E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Types of cancer for which capecitabine and 5-fluorouracil are authorized, this includes colorectal cancer, gastric cancer and locally advanced or metastatic breast cancer |
Types kanker waarvoor capecitabine en 5-fluorouracil zijn geregistreerd, dit omvat colorectaalcarcinoom, maagcarcinoom, lokaal voortgeschreden of gemetastaseerd mammacarcinoom. |
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E.1.1.1 | Medical condition in easily understood language |
Cancer for which the medicines capecitabine and 5-fluorouracil are used. This includes colorectal cancer, gastric cancer and breast cancer. |
Kanker waarvoor de geneesmiddelen capecitabine en 5-fluorouracil worden gebruikt. Dit omvat darmkanker, maagkanker en borstkanker. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether the rate of severe toxicity (grade 3 to 5, grading according to CTC-AE version 4.03) associated with fluoropyrimidine treatment can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront genotypic assessment of DPD deficiency. |
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E.2.2 | Secondary objectives of the trial |
To determine whether individualized dosing based on upfront genotypic assessment of DPD deficiency is cost-effective.
To determine the additional value of an array-based screening of additional decreased activity DPYD-alleles, by determining associations between these variants and occurrence of severe fluoropyrimidine-induced toxicity.
To assess the pharmacokinetic profile of capecitabine and 5-FU in DPD deficient patients (e.g. patients carrying variant DPYD alleles) given reduced dosages of the respective drugs.
To determine the clinical sensitivity, specificity, positive predictive value and negative predictive value of phenotype-based screening using the endogenous DHU/U ratio, uracil breath test and uracil test dose.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient’s best interest
2. Age 18 years
3. Able and willing to give written informed consent
4. WHO performance status of 0, 1 or 2
5. Life expectancy of at least 12 weeks
6. Able to swallow and retain oral medication
7. Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis
8. Minimal acceptable safety laboratory values
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 as defined by serum creatinine 1.5 x ULN or creatinine clearance 60 ml/min (by Cockcroft-Gault formula).
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E.4 | Principal exclusion criteria |
1. Prior treatment with fluoropyrimidines
2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient’s safety
3. Women who are pregnant or breast feeding
4. Both men and women who refuse to use reliable contraceptive methods throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms)
5. Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this study is the incidence of severe treatment-related toxicity (CTC grade 3 to 5) in patients carrying DPYD variants compared to wild type patients and compared to a historical cohort of DPYD heterozygous patients treated with a full dose of fluoropyrimidines. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary endpoints are: cost-effectiveness, assessment of pharmacokinetics and DPD enzyme activity. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | Yes |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of trial is defined as the date of the last visit of the last patient enrolled in the trial. The analysis time point is defined as all enrolled patients that have undergone the 30 day post safety follow up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |