| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed, BRCA-Mutant, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer |
| Recaida, mutacion-BRCA, ovarico epithelial alto grado, trompas de Falopioo cancer peritoneal pimario. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian, Fallopian Tube, or Primary Peritoneal Cancer |
| ovario, trompas de Falopio, o cancer peritoneal primario |
|
| 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 | PT |
| E.1.2 | Classification code | 10038977 |
| E.1.2 | Term | Retroperitoneal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061328 |
| E.1.2 | Term | Ovarian epithelial cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube 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 |
| To determine investigator-assessed progression-free survival (invPFS) by RECIST Version 1.1 for rucaparib versus chemotherapy. |
| Determinar la supervivencia sin progresión evaluada por el investigador (invPFS) conforme a la versión 1.1 de RECIST para el rucaparib frente a quimioterapia. |
|
| E.2.2 | Secondary objectives of the trial |
-To compare efficacy of rucaparib versus chemotherapy as measured by overall survival (OS)
-To compare efficacy of rucaparib versus chemotherapy as measured by ORR using RECIST Version 1.1 by investigator assessment
-To compare efficacy of rucaparib versus chemotherapy as measured by DOR by investigator assessment
-To compare efficacy of rucaparib versus chemotherapy as measured by ORR using RECIST Version 1.1 by investigator assessment and Gynecologic Cancer InterGroup (GCIG) CA-125 response criteria
-To evaluate patient-reported outcome (PRO) for rucaparib versus chemotherapy as assessed by the:
-European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30
-EORTC ovarian cancer module QLQ-OV28
-To evaluate the safety and tolerability of rucaparib versus chemotherapy |
- Comparar la eficacia de rucaparib frente a la quimioterapia en términos de supervivencia total
- Comparar la eficacia de rucaparib frente a la quimioterapia en términos del IRG empleando la versión 1.1 de RECIST y mediante la evaluación del investigador
- Comparar la eficacia de rucaparib frente a la quimioterapia en términos de DdR conforme a la evaluación del investigador
- Comparar la eficacia de rucaparib frente a la quimioterapia en términos de DdR empleando la versión 1.1 de RECIST, conforme a la eva. del investigador y los criterios de respuesta de CA-125 del Gynecologic Cancer InterGroup (GCIG)
- Eva. los resultados comunicados por la paciente (RCP) para rucaparib frente a la quimioterapia, conforme a la evaluación del:
•Cuestionario sobre calidad de vida (EORTC QLQ) C30 de la Asociación europea para la inv. y tto. del cancer
•Módulo QLQ OV28 para el cáncer ovárico de la EORCT
- Eva. la seguridad terapéutica y la tolerabilidad del rucaparib frente a la quimioterapia |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form prior to any study-specific evaluation
2. Be ≥ 18 years of age at the time the informed consent form is signed
3. Have a histologically confirmed diagnosis of high-grade serous or Grade 2 or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer
a. If mixed histology, > 50% of the primary tumor must be confirmed to be high-grade serous or endometrioid upon review by local pathology
b. Patients with a histology of other than serous or endometrioid are also eligible if they are known to harbor a deleterious germline or somatic BRCA1/2 mutation
4. Received ≥ 2 prior chemotherapy regimens and have relapsed or progressive disease as confirmed by radiologic assessment
a. Had documented treatment-free interval of ≥ 6 months following the first chemotherapy regimen received
b. Hormonal agents (eg, tamoxifen, letrozole, etc), anti-angiogenic agents (eg, bevacizumab, pazopanib, cediranib, etc), and other non-chemotherapy agents will not be counted as a chemotherapy regimen for the purpose of determining patient eligibility
c. Agents administered in the maintenance setting will not be counted as a separate regimen
5. Have a deleterious BRCA1/2 mutation as confirmed by the central laboratory.
Note: patients known to harbor a deleterious germline or somatic BRCA1/2 mutation based on local assessment may be enrolled without central tissue analysis provided there is confirmation that tumor tissue is available to be provided to the central laboratory.
a. Sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue must available for planned analyses; cytospin blocks from ascites are not acceptable i. The most recently obtained tumor tissue that is of adequate quality (at least 20% tumor content with a minimum of 80% nucleated cellular content) should be submitted.
