Primary objective is to determine the plasma pharmacokinetics of ModraCape001 and compare these to the pharmacokinetic profile of Xeloda®.Secondary objectives are:• To determine the AUC in blood plasma of capecitabine and its metabolites 5-dFCR, 5-…
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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
Primary study parameters correspond to the primary endpoints and include the
following: pharmacokinetic parameters (Cmax, Tmax, t*, AUC0-t, AUCinf, MRT, Vd
and Cl).
Secondary outcome
Secondary study parameters correspond to the secondary endpoints and include
the following:
• AUC of capecitabine, 5-dFCR, 5-dFUR and 5-FU;
• AUC of intracellular metabolites: FUMP, FUDP, FUTP, FdUMP, FdUDP and FdUTP;
• Enzyme activity of dihydropyrimidine dehydrogenase (DPD) in PBMCs;
• Preliminary safety (NCI CTCAE criteria version 4)
Background summary
Capecitabine ( Xeloda®) is an orally administered chemotherapeutic drug, which
is used in the treatment of cancer. Capecitabine is a pro-drug of the
well-known commonly used cytostatic agent 5-fluorouracil (5-FU), however 5-FU
can only be administered intravenously (IV). Capecitabine was approved by the
US Food and Drug Administration (FDA) in 1998 for the treatment of women with
advanced mamma carcinoma. Capecitabine was authorized by the European Medicine
Agency (EMA) in 2001 for use within the European Union (EU) including the
Netherlands. These days capecitabine is approved for the following therapeutic
indications: adjuvant treatment of stage III (Dukes stage C) colon cancer
following surgery, treatment of metastatic colorectal cancer, first-line
treatment of advanced gastric cancer in combination with a platinum-based
regimen and in combination with docetaxel in locally advanced breast cancer or
metastatic breast cancer after failure of taxanes and cytotoxic treatment
(which included an anthracycline) or if further treatment with an anthracycline
is not indicated.
In the Netherlands, the amount of prescriptions for capecitabine increased over
the past years. In 2005, capecitabine was prescribed about 31,000 times. In
2009, this amount was increased to over 67,000 prescriptions.
Administered twice daily, capecitabine has a Tmax of about 90 minutes. The
three-step metabolism is quick and follows the pharmacokinetic profile of
capecitabine. This way, 5-FU is cleared rapidly and is not detectable after
approximately 6 hours. This schedule shows a gap in exposure to capecitabine
and 5-FU of 6 hours until next administration. Therefore, a new oral form of
capecitabine, ModraCape001, was developed. The new formulation releases
capecitabine in vitro in ~18 hours instead of 45 minutes. This way, the
exposure to 5-FU might become more continuous.
Study objective
Primary objective is to determine the plasma pharmacokinetics of ModraCape001
and compare these to the pharmacokinetic profile of Xeloda®.
Secondary objectives are:
• To determine the AUC in blood plasma of capecitabine and its metabolites
5-dFCR, 5-dFUR and 5-FU;
• To determine the intracellular pharmacokinetics of 5-FU nucleotides during
capecitabine therapy;
• To determine enzyme activity of dihydropyrimidine dehydrogenase (DPD) in
peripheral blood mononuclear cells (PBMCs);
• To investigate the preliminary safety of ModraCape001.
Study design
This is a single center, open-label, proof of concept and pharmacological phase
0 crossover study in which a new oral formulation of capecitabine,
ModraCape001, will be investigated in patients potentially responsive to
capecitabine treatment.
Intervention
This is a proof of concept and pharmacological phase 0 crossover study whereby
the new oral formulation of capecitabine, ModraCape001, will be investigated.
The primary endpoint is to determine the pharmacokinetic profile of
ModraCape001 and to compare this profile with the pharmacokinetic properties of
Xeloda®.
Patients will be hospitalized for three days. At the first day they will
receive one dose of 1000 mg Xeloda® at approximately 09:00 h. After intake at
blood samples will be collected up to 12 hours after intake to determine
pharmacokinetics (PK) and pharmacodynamics (PD). At day 2 patients will receive
one dose of 1000 mg ModraCape001 at approximately 9:00 h and blood sample
collection will be done at similar time points for the next 36 hours postdose.
After the final blood sample is collected the patient will be released from the
hospital. A follow-up visit after one week will be planned for safety reasons.
If no further follow-up is needed for safety reasons the patient will be
declared off-study. Further treatment is determined in the best interest of the
patient in consultation with the treating physician.
Proof of principle is achieved when the mean AUC of capecitabine after intake
of ModraCape001 is >= 50% of the mean AUC of capecitabine is after intake of the
same dose of Xeloda® and if the mean AUC of capecitabine up to 2 hours (AUC0-2)
of ModraCape001 is <50 % of that of Xeloda®. The latter indicating that
ModraCape001 is indeed a slow release formulation compared to Xeloda®. If these
conditions are not met, than ModraCape001 will not be developed.
Study burden and risks
Participating patients will be hospitalized for three consecutive days in which
blood samples will be drawn for pharmacokinetic and pharmacodynamic
measurements. Approximately 300 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
• Histological or cytological proof of cancer;• Patients who might benefit from treatment with capecitabine, e.g. colon, breast, adenocarcinoma of unknown primary (ACUP), pancreatic and gastric carcinoma;;• Age >= 18 years;• WHO performance status of 0, 1 or 2;;• Able and willing to give written informed consent;• Able and willing to undergo blood sample collection for PK measurements;;• Life expectancy >= 3 months;;• 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 <= 2.5 x ULN;;e. Renal function as defined by serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula).;• No radio- or chemotherapy within the last 21 days prior to study entry (palliative limited radiation of 1 x 8 Gy for pain reduction is allowed);;• Able and willing to swallow oral medication;;• Negative pregnancy test (urine/serum) for female patients with childbearing potential.
Exclusion criteria
• Dihydropyrimidine dehydrogenase (DPD) deficiency as assessed on the basis of DPYD mutation analysis (DPYD*2A);;• Women who are pregnant or breast feeding;;• 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);;• Bowel obstructions or motility disorders that may influence the absorption of drugs;;• Pre-existing neuropathy > grade 1;;• Unresolved (> grade 1) toxicities of previous chemotherapy;;• Patients with known alcoholism, drug addiction and/or psychotic disorders in the history that are not suitable for adequate follow up;;• The use of any drug or complementary alternative medicine that might interfere with the biotransformation of capecitabine and/or 5FU, like: acenocoumarol, allopurinol, folic acid, folinic acid (leucovorin), interferon alpha, metronidazol, phenprocoumon, phenytoin, sorivudine (and analogues) and warfarin;;• 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 of 1 x 8 Gy for pain reduction is allowed);;• Prior stem cell or bone marrow transplant; ;• Known hypersensitivity to the components of the combination study therapy or its analogs;;• Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;;• Patients with a known history of hepatitis B or C;;• Symptomatic cerebral or leptomeningeal metastases;;• Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity;;• 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 an investigational drug 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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023541-30-NL |
| CCMO | NL34431.031.11 |