UGT1A1 genotype-guided dosing of irinotecan

Rationale: Irinotecan is a commonly prescribed anti-cancer drug that is registered for the treatment of advanced colorectal and pancreatic cancer. Irinotecan is metabolized to inactive metabolites by the enzyme UGT1A1. The gene encoding UGT1A1 is polymorphically expressed. The polymorphism UGT1A1*28 is significantly associated with reduced metabolism capacity of irinotecan with subsequent increased systemic exposure and irinotecan-associated severe toxicity such as (febrile) neutropenia and diarrhea. Severe toxicity of irinotecan is undesirable as it may lead to hospitalization for treatment of toxicity, treatment delay and/or even treatment discontinuation. Based on multiple clinical trials and meta-analyses, the Food and Drug Administration (FDA) and international clinical guidelines therefore suggest dose reductions for patients homozygous polymorphic for UGT1A1*28to be treated with irinotecan (at doses of 180 mg/m2 or higher) in order to prevent severe toxicity; nonetheless, prospective screening is not yet routinely performed internationally. Another polymorphism, i.e. UGT1A1*93, is in partial linkage with UGT1A1*28 and is also strongly associated with irinotecan-induced severe toxicity. We hypothesize that prospective screening for UGT1A1*28 and UGT1A1*93 prior to start of treatment with irinotecan followed by genotype-based dose adjustment in homozygous variant allele carriers improves patient safety by decreasing the risk of severe toxicity and hospitalization, and is cost-effective.

Therefore we will develop a dosing nomogram of irinotecan in patients homozygous polymorphic for UGT1A1*28 and/or UGT1A1*93 in order to reduce the incidence of severe irinotecan-associated toxicity, defined as febrile neutropenia



Study design: Prospective, multi-center, non-randomized clinical implementation study.



Study population: Patients with a pathologically confirmed malignancy intended to be treated with irinotecan at a dosage of ≥ 180 mg/m2 or 450-600mg flat dose.



Intervention: Patients intended to be treated with irinotecan will be prospectively genotyped for UGT1A1*28 and UGT1A1*93. Patients that prove to be wildtype or heterozygous polymorphic will be treated with the standard-dose treatment of irinotecan. In patients homozygous polymorphic for UGT1A1*28 and/or UGT1A1*93 an initial 30% dose reduction in the first cycle will be applied. Based on clinical tolerability and absolute neutrophil count (ANC), the dose in subsequent cycles may be increased or further decreased in order to optimize the dose for the individual patient. Doses of other concomitant anticancer drugs will be left unchanged. Homozygous variant allele carriers will also be asked to provide additional blood for pharmacokinetic measurement of irinotecan and SN-38 on day 1, in order to confirm adequate drug exposure following genotype-guided dosing. Furthermore, after inclusion of the last patient, the patient cohort will be retrospectively genotyped for other polymorphisms than UGT1A1*28 and *93, in order to identify additional genetic biomarkers that are associated with treatment outcome.
(amendment 2019)

To develop a dosing nomogram of irinotecan in patients homozygous polymorphic for UGT1A1*28 and/or UGT1A1*93 in order to reduce the incidence of severe irinotecan-associated toxicity, defined as febrile neutropenia in the first 2 cycles (amendment 2019)

During chemotherapy with irinotecan

dosing nomogram of irinotecan in patients homozygous polymorphic for UGT1A1*28 and/or UGT1A1*93