To determine the maximum tolerated dose (MTD) of ModraDoc006/r (as ModraDoc006 10 mg tablets in combination with one tablet of 100 mg ritonavir) that can safely be administered in a bi-daily weekly schedule in combination with high-dose intensity…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the maximum tolerated dose (MTD) of ModraDoc006/r (as ModraDoc006
10 mg tablets in combination with one tablet of 100 mg ritonavir) that can
safely be administered in a bi-daily weekly schedule in combination with
high-dose intensity modulated radiation therapy and androgen-deprivation
therapy (ADT)
Secondary outcome
1. To determine the safety profile of ModraDoc006/r in combination with ADT and
high dose radiotherapy by looking closely at
- Acute toxicity: severity, duration and relation with treatment of all adverse
events according to NCI-CTCAE version 4.03 and /or the RTOG acute radiation
morbidity scoring criteria occurring from start of treatment until 3 month
after end of radiotherapy.
- Late toxicity: severity, duration and relation with treatment of all adverse
events according to NCI-CTCAE version 4.03 and /or the RTOG late radiation
morbidity scoring criteria occurring from 3 months until 1 year after end of
radiotherapy.
2. To preliminary assess anti-tumour activity of ModraDoc006/r in combination
with radiotherapy and ADT
3. To explore the feasibility and toxicity profile of use of ModraDoc006/r
4. In part 1A: To determine the pharmacokinetics (PK) of docetaxel in this
regime.
Background summary
The treatment with chemotherapy in the field of prostate cancer is expected to
change, based on recent large randomised controlled trials, that have evaluated
early systemic treatment for high risk or metastatic hormone naive disease. In
the metastatic hormone-sensitive group, an improvement in failure free survival
and overall survival was seen with addition of docetaxel in the primary
treatment. In high risk prostate cancer without metastatic disease, a
statistically significant effect of docetaxel on overall survival has not been
established yet and longer follow up of currently ongoing studies is needed.
Based on these recent developments, this study aims to improve the standard of
care in patients with high risk non-metastatic prostate cancer with aggressive
primary tumour characteristics, for whom early chemotherapy treatment could be
beneficial.
This study provides 3 new approaches;
1. better selection of truly high risk patients with an agressive form of
prostate cancer, for whom prevention or delaying the development of recurrent
disease is considered clinically beneficial.
2. combined modality treatment with chemotherapy during the radiotherapy. With
the fact that docetaxel is a known radiosensitizer, this could also lead to
better local control and reduction of local recurrence. The safety of the
combination of high dose radiotherapy of the prostate and concurrent weekly
infusions with docetaxel, has been evaluated in six phase I/II trials.
3. advantages of oral above intravenous treatment with docetaxel. Besides the
higher patient convenience, possibly longer treatment duration can be achieved
due to better safety (neutropenia, hypersensitivity reactions and peripheral
polyneuropathy)
Study objective
To determine the maximum tolerated dose (MTD) of ModraDoc006/r (as ModraDoc006
10 mg tablets in combination with one tablet of 100 mg ritonavir) that can
safely be administered in a bi-daily weekly schedule in combination with
high-dose intensity modulated radiation therapy and androgen-deprivation
therapy (ADT) in patients with high risk prostate cancer.
Study design
This is an open-label, dose-escalating, non-randomized, single centre phase I
study of ModraDoc006/ritonavir combined with ADT and radiotherapy in patients
with high risk, histologically proven node positive prostate cancer.
Patients will be treated with standard hormonal therapy (HT) for 36 months. At
a maximum of 12 weeks after the start of the HT, treatment starts with
radiotherapy (5 fractions a week for 7 weeks) and weekly ModraDoc006/r in the
dose escalation part (during the radiotherapy) followed by the adjuvant part up
to 18 weeks.
The safety profile and maximal tolerated dose of the treatment will be
determined by evaluation of the acute and late toxicity.
Evaluation of efficacy and tumour respons will be done by clinical evaluation,
PSA measurements and MRI-scans.
Intervention
Addition of treatment with ModraDoc006/ritonavir to the standard treatment with
radiotherapy and hormonal therapy.
Study burden and risks
The risk of the study is qualified as *moderate*. This is motivated by the
following:
1) the study drug is has been tested in two prior phase I trials.
2) The safety of docetaxel as i.v. formulation in combination with radiotherapy
of the prostate has been tested in six prior phase I and II trials.
3) The dose of study drug will only be increased during this trial after brief
evaluation of the acute and late toxicity. DLT*s were listed after brief
multidisciplinary evaluation and reviewing of current literature. The
restrictions on maximal accepted incidence of DLTs in the TITE CRM will be more
strict, as compared to a general phase I/II design.
Patients are at risk for toxicity associated with treatment with docetaxel and
radiotherapy. Known docetaxel related toxicity consists of myelosuppression,
gastro-intestinal complaints (nausea, vomiting, diarrhea), alopecia, nail
changes, peripheral neuropathy and edema.
Ritonavir is not expected to cause any or only mild toxicity, most common of
the gastro-intestinal tract.
Main toxicities associated with radiotherapy of the prostate are diarrhea and
urinary complaints.
Diarrhea and urinary complaints were also the main toxicities in the prior
phase I/II trials with combined modality treatment with docetaxel and
radiotherapy of the prostate.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Histologically proven prostate cancer.
2. All eligible patients have hormone naïve non-metastatic radiographic node
positive (>4 nodes) high risk prostate cancer.
3. High risk prostate cancer will be defined as node positive with all of the
following primary tumour characteristics: Tumour stage >=cT2c and Gleason score
>=4+3, any PSA
4. Age above 18 years
5. No signs of metastatic disease on standard diagnostic scans.
6. Adequate haematological, renal and hepatic functions
7. WHO performance status of 0-2
8. For Phase 1A only: Able and willing to undergo blood sampling for PK and PD
analysis;
9. Life expectancy above 3 months allowing adequate follow up of toxicity
evaluation and antitumor activity;
10. Able and willing to swallow oral medication
11. Able and willing to give written informed consent
Exclusion criteria
1. Any treatment with investigational drugs, chemotherapy or immunotherapy
within 30 days prior to receiving the first dose of investigational treatment;
Patients may be on ADT as long as this is has not been longer than 12 weeks
prior the start of the radiotherapy.
2. Patients who have had prior pelvic radiation therapy
3. Patients who have had prior treatment with taxanes
4. TURP within 3 months before start of the study
5. Patients who have had a prostatectomy.
6. Any contra-indication for MRI
7. Major difficulties for marker implantation
8. Unreliable contraceptive methods. Men enrolled in this trial must agree to
use a reliable contraceptive method throughout the study (adequate
contraceptive methods are: condom, sterilization)
9. Unresolved (> grade 1) toxicities of previous chemotherapy, excluding
alopecia.
10. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1
or HIV-2 type patients;
11. Patients with a known history of hepatitis B or C;
12. Bowel obstructions or motility disorders that may influence the resorption
of drugs as judged by the treating physician
13. 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 analoga, or St. John*s wort.
14. Pre-existing neuropathy greater than NCI-CTCAE v4.03 grade 1.
15. Patients with known alcoholism, drug addiction and/or psychiatric of
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.
16. 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 | EUCTR2015-004272-30-NL |
| CCMO | NL55216.031.15 |