| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone Naive Prostate Cancer |
| Cáncer de próstata sin tratamiento hormonal previo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hormone Naive Prostate Cancer |
| Cáncer de próstata sin tratamiento hormonal previo |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071119 |
| E.1.2 | Term | Hormone-dependent prostate cancer |
| 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 |
| The primary trial objective is to demonstrate that ODM-201 produces prostate-specific antigen (PSA) response rates at 24 weeks (defined as ≥ 80% reduction compared to baseline) that are in the range of those achieved with 24 weeks of ADT. |
| objetivo principal del ensayo es demostrar la eficacia del fármaco ODM-201 en la reducción deldell antígeno prostático específico (PSA) a las 24 semanas ( reducción ≥80 % en comparación con el valor inicial)en aquellos pacientes tratados con TDA |
|
| E.2.2 | Secondary objectives of the trial |
• To document the effects of ODM-201 compared to ADT in terms of patient-reported side effects of hormonal therapy, based on the HTR symptom scale of EORTC QLQ PR25 at 24 weeks;
• To document the effects of ODM-201 compared to ADT in terms of patient-reported side effects of hormonal therapy, based on EORTC QLQ C30 and PR25 at 24 weeks;
• To document the effect of ODM-201 on PSA complete response at 24 weeks (defined as ≥ 90% reduction from baseline);
• To document the effect of ODM-201 on objective response rate at 24 weeks in patients with RECIST 1.1 measurable disease at baseline;
• To document the safety and tolerability of ODM-201 vs. ADT in subjects who have not previously received hormone treatment for prostate cancer;
• To document the effects of ODM-201 on androgen deprivations symptoms using the AMS questionnaires;
• To document the proportion of patients who opted to continue treatment with ODM-201 beyond the 24 weeks evaluation time point. |
•Determinar la seguridad del ODM-201 en comparación con el TDA en cuanto a los efectos secundarios del tratamiento hormonal a las 24 semanas
•Determinar la seguridad del ODM-201 en comparación con el TDA en cuanto a los efectos secundarios del tratamiento hormonal mediante los cuestionarios EORTC QLQ C30 y PR25 a las 24 semanas
•Determinar el efecto de ODM-201 sobre la respuesta completa del PSA a las 24 semanas
•Determinarr el efecto de ODM-201 sobre la tasa de respuesta objetiva a las 24 semanas en pacientes según los criterios RECIST 1.1 al inicio
•Determinar la seguridad y la tolerabilidad de ODM-201 frente al TDA en pacientes que no han recibido previamente tratamiento hormonal para el cáncer de próstata
•Determinar los efectos de ODM-201 en los síntomas de deprivación androgénica mediante los cuestionarios AMS
•Determinar la proporción de pacientes que optaron por continuar con el tratamiento con ODM-201 después de las 24 semanas del protocolo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Aged 18 years or older
• Histologically confirmed prostate cancer (all stages) for whom continuous ADT is indicated for a minimum period of 24 weeks
• Patient presenting with a maximum of 4 confirmed metastatic lesions, including bone, extra-pelvic lymph nodes, and > 2 cm pelvic lymph nodes by imaging (contrast enhanced CT scans or MRI, Tc-99m BS according to local practice). Visceral metastases are excluded
• Asymptomatic for metastatic prostate cancer; urinary symptoms are allowed
• Baseline total testosterone ≥ 8 nmol/L or 230 ng/dL
• Two subsequent PSA values ≥ 2 ng/ml, done in the past 3 months with a minimum of 2 weeks between the two, with the second being equal to or higher than the first
• WHO performance status (PS) of 0-1
• G8 score ≥ 14 for patients aged ≥ 70 years old
• A life expectancy of at least 12 months
• Able to swallow the study drug whole as a tablet
• Adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1.5 10^9/L; hemoglobin ≥ 10.0 g/dl; platelets ≥ 100 10^9/L)
• Adequate renal function: creatinine ≤ 1.5 x ULN
• Albumin > 25 g/L
• Adequate hepatic function:
- Bilirubin: total bilirubin ≤ 1.5 × upper limit of normal (ULN).
- AST and/or ALT ≤ 2.5 × ULN.
NOTE: patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry (except for serum creatinine) are acceptable.
• Normal 12-lead ECG as per local standard
• Patients of reproductive potential should use adequate birth control measures, during the study treatment period and for at least 3 months after the last study treatment. 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
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
•Edad de 18 años o más
•Cáncer de próstata histológicamente confirmado (todos los estadios) para el cual está indicado el TDA continuo durante un período mínimo de 24 semanas.
•Paciente con un máximo de 4 lesiones metastásicas confirmadas, incluyendo huesos, ganglios linfáticos extrapélvicos y ganglios linfáticos pélvicos >2 cm confirmados mediante imágenes radiológicas
•Asintomático para cáncer de próstata metastásico; se permiten síntomas urinarios.
•Testosterona total inicial ≥8 nmol/l o 230 ng/dl.
