To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs) and recommended dose (RD) of continuous and intermittent chronomodulated capecitabine.Secondary study objectives are:To determine plasma pharmacokinetics of capecitabine…
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Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs)
and recommended dose (RD) of continuous and intermittent chronomodulated
capecitabine.
Secondary outcome
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.
Background summary
Capecitabine is a widely used oral prodrug of 5-fluorouracil (5-FU).
Enzymatical conversion of capecitabine subsequently by carboxyl esterase (CES),
cytidine deaminase (CDA) and thymidine phophorylase (TP) is warranted for the
formation of 5-FU. However, the clinical application of capecitabine is limited
by treatment failure and poorly predictable severe toxicity (especially
diarrhea and palmar-plantar erythrodysesthesia (PPE)). Treatment safety and
efficacy may be improved by synchronization capecitabine therapy to the
circadian rhythm of the 5-FU degrading enzyme dihydropyrimidine dehydrogenase
(DPD) and its drug target thymidylate synthase (TS).
Approximately 80 percent of 5-FU is metabolized by DPD. Earlier studies,
including an observational study performed by our research group, showed that
DPD activity fluctuates over the twenty-four hours of the day. This so called
circadian rhythm of DPD is characterized by low metabolic capacity during
day-time and peak metabolic capacity during the night. Nocturnal DPD activity
is approximately 60% higher compared to DPD activity in the afternoon.
Consequently, metabolism of 5-FU is most likely increased during the night
because of high DPD activity. Besides circadian activity of DPD the enzyme
thymidylate synthase (TS) also shows circadian activity. The enzyme TS displays
trough activity during the night. Exposure to 5-FU when TS activity is low has
been associated with improved 5-FU tolerability.
Circadian rhythms of DPD and TS presumably affect capecitabine treatment
pharmacokinetics, safety and tolerability. Safety and the maximum tolerated
dose (MTD) for Xeloda® have been determined in earlier phase I trials for
continuous and intermittent (day 1-14 of a 21-day course) BID treatment
schedules with Xeloda®. Major limitations of these studies were that circadian
rhythms in 5-FU metabolism and patient tolerability to Xeloda® were not taken
into account. Chronomodulated capecitabine therapy, indicating that
capecitabine therapy is synchronized to circadian rhythms of DPD and TS, might
be advantageous for Xeloda® BID treatment.
Therefore, we aim to determine the feasibility of chronomodulated capecitabine
in a pharmacological phase I clinical study. A new capecitabine dosing schedule
is developed by population modeling of capecitabine pharmacokinetics and DPD
activity. Capecitabine will be administered continuously on day 1-21 (arm A)
and intermittently on day 1-14 (arm B) of 21-day BID dosing schedules. For both
study arms, the morning will be administered at 9:00 hours (h) and the late
evening dose at 24:00 h. Chronomodulation will be obtained by using a
relatively high evening dose of capecitabine.
Study objective
To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs)
and recommended dose (RD) of continuous and intermittent chronomodulated
capecitabine.
Secondary study objectives are:
To determine plasma pharmacokinetics of capecitabine and its metabolites
5-dFCR, 5-dFUR, 5-FU and FBAL;
To determine the inter- and intra-patient variability in plasma
pharmacokinetics;
To determine 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;
To determine baseline and circadian thymidylate synthase (TS) activity in PBMCs;
To determine baseline thymidine phosphorylase (TP) activity in PBMCs.
To explore pharmacokinetic/pharmacodynamic (PK/PD) relationships;
To investigate the preliminary antitumor activity of chronomodulated
capecitabine;
To explore associations of polymorphisms in DPYD or TYMS with DPD or TS enzyme
activity in PBMCs and clinical response;
To explore the intracellular pharmacokinetics of 5-FU nucleotides in PBMCs.
Study design
Phase I, single centre, pharmacological, open label, dose-escalation study
Study burden and risks
Participating patients will be hospitalized for two consecutive days in which
blood samples will be drawn for pharmacokinetic and pharmacodynamic
measurements. Approximately 270 ml blood will be collected plus blood for
pharmacogenetics, hematology and serum chemistry. Patients are at risk for
capecitabine related adverse effects.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
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 <= 1.5 x ULN, ALAT and ASAT <= 3.0 x ULN (<=
5 x ULN in case of liver metastases);
e. Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine clearance >= 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
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
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000889-22-NL |
| CCMO | NL48425.031.14 |
| OMON | NL-OMON24089 |