b. In the event archival tumor tissue is not available a screening biopsy sample may be collected and provided to the central laboratory
6. Have evaluable disease: ie at least 1 target or non-target lesion that can be assessed per RECIST Version 1.1 (Appendix 1)
7. Have adequate organ function confirmed by the following laboratory values obtained within 14 days prior to randomization:
a. Bone Marrow Function
i. Absolute neutrophil count (ANC) ≥ 2.0 × 109/L
ii. Platelets > 100 × 109/L
iii. Hemoglobin > 10 g/dL
b. Hepatic Function
i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); if liver metastases, then ≤ 5 × ULN
ii. Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert’s syndrome
iii. Serum albumin ≥ 30 g/L (3.0 g/dL)
c. Renal Function
i. Serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-Gault formula
8. Women of childbearing potential must have a negative serum pregnancy test ≤ 3 days prior to administration of the first dose of study drug
9. Have an ECOG performance status of 0 or 1 (Appendix 2) |
1.Haber firmado un formulario de consentimiento informado autorizado por una Junta de Revisión Institucional (JRI) o Comité de Ética de Investigación Clínica (CEIC) antes de iniciar cualquier evaluación específica del studio
2.Tener ³ 18 años de edad en el momento de firmar el formulario de consentimiento informado
3.Tener un diagnóstico confirmado histológicamente de cáncer de tipo ovárico epitelial endometrioide seroso de alto grado o de grado 3 o 2, de trompas de falopio o peritoneal primario
a.Si la histología es mixta, se deberá confirmar que > 50 % del tumor principal es seroso o endometrioide de alto grado mediante revisión por el laboratorio de patología local
b.Las pacientes con una histología que no sea de tipo seroso o endometrioide también serán aptas para participar en el estudio, si se confirma que presentan una mutación deletérea de línea germinal o somática de BRCA1/2
4.Haber recibido ≥ 2 tratamientos con quimioterapia anteriores y presentar una evolución o recaída de la enfermedad confirmada por evaluación radiológica
a.Haber pasado un intervalo sin tratamiento documentado de ≥ 6 meses tras el primer régimen de quimioterapia recibido
b.Los agentes hormonales (p. ej., tamoxifeno, letrozol, etc.), los agentes antiangiogénicos (p. ej., bevacizumab, pazopanib, cediranib, etc.) y otros agentes que no sean propios de la quimioterapia no se considerarán como regímenes de quimioterapia a la hora de determinar la idoneidad de las pacientes
c.Los agentes administrados en una situación de mantenimiento no se considerarán como un régimen aparte
5.Presentar una mutación deletérea de BRCA1/2 confirmada por el laboratorio central. Nota: Las pacientes que, según una evaluación local, presenten una mutación deletérea de línea germinal o somática de BRCA1/2 podrán inscribirse sin el análisis de tejido del laboratorio central, siempre que se confirme que se puede proporcionar tejido tumoral al laboratorio central
a.Deberá haber suficiente tejido tumoral de archivo, fijado con formol e incluido en parafina, disponible para los análisis planificados; los bloques de cytospin procedentes de ascitis no son aceptables.
i. Se deberá enviar el tejido tumoral más reciente que presente la calidad adecuada (al menos 20 % de contenido tumoral con un mínimo del 80 % de contenido celular nucleado)
b.En el caso de que no se disponga de tejido tumoral de archivo, se obtendrá una muestra de una biopsia de selección que se enviará al laboratorio central.
6.Tener una enfermedad evaluable, es decir, con al menos 1 lesión objetivo o no objetivo que se pueda evaluar conforme a los criterios RECIST versión 1.1.
7.Presentar una actividad de los órganos adecuada, confirmada mediante las valoraciones analíticas siguientes obtenidas dentro de los 14 días anteriores a la aleatorización:
a.Actividad de la médula ósea
i.Recuento absoluto de neutrófilos (RAN) ³ 2,0 × 109/l
ii.Plaquetas > 100 × 109/l
iii.Hemoglobina > 10 g/dl
b.Actividad hepatica
i.Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) £ 3 × límite superior de la normalidad (LSN); £ 5 × LSN en caso de metástasis hepática
ii.Bilirrubina £ 1,5 × LSN; < 2 × LSN si la hiperbilirrubinemia se debe al síndrome de Gilbert
iii.Albúmina en suero ≥ 30 g/l (3,0 g/dl)
c.Actividad renal
i.Creatinina en suero ≤ 1,5 x LSN o tasa de filtración glomerular estimada ≥ 45 ml/min mediante la fórmula de Cockcroft-Gault
8.Las pacientes con capacidad para procrear deberán disponer de una prueba de embarazo en suero con resultado negativo en un plazo de ≤ 3 días previo a la primera dosis de fármaco del estudio.
