The primary aim of this trial is to determine the recommended safe dose and schedule of ModraDoc006/r in castration-resistant prostate cancer (CRPC) patients. The first 5 CRPC patients in this study showed a different pharmacokinetic profile, as…
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Brief title
Condition
- Reproductive neoplasms male malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is to determine the recommended dose determined as the
maximum tolerated dose (MTD) of docetaxel (as ModraDoc006 10 mg tablets) that
can safely be administered in combination with ritonavir to patients with
metastatic castration-resistant prostate cancer in a bi-daily weekly schedule
without interruption and results in an adequate systemic exposure to docetaxel.
Secondary outcome
• The systemic exposure of docetaxel and ritonavir given as bi-daily
ModraDoc006 10 mg tablets in combination with ritonavir.
• The hematological and non-hematological toxicity profile of oral docetaxel in
combination with ritonavir.
• The preliminary anti-tumor activity of oral docetaxel.
• The dose limiting toxicities (DLT) and recommended dose (RD) of ModraDoc006/r
that can safely be administered to patients with metastatic
castration-resistant prostate cancer in a bi-daily weekly schedule.
Background summary
For patients oral administration of anticancer drugs has several advantages
above intravenous administration of these drugs. Besides the need for hospital
admission, intravenous administration of docetaxel has the drawback of
frequently observed infusion related reactions. For this reason dexamethasone
is given prophylactically to all patients receiving intravenous docetaxel. As
mentioned, the standard intravenous docetaxel treatment for castration
resistant metastatic prostate cancer dictates the long-term use of
prednisolone. With oral docetaxel treatment, toxicity of long-term treatment
with corticosteroids can be avoided. In addition to the higher patient
convenience, possibly longer treatment duration can be achieved due to better
safety. If non-inferiority in efficacy and improved safety and patient
convenience can be demonstrated, ModraDoc006/r treatment will have advantages
for patients with advanced prostate cancer.
The maximum tolerated dose of ModraDoc006/r has been established as 30 mg of
docetaxel in the morning combined with 100 mg ritonavir and 20 mg in the
afternoon combined with 100 mg ritonavir. This scheme is given once weekly
without interruption. This dose and schedule have been established in patients
with advanced solid tumours, however the feasibility and pharmacokinetics have
not yet been explored in the target patient population of the projected pivotal
non-inferiority study. Therefore, the current safety, feasibility and
pharmacokinetic study was proposed.
The primary aim of this trial is to determine the recommended safe dose and
schedule of ModraDoc006/r in castration-resistant prostate cancer (CRPC)
patients. The first 5 CRPC patients in this study showed a different
pharmacokinetic profile, as compared to the patients receiving the same dose in
a previous phase I study. Because of these results, a classical dose
escalation design will be used to determine the recommended dose of
ModraDoc006/r that is safe and feasible and provides an adequate systemic
docetaxel exposure in the target population of the projected pivotal study in
patients with CRPC
Study objective
The primary aim of this trial is to determine the recommended safe dose and
schedule of ModraDoc006/r in castration-resistant prostate cancer (CRPC)
patients. The first 5 CRPC patients in this study showed a different
pharmacokinetic profile, as compared to the patients receiving the same dose in
a previous phase I study. Because of these results, a classical dose
escalation design will be used to determine the recommended dose of
ModraDoc006/r that is safe and feasible and provides an adequate systemic
docetaxel exposure in the target population of the projected pivotal study in
patients with CRPC
Study design
This is an open label, multicenter, safety, feasibility and pharmacokinetic
phase I trial.
Three castration-resistant metastatic prostate cancer (CRPC) patients will be
assigned to the starting dose level 1A of 30-20 mg ModraDoc006 in a bidaily
weekly schedule, each intake of ModraDoc006 will be combined with 200 mg
ritonavir.
