| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-resistant Prostate Cancer (CRPC) |
| Cáncer de próstata metastásico resistente a la castración |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prostate Cancer |
| Cáncer de próstata |
|
| 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 | 14.1 |
| 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 |
| The objective of this study is to evaluate the effect of cabozantinib compared to prednisone on overall survival in men with previously treated metastatic castration-resistant prostate cancer with bone-dominant disease who have experienced disease progression on docetaxel-containing chemotherapy and abiraterone or MDV3100. |
| El objetivo de este estudio consiste en evaluar el efecto de cabozantinib en comparación con prednisona sobre la supervivencia global en varones con cáncer de próstata resistente a la castración, metastásico, tratado previamente y con afectación predominantemente ósea que han presentado progresión de la enfermedad con quimioterapia con docetaxel y con abiraterona o MDV3100. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented histological or cytological diagnosis of prostate cancer.
2. Serum testosterone levels less than 50 ng/dL within 28 days before randomization.
3. Evidence of bone metastasis related to prostate cancer on bone scans
from a protocol-credentialed scanner within 28 days before
randomization.
4. The subject must have received prior docetaxel (minimum cumulative dose of 225 mg/m2) and either abiraterone or MDV3100 treatment and have evidence of investigator-assessed prostate cancer progression on each agent independently.
For docetaxel: subjects must have progressed during or after docetaxel-containing therapy.
For abiraterone or MDV3100: subjects must have discontinued abiraterone or MDV3100 due to disease progression.
Prostate cancer progression is defined as:
a. PSA progression according to PCWG2 (Prostate Cancer Working Group 2) criteria: PSA level of at least 2 ng/mL which has subsequently risen on at least 2 successive occasions, at least 2 weeks apart. If the second risen value is lower than the first risen value, then an additional test for rising PSA will be required to document progression. The value of the additional test must be higher than the first risen value (Scher et al. 2008).
or
b. Radiographic progression in soft tissue or bone lesions.
Note: There is no limit on other prior anti-cancer treatments, including prior cabazitaxel (except Exclusion Criterion #1).
5. Subjects without prior orchiectomy must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) therapy until permanent discontinuation of study treatment.
6. Subject must have recovered to baseline or CTCAE v.4.0 (Common Terminology Criteria for Adverse Events, version 4.0) <= Grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non significant and/or stable on supportive therapy.
7. > =18 years old on the day of consent.
8. ECOG performance status: 0-2
9. Adequate organ and marrow function, defined as follows, based upon laboratory tests performed within 7 days before randomization:
a. Absolute neutrophil count (ANC) >= 1500/mm3
b. Platelets >= 100,000/mm3
c. Hemoglobin >= 9 g/dL
d. Total bilirubin >= 1.5 x the upper limit of normal (for subjects with Gilbert's disease, <= 3 mg/dL)
e. Serum albumin >= 2,8 g/dL
f. Serum creatinine <= 1.5 x the upper limit of normal or calculated creatinine clearance >= 50 mL/min or GFR > 30 mL/min.
Note: For GFR estimation, the Cockcroft and Gault equation should be used [GFR = CrCl (mL/min) = (140 - age) x wt (kg)/(serum creatinine x 72)]
g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x the upper limit of normal
h. Lipase < 1.5 times the upper limit of normal
i. Serum phosphorus >= lower limit of normal
j. Urine protein/creatinine ratio (UPCR) <= 1
10. The subject must be capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
11. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the
course of the study and for 3 months after the last dose of study treatment. |
1. Diagnóstico histológico o citológico documentado de cáncer de próstata.
2. Concentración sérica de testosterona inferior a 50 ng/dl en los 28 días previos a la aleatorización.
3. Evidencia de metástasis óseas relacionadas con el cáncer de próstata en las gammagrafías óseas realizadas con un equipo autorizado por el protocolo en los 28 días previos a la aleatorización.
4. El paciente deberá haber recibido docetaxel (dosis acumulada mínima de 225 mg/m2) y abiraterona o MDV3100 con anterioridad y presentar evidencia de progresión del cáncer de próstata evaluada por el investigador con cada fármaco por separado.
Para docetaxel: los pacientes deberán haber presentado progresión durante o después del tratamiento con docetaxel.
Para abiraterona o MDV3100: los pacientes deberán haber suspendido la administración de abiraterona o MDV3100 por progresión de la enfermedad.
La progresión del cáncer de próstata se define como:
a. Progresión del PSA según los criterios PCWG2 (Prostate Cancer Working Group 2): concentración de PSA de al menos 2 ng/ml que ha aumentado posteriormente en al menos 2 ocasiones consecutivas, con 2 semanas de diferencia como mínimo. Cuando el segundo valor elevado sea menor que el primero, será necesario un nuevo análisis con elevación del PSA para documentar la progresión. El valor del nuevo análisis deberá ser mayor que el primer valor elevado (Scher y cols. 2008).
o bien
b. Progresión radiológica en lesiones de tejidos blandos u óseas.
