cancer malignancies
Conditions
Interventions
None listed
Sponsors
Antoni van Leeuwenhoek Ziekenhuis
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Histological or cytological proof of cancer 2. Patient who might benefit from treatment with capecitabine, e.g. colon, breast, pancreatic and gastric cancer, ACUP; 3. Age >= 18 years 4. WHO performance status of 0, 1 or 2; 5. Able and willing to give written informed consent 6. Able and willing to undergo blood sample collection during day-time and during the night for pharmacokinetic (PK) measurements and pharmacodynamic (PD) analysis; 7. Life expectancy >= 3 months allowing adequate follow up; 8. Minimal acceptable safety laboratory values a. ANC of >= 1.5 x 10^9 /L; b. Platelet count of >= 100 x 10^9 /L; c. Hemoglobin>= 6.5 mmol/L; d. Hepatic function as defined by serum bilirubin = 60 ml/min (by Cockcroft-Gault formula). 9. No radio- or chemotherapy within 3 weeks of receiving first dose of study medication (palliative limited radiation for pain reduction is allowed); 10. Able and willing to swallow oral medication; 11. Negative pregnancy test (urine/serum) for female patients with childbearing potential.
Exclusion criteria
Exclusion criteria: 1. Dihydropyrimidine dehydrogenase (DPD) deficiency as assessed on the basis of DPYD IVS14+1G>A (DPYD*2A) and 2846A>T mutation analysis; 2. Women who are pregnant or breast feeding; 3. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms); 4. Bowel obstructions or motility disorders that may influence the absorption of drugs; 5. Pre-existing neuropathy > grade 1; 6. Unresolved (> grade 1) toxicities (except alopecia) of previous chemotherapy; 7. Patients with known alcoholism, drug addiction and/or psychotic disorders in the history that are not suitable for adequate follow up; 8. The use of any drug or complementary alternative medicine that might interfere with the biotransformation of capecitabine and/or 5FU, like CYP2C9 substrates with narrow therapeutic windows (e.g., vitamin K antagonizing anticoagulants (acenocoumarol, phenprocoumon, warfarin), phenytoin), allopurinol, folic acid, folinic acid, interferon alpha, metronidazol, sorivudine (and analogues). Aluminium hydroxide and magnesium hydroxide can not be administered in the morning and evening/night: the use of aluminium hydroxide and magnesium hydroxide is not an exclusion criterion when administered in the afternoon between 12:00 - 18:00 h; 9. Current participation or previous participation in a study with an investigational compound, or chemo- and/or radiotherapy within 21 days of receiving first dose of study medication. (Palliative limited radiation for pain reduction is allowed); 10. Prior stem cell or bone marrow transplant; 11. Known hypersensitivity to the components of the study drug or its analogs; 12. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients; 13. Patients with a known history of hepatitis B or C; 14. Symptomatic cerebral or leptomeningeal metastases; 15. Evidence of any other disease, neurological or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of capecitabine according to this protocol or puts the patient at high risk for treatment-related complications.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs) and recommended dose (RD) of continuous and intermittent chronomodulated capecitabine. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary study parameters/outcomes include the following: The plasma pharmacokinetics of capecitabine and its metabolites 5-dFCR, 5-dFUR, 5-FU and FBAL; The inter- and intra-patient variability in plasma pharmacokinetics; Baseline and circadian dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMCs) and in plasma by means of the dihydrouracil (UH2) / uracil (U) ratio; Baseline and circadian thymidylate synthase (TS) activity in PBMCs; Baseline thymidine phosphorylase (TP) activity in PBMCs; The description of pharmacokinetic/pharmacodynamic (PK/PD) relationships; The preliminary antitumor activity of chronomodulated capecitabine; Associations of polymorphisms in DPYD or TYMS with DPD or TS enzyme activity in PBMCs and clinical response; Intracellular pharmacokinetics of 5-FU nucleotides in PBMCs. | — |
Countries
Netherlands
Outcome results
None listed