If no more than one DLT has occurred during the first four weeks of treatment
on dose level 1A (30-20 mg ModraDoc006 and bidaily 200 mg ritonavir) and the
pharmacokinetic results are favourable than three extra patients will be added
to this dose level. If no more than 1 DLT in these first 6 patients has
occurred, this will be the recommended dose and this dose level will be
expanded until a total of 20 for toxicity evaluable patients have been treated
on this dose level.
If 2 DLTs have occurred directly in the first 3 patients or in the first 6
patients (after the previous described addition of 3 patients), during the
first four weeks of treatment on dose level 1A (30-20 mg ModraDoc006 and
bidaily 200 mg ritonavir) and the pharmacokinetic results are favourable the
dose may be de-escalated to the next lower dose-level, depending on the type of
DLT and the study schedule will start again from the beginning.
If no more than one DLT has occurred in the first 6 patients during the first
four weeks of treatment on dose level 1A (30-20 mg ModraDoc006 and bidaily 200
mg ritonavir) and the pharmacokinetic results are not favourable, than the dose
will be escalated depending on the pharmacokinetic results and the study
schedule will start again from the beginning.
If two or more DLTs have occurred in the first 6 patients during the first four
weeks of treatment on dose level 1A (30-20 mg ModraDoc006 and bidaily 200 mg
ritonavir) and the pharmacokinetic results are not favourable the dose will be
altered within the same digital doselevel, according to the type of DLT.
Study burden and risks
Patients are at risk for docetaxel-related side effects. They will be
hospitalized 2 times for 1 day for pharmacokinetic blood sampling.
Louwesweg 6
Amsterdam 1066 EC
NL
Louwesweg 6
Amsterdam 1066 EC
NL
Listed location countries
Age
Inclusion criteria
1. Histological or cytological proven castration-resistant metastatic prostate cancer with an indication for systemic treatment with intravenous docetaxelat the discretion of the physician
2. Progressive disease defined as biochemical and/or radiological progression according to the Prostate Cancer Working group 3 recommendations
3. Chemotherapy naïve patients. Prior treatment with abiraterone or enzalutamide as first line therapy is allowed.
4. Disease evaluable for biochemical and/or radiological response
5. Castrate levels of testosterone
6. Age equal or above 18 years
7. Adequate haematological, renal and hepatic functions
8. WHO performance status of 0-2
9. Life expectancy above 3 months
10. Able and willing to swallow oral medication
11. Able and willing to undergo blood sampling for pharmacokinetics and assessment of CTCs.
12. Able and willing to give written informed consent
Exclusion criteria
1.Any treatment with investigational drugs, chemotherapy or immunotherapy within 28 days prior to receiving the first dose of investigational treatment. Palliative radiotherapy is allowed before and during the study as long as this is scheduled outside the DLT period (first 28 days) at least 4 days after intake of study medication and no intestinal toxicity is expected from the radiotherapy
2. Patients with symptomatic brain metastases. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy for at least 6 weeks are allowed to enroll. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening, demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive anti-epileptic drugs or corticosteroid treatment indicated for brain metastasis. Patients with a history of leptomeningeal metastases are not eligible.
3.Unreliable contraceptive methods.
4.Unresolved (> grade 1) toxicities of previous therapy, excluding alopecia.
5. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
6. Patients with a known history of hepatitis B or C;
7. Bowel obstructions or motility disorders that may influence the resorption of drugs as judged by the treating physician
8. Concomitant use of MDR and CYP3A modulating drugs such as Ca+- entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine, tamoxifen, megestrol and grapefruit juice, concomitant use of HIV medications, other protease inhibitors, (non) nucleoside analogues, or St. John*s wort.
9. Use of Bicalutamide within 14 days prior to receiving the first dose of investigational treatment
10. Patients with known alcoholism, drug addiction and/or psychiatric or physiological condition which in the opinion of the investigator would impair study compliance; 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.
11. 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 | EUCTR2016-005056-13-NL |
| CCMO | NL60262.031.16 |