| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| castration Resistant prOstate caNcer |
| carcinoma della prostata resistente alla castrazione |
|
| E.1.1.1 | Medical condition in easily understood language |
| prOstate caNcer |
| carcinoma della prostata |
|
| 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 demonstrate the candidate efficacy of docetaxel plus prednisone plus enzalutamide (Arm A) versus docetaxel plus prednisone(Arm B) in chemo-naïve mCRPC. |
| Obiettivo primario: dimostrare la superiorità dell’associazione di enzalutamide + docetaxel (braccio A) rispetto a docetaxel da solo (braccio B) in termini di percentuale di pazienti liberi da progressione a 6 mesi dall’inizio del trattamento |
|
| E.2.2 | Secondary objectives of the trial |
To compare the two study arms for:
•activity, disease control and survival
•symptom control and quality of life
•toxicity profile
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following criteria will be considered for enrollment into the study:
1. Histologically- or cytologically-confirmed prostate adenocarcinoma.
2. Metastatic disease.
3. Progressive disease while receiving hormonal therapy or after surgical castration documented by at least one of the following:
a. Increase in measurable disease (RECIST 1.1) [15], and/or
b. Appearance of new lesions, including those on bone scan (≥2 new lesions on 2 consecutive bone scans if progression disease diagnosed on bone scan only) consistent with progressive prostate cancer, and/or
c. Rising PSA defined as 2 sequential increases above a previous lowest reference value. Each value must be obtained at least 1 week apart. A PSA value of at least 2 ng/ml is required at study entry.
d. Effective castration (serum testosterone levels ≤0.50 ng/dL) by orchiectomy and/or LHRH agonists or antagonist with or without anti-androgens.
i. If the patient has been treated with LHRH agonists or antagonist (i.e., without orchiectomy), then this therapy should be continued.
ii. If patients were either started on complete androgen blockade, or had a PSA response (defined by any reduction in PSA sustained for at least 3 months) after adding an antiandrogen, prior anti-androgen therapy should be stopped before randomization: at least 6 weeks for bicalutamide and nilutamide, and at least 4 weeks for flutamide, megestrol acetate and any other hormonal therapy.
4. More than 18 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status <2 (see Appendix 2).
6. Ability to fill the quality of life questionnaire
7. Patient compliance and geographic proximity that allow adequate follow-up.
8. Presence of signed and dated IRB-approved patient informed consent form prior to enrollment into the study.
|
Criteri di inclusione
1. Diagnosi istologica o citologica di adenocarcinoma della prostata
2. Presenza di malattia metastatica
3. Progressione di malattia secondo i criteri PCWG2
4. Livelli di testosteronemia ≤0.50 ng/mL
5. Età superiore ai 18 anni
6. Performance status ECOG 0 o 1
7. Adeguata riserva midollare
8. Adeguata funzionalità epatica
9. Adeguata funzionalità renale
10. Capacità di compilare il questionario di qualità di vita
11. Compliance del paziente e vicinanza geografica che consenta adeguato follow-up.
12. Firma del consenso informato
|
|
| E.4 | Principal exclusion criteria |
Patients who have met all the above inclusion criteria listed in Section 4.2. will be screened for the following exclusion criteria:
1. Prior chemotherapy for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed >3 years ago.
2. Prior treatment with abiraterone acetate and/or enzalutamide
3. Less than 28 days elapsed from prior treatment with estramustine, radiotherapy or surgery to the time of randomization. Patients may be on biphosphonates prior to study entry.
4. Prior isotope therapy, whole pelvic radiotherapy, or radiotherapy to >30% of bone marrow.
5. History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease.
6. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of loss of consciousness or transient ischemic attack within 12 months of randomization;
7. 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 and/or ALT >1.5 x ULN;
e. Total bilirubin >1.5 x ULN,
f. Serum Creatinine >1.5 x ULN. If creatinine 1.0 - 1.5 x ULN, creatinine clearance will be calculated either according to Cockcroft-Gault formula. Creatinine clearance <60 mL/min will exclude the patient (see Appendix 3 for calculation formula)
8. Contraindications to the use of corticosteroid treatment.
9. Clinically significant cardiovascular disease including the following:
a. Myocardial infarction within 6 months before screening;
b. Uncontrolled angina within 3 months before screening;
c. Congestive heart failure New York Heart Association class 3 or 4, or a history of congestive heart failure New York Heart Association class 3 or 4, unless a screening echocardiogram or multigated acquisition scan performed within 3 months before randomization demonstrates a left ventricular ejection fraction ≥ 50%;
d. History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes);
e. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place;
f. Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mm Hg) at screening;
g. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening electrocardiogram (ECG) and on physical examination;
h. Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening.