9.Tener un estado funcional del Grupo Oncológico Cooperativo de la Costa Este (ECOG) de 0 o 1 |
|
| E.4 | Principal exclusion criteria |
1. Active second malignancy, ie, patient known to have potentially fatal cancer present for which she may be (but not necessarily) currently receiving treatment
a. Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed > 6 months prior and/ or bone marrow transplant > 2 years prior to first dose of study drug
2. Prior treatment with any PARP inhibitor, including rucaparib.
3. Prior treatment with single-agent paclitaxel for platinum-resistant disease.
4. Prior known hypersensitivity to paclitaxel (for patients with progression-free interval of < 12 months after last platinum-based regimen) or prior known hypersensitivity to platinum (for patients with progression-free interval of ≥ 12 months after last platinum-based regimen.
5. Platinum refractory disease: disease progressed by radiologic assessment during or within 4 weeks after completing treatment with most recent platinum-based therapy
6. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with asymptomatic previously-treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks after completion of therapy
7. Pre-existing duodenal stent and/ or any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
8. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or history of chronic hepatitis B or C
9. Women who are pregnant or breast feeding
10. Received treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs ≤ 14 days prior to first dose of study drug
11. Ongoing toxicity ≥ Grade 2 by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (ongoing Grade 2 non-hematologic toxicity, with the exception of peripheral neuropathy, may be permitted with prior advanced approval from sponsor).
12. Non study-related minor surgical procedure ≤ 5 days, or major surgical procedure ≤ 21 days, prior to first dose of study drug; in all cases, the patient must be sufficiently recovered and stable before treatment administration
13. Requires regular blood transfusions, granulocyte colony-stimulating factor, or platelet transfusions
14. Drainage of ascitic fluid 2 or more times in the 4 weeks prior to the first dose of study drug, uncontrolled pleural effusion, or permanent drain in place (eg, PleurX®) for ascites or pleural effusion
15. Hospitalization for bowel obstruction within 3 months prior to randomization
16. Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study |
1.Una neoplasia maligna secundaria activa, es decir, se sabe que la paciente padece un cáncer potencialmente mortal para el que puede (aunque no necesariamente) estar siendo tratado en la actualidad.
a.Las pacientes con antecedentes de neoplasia maligna que hayan sido completamente tratados y actualmente no presenten indicios de dicha neoplasia podrán inscribirse en el ensayo siempre y cuando todo el proceso quimioterapéutico haya finalizado > 6 meses antes o hayan recibido cualquier transplante de médula > 2 años antes de la primera dosis de fármaco del estudio.
2.Tratamiento previo con cualquier inhibidor de PARP, incluido el rucaparib.
3.Tratamiento previo con paclitaxel de agente único en caso de enfermedad resistente al platino.
4.Hipersensibilidad previa conocida al paclitaxel (en el caso de las pacientes con un intervalo sin progresión de < 12 meses tras el último régimen con platino) o hipersensibilidad previa conocida al platino (en el caso de las pacientes con un intervalo sin progresión de ≥ 12 meses tras el último régimen con platino).
5.Enfermedad resistente al platino: evolución de la enfermedad según evaluación radiológica durante o dentro de 4 semanas después de finalizar el tratamiento con la terapia más reciente basada en platino.
6.Metástasis del sistema nervioso central (SNC) sintomáticas y/o sin tratar. Las pacientes con metástasis del SNC tratadas previamente y asintomáticas serán aptas siempre que hayan estado clínicamente estables durante al menos 4 semanas tras completar la terapia.
7.Prótesis duodenal preexistente o trastornos o defectos digestivos que, en opinión del Investigador, pudieran interferir con la absorción del rucaparib.
8.Constancia de alguna enfermedad relacionada con el virus de la inmunodeficiencia humana (VIH) o el síndrome de inmunodeficiencia adquirida (SIDA), o antecedentes de hepatitis B o C crónica.
9.Mujeres embarazadas o en periodo de lactancia.
10.Haber recibido tratamiento con quimioterapia, radioterapia, tratamiento con anticuerpos o cualquier otra inmunoterapia, terapia génica, terapia con vacunas, inhibidores de la angiogénesis o con fármacos experimentales £ 14 días antes de la primera dosis de fármaco del estudio.
11.Toxicidad ≥ grado 2 en curso conforme a los criterios terminológicos comunes para acontecimientos adversos del National Cancer Institute (NCI CTCAE) (la toxicidad en curso de grado 2 no hematológica, excepto la neuropatía periférica, se podrá permitir previa autorización del promotor).
12.Intervención quirúrgica menor no relacionada con el estudio £ 5 días antes, o bien cirugía mayor £ 21 días antes de la primera dosis de fármaco del estudio; en todos los casos, la paciente deberá estar suficientemente recuperada y estable antes de administrar el tratamiento.
13.Pacientes que necesiten