•Dos valores consecutivos de PSA ≥2 ng/ml, obtenidos en los últimos 3 meses con un mínimo de 2 semanas de diferencia entre ambos, donde el segundo es igual o superior al primero.
•Estado funcional (EF) 0-1 según la OMS.
•Puntuación G8 ≥14 en pacientes ≥70 años de edad.
•Esperanza de vida de al menos 12 meses.
•Capacidad de tragar el medicamento del estudio en forma de comprimido.
•Función adecuada de la médula ósea (recuento absoluto de neutrófilos [RAN] 1,5 109/l; hemoglobina ≥10,0 g/dl; plaquetas 100 109/l).
•Función renal adecuada: creatinina ≤1,5 veces el límite superior de la normalidad (LSN).
•Albúmina >25 g/l.
•Función hepática adecuada
-Bilirrubina: bilirrubina total 1,5 LSN.
-AST y/o ALT ≤2,5 LSN.
NOTA: se aceptan los pacientes con un margen de desviación con respecto a los valores normales de +/- 5 % para la hematología y +/- 10 % para la bioquímica (excepto para la creatinina sérica).
•ECG normal de 12 derivaciones según la normativa local.
•Las mujeres con capacidad de concebir deben utilizar métodos anticonceptivos adecuados durante el período de tratamiento del estudio y durante al menos 3 meses tras el último tratamiento del estudio. Un método anticonceptivo altamente eficaz se define como aquel que tiene una baja tasa de fallo
•Ausencia de cualquier afección psicológica o situación familiar, sociológica o geográfica que pudiera potencialmente dificultar el cumplimiento del protocolo del estudio y el calendario de seguimiento; estas situaciones deben comentarse con el paciente antes del registro en el ensayo.
•Antes del registro/la aleatorización del paciente, se debe dar el consentimiento informado por escrito conforme a las ICH/BPC y a los reglamentos nacionales/locales. |
|
| E.4 | Principal exclusion criteria |
• Previously or currently receiving hormonal therapy with intent to treat prostate cancer disease (surgical castration or other hormonal manipulation, e.g. LHRH agonists, LHRH antagonists, anti-androgens, oestrogens, 5α-reductase inhibitor). For patients that have received (neo)adjuvant ADT before radiotherapy, it should have been stopped for more than 1 year
• Prior use of investigational agents that block androgen synthesis or block androgen receptor
• Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g. saw palmetto)
• Has received systemic glucocorticoids within 24 weeks prior to enrollment or is expected to require systemic glucocorticoids during the study period, unless determined to be medically necessary by the investigator for other indications than prostate cancer.
• Radiation therapy for treatment of the primary tumor within 3 months prior to enrollment
• Use of an investigational agent within 4 weeks prior to enrollment is not allowed.
• Gastrointestinal disorder affecting absorption (e.g. gastrectomy, active peptic ulcer disease within 3 months prior to enrollment)
• Known hypersensitivity to the study treatment or any of its ingredients (refer to Investigator's brochure).
• Severe or uncontrolled concurrent disease, infection or co-morbidity including active viral hepatitis, known human immunodeficiency virus infection with detectable viral load (HIV) or chronic liver disease (Child Pugh C, see Appendix J)
• History of prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e. pTis, pTa, and pT1) is allowed, as well as any other cancer from which the patient has been disease-free for a period of at least 5 years.
• Clinically significant cardiovascular disease including:
- Myocardial infarction within six months prior to randomization
- Uncontrolled angina within 3 months prior to randomization
- Coronary/peripheral artery bypass within 6 months prior to randomization
- Stroke within 6 months prior to randomization
- Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 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 >170 mm Hg or diastolic blood pressure >105 mm Hg at the screening visit |
•Tratamiento hormonal previo o actual con intención de tratar el cáncer de próstata (castración quirúrgica u otra manipulación hormonal, como agonistas de LHRH, antagonistas de LHRH,antiandrógenos, estrógenos, inhibidores de 5α-reductasa). En los pacientes que hayan recibido TDA (neo) adyuvante antes de la radioterapia, debe haberse interrumpido más de 1 año antes.
•Uso previo de productos en investigación que bloquean la síntesis de andrógenos o bloquean el receptor androgénico.
•Uso de productos derivados de hierbas que puedan tener actividad hormonal contra el cáncer de próstata o se sabe que disminuyen los niveles de PSA (por ejemplo, el palmito de sierra).
•Haber recibido tratamiento con glucocorticoides sistémicos en las 24 semanas anteriores a la inscripción o se prevé la necesidad de glucocorticoides sistémicos durante el período del estudio, salvo que el investigador determine que es médicamente necesario para otras indicaciones distintas del cáncer de próstata.
•Radioterapia para el tratamiento del tumor primario durante los 3 meses previos a la inscripción.
•No se permite el uso de un producto en investigación durante las 4 semanas anteriores a la inscripción.
•Trastorno gastrointestinal que afecta a la absorción (por ejemplo, gastrectomía, úlcera péptica activa en los 3 meses anteriores a la inscripción).
