primary site patients only) from the last patient recruited to the program to enable data on follow-up to that date to be collected, where possible, on all living patients. All events occurring after this date will be ignored in the analysis in order to minimise reporting bias. All patients in the consented population will be included in this analysis.
Clinical predictors of toxicity: association between patient factors (including age, sex, ethnicity, performance status) and clinical factors (including cancer diagnosis, stage of disease, cancer treatment), with incidence of toxicity of grade 3 or higher will be assessed.

There are 2 analyses planned for the study:
- Primary and secondary objectives: at pre C3D1 review of fluoropyrimidine and irinotecan drug therapy after the last patient accrued to the study. Patients who cease drug prior to pre C3D1 review will be followed for adverse events and cost data collection until equivalent pre C3D1 review date had they continued on the same treatment regimen.
- Exploratory objective: at 12 months after the last patient accrued to the study for Primary Site patients only.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
17/03/2021
Actual
7/01/2021
Date of last participant enrolment
Anticipated
17/05/2022
Actual
25/02/2022
Date of last data collection
Anticipated
28/02/2025
Actual
Sample size
Target
630
Accrual to date
Final
493
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 18118 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 18119 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [3] 18120 0
Border Medical Oncology - Albury
Recruitment hospital [4] 21395 0
Swan Hill District Health - Swan Hill
Recruitment postcode(s) [1] 32111 0
3000 - Melbourne
Recruitment postcode(s) [2] 32112 0
3550 - Bendigo
Recruitment postcode(s) [3] 32113 0
2640 - Albury
Recruitment postcode(s) [4] 36285 0
3585 - Swan Hill

Funding & Sponsors
Funding source category [1] 307322 0
Hospital
Name [1] 307322 0
Peter MacCallum Cancer Centre
Country [1] 307322 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan St, Melbourne, 3000, VICTORIA
Country
Australia
Secondary sponsor category [1] 307960 0
None
Name [1] 307960 0
Address [1] 307960 0
Country [1] 307960 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307412 0
Peter MacCallum Cancer Centre Research Ethics Committee
Ethics committee address [1] 307412 0
305 Grattan St, Melbourne, 3000, VICTORIA
Ethics committee country [1] 307412 0
Australia
Date submitted for ethics approval [1] 307412 0
04/11/2020
Approval date [1] 307412 0
27/11/2020
Ethics approval number [1] 307412 0
HREC/66681/PMCC-2020

Summary
Brief summary
A multi-site prospective study to implement and evaluate the feasibility of a Pharmacogenetics Screening Program for 5-fluorouracil [5-FU], capecitabine and irinotecan chemotherapies for patients with cancer

Who is it for?
You may be eligible to join this study if you are aged 18 and above, have been diagnosed with cancer and will receive fluorouracil [5-FU], capecitabine and/or irinotecan chemotherapy for the first time.

Study details
All participants in this study will receive a genetic screening for DPYD gene test if commencing on 5-FU or capecitabine and/or screening for UGT1A1 gene if commencing on irinotecan anticancer treatment, 7 to 10 days before starting chemotherapy. It is the responsibility and choice of the treating clinician to implement/not implement dosing recommendations based on genetic tests and to manage all aspects of cancer treatment.

The feasibility of operating a Pharmacogenetics Screening Program will be assessed using recruitment data from study databases and patient and clinician surveys. Participants will also be followed for up to 12 months to assess toxicities and 24 months to assess treatment response and status.

This research will contribute to improve health outcomes for patients with cancer in terms of safety and survival in particular patients who carry altered/deficient genes; dose individualisation prior to administration to 5-FU or capecitabine and/or irinotecan will assist with better tolerance to treatment and hospitalisations (given better toxicity management).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107146 0
Prof Michael Michael
Address 107146 0
Peter MacCalum Cancer Centre, Medical Oncology Department, 305 Grattan Street, Melbourne, 3000, VICTORIA
Country 107146 0
Australia
Phone 107146 0
+61 385595628
Fax 107146 0
Email 107146 0
[email protected]
Contact person for public queries
Name 107147 0
Mrs Sarah Glewis
Address 107147 0
Peter MacCalum Cancer Centre, Pharmacy Department, 305 Grattan Street, Melbourne, 3000, VICTORIA
Country 107147 0
Australia
Phone 107147 0
+61 385595628
Fax 107147 0
Email 107147 0
[email protected]
Contact person for scientific queries
Name 107148 0
Mrs Sarah Glewis
Address 107148 0
Peter MacCalum Cancer Centre, Pharmacy Department, 305 Grattan Street, Melbourne, 3000, VICTORIA
Country 107148 0
Australia
Phone 107148 0
+61 385595628
Fax 107148 0
Email 107148 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Awaiting decision from data monitoring committee still to be formed
For any data released all relevant protocol and data dictionaries would be made available


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo Interim results 1. 493 patients recruited over 1... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePharmacogenomics guided dosing for fluoropyrimidine and irinotecan chemotherapies for patients with cancer (PACIFIC-PGx): study protocol of a multicentre clinical trial.2022https://dx.doi.org/10.1080/0284186X.2022.2109423
EmbaseA systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.2022https://dx.doi.org/10.1038/s41416-022-01779-6
N.B. These documents automatically identified may not have been verified by the study sponsor.