E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with prostate cancer (PCa) who experience PSA progression
and who are without detectable metastases following maximal local
treatment consisting of radical prostatectomy (RP) + pelvic
lymphadenectomy (PLND) and external beam radiotherapy (EBRT), or
who present only with biochemical relapse after salvage lymph node
dissection. Among patients with PSA relapse, those at major risk of
metastatic progression will be studied. |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with prostate cancer (PCa) who experience PSA progression
and who are without detectable metastases following maximal local
treatment. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 safety/tolerability of Radium-223 treatment in
patients affected by prostate cancer with biochemical relapse after
maximal local treatment with high risk of metastatic progression. Safety
and feasibility results could be used to plan an eventual phase II/III
trial. |
|
E.2.2 | Secondary objectives of the trial |
To assess biomarkers (PSA and bALP) and imaging progression to
metastatic disease after Radium-223 treatment. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all the following criteria to be enrolled in the study:
1. Male aged 18 years or older with histological confirmation of prostatic adenocarcinoma.
2. Ability to provide informed consent and demonstration of willingness to follow all study phases.
3. Patient has to agree to use effective birth control method during and for 6 months after discontinuation of study treatment.
4. Patient is experiencing biochemical progression according to the following definition:
a. PSA >0.2 ng/ml following maximal local treatment consisting of RP and PLND and adjuvant or salvage EBRT
b. PSA >0.2 ng/ml following maximal local therapy consisting of salvage LND in patients treated primarily by RP + PLND and adjuvant or
salvage EBRT.
5. Negative prognostic factors for metastatic progression.
a. At least 1 of the risk factors should be present according to the
following specific patient scenarios (for group at point 4a).
• Salvage EBRT group (at least one of subsequent factors)
- PSADT <12 months (postoperative PSA)
- pT ≥3
- pGS ≥8
• Adjuvant EBRT group (at least one of subsequent factors):
- pT ≥3 and pGS ≥8
- pT ≥3 and detectable postoperative PSA
- PSADT <12months (PSA post adjuvant EBRT)
• pN1 (at least one of subsequent factors):
- pGS ≥8
- pT ≥3
- ≥3 positive nodes
- Positive surgical margins
b. At least 1 of the risk factors should be present according to the
following specific patient scenarios (for group at point 4b):
• PSA≥0.2 ng/ml relapse within 40 days after salvage lymph node
dissection
• Retroperitoneal lymph node positivity at salvage lymph node
dissection
6. Absence of metastatic disease at Choline PET-CT, 18F-Fluoride PETCT and whole-body MRI.
7. Adequate haematological, liver and renal function:
• Absolute neutrophil count (ANC) ≥ 1.5 x109/l
• Platelet count ≥ 100 x109/L
• Hemoglobin ≥10.0 g/dl (100 g/l; 6.2 mmol/l)
• Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN)
or Gilbert Syndrome without any other liver dysfunction.
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN
• Creatinine ≤ 1.5 x ULN
• Albumin > 25 g/l |
|
E.4 | Principal exclusion criteria |
Patients should not meet any of the following criteria:
1. Previous (ADT stopped at least 6 months before screening is allowed
and serum testosterone assay should be evaluated in these patients to
exclude levels <20ng/dl. If testosterone levels have been demonstrated
as ≥20ng/dl after interruption of ADT, further testosterone evaluations
can be avoided) and ongoing systemic PCa therapies or other PCa
investigational treatments including also 5-alpha reductase inhibitors,
azole antifungal agents, corticoids, food supplements containing soy
isoflavones.
2. Radiotherapy to approximately >25% of bone marrow, including
hemibody radiation.
3. Bone systemic therapy.
4. Other malignancy treated within the last 3 years.
5. Have any contraindication to imaging diagnostic procedures (Choline
PET-CT,18F- Fluoride PET-CT and whole-body MRI).
6. Diagnosis of visceral and/or node and/or bone metastases at Choline
PET-CT and/or 18F- Fluoride PET-CT and/or whole-body MRI.
7. Any other serious illness or medical condition, such as but not limited to:
- Any major infection
- Cardiac failure New York Heart Association (NYHA) III or IV
- Crohn's disease or ulcerative colitis
- Bone marrow dysplasia
- Fecal incontinence
8. Medical condition or other elements that, in the investigator's opinion, could decrease the possibility to reach objectives of the study.
9. ECOG performance status ≥2
10. Life expectancy < 6 months |
|
E.5 End points |
E.5.1 | Primary end point(s) |
•Throughout the entire study, safety data will be collected as
frequencies of different AE/SAE obtaining proportions of side effects in
order to confirm tolerability patterns for the present study population.
•Feasibility variables will be collected as: recruitment rates, consent
rates, completion rates; completion of the study will test logistic,
procedural and administrative feasibility. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Throughout the entire study, safety data will be collected: from the first
visit before the first dose and then every 4 weeks before drug injection
(for a total of 6 injections). Every 3 months for 4 visits after the last
dose and thyen every 3 months until the end of the study.
•Feasibility variables will be collected at the end of the study. |
|
E.5.2 | Secondary end point(s) |
evaluate PSA progression kinetics (median time to PSA progression).
PSA progression is every confirmed (3 confirmatory PSA measurements,
at least 1 week apart) PSA relapse with an increase superior to 50%
from PSA nadir or confirmed PSA (3 confirmatory PSA measurements, at
least 1 week apart) detectability when PSA became not more detectable.
•bALP will be sampled during treatment and follow-up. bALP will be
assessed as the proportion of patients who have biochemical values out
of normality range. Time to bALP progression will be measured in order
to better understand the bALP variations (median time to bALP
progression) during the study.
•Metastasis outbreak will be detected by medical imaging (Choline PETCT,
18F-Fluoride PET-CT and whole-body MRI ) before treatment and
follow up with a maximum number of 2 imaging sessions (screening
included). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
•PSA will be assessed: from screening visit, at every visit time.
•bALP will be assessed: from screening visit, at every visit time.
•Metastasis outbreak will be detected by medical imaging (Choline PETCT,
18F-Fluoride PET-CT and whole-body MRI ) before treatment and
follow up ( at PSA progression or end of follow up). |
|
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 | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
The study drug is going to be tested in a novel population. |
|
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | |