| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Castration resistant prostate cancer patients metastatic to bone. |
| Prostata resistente alla castrazione pazienti affetti da carcinoma metastatico alle ossa. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Castration resistant prostate cancer patients metastatic to bone. |
| Prostata resistente alla castrazione pazienti affetti da carcinoma metastatico alle ossa. |
|
| 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) |
|
| 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 if upfront combination of enzalutamide and Ra223 improves radiological progression-free survival (rPFS1) compared to enzalutamide single agent in CRPC patients metastatic to bone. |
| Determinare se Ra-223 + enzalutamide migliora il tempo di progression radiologica se confrontato alla sola somministrazione di enzalutamide. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess if upfront combination of enzalutamide with Ra223 (experimental arm) offers further benefits over enzalutamide alone in terms of the secondary efficacy endpoints listed below, to compare the safety profile of the approaches and to document their impact on patient reported outcomes (pain and quality of life (QoL). |
| Determinare la sicurezza di Ra-223 + enzalutamide e verificare se l¿associazione migliora il dolore e la qualit¿ della vita riportati dal paziente. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
¿ Histologically confirmed diagnosis of prostate adenocarcinoma
¿ Asymptomatic or mildly symptomatic (defined as no opioids and short
form question #3 in Brief Pain Inventory worst pain must be < 4.
¿ Metastatic to bone with = 4 bone metastases (ambiguous areas of
increased uptake on 99mTC Bone Scan (BS) should be confirmed by CT
or MRI) with or without additional lymph node metastases. Patients with
visceral metastases are not allowed. Patients with multifocal bone
lesions are allowed, while patients with diffuse confluent bone lesions
(superscan) are not allowed in the trial.
Note: Patients must start treatment with a bone protecting agent (at
doses used to reduce the incidence of skeletal related events) ideally
before or at the time of randomization, if patient is not already on one. A
minimum of two doses is recommended before the first administration of
Ra223 in the experimental arm. The first administration of Ra223 should
be scheduled at least 6 weeks after the first administration of bone
protecting agent.
¿ Progressive CRPC according to Prostate Cancer Working Group 3
(PCWG3) i.e. either:
-For patients who manifest disease progression solely as a rising PSA
level, PCWG3 criteria require documentation of a sequence of rising PSA
values at a minimum of 1-week intervals with the last value = 2 ng/mL.
-For patients with disease progression manifest in the bone,
irrespective of progression by rising PSA, PCWG3 guidelines require
appearance of 2 or more new lesions. Ambiguous results should be
confirmed by other imaging modalities than bone scan (e.g.: CT-scan or
MRI).
-For patients with disease progression manifest at nodal sites,
irrespective of progression by rising PSA, PCWG3 requires progression
according to RECIST 1.1.
¿ Ongoing androgen deprivation therapy (ADT) with luteinizing
hormone-releasing hormone (LHRH) agonist or antagonist or bilateral
orchiectomy.
Patients must be at least 18 years old
¿ WHO Performance status 0-1
¿ Charlson score = 3
¿ T-score = -2.5 on a DXA scan done in the past 12 months
¿ Castrate serum levels of testosterone < 50 ng/dL
¿ Biochemistry and hematology:
-Adequate bone marrow function (absolute neutrophil count (ANC) =
1.5 109/L; platelets = 100 109/L, and hemoglobin = 10.0 g/dl.).
-Total bilirubin level = 1.5 x institutional upper limit of normal (ULN),
except for patient with Gilbert's disease where = 5.0 × ULN applies.
-Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) = 2.5 x ULN.
-Creatinine = 1.5 x ULN
-Albumin > 25 g/L
¿ Normal cardiac function according to local standard by 12-lead ECG
(complete, standardized 12-lead recording).
¿ Able to swallow the study drug and comply with study requirements
¿ Prior or concomitant therapy.
-Prior docetaxel or abiraterone is permitted if given in the castration
sensitive state and if it was started within 4 months of ADT initiation.
Note: patients having received docetaxel or abiraterone for CRPC are
excluded.
¿ Prior treatment with abiraterone is allowed if it was stopped at least 4
weeks prior to randomization.
¿ Previous treatment with bicalutamide, or flutamide is allowed if it was
stopped at least 48 hours prior to randomization.
¿ Corticosteroids are allowed only at a dose = 10 mg of prednisone (or
equivalent) no matter the indication.
¿ Drugs known to lower the seizure threshold or prolong QT interval are
not permitted.
¿ Participants who have pregnant partners must use a condom and those with partners of childbearing potential must use a condom and another adequate birth control measure if engaging in sexual activities during the study treatment period and for at least 3 months after last dose of enzalutamide and 6 months after the last dose of Ra223. A highly
effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. |
Firma del Consenso Informato.
Conferma istologica di Ca prostata
Paziente asintomatico o lievemente sintomatic
Presenza di almeno 4 metastasi ossee
Prograssione secondo i criteri PCWG3
WHO Performance status 0-1
testosterone < 50 ng/dL
Adeguata funzione midollare
T-Score = -2.5 in mineralometria ossea computerizzata (MOC DXA) eseguita negli ultimi 12 mesi |
|
| E.4 | Principal exclusion criteria |
¿ Known central nervous system metastases or leptomeningeal tumor
spread.
¿ Significant cardiovascular disease including:
-Myocardial infarction within 6 months prior to screening.
-Uncontrolled angina within 3 months prior to screening.
-Congestive heart failure New York Heart Association (NYHA) class III
or IV, or patients with history of congestive heart failure NYHA class III
or IV in the past, unless a screening echocardiogram or multi-gated
acquisition scan (MUGA) performed within 3 months results in a left
ventricular ejection fraction that is = 45%
-History of clinically significant ventricular arrhythmias (e.g.,
ventricular tachycardia, ventricular fibrillation, torsades de pointes).
-History of Mobitz II second degree or third degree heart block without
a permanent pacemaker in place.
-Uncontrolled hypertension as indicated by a resting systolic blood
pressure > 140 millimeters of mercury (mm Hg) or diastolic blood
pressure > 90 mm Hg at screening.
Note: Initiation or adjustment of antihypertensive medication(s) is
permitted prior to randomization. Blood pressure must be re-assessed
on two occasions that are separated by a minimum of 1 hour. The mean
SBP / DBP values from all blood pressure assessment timepoints must
be = 140/90 mm Hg in order for a patient to be eligible for the study.
-Hypotension as indicated by systolic blood pressure < 86 mm Hg at
screening.
-Bradycardia as indicated by a heart rate of < 45 beats per minute on
the screening ECG and on physical examination.
-Uncontrolled hyperglycemia as indicated by a fasting glucose = 7
mmol/L.
¿ Prior treatment with enzalutamide or Ra223.
¿ Concomitant treatment with Cyp17 inhibitors (abiraterone, orteronel)
and ketoconazole.
¿ Prior hemibody external radiotherapy. Patients who received other
types of prior external radiotherapy are allowed provided that the bone
marrow function is assessed and meets the protocol requirements for
hemoglobin, absolute neutrophil count and platelets.
¿ Prior therapy with other radionuclides (e.g., strontium-89, samarium-
153, rhenium-186, or rhenium-188).
¿ Involvement in another therapeutic trial involving an experimental
drug.
¿ Anticancer therapy (except ADT) or treatment with another
investigational agent within the last 4 weeks prior to randomization.
¿ Known hypersensitivity to compounds related to enzalutamide or
Ra223 .
¿ Prior history of malignancies other than prostate adenocarcinoma
(except patients with basal cell, squamous cell carcinoma of the skin, insitu
carcinoma or low-grade superficial bladder cancer), or the patient
has been free of malignancy for a period of 3 years prior to
randomization date.
¿ History of seizure, including any febrile seizure, loss of consciousness,
or transient ischemic attack within 12 months of randomization, OR any
condition that may pre-dispose to seizure (e.g., prior stroke, brain
arterio-venous malformation, head trauma with loss of consciousness
requiring hospitalization).
¿ Major surgery within 4 weeks prior to treatment.
¿ Drug or alcohol abuse.
¿ Other serious illness or medical condition, such as but not limited to:
-Any infection = Grade 2 according to National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.
-No gastrointestinal disorder affecting absorption (e.g., gastrectomy or
active peptic ulcer disease).
-Crohn's disease or ulcerative colitis.
-Osteonecrosis of the jaw.
-Any bone disease with an osteoblastic activity.
-Bone marrow dysplasia.
-Fecal incontinence.
-Life-threatening illness unrelated to cancer.
¿ Condition which, in the investigator's opinion, makes the patient
unsuitable for trial participation. |
metastasi cerebrali
Patologie concomitanti che possono alterare influenzare i risultati dello studio
Precedente trattamento con enzalutamide o Ra223. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Radiological Progression free survival (rPFS1). |
| Sopravvivenza libera da progressione radiologica. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Radiological Progression free survival (rPFS1) counted from randomization to the first progression defined as per the Prostate Cancer clinical trials Working Group version 3 and referred to as the "PCWG3" for the setting "delay/prevent" progression or to death from any cause. |
| Tempo dalla randomiozzazione alla prima profgressione radiologica. |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival;
2. Prostate-cancer specific survival;
3. First symptomatic skeletal event (SSE);
4. Time and incidence of first skeletal progression-free survival;
5. Time to next systemic anti-neoplastic therapy;
6. Treatments elected after first disease progression;
7. Second progression-free survival
8. Safety according to Common Terminology Criteria for Adverse Events.
9. Pain: Brief Pain Inventory (BPI). In this study only pain related to
prostate cancer is considered.
10. Time to pain progression (defined as an increase of 2 or more points
in the "worst pain in 24 hours" score from baseline observed at 2
consecutive evaluations >= 4 weeks apart OR initiation of short or long-acting
opioid use for pain)
11. Time to opiate use for cancer-related pain
12. Quality of Life (EQ-5D-5L)
13. Rate of skeletal fractures |
1. Sopravvivenza globale;
2. Sopravvivenza specifica per carcinoma della prostata;
3. Primo evento scheletrico sintomatico (SSE);
4. Tempo e incidenza della prima sopravvivenza libera da progressione scheletrica;
5. Tempo alla prossima terapia anti-neoplastica sistemica;
6. Trattamenti eletti dopo la prima progressione della malattia;
7. Seconda sopravvivenza libera da progressione
8. Sicurezza secondo i criteri terminologici comuni per gli eventi avversi.
9. Pain: Brief Pain Inventory (BPI). In questo studio solo il dolore riguardava
il cancro alla prostata è considerato.
10. Tempo di progressione del dolore (definito come un aumento di 2 o più punti
nel punteggio "peggior dolore in 24 ore" rispetto al basale osservato a 2
valutazioni consecutive> = a 4 settimane di distanza OPPURE inizio di breve o lunga durata d'azione
uso di oppioidi per il dolore)
11. Tempo di oppiacei da usare per il dolore correlato al cancro
12. Qualità della vita (EQ-5D-5L)
13. Tasso di fratture scheletriche |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Randomization until death (any cause)
2.Randomization until death prostate cancer
3.Randomization until day 1st SSE recorded
4.Between randomization and day 1st skeletal radiological progression
5.Treatment+F-up
6.Between randomization and 1st day next systemic anti-neoplastic
therapy
7.Every 12w from first PD until 2nd PD
8.Randomization to 1st clinical PD on 2nd line treatment,or to death
9.From 21d prior to randomization,at the end of every cycle,every 12w
after PD,at discontinuation of treatment in absence of progression
10&13.Screening,every 3 cycles,at treatment discontinuation in absence
of PD,every 12w during f/up until PD.
11.Randomization to 1st report of pain progression.
12.Interval between randomiz and the 1st report of intake of opioids for
cancer-related pain.; 1.Randomizz |
|
| 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 | No |
| E.6.4 | Safety | No |
| 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) | 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 | 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | Information not present in EudraCT |
| 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 |
| Brazil |
| Canada |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
Fine di studio si verifica quando tutti i seguenti criteri sono stati soddisfatto:
1. Trenta giorni dopo tutti i pazienti hanno interrotto il trattamento protocollo.
2. Il processo ¿ maturo per l'analisi dell'endpoint primario come definito nel protocollo.
3. Il database ¿ stato completamente ripulito e congelati per questa analisi. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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