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van CCT (UK)

van CCT (UK)

UGT1A1 genotype-guided dosing of irinotecan

- candidate number27458
- NTR NumberNTR6612
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR25-jun-2017
- Secondary IDsEudraCT NL59765.100.17
- Public TitleUGT1A1 genotype-guided dosing of irinotecan
- ACRONYMUGT1A1 genotype-guided dosing of irinotecan
- hypothesisTo 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 neutropenia ≥grade 3.
- Healt Condition(s) or Problem(s) studiedToxicity, Irinotecan, UGT1A1 gene
- Inclusion criteria1. Pathologically confirmed malignancy for which treatment with irinotecan is indicated at a dosing regimen of ≥ 180 mg/m2 or 450-600mg flat dose in 2- or 3-weekly treatment schedules (see table 1)
2. Age ≥ 18 years
3. Able and willing to give written informed consent
4. WHO performance status 0-2
5. Minimal acceptable safety laboratory values defined as
a. ANC of ≥ 1.5 x 109 /L
b. Platelet count of ≥ 100 x 109 /L
c. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 2.5 x ULN; in case of liver metastases ALAT and ASAT ≤ 5 x ULN.
d. Renal function (eGFR) ≥ 50 ml/min OR creatinine ≤ 1.5 x ULN
- Exclusion criteria1. Prior treatment with irinotecan
2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient’s safety
3. Patients of Asian origin
4. Patients unable or unwilling to stop the use of (over the counter) medication or (herbal) supplements which can interact with irinotecan (e.g. by induction of inhibition of CYP3A4)
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-sep-2017
- planned closingdate31-dec-2018
- Target number of participants150
- Interventionsdosing nomogram of irinotecan in patients homozygous polymorphic for UGT1A1*28 and/or UGT1A1*93
- Primary outcomeincidence of neutropenia ≥grade 3
- Secondary outcome• Incidence of grade ≥3 toxicity other than neutropenia
• Incidence of toxicity-related hospital admissions
• Number of patients with treatment delay, defined as a delay of more than 2 days
• Incidence of early treatment withdrawal
• Pharmacokinetics of irinotecan and its metabolite SN-38 in UGT1A1*28 and/or *93 homozygous variant allele carriers.
• Incidence of treatment delay due to prospective screening of UGT1A1
• Direct medical costs of irinotecan-based treatment
• Progression free survival and overall survival
• Bilirubin / conjugated bilirubin concentration ratio
• The effect of additional polymorphisms other than UGT1A1*28 and *93 on treatment outcome in terms of toxicity and efficacy (survival and progression-free survival)
- TimepointsDuring chemotherapy with irinotecan
- Trial web site
- statusopen: patient inclusion
- Sponsor/Initiator Catharina Hospital Eindhoven
- Funding
(Source(s) of Monetary or Material Support)
Catharina Hospital Eindhoven
- Publications
- Brief summaryRationale: 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 neutropenia ≥grade 3.

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.
- Main changes (audit trail)
- RECORD25-jun-2017 - 10-sep-2017

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