E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Castration Resistant Prostate cancer patients with bone metastases |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with prostate cancer which has spread to the bone |
|
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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036916 |
E.1.2 | Term | Prostate cancer stage D |
E.1.2 | System Organ Class | 100000004864 |
|
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 safety of re-treatment with up to 6 doses of radium-223 dichloride 50 kBq/kg given every 4 weeks in subjects with castration-resistant prostate cancer (CRPC) with bone metastases who received an initial course of 6 doses of radium-223 dichloride 50 kBq/kg. |
|
E.2.2 | Secondary objectives of the trial |
• Radiological progression free survival (rPFS)
• Time to radiological bone progression
• Total alkaline phosphatase (ALP) response rate
• Time to total ALP progression
• Percentage change in total ALP
• Prostate specific antigen (PSA) response rate
• Time to PSA progression
• Overall survival
• Pain improvement rate
• Time to pain progression
• Time to first symptomatic skeletal event (SSE)
• SSE-free survival (SSE-FS) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically or cytologically confirmed adenocarcinoma of the prostate at any given point in time during disease history
- CRPC (castration-resistant prostate cancer) with clinical or radiologically confirmed bone progression
- Treatment with 6 injections of radium-223 dichloride 50 kBq/kg and no evidence of progression to bone (according to Prostate Cancer Clinical Trials Working Group 2 [PCWG2] criteria) during the first course of treatment
- Re-treatment with radium-223 dichloride is indicated based on one or
more of the following:
o Radiological progression (according to PCWG2 criteria) in bone after the initial course of radium-223 dichloride treatment or
o Clinical progression defined as:
- Confirmed rising PSA (2 subsequent values showing PSA increase [a minimum value of 2 ng/mL {μg/L}], at least 1 week apart) after the initial course of radium-223 dichloride treatment or
- Substantial worsening of pain after the initial course of radium-223 dichloride treatment, based on the investigator’s determination. This pain should be due to the existing bone metastasis.
- Signed written informed consent prior to participating in any study related procedures. Willing and able to comply with the protocol, including follow-up visits and examinations |
|
E.4 | Principal exclusion criteria |
- History of a radium-223 dichloride-related serious adverse event (SAE) or CTCAE Grade 3 or 4 adverse event (AE) during or after the initial course of radium-223 dichloride treatment that led to the discontinuation of treatment
- Less than 30 days from the last dose administered in the initial course of radium-223 dichloride treatment
- Visceral metastases 1 cm or greater in largest diameter and / or requiring local or systemic therapeutic intervention, as assessed by abdominal and pelvic magnetic resonance imaging (MRI) / computed tomography (CT) scan and / or chest X-ray within 30 days of the start of treatment
- Lymphadenopathy with lymph nodes exceeding 6 cm in short-axis diameter and / or requiring local or systemic therapeutic intervention. Enlarged lymph nodes of any size if the lymphadenopathy is thought to be a contributor to concurrent hydronephrosis
- Current central nervous system (CNS) metastases
- Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget’s disease of bone)
- Treatment with chemotherapy after the initial course of radium-223 dichloride treatment
- Prior hemibody external radiotherapy
- Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188
- Any other serious illness or medical conditions
-- Crohn’s disease or ulcerative colitis
-- History of documented bone marrow dysplasia
-- Unmanageable fecal incontinence
- Imminent or established spinal cord compression based on clinical findings and / or MRI that has not yet been treated
- Other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1) Number of participants with either treatment-related AEs (adverse events) or SAEs (serious adverse events)
2) Number of participants with Radium-223 dichloride-related SAEs in the active follow-up period
3) Change in complete blood count
4) Number of participants who discontinue Radium-223 dichloride treatment due to treatment emergent AEs or death |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Up to 7 months - Treatment 2 (Day 1, 8, 15, 22), Day 1 of Treatment 2,3,4,5,6
2) Up to 2 years after last treatment - q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose and end of follow-up
3) Up to 2.5 years - screen, visit 2-10 then q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose and end of follow-up
4) Up to 7 months |
|
E.5.2 | Secondary end point(s) |
1) Radiological progression free survival
2) Time to radiological bone progression
3) Pain improvement rate (defined as the number of subjects with pain improvement, divided by the total number of subjects evaluable for pain improvement.)
4) Time to pain progression (defined as the occurrence of either a pain increase or an increase in pain management with respect to baseline, whichever occurs first).
5) Overall survival
6) Time to first symptomatic skeletal event (SSE)
7) SSE-free survival
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1)Visit 8, 30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
2)Visit 8, 30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
3)Visit 2, 6, 7, 8, 9, 10 and 30 days post-last-dose
4)Visit 2, 6, 7, 8, 9, 10 and 30 days post-last-dose
5)Visit 1-10,30 days post-last-dose, q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose and end of follow-up,q6 mo until 7 yrs post-late-dose
6)Visit 1-10,30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
7)Visit 1-10,30 days post-last-dose,q4 weeks for 12 weeks then q12 weeks until 2 years post-last dose & end of follow-up
Refer to protocol section 7.6 for further details |
|
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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Finland |
Germany |
Israel |
Italy |
Norway |
Spain |
Sweden |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |