E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastasized Castration Resistant Prostate Cancer |
Gemetastaseerd Castratieresistent Prostaat carcinoom |
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E.1.1.1 | Medical condition in easily understood language |
Prostate cancer |
Prostaatkanker |
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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 | 21.1 |
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) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060862 |
E.1.2 | Term | Prostate cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036911 |
E.1.2 | Term | Prostate cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066489 |
E.1.2 | Term | Progression of prostate cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076506 |
E.1.2 | Term | Castration-resistant prostate cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
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) |
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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 assess the Clinical Benefit Rate (CBR) in patients with mCRPC and poor prognostic factors treated with cabazitaxel (Arm A) or novel hormonal agents (abiraterone OR enzalutamide) as second-line therapy (Arm B) who have been treated with docetaxel.
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E.2.2 | Secondary objectives of the trial |
• compare the Clinical Benefit Rate (CBR) in both study arms A and B.
• determine duration of treatment (DOT), Time To Symptomatic Progression (TTSP), Time To PSA Progression (TTPP), and Time To Radiologic Progression (TTRP)
• determine the Progression Free Survival (PFS)
• determine the Overall Survival (OS)
• evaluate safety and toxicity profile of cabazitaxel and novel hormone agents (abiraterone OR enzalutamide) as a second line treatment.
• Quality of Life (QoL) as assessed by FACT-P questionnaire and Pain response as assessed by BPI-S questionnaire and opiate use |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Three biomarker studies are included in this randomized trial. The value of the neutrophil to lymphocyte ratio, mutations in cfDNA and epigenetic modifications of cfDNA as predictive biomarkers will be explored.
These three biomarkerstudies don't have their own title, and will start when the OSTRICh study start.
Another sub-study was added in December 2018; in this sub-study ChIP-sequencing on biopsies from metastases will be perfomed to to validate drug sensitivity of the previous identified clusters of metastases based on epigenetic regulation. |
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E.3 | Principal inclusion criteria |
1. Histological diagnosis of prostate adenocarcinoma.
2. Able and willing to provide informed consent and to comply with the study procedures
3. Age ≥18
4. Evidence of bone, visceral and/or lymph node metastases on bone scan, CT-scan or MRI.
5. Must have received at least one prior regimen of docetaxel treatment for at least 12 weeks (four courses) and no other prostate cancer treatments between docetaxel and randomization, other than prednisone.
6. Continued androgen deprivation therapy either by LHRH agonist/ antagonist or orchiectomy.
7. Treatment with curative intent is not an option and patient has an indication for systemic treatment as judged by the medical care provider
8. Evidence of progressive metastatic disease by PSA progression (Prostate Cancer Working Group 3 (PCWG3) criteria: at least 2 rises at a minimum of 1-week intervals. The first PSA value must be ≥ 2 ng/ml) and/or radiological progression as evaluated by chest, abdominal, or pelvic CT/MRI scan and/or bone scan within 28 days of registration (see Appendix III)
9. Poor prognosis disease as defined by any of the following:
a) The presence of liver metastases AND/OR
b) Development of castration-resistance within 12 months of orchiectomy or commencement of LHRH antagonist/agonist for metastatic disease AND/OR
c) Progressive disease during docetaxel treatment or <6 months after completion of docetaxel treatment
10. WHO PS 0-2.
11. Serum testosterone < 50 ng/dL (< 1.7 nmol/L) within 28 days before treatment group allocation
12. At least 21 days have passed since completing radiotherapy (exception for a single fraction of ≤ 800 cGy to a restricted field or limited-field radiotherapy to non-marrow bearing area such as an extremity or orbit: at least 7 days prior to randomization).
13. At least 21 days have passed since major surgery.
14. Neuropathy ≤ grade 1 at the time of registration.
15. Has recovered from all therapy-related toxicity to ≤ grade 2 (except alopecia, anemia and any signs or symptoms of androgen deprivation therapy) at the time of registration.
16. Eligible for cabazitaxel, abiraterone acetate or enzalutamide as per standard of care practices.
17. Men treated with cabazitaxel should use effective contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of cabazitaxel. Due to potential exposure via seminal liquid, men treated with cabazitaxel should prevent contact with the ejaculate by another person throughout treatment. Men being treated with cabazitaxel are advised to seek advice on conservation of sperm prior to treatment.
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E.4 | Principal exclusion criteria |
1. Histologic evidence of small cell/neuroendocrine prostate cancer
2. Any treatment other than prednisone between docetaxel and cabazitaxel/abiraterone OR enzalutamide sequence
3. Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus).
4. History of severe hypersensitivity reaction (≥ grade 3) to docetaxel, abiraterone or enzalutamide (whichever applies).
5. History of severe hypersensitivity reaction (≥ grade 3) to polysorbate 80 containing drugs.
6. Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments).
7. Patients who have a concurrent yellow fever vaccination (several weeks before start of treatment) must be excluded.
8. Dementia, altered mental status, or any psychiatric condition, if this is in conflict with the study.
9. Unable to swallow a whole tablet or capsule
10. Contraindications to the use of corticosteroid treatment
11. Symptomatic peripheral neuropathy Grade ≥2 (National Cancer Institute Common Terminology Criteria [NCI CTCAE] v.4.0).
12. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured and needing no subsequent therapy.
13. Inadequate organ and bone marrow function as evidenced by:
a. Hemoglobin <10.0 g/dL
b. Absolute neutrophil count <1.5 x 109/L
c. Platelet count < 100 x 109/L
d. AST/ SGOT and/ or ALT/ SGPT > 1.5 x ULN
Total bilirubin >1 x ULN (except for patients with documented Gilbert’s disease).
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E.5 End points |
E.5.1 | Primary end point(s) |
To establish the Clinical Benefit Rate (CBR) in both study arms:
Percentage of patients that fulfill the criteria of clinical benefit. Patients are considered to have had a clinical benefit if they have a radiological response of any duration or stable disease for 12 weeks, in the absence of symptomatic progression, or objective disease progression.
Radiological Response
Subjects that have measurable disease at screening will be evaluated for response on the basis of RECIST criteria v1.1, Tumor measurements using physical examination, chest, abdomen, pelvic CT scan, and/or MRI or other appropriate techniques deemed suitable by the investigator will be performed at screening within 28 days of subject registration and repeated at week 6, 12, 18 and 24 followed by every 12 weeks.
Symptomatic or objective disease Progression
Disease Progression is defined as the development of symptomatic or radiological progression at any time. Progression will be classified as any of the following:
1. Symptomatic progression: worsening of cancer-related symptoms mandating a change in anti-cancer therapy (radiation, chemotherapy or antihormonal therapy) or ≥ 2 level decrease in WHO PS.
2. Radiological progression: RECIST criteria v1.1 for measurable disease and/or appearance of 2 or more 2 new bone lesions on whole body bone scan confirmed on a subsequent scan31.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Formal comparison of the CBR in both study arms.
2. Duration of treatment (DOT); time from randomization to last day of treatment.
3. Time To Symptomatic Progression TTSP; time from randomization to day of worsening of cancer-related symptoms mandating a change in anti-cancer therapy (radiation, chemotherapy or antihormonal therapy) or ≥ 2 level decrease in WHO PS.
4. Time To Radiological Progression (TTRP); time from randomization to day of radiological progression: RECIST criteria v1.1 for measurable disease or appearance of 2 new bone lesions on whole body bone scan confirmed on a subsequent scan.
5. Time To PSA Progression (TTPP); time from randomization to PSA progression (PCWG3 criteria: at least 2 rises at a minimum of 1-week intervals. The first PSA value must be ≥ 2 ng/ml).
6. Progression Free Survival (PFS) is defined as the time of start of treatment and the first date of progression on second line treatment as measured by PSA progression, tumor progression, pain progression during treatment, or death. Assessed in patients who are treated with either arms as second line treatment and in patients who crossed over to the other treatment arm.
7. Overall Survival; time from randomization to date of death. Follow up will be maximum 3 years.
8. To evaluate safety and toxicity profile of cabazitaxel and novel hormone agents (abiraterone OR enzalutamide) all Adverse Events (AEs; assessed by CTCAE 4.03 grading) and Serious Adverse Events (SAEs) will be recorded during second line cabazitaxel/abiraterone OR enzalutamide treatment.
9. Quality of Life (QoL) as assessed by FACT-P questionnaire and Pain response as assessed by BPI-S questionnaire and opiate use will be recorded during second line cabazitaxel/abiraterone OR enzalutamide treatment
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After max 3 years of followup |
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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 | No |
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 | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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
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After 152 participants are included in the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |