Page 168 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
Supplementary methods
Inclusion and exclusion criteria
Patients with a pathologically confirmed malignancy for which treatment with a fluoropyrimidine drug was considered to be in the patient’s best interest could be included in this study. Eligible patients were 18 years or older and were willing to undergo blood sampling for the purpose of this study (pharmacogenetic and phenotyping analysis). Patients had to have a WHO performance status of 0, 1 or 2, a life expectancy of at least 12 weeks, and acceptable safety laboratory values (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 (ALAT), and aspartate aminotransferase (ASAT) ≤2.5 x ULN, or in case of liver metastases ALAT and ASAT≤5 x ULN, renal function as defined by serum creatinine ≤1.5 x ULN, or creatinine clearance ≥60 ml/min (by Cockcroft-Gault formula).
Exclusion criteria were prior treatment with fluoropyrimidines, patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient’s safety, women who were pregnant or breast feeding, man and women who refused to use reliable contraceptive methods throughout the study, and patients with a homozygous polymorphic DPYD genotype or compound heterozygous DPYD genotype.
Toxicity assessments
For causality assessment of toxicity the following definitions were used:
- Possible: the event follows a reasonable temporal sequence from the time of drug administration, but could have been produced by other factors such as the patient’s
clinical state, other therapeutic interventions or concomitant drugs.
- Probable: the event follows a reasonable temporal sequence from the time of drug administration, and follows a known response pattern to the study drug. The toxicity cannot be reasonably explained by other factors such as the patient’s clinical state,
therapeutic interventions or concomitant drugs.
- Definite: the event follows a reasonable temporal sequence from the time of drug
administration, and follows a known response pattern to the study drug, cannot be reasonably explained by other factors such as the patient’s condition, therapeutic interventions or concomitant drugs; AND occurs immediately following study drug administration, improves on stopping the drug, or reappears on re-exposure.
Sample size calculation
A sample size calculation was made based on the primary aim of the study, which was to determine whether fluoropyrimidine-related severe toxicity can be reduced by individualized dosing in DPYD variant allele carriers compared to standard dosing in these patients. Using a one stage A’Hern (phase II) design and a null hypothesis of a probability of toxicity of 60% (the estimated severe treatment-related toxicity probability if DPYD variant allele carriers received standard dose)1,2 and an alternative hypothesis of 20% (estimated toxicity probability of DPYD variant allele carriers receiving individualized dose), a sample size of eleven DPYD variant allele carriers would give a one-sided type I error probability α of 2.93% and power of 83.9%. It was decided that the frequency of c.2846A>T carriers (approximately
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