•Hipersensibilidad conocida al tratamiento del estudio o a cualquiera de sus componentes (consulte el Manual del investigador).
•Enfermedad concurrente grave o incontrolada, infección o comorbilidad, incluyendo hepatitis viral activa, infección conocida por el virus de inmunodeficiencia humana con carga viral detectable (VIH) o enfermedad hepática crónica
•Antecedentes de neoplasias malignas previas. Se permite el carcinoma de piel de células basales o de células escamosas tratado adecuadamente o el cáncer de vejiga superficial que no se ha diseminado detrás de la capa de tejido conjuntivo (es decir, pTis, pTa y pT1), así como cualquier otro cáncer del paciente que haya remitido durante un período de al menos 5 años.
•Enfermedades cardiovasculares clínicamente significativas incluyendo:
•Infarto de miocardio en los seis meses previos a la aleatorización
•Angina no controlada en los 3 meses previos a la aleatorización
•Cirugía de derivación coronaria/periférica en los 6 meses anteriores a la aleatorización
•Accidente cerebrovascular en los 6 meses anteriores a la aleatorización
•Insuficiencia cardíaca congestiva de clase 3 o 4 según la Nueva York Heart
•Association (NYHA), o pacientes con antecedentes de insuficiencia cardíaca congestiva de clase 3 o 4 según la NYHA en el pasado, salvo que un ecocardiograma o una ventriculografía nuclear (MUGA) de detección realizados en los 3 meses anteriores muestre una fracción de eyección ventricular izquierda ≥45 %
•Antecedentes de arritmias ventriculares clínicamente significativas (por ejemplo, taquicardia ventricular, fibrilación ventricular, torsades de pointes)
•Antecedentes de bloqueo cardíaco de segundo grado o tercer grado de Mobitz II sin colocación de un marcapasos permanente
•Hipertensión no controlada determinada por una presión arterial sistólica en reposo >170 mmHg o una presión arterial diastólica en reposo >105 mmHg en la visita de selección. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the PSA response assessed at 24 weeks. PSA response is defined as a ≥ 80% decline in PSA measurement taken at week 24 relative to the measurement taken at baseline, in the ODM-201 study arm. The ADT arm is used as an internal control. |
| El criterio de valoración principal es la respuesta del PSA evaluada a las 24 semanas. La respuesta del PSA se define como una disminución ≥80 % en la medida del PSA tomada en la semana 24 en relación con la medida tomada al inicio, en el grupo del estudio de ODM-201. El grupo de TDA se utiliza como un control interno. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The main key secondary endpoint is this study is the change in hormone-treatment related symptoms scale of the EORTC QLQ-PR25 at 24 weeks compared to baseline in the ODM-201 study arm.
Further key secondary endpoints are:
• Safety according to NCI-CTC version 4.0
• Objective response rate at 24 weeks in patients with RECIST 1.1 measurable disease at baseline
• PSA response at 24 weeks defined as a ≥ 90% decline in PSA compared to baseline.
• Overall survival rate at 24 weeks
• Cumulative incidence rate of patients who started further antineoplastic systemic therapy for progressive disease at 24 weeks
• The EORTC QLQ-C30 scales and the scales of the QLQ-PR25 other than the hormone-treatment related symptoms scale
• The AMS (Aging male symptoms)
• G8 baseline measurements in patients older than 70 years of age
• EQ-5D-5L to support the development of future hypotheses on HTA in a subsequent study
• Measurement of circulating levels of testosterone (free and total), DHT, SHBG, androstenedione, DHEA, LH, FSH, estradiol, prolactin
Long term outcomes at 2 year follow-up:
• Cumulative incidence rate of patients who started further antineoplastic systemic therapy for progressive disease
• Overall survival
• Percentage of patients who continued treatment with ODM-201 beyond 24 weeks and their total treatment duration |
Criterios de valoración secundarios clave:
•Cambio en la escala de síntomas relacionados con el tratamiento hormonal del cuestionario EORTC QLQ-PR25 a las 24 semanas en comparación con el inicio en el grupo del estudio de ODM-201. Se considera que una diferencia de 10 puntos es un beneficio clínicamente significativo.
•Tasa de respuesta objetiva a las 24 semanas en pacientes con enfermedad medible según los criterios RECIST 1.1 al inicio.
•La respuesta del PSA a las 24 semanas se define como una disminución ≥90 % del PSA en comparación con el valor inicial.
•Seguridad según la versión 4.0 de los criterios NCI-CTC. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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) | 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 | 5 |
| 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 |
| Austria |
| Belgium |
| Egypt |
| France |
| Italy |
| Norway |
| Spain |
|
| 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. At least thirty days after the end of the protocol treatment of the last patient and
2. Provided all patients have finished protocol specific procedures, not being otherwise part of the standard clinical practice. and
3. Provided the trial is mature for the analysis of the primary endpoint as defined in the protocol and
4. The database has been fully cleaned and frozen for this analysis. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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