E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Castration Resistant Prostate Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Prostate Cancer that has spread beyond the prostate and no longer responds to hormonal therapies |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062904 |
E.1.2 | Term | Hormone-refractory prostate cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036920 |
E.1.2 | Term | Prostate cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036909 |
E.1.2 | Term | Prostate cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine if a weekly regime improves tolerability of cabazitaxel compared to the standard 3 week regimen |
|
E.2.2 | Secondary objectives of the trial |
To compare drug efficacy, drug safety and patient quality of life in a weekly and three week scheduling of cabazitaxel |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Written informed consent
• Histological confirmed prostate cancer
• Macroscopic metastatic disease
• Prior treatment with Docetaxel
• Castration resistant disease defined as :
Serum testosterone (< 0.5 ng/ml) and :
* Increase in measurable disease (Recist 1.1) Or
* Appearance of new lesions
Or
* Rising PSA
|
|
E.4 | Principal exclusion criteria |
• Less than 21 days since prior treatment with chemotherapy,
• Less than 14 days since radiotherapy or surgery to the start of cabazitaxel
• Less than 4 weeks after stopping abiraterone or other new anti-hormonal drugs
• Prior isotope therapy or radiotherapy to > 30% of bone marrow (whole pelvic radiotherapy is not an exclusion criteria)
• Adverse events from previous cancer therapies > grade 1 (NCI CTCAE V4.03) with the exception of alopecia. (With respect to peripheral neuropathy grade 2 is acceptable)
• Age less than 18 years
• ECOG performance status > 2
• Known CNS malignancy
• Within 6 months of randomization: myocardial infarction , unstable angina, angioplasty, bypass surgery, stroke, TIA, or congestive heart failure NYHA class III or IV
• Within 3 months prior to randomization: treatment resistant peptic ulcer disease, infectious or inflammatory bowel disease, pulmonary embolism
• Any severe acute or chronic medical condition that places the patient at increased risk of serious toxicity or interferes with the interpretation of study results
• Unable to comply with study procedures
• History of hypersensitivity to docetaxel or polysorbate 80
• Inadequate organ and bone marrow function as defined below
• Concurrent or planned treatment with potent inhibitors or inducers of cytochrome P450 3A4/5 ( eg simvastatin, keotconazole. For comprehensive list please see Appendix ) a one week wash out period is necessary for patients who are already on these treatments).
• Patients with reproductive potential not implementing accepted and effective method of contraception.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is to compare dose intensity of the 3-weekly and the weekly schedules after 18 weeks of planned therapy.
The defininition of dose intensity is based upon the total dose the patient actually receives in relation to the total dose that the patient is expected to receive by 18 weeks of therapy. This definition applies to patients discontinuing therapy for reasons other than disease progression. For patients stopping treatment due to lack of efficacy, dose-intensity is based on the total dose received over the interval of time from the start of chemotherapy until the date of the last dose given. Both treatment arms are designed to have the same dose-intensity at the outset ie 150 mg/m2 as the total dose given over 18 weeks representing 100 % dose intensity in relation to the planned total dose at the start of treatment. Dose delays, dose reductions and especially stopping treatment for reasons other than disease progression will be mirrored by lowering the dose given in relation to the dose planned and as such is an objective measure of drug tolerability.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
By definition all patients discontinuing treatment before 18 weeks from the start of therapy or patients who reach 18 weeks of therapy will be evaluated for the primary endpoint. |
|
E.5.2 | Secondary end point(s) |
Overall Survival
Disease Specific Survival
Progression Free Survival
Progression free survival is defined as the length of time from randomization to the first documentation of one of the following:
PSA progression
or
Pain progression
or
Death due to any cause
or
Radiological disease progression
PSA progression is defined as either a 25% increase (at least 2 ng/ml) from baseline in patients not achieving a prior > 50% decrease in PSA or a 50% increase in PSA (at least 2 ng/ml) above the nadir value in patients who have achieved a prior > 50% decrease in PSA. A confirmatory PSA will be taken at least 3 weeks later. During the first twelve weeks of therapy increases in PSA may reflect treatment induced PSA-flare and can therefore be misleading. A rising PSA, during the first 12 weeks of treatment, without clinical and/or radiological signs of progression is therefore not considered as disease progression.
Pain will be assessed using the Present Pain Intensity (PPI) scale (see appendix). Pain assessment will be made at baseline and before each treatment until the patient discontinues therapy. Diaries will be used to assess analgesic consumption. Pain progression is defined as
1) the need for palliative radiotherapy if the symptoms giving rise to radiotherapy were not present at baseline or
2) they were present but the pain have worsened to the extent that the physician in question feels that it is in the patients best interest to radiate. Pain progression exists when the patients`
3) median PPI score increases by at least one point from nadir or
4) there is an increase in analgesic consumption of 25% over baseline.
Radiological disease progression and tumour response are defined according to Recist 1.1 criteria. If lesions are present only in bone and assessed by bone scan, size and intensity of target lesions may not be used to determine disease progression. The appearance of two new lesions confirmed six weeks later is considered as disease progression.
PSA Response
Only considered after 12 weeks of treatment. PSA response is defined as a 50% or greater decline in serum PSA from baseline given that baseline PSA is at least 10 ng/ml.
Quality of Life
Quality of life will be assessed using the FACT-P-T self administered questionnaire. Patients will complete the questionnaire at baseline and the day before the three week general assessments. The questionnaire is to be answered at home.
Dose Intensity at 24 and 36 weeks
Dose intensity is defined in the same manner as for the primary endpoint.
Tolerability
The primary endpoint in this protocol is chosen as a means of estimating tolerability. Another estimate of tolerability will be made by examining the frequency of patients requiring a dose reduction, a dose delay as well as patients. At each cycle of therapy evaluation, three questions will apply:
Is the patient stopping treatment for reasons of toxicity and not disease progression?
Is there a dose delay due to toxicity?
Is there dose reduction?
If the answer is yes to any of the three questions, this will be recorded as an event. A patient may subsequently have more than one event, (i.e. dose delay (1 ev.), dose reduction (1 event), stopping treatment (1 event)
Duration of Treatment
Duration of treatment is defined as the length of time from the first day of treatment to the last day of treatment with cabazitaxel.
Efficacy of cabazitaxel in relation to the total cumulative dose of prior treatment with docetaxel
Efficacy endpoints described above will be correlated to the cumulative dosage of docetaxel prior to study treatment
Frequency and time to skeletal related events |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
When the last patient enrolled has either stopped treatment prior to week 18 or has reached the 18 th week of therapy all patients will be evlauated for all endpoints. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
the comparator is standard 3 weekly cabazitaxel |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Trail is stopped when the last enrolled patient has completed 18 weeks of therapy or has stopped therapy at an earlier date due to toxicity or disease progression.
Interim analysis when 43 patients have been randomised and the last patient has passed the time interval stipulated for the primary endpoint. If arm B has a lower dose intensity than arm A at a level of statistical significance of 0.05 or less, the independent data monitoring committee will prematurely end the trial. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |