To quantitatively determine the absorption and excretion of docetaxel (as ModraDoc005 10 mg tablets) after administration of a single low dose and a single high dose of oral docetaxel in combination with ritonavir.
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To quantitatively determine the absorption and excretion of docetaxel (as
ModraDoc005 10 mg tablets) after administration of a single low dose and a
single high dose of oral docetaxel in combination with ritonavir.
Secondary outcome
* To investigate the presence or absence of quantitatively relevant metabolites
of docetaxel as ModraDoc005 10 mg tablets in plasma, faeces and urine.
* To preliminary assess anti-tumor activity of oral docetaxel as ModraDoc005 10
mg tablets combined with ritonavir
* To further characterize the safety and tolerability of oral docetaxel as
ModraDoc005 10 mg tablets in combination with ritonavir.
Background summary
Oral administration of (anticancer) drugs has many advantages over the
intravenous route. However, oral bioavailability of the docetaxel
IV-formulation is low and variable. The bioavailability of docetaxel is limited
due to metabolising cytochrome P450 (CYP) enzymes, especially CYP3A, which are
abundantly present in the gastrointestinal tract. Inhibition of CYP3A4 enzymes
with ritonavir has proven to enhance the bioavailability of oral docetaxel in
several trials.
The department of pharmacy of the Slotervaart Hospital and The Netherlands
Cancer Institute have developed several solid oral dosage forms of docetaxel,
including ModraDoc001 (10 mg capsules) and ModraDoc005 (10 mg tablets).
ModraDoc001 (10 mg capsules) has been administered to more than 90 patients in
Phase I clinical trials. Currently, pharmacokinetics of docetaxel after
administration of ModraDoc005 (10 mg tablets) and ModraDoc001 (10 mg capsules)
are compared in an ongoing study. A tablet formulation is preferred over a
capsule for further clinical development because the tablet production process
is more suitable for large-scale productions. Therefore in the present study
ModraDoc005 (10 mg tablets) will be used.
The metabolism of docetaxel (as ModraDoc 001 or 005) after oral administration
in combination with ritonavir has not been investigated yet, nor have the
routes of elimination been investigated. Phase I clinical trials have focused
on safety and pharmacokinetics of oral docetaxel after once daily and bi-daily
administration. Absorption of a similar daily dose of oral docetaxel can
differ between once daily and bi-daily administration, since absorption of
docetaxel can be hampered by its low solubility in the intestinal tract.
An absorption and excretion study after oral administration of a low dose and a
high dose of ModraDoc 005 can provide essential knowledge on the absorption,
metabolism and excretion of this formulation of docetaxel. This knowledge can
be used for further development of once daily and bi-daily oral administration
schedules of docetaxel. Using validated LC-MS/MS assays, docetaxel can be
quantified in plasma, urine and feces. Further analysis using a combination of
chromatography, UV spectrometry and mass spectrometry may result in detection
and quantification of its known metabolites M1, M2, M3 and M4 and as yet
unidentified metabolites.
Study objective
To quantitatively determine the absorption and excretion of docetaxel (as
ModraDoc005 10 mg tablets) after administration of a single low dose and a
single high dose of oral docetaxel in combination with ritonavir.
Study design
In this study patients will receive a single dose of 20 or 60 mg oral docetaxel
(as ModraDoc005 10 mg tablets) and 100 mg
ritonavir in week 1. This will be followed by collection of pharmacokinetic
samples and excreta (urine and faeces). In the third week, patients will
receive a single dose of 60 or 20 mg oral docetaxel (as ModraDoc005 10 mg
tablets) and 100 mg
ritonavir, again followed by collection of samples. Patients will be randomised
over 2 groups. Group one will receive 20 mg docetaxel in week 1 and 60 mg in
week 3. Group two will receive 60 mg docetaxel in week 1 and 20 mg in week 3.
In the subsequent or so-called extension phase of this study, which starts in
week 4, patients continue with weekly
docetaxel (60 mg) and ritonavir (100 mg) until progressive disease or until
unacceptable toxicity is observed.
Intervention
See section study design
Study burden and risks
- Patients participating will be hospitalized for 2 times 48 hours, during
which all urine and feces will be collected.
- Blood will be drawn for pharmacokinetic research, hematology, and serum
chemistry.
- 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
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 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 * 18 years;
5. Able and willing to give written informed consent;
6. WHO performance status of 0, 1 or 2;
7. Able and willing to undergo blood sampling , urine and faeces sampling for PK;
8. Able and willing to comply with the study protocol for the duration of the study;
9. Life expectancy * 3 months allowing adequate follow up of toxicity evaluation and antitumor activity;
10. Evaluable disease according to RECIST 1.1 criteria;
11. 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 (or * 5 x ULN in case of liver metastases)
d. Renal function as defined by serum creatinine * 1.5 x ULN or creatinine clearance * 50 ml/min (by Cockcroft-Gault formula).
12. Negative pregnancy test (urine/serum) for female patients with childbearing potential;
13. No radio- or chemotherapy within the last 4 weeks prior to study entry (palliative limited radiation for pain control is allowed)
14. Able and willing to swallow oral medication
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, including but not limited to Ca¬¬+-entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine, quinine, tamoxifen, megestrol and grapefruit juice, concomitant use of HIV medications; other protease inhibitors, (non) nucleoside analogs, 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, excluding alopecia
7. Bowel obstructions or motility disorders that may influence the absorption of drugs
8. Neurologic disease that may render a patient at increased risk for peripheral or central neurotoxicity
9. Pre-existing neuropathy greater than CTC grade 1
10. Symptomatic cerebral or leptomeningeal metastases
11. 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.
12. 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 | EUCTR2013-002851-14-NL |
| CCMO | NL45385.031.13 |