Nota: No hay ningún límite en relación con otros tratamientos antineoplásicos previos, incluido cabazitaxel (excepto el criterio de exclusión n.º 1).
5. Los pacientes que no se hayan sometido a una orquiectomía previa deberán estar tomando y mostrarse dispuestos a mantener el tratamiento con un análogo (agonista o antagonista) de la luliberina (LHRH) hasta la suspensión permanente del tratamiento del estudio.
6. El paciente deberá haberse recuperado hasta la situación basal o un grado <= 1 según los CTCAE v.4.0 (Criterios terminológicos comunes para acontecimientos Adversos, versión 4.0) de la toxicidad relacionada con cualquier tratamiento previo, a menos que los acontecimientos adversos (AA) no sean clínicamente significativas o permanezcan estables con el tratamiento concomitante.
7. Edad mínima de 18 años en el momento del consentimiento.
8. Estado funcional del ECOG: 0 a 2.
9. Función orgánica y medular adecuada, según se define a continuación, basándose en las pruebas analíticas realizadas en los 7 días previos a la aleatorización:
a. Recuento absoluto de neutrófilos (RAN) >= 1500/mm3.
b. Plaquetas >= 100.000/mm3.
c. Hemoglobina >= 9 g/dl.
d. Bilirrubina total <= 1,5 veces el límite superior de la normalidad (para los pacientes con enfermedad de Gilbert, <= 3 mg/dl).
e. Albúmina sérica >= 2,8 g/dl.
f. Creatinina sérica <= 1,5 veces el límite superior de la normalidad, aclaramiento de creatinina calculado >= 50 ml/min o filtración glomerular (FG) > 30 ml/min.
Nota: Para calcular la FG, se utilizará la ecuación de Cockcroft y Gault [FG = ClCr (ml/min) = (140 - edad) x peso (kg)/(creatinina sérica x 72)].
g. Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) < 3,0 veces el límite superior de la normalidad.
h. Lipasa < 1,5 veces el límite superior de la normalidad.
i. Fósforo sérico >= límite inferior de la normalidad.
j. Cociente proteínas/creatinina en orina (CPCO) <= 1.
10. El paciente ha de ser capaz de comprender y cumplir los requisitos del protocolo y deberá haber firmado el documento de consentimiento informado.
11. Los paciente fértiles sexualmente activos y sus parejas deberán comprometerse a utilizar métodos anticonceptivos médicamente aceptables (por ejemplo, métodos de barrera, como preservativo masculino, preservativo femenino o diafragma con gel espermicida) durante el estudio y durante 3 meses después de la última dosis del tratamiento del estudio. |
|
| E.4 | Principal exclusion criteria |
1. The subject has received prior cabozantinib.
2. The subject has received docetaxel, abiraterone, or MDV3100 within 2 weeks before randomization.
3. The subject has received any other type of anti-cancer agent (except agents to maintain castrate status) within 2 weeks before randomization.
4. The subject has received radiation therapy within 4 weeks (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of randomization. Subject is excluded if there is any prior history of radiation therapy to the mediastinum (unless radiation targeted bone metastases).
5. The subject has known brain metastases or cranial epidural disease
6. The subject requires at the time of randomization therapeutic doses of anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or FXa inhibitors, antiplatelet agents (eg, clopidogrel), aspirin above low dose levels for cardioprotection per local applicable guidelines, or aspirin in combination with dipyridamole.
Note: Therapeutic doses of heparin are allowed as clinically indicated for
supportive treatment after randomization (see Section 7.2).
7. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort).
8. Uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders such as symptomatic congestive heart failure (CHF), uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening), unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke (including TIA, or other ischemic event) within 6 months before randomization, myocardial infarction within 6 months before randomization, history of thromboembolic event within 6 months before randomization
b. Gastrointestinal disorders such as malabsorption syndrome or gastric outlet obstruction.
c. Risks for GI perforation or fistula formation which include intra-abdominal tumor/metastases invading GI tract; active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis or symptomatic cholangitis or appendicitis; history of abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess, or prior GI surgery (particularly when associated with delayed or incomplete healing) within 6 months before first dose of study treatment. Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib.
d. Risk for non-GI fistula formation which includes previous surgical intervention (such as PEG tube placement) and evidence of intraluminal disease involving the trachea or esophagus.
e. Other disorders such as active infection requiring systemic treatment; serious non-healing wound/ulcer/bone fracture; organ transplant; uncompensated hypothyroidism, uncontrolled diabetes mellitus
f. History of surgery within 6 months before randomization:
- With wound healing complications - major surgery within 6 months, minor surgery within 3 months;
- Without wound healing complications - major surgery within 3 months, minor surgery within 1 month
- Note: Complete wound healing from prior surgery is required at least 30 days before randomization.
9. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months, or history of other significant bleeding within 6 months before randomization.
