Gastrointestinal Cancer
Conditions
Keywords
Gastrointestinal Neoplasms, Fluorouracil, Capecitabine, Irinotecan, Fluoropyrimidines, Topoisomerase I inhibitors, Antimetabolites, Antineoplastics, Molecular Mechanisms of Pharmacological Action
Brief summary
Pharmacogenomics (PGx) is the study of how genes affect a person's response to drugs. PGx testing for certain genes can help predict the risk of side effects from chemotherapy agents. Testing is not regularly performed in clinical practice due to long wait times for results and challenges with integrating test results in the electronic health record. Investigators leading this study hope to find out if providing cancer care providers with the ability to order a PGx test and electronically receive results with dosing recommendations will increase the use of these tests to guide treatment decisions and improve patient outcomes. This is a non-randomized implementation study, which means that all participants in this study will undergo genotyping for a pharmacogenetic test. The investigators will primarily measure the feasibility of using this test to guide cancer care.
Interventions
DEVICEPharmacogenetic test
Patients with reduced function alleles (DPYD intermediate or poor metabolizer and/or UGT1A1 poor metabolizer) will be recommended to receive dose reductions per clinical pharmacogenetic guidelines. Patients that do not carry actionable alleles (DPYD normal metabolizer and/or UGT1A1 normal or intermediate metabolizer) will receive standard dosing.
Sponsors
Abramson Cancer Center at Penn Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
This is a nonrandomized, open-label study to investigate the feasibility of establishing and integrating a pharmacogenetic test into clinical oncology care. A historical control group of patients with gastrointestinal cancers enrolled in a biobank will be used to compare toxicity outcomes of the prospectively-genotyped patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Able and willing to provide informed consent 2. Male or female, aged 18 years or older at the time of study initiation 3. Pathologically confirmed gastrointestinal malignancy for which treatment with a fluoropyrimidine and/or irinotecan is indicated 4. Willing to undergo blood or saliva sampling for PGx testing and comply with all study-related procedures 5. Life expectancy of at least 6 months
Exclusion criteria
1. Prior treatment with irinotecan 2. DPYD or UGT1A1 genotype already known 3. Severe renal or hepatic impairment (or unacceptable laboratory values), including: * Neutrophil count of \<1.5 x 109/L, platelet count of \<100 x 109/L * Hepatic function as defined by serum bilirubin \>1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \>2.5 x ULN, or in case of liver metastases ALT and AST\>5 x ULN * Renal function as defined by serum creatinine \>1.5 x ULN, or creatinine clearance \<60 ml/min (by Cockcroft-Gault Equation) 4. Women who are pregnant or breast feeding, or subjects who refuse to use reliable contraceptive methods throughout the study 5. Treating physician does not want subject to participate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility: Number and Percentage of Participants Who Had Their Pharmacogenetic Tests Returned Prior to Initial Dose | 14 days | The Number and percentage of participants who had their pharmacogenetic tests returned prior to the first determined dose of chemotherapy. |
| Fidelity: Level of Agreement With Dose Recommendations | 14 days | The number and percentage of participants with dose modifications made in agreement with the genotype-guided dosing recommendations for the first dose of chemotherapy. |
| Penetrance: Proportion of Pharmacogenetic Tests Ordered by Providers | 14 days | The number and percentage of participants with pharmacogenetic tests ordered compared to the number of patients eligible for testing at participating sites during the study timeframe |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severe Treatment Related Adverse Events (TRAE) | 6 months | Percentage of patients experiencing a severe TRAE (an event requiring hospitalization, emergency room visits, or oncology evaluation center). Severe TRAEs were one of the outcomes measured by the study. |
Countries
United States
Participant flow
Pre-assignment details
Of the 552 enrolled participants, 531 were eligible to begin study procedures.
Participants by arm
| Arm | Count |
|---|---|
| Prospective Cohort Enrollees were given DPYD and UGT1A1 testing before starting chemotherapy | 276 |
| Confirmatory Cohort Enrollees were given DPYD and UGT1A1 testing after starting chemotherapy at physician's request | 20 |
| BioBank Cohort Enrollees with biobank samples were tested for DPYD and UGT1A1 variants, and retrospectively chart reviewed for outcomes | 235 |
| Total | 531 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 48 | 0 | 6 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Prospective Cohort | Confirmatory Cohort | BioBank Cohort | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 114 Participants | 9 Participants | 86 Participants | 209 Participants |
| Age, Categorical Between 18 and 65 years | 162 Participants | 11 Participants | 149 Participants | 322 Participants |
| ECOG at Enrollment 0 | 151 Participants | 12 Participants | 102 Participants | 265 Participants |
| ECOG at Enrollment 1 | 89 Participants | 6 Participants | 109 Participants | 204 Participants |
| ECOG at Enrollment 2 | 20 Participants | 1 Participants | 21 Participants | 42 Participants |
| ECOG at Enrollment 3 | 8 Participants | 1 Participants | 3 Participants | 12 Participants |
| ECOG at Enrollment NA | 8 Participants | 0 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 0 Participants | 1 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 265 Participants | 19 Participants | 0 Participants | 284 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 234 Participants | 237 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 0 Participants | 3 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 50 Participants | 0 Participants | 38 Participants | 88 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 1 Participants | 5 Participants | 16 Participants |
| Race (NIH/OMB) White | 205 Participants | 19 Participants | 189 Participants | 413 Participants |
| Region of Enrollment United States | 276 participants | 20 participants | 235 participants | 531 participants |
| Sex: Female, Male Female | 125 Participants | 12 Participants | 114 Participants | 251 Participants |
| Sex: Female, Male Male | 151 Participants | 8 Participants | 121 Participants | 280 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 35 / 225 | 3 / 20 | 47 / 229 |
| other Total, other adverse events | 214 / 225 | 20 / 20 | 140 / 229 |
| serious Total, serious adverse events | 69 / 225 | 10 / 20 | 76 / 229 |
Outcome results
Primary
Feasibility: Number and Percentage of Participants Who Had Their Pharmacogenetic Tests Returned Prior to Initial Dose
The Number and percentage of participants who had their pharmacogenetic tests returned prior to the first determined dose of chemotherapy.
Time frame: 14 days
Population: Number and percentage of participants with both PGx test results and who began a qualifying chemotherapy. The BioBank Cohort and Confirmatory Cohort are not included in this measure as their PGx testing was intentionally ordered after their first dose of chemotherapy, therefore how many results were returned prior to first dose was not applicable.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prospective Cohort | Feasibility: Number and Percentage of Participants Who Had Their Pharmacogenetic Tests Returned Prior to Initial Dose | PGx Result Returned before Chemotherapy | 130 Participants |
| Prospective Cohort | Feasibility: Number and Percentage of Participants Who Had Their Pharmacogenetic Tests Returned Prior to Initial Dose | PGx Result Returned After Chemotherapy | 95 Participants |
Primary
Fidelity: Level of Agreement With Dose Recommendations
The number and percentage of participants with dose modifications made in agreement with the genotype-guided dosing recommendations for the first dose of chemotherapy.
Time frame: 14 days
Population: Number and percentage of participants with an actionable genetic variant also receiving an interacting chemotherapy (DPYD Poor and Intermediate Metabolizers receiving fluoropyrimidine and UGT1A1 Poor Metabolizers receiving irinotecan). The BioBank Cohort and Confirmatory Cohort are not included in this measure as their PGx testing was intentionally ordered after their first dose of chemotherapy, therefore modifying their chemotherapy to match PGx results was not applicable.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prospective Cohort | Fidelity: Level of Agreement With Dose Recommendations | Number and percent of participants with PGx test results returned before chemotherapy initiation | 11 Participants |
| Prospective Cohort | Fidelity: Level of Agreement With Dose Recommendations | Number and percent of participants with DPYD dose mods in agreement to genotype-recommendations | 6 Participants |
| Prospective Cohort | Fidelity: Level of Agreement With Dose Recommendations | Number and percent of participants with UGT1A1 dose mods in agreement to genotype-recommendations | 5 Participants |
Primary
Penetrance: Proportion of Pharmacogenetic Tests Ordered by Providers
The number and percentage of participants with pharmacogenetic tests ordered compared to the number of patients eligible for testing at participating sites during the study timeframe
Time frame: 14 days
Population: In order to calculate the penetrance of the intervention, as this was an implementation trial, it is necessary to consider the total number of patients who would have been eligible for recruitment. This includes both the prospective arms, as well as individuals in participating clinics during the study timeframe who were not approached for consent due to personnel and screening limitations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prospective Cohort | Penetrance: Proportion of Pharmacogenetic Tests Ordered by Providers | 288 Participants |
Secondary
Severe Treatment Related Adverse Events (TRAE)
Percentage of patients experiencing a severe TRAE (an event requiring hospitalization, emergency room visits, or oncology evaluation center). Severe TRAEs were one of the outcomes measured by the study.
Time frame: 6 months
Population: Prospective and BioBank Cohorts are broken out into DGI and Non-DGI groups to compare participant outcomes by genotype.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prospective Cohort | Severe Treatment Related Adverse Events (TRAE) | Severe TRAEs | 6 Participants |
| Prospective Cohort | Severe Treatment Related Adverse Events (TRAE) | Treatment Discontinuation | 5 Participants |
| Prospective Cohort | Severe Treatment Related Adverse Events (TRAE) | Treatment Modifications | 6 Participants |
| Prospective Cohort, Non-DGI Group | Severe Treatment Related Adverse Events (TRAE) | Treatment Modifications | 107 Participants |
| Prospective Cohort, Non-DGI Group | Severe Treatment Related Adverse Events (TRAE) | Severe TRAEs | 63 Participants |
| Prospective Cohort, Non-DGI Group | Severe Treatment Related Adverse Events (TRAE) | Treatment Discontinuation | 49 Participants |
| BioBank Cohort, DGI Group | Severe Treatment Related Adverse Events (TRAE) | Treatment Modifications | 13 Participants |
| BioBank Cohort, DGI Group | Severe Treatment Related Adverse Events (TRAE) | Severe TRAEs | 10 Participants |
| BioBank Cohort, DGI Group | Severe Treatment Related Adverse Events (TRAE) | Treatment Discontinuation | 8 Participants |
| BioBank Cohort, Normal Metabolizers Group | Severe Treatment Related Adverse Events (TRAE) | Severe TRAEs | 66 Participants |
| BioBank Cohort, Normal Metabolizers Group | Severe Treatment Related Adverse Events (TRAE) | Treatment Discontinuation | 60 Participants |
| BioBank Cohort, Normal Metabolizers Group | Severe Treatment Related Adverse Events (TRAE) | Treatment Modifications | 108 Participants |
| Confirmatory Cohort | Severe Treatment Related Adverse Events (TRAE) | Treatment Modifications | 12 Participants |
| Confirmatory Cohort | Severe Treatment Related Adverse Events (TRAE) | Severe TRAEs | 10 Participants |
| Confirmatory Cohort | Severe Treatment Related Adverse Events (TRAE) | Treatment Discontinuation | 8 Participants |
Comparison: Severe TRAEsp-value: 0.224Fisher Exact
Comparison: Severe TRAEsp-value: 0.025Fisher Exact