10. Any of the following within 3 months prior to randomization: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event.
11. Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene;
12. Prior malignancy. Adequately treated basal cell or squamous cell skin or superficial (pTis, pTa, and pT1) bladder cancer are allowed, as well as any other cancer for which chemotherapy has been completed >5 years ago and from which the patient has been disease-free for >5 years.
13. Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization.
14. Any other condition which in the judgment of the investigator would place the subject at undue risk or interfere with the study.
|
Criteri di esclusione
1. Antecedente chemioterapia sistemica (salvo i casi previsti dal protocollo)
2. Pregressa terapia con enzalutamide o abiraterone
3. Pregresso trattamento chirurgico, radiante o con estramustina concluso da meno di 28 giorni
4. Pregressa terapia con radioisotopi o radioterapia >30% della riserva midollare
5. Metastasi cerebrali o leptomeningee o compressione midollare
6. Pregressi episodi di epilessia o episodi di TIA nell’ultimo anno
7. Controindicazioni all’uso di corticosteroidi
8. Significative patologie cardiovascolari
9. Patologie tromboemoboliche, disturbi irritativi gastroenterici, ulcera gastroduodenale
10. Ipersensibilità nota verso i farmaci in studio o verso i loro eccipienti
11. Partecipazione a studi clinici con farmaci sperimentali nell’ultimo mese
12. Neoplasie precedenti (tranne i casi previsti dal protocollo)
13. Importanti patologie sistemiche concomitanti, incompatibili con lo studio
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PRIMARY ENDPOINT
•rate of patients without progression (according to guideline of Prostate Cancer Clinical Trials Working Group 2 - PCWG2) at 6 months after docetaxel first administration
•This end point may be preferred over PFS (using actual progression times) because phase II randomized trials are not usually blinded and there is a potential for bias in determining progression times because of a tendency for more frequent response assessments for case control patients. Using progression-free rate at a predetermined time from treatment initiation as the primary endpoint minimizes the chance for bias related to earlier outcome determinations for patients on the control arm. |
Endpoint primario
•Percentuali di pazienti liberi da progressione a 6 mesi dall’inizio del trattamento secondo PCWG2
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months after docetaxel first administration
|
6 mesi dall’inizio del trattamento con docetaxel
|
|
| E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
•Rate of objective response according to RECIST criteria
•Rate of biochemical response according to PCWG2
•Kaplan-Meier estimates of progression-free survival
•Kaplan-Meier estimates of overall survival
•Kaplan-Meier estimates of biochemical progression-free survival
•Rate of treatment-related mortality
•Rate of toxicity-related protocol withdrawal
•Scales of brief pain inventory (BPI) and analgesic score
•Functional scales and items of Functional Assessment of Cancer Therapy-Prostate (FACT – P) questionnaire
•Type and grade of any adverse reaction to treatment, according to Common toxicity criteria – adverse events (CTC-AE) v. 4.03
|
Endpoint secondari
•percentuale di risposte obiettive secondo criteri RECIST
•percentuale di risposte biochimiche
•Stima secondo Kaplan-Meier della sopravvivenza globale
•Stima secondo Kaplan-Meier della sopravvivenza libera da progressione (PFS)
•Stima secondo Kaplan-Meier della sopravvivenza libera da progressione biochimica
•Tasso di mortalità dovuta al trattamento
•Percentuale di sospensione del trattamento dovuta a tossicità
•Scale funzionali ed items del questionario FACT-P, BPI e analgesic score
•Tipo e grado di qualsiasi reazione avversa al trattamento, secondo CTC-AE vers. 4.03
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The study period will include the study treatment period (until 30 days after last docetaxel administration) and the follow-up period (until death or cut-off date, whichever comes first) |
|
| 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 | 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) | 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 | 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 | 28 |
| 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
|
| The patient will be considered in the study from informed consent signature until death or cut-off date, whichever comes first. After study treatment discontinuation, patient will be followed every 2 months until disease progression and after progression at the investigator’s discretion until death or cutoff date, whichever comes first |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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