10. Cavitating pulmonary lesion(s) or a pulmonary lesion invading or encasing a major blood vessel.
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 7 days before randomization (see Section 5.5.4 for Fridericia formula).
Three ECGs separated by at least 3 minutes must be performed. If the average of these three consecutive results for QTcF is <= 500 msec, the subject meets eligibility in this regard.
12. Unable to swallow tablets or capsules.
13. A previously-identified allergy or hypersensitivity to components of the study treatment formulations.
14. The subject has had another diagnosis of malignancy (except non-melanoma skin cancer, adequately treated stage I colon cancer, superficial transitional carcinoma of the bladder) within 2 years before randomization. |
1. El paciente ha recibido cabozantinib previamente.
2. El paciente ha recibido docetaxel, abiraterona o MDV3100 en las 2 semanas previas a la aleatorización.
3. El paciente ha recibido cualquier otro tipo de fármaco antineoplásico (excepto fármacos para mantener un estado de castración) en las 2 semanas previas a la aleatorización.
4. El paciente ha recibido radioterapia (incluye radioterapia dirigida contra metástasis óseas) en las 4 semanas previas o tratamiento con radionúclidos en las 6 semanas previas a la aleatorización. Se excluirá a los pacientes con antecedentes de radioterapia del mediastino (a menos que se trate de radioterapia dirigida contra metástasis óseas).
5. El paciente tiene metástasis cerebrales conocidas o afectación epidural craneal.
6. El paciente necesita en el momento de la aleatorización dosis terapéuticas de anticoagulantes como warfarina o productos afines, heparina, inhibidores de la trombina o el FXa, antiagregantes plaquetarios (por ejemplo, clopidogrel), ácido acetilsalicílico en dosis superiores a las dosis bajas para cardioprotección según las directrices locales aplicables, o aspirina en combinación con dipiridamol.
Nota: Se permiten dosis terapéuticas de heparina según estén indicadas clínicamente para el tratamiento de apoyo después de la aleatorización (véase la Sección 7.2).
7. El paciente necesita tratamiento concomitante crónico con inductores potentes de la CYP3A4 (por ejemplo, dexametasona, fenitoína, carbamazepina, rifampicina, rifabutina, rifapentina, fenobarbital e hipérico).
8. Presencia de una enfermedad intercurrente importante y no controlada, entre otras, las siguientes:
a. Trastornos cardiovasculares,
b. Trastornos digestivos,
c. Riesgos de perforación digestiva o formación de fístulas,
d. Riesgo de formación de fístulas no digestivas,
e. Otros trastornos,
f. Antecedentes de cirugía en los 6 meses previos a la aleatorización.
9. Hematemesis o hemoptisis clínicamente importante de > 2,5 ml de sangre roja u otros signos indicativos de hemorragia pulmonar en los 3 meses previos o antecedentes de otro tipo de hemorragia significativa en los 6 meses previos a la aleatorización.
10. Lesión pulmonar con cavitación o lesión pulmonar que invade o engloba un vaso sanguíneo importante.
11. Intervalo QT corregido calculado con la fórmula de Fridericia (QTcF) > 500 ms en los 7 días previos a la aleatorización (véase la fórmula de Fridericia en la sección 5.5.4).
Han de realizarse tres ECGs con 3 minutos de diferencia como mínimo. Si la media de estos tres resultados de QTcF consecutivos es <= 500 ms, el paciente cumple los requisitos a este respecto.
12. Incapacidad de tragar comprimidos o cápsulas.
13. Alergia o hipersensibilidad conocida a componentes de las formulaciones del tratamiento del estudio.
14. El sujeto ha tenido otro diagnóstico de una neoplasia maligna (excepto cáncer de piel distinto del melanoma, cáncer de colon en estadio I tratado adecuadamente, carcinoma de transición superficial de la vejiga) en los 2 años previos a la aleatorización. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival |
| Supervivencia global |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall survival is defined as the time from the date of randomization to the date of death (due to any cause). Subjects not known to have expired at the time of analysis will generally be censored at the date last known alive. Detailed censoring rules for overall survival will be described in the SAP. |
| La supervivencia global (SG) se define como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de la muerte por cualquier causa. A los pacientes que no hayan fallecido en el momento del análisis se registrarán, en general, en la última fecha con certeza de que seguían vivos. En el PAE se describirán unas normas detalladas de registro en relación con la supervivencia global. |
|
| E.5.2 | Secondary end point(s) |
| Bone scan response at the end of Week 12 by IRF. The stratified CMH test will be used as the primary analysis of this endpoint. |
| Respuesta en la gammagrafía ósea al final de la semana 12, según el CRI. Se utilizará la prueba de CMH estratificada como análisis principal de este criterio de valoración. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 148 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Puerto Rico |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| Subjects will be followed until death or the Sponsor decides to no longer collect these data. |
| Los pacientes se seguirán hasta que mueran o hasta que el promotor tome la decisión de dejar de recopilar estos datos. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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