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 during the first two cycle of…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is the incidence of febrile neutropenia of
UGT1A1 genotype-guided dosing during the first two cycle of irinotecan
treatment.
Secondary outcome
* Incidence of grade *3 toxicity
* 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)
Background summary
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*28 to 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.
Study objective
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 during the first
two cycle of irinotecan treatment.
Study design
Prospective, multi-center, non-randomized clinical implementation study
Study burden and risks
In order to determine the UGT1A1*28 and *93 genotype prior to start of therapy,
a total of 4 mL of EDTA blood will be drawn from the patients intended to be
treated with irinotecan. This will not however require an extra venepuncture,
as it is combined with other standard laboratory pre-treatment tests, such as
determination of white blood cell count and liver and renal function.
Therefore, the risk and burden associated with genotyping is minimized. It is
hypothesized that genotype-guided dosing improves patient safety of treatment
by reducing the risk of severe toxicity and toxicity-associated
hospitalization. There is no risk of under dosing as previous pharmacokinetic
measurements have demonstrated the increased (toxic) systemic exposure of
irinotecan/SN38 in UGT1A1 poor metabolizers, and the dose is further
individualized in subsequent cycles of treatment based on clinical tolerability
and absolute neutrophil count.
By use of a limited sampling strategy, the pharmacokinetics of irinotecan and
its metabolite SN-38 will be measured on day 1 and day 3 of therapy in patients
homozygous polymorphic for UGT1A1*28 and/or *93. To this purpose, 2 additional
venapunctures will be performed in an expected total of 15 patients. There is
no significant risk associated with this venepuncture, besides a small risk of
thrombophlebitis, which is similar to the risk of other venapunctures performed
during routine treatment of the patient.
Michelangelolaan 2
Eindhoven 5623 EJ
NL
Michelangelolaan 2
Eindhoven 5623 EJ
NL
Listed location countries
Age
Inclusion criteria
1. 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 criteria
1. 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) (see Appendix 2 study protocol).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 27458 (Nederlands Trial Register) |
| EudraCT | EUCTR2016-004576-22-NL |
| CCMO | NL59765.100.17 |