The primary objective of this study is to quantitatively determine the pharmacokinetics (absorption, distribution, metabolism and excretion) of docetaxel (as ModraDoc003 10mg tablets) after administration of a single dose of oral docetaxel in…
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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
The primary objective of this study is to quantitatively determine the
pharmacokinetics (absorption, distribution, metabolism and excretion) of
docetaxel (as ModraDoc003 10mg tablets) after administration of a single dose
of oral docetaxel in combination with ritonavir.
Secondary outcome
- To determine the presence or absence of quantitatively relevant metabolites
of docetaxel.
- To elucidate the structures of potential new metabolites of docetaxel
- To preliminary assess anti-tumor activity of oral docetaxel combined with
ritonavir.
- To further characterize the safety and tolerability of oral docetaxel in
combination with ritonavir.
Background summary
Oral administration has many advantages above intravenously administrated drugs
for patients. However, oral bioavailability of docetaxel IV-solution is
frequently low and variable. The bioavailability of docetaxel is limited due to
metabolising cytochrome P450 (CYP) enzymes, which are abundantly present in the
gastrointestinal tract. Inhibition of CYP3A4 enzymes with ritonavir (an
anti-retroviral drug) has proven to enhance the bioavailability of oral
docetaxel in several trials.
The department of pharmacy of the Slotervaart Hospital and Netherlands Cancer
Institute has developed several solid oral dosage forms for docetaxel,
including ModraDoc001 (10 mg capsules) and ModraDoc003 (10 mg tablets). The
ModraDoc001 (10 mg capsules) have been used in more than 90 patients in a Phase
I clinical trial.
The metabolism of docetaxel, after oral administration in combination with
ritonavir has not been investigated, nor has the route of elimination been
determined. A mass balance study can provide essential knowledge on the
absorption, metabolism and excretion of the drug.
Study objective
The primary objective of this study is to quantitatively determine the
pharmacokinetics (absorption, distribution, metabolism and excretion) of
docetaxel (as ModraDoc003 10mg tablets) after administration of a single dose
of oral docetaxel in combination with ritonavir.
Study design
In this study patients will receive a single dose of 60 mg oral docetaxel (as
ModraDoc003 10 mg tablets) and 200 mg ritonavir. This will be followed by
collection of pharmacokinetic samples and excreta (urine and faeces). This is
the mass balance part of the study. The samples of the first patient will be
used as a proof of principle. The aim is to recover >80% of the administered
docetaxel in the collected excreta. The 2nd patient will only enter the trial
after analysis of the samples from the first patient and after evaluation of
the results. Based on the recovery of docetaxel-derived products in the excreta
of the first patient, a decision will be made either to continue with the
sample collection and analysis procedures in the same way or to
increase/decrease the collection period for excreta and/or to expand the
bioanalytical assays for quantification of metabolites with additional
metabolite(s).
In the subsequent or so-called extension phase of this study, which starts on
day 15, patients continue with weekly docetaxel (60 mg) and ritonavir (200 mg)
until progressive disease or until adverse events, which require dose
modification or discontinuation of therapy, are observed.
Study burden and risks
- Patients participating will be hospitalized for 3 to 8 days, during which all
urine and feces will be collected. Patients who collect their excreta on an
out-patient basis (in consultation with principal investigator possible after
at least 72h) will have to return to the hospital daily, up to day 8 for
collection of blood and delivery of urine and fecal samples. Thereafter,
collection of excreta is continued on an out-patient basis until day 15 or
less, depending on the recovery-time profile of docetaxel-related products of
the first patient.
- Blood will be drawn for pharmacokinetic research, hematology, and serum
chemistry.
- After the first cycle, all patients will have to visit the hospital on a
weekly basis. After the first tumor evaluation (6-8 weeks after start
treatment), this is changed to every two weeks.
- Patients are at risk for docetaxel related side effects.
Plesmanlaan 121
1066 CX Amsterdam
NL
Plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
1. Histological or cytological proof of cancer
2. Patient for whom no standard therapy of proven benefit exist
3. Patients who might benefit from treatment with docetaxel, e.g. advanced breast, gastric, esophagus, bladder, ovarian cancer and non-small cell lung cancer, head and neck cancer, prostate cancer and carcinoma of unknown primary site.
4. Age GE 18 years
5. Able and willing to give written informed consent
6. Able and willing to undergo blood sampling for pharmacokinetics
7. Able and willing to comply with the study protocol for the duration of the study
8. Life expectancy GE 3 months allowing adequate follow up of toxicity evaluation and antitumor activity
9. Minimal acceptable safety laboratory values
a. ANC of GE 1.5 x 10^9 /L
b. Platelet count of GE 100 x 10^9 /L
c. Hepatic function as defined by serum bilirubin LE 1.5 x ULN, ALAT and ASAT LE 2.5 x ULN
d. Renal function as defined by serum creatinine LE 1.5 x ULN or creatinine clearance GE 50 ml/min (by Cockcroft-Gault formula).
10. WHO performance status of 0, 1 or 2
11. No radio- or chemotherapy within the last 4 weeks prior to study entry (except for palliative single dose radiotherapy for pain reduction)
12. Able and willing to swallow oral medication;GE = Greater or Equal than
LE = Less or Equal than
Exclusion criteria
1. Patients with known alcoholism, drug addiction and/or psychotic disorders in the history that are not suitable for adequate follow up
2. Women who are pregnant or breast feeding.
3. Unreliable contraceptive methods. 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. Concomitant use of MDR and CYP3A modulating drugs such as Ca+ -entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine, quinine, tamoxifen, megestrol and grapefruit juice, concomitant use of HIV medications; other protease inhibitors, (non) nucleoside analoga, St. Johns wort or macrolide antibiotics as erythromycin and clarithromycin.
5. Uncontrolled infectious disease or known HIV-1 or HIV-2 type patients
6. Unresolved (>grade 1) toxicities of previous chemotherapy
7. Bowel obstructions or motility disorders that may influence the absorption of drugs
8. Chronic use of H2-receptor antagonists or proton pump inhibitors
9. Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity
10. Pre-existing neuropathy greater than CTC grade 1
11. Symptomatic cerebral or leptomeningeal metastases
12. 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.
13. Legal incapacity
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 | EUCTR2011-004263-77-NL |
| CCMO | NL38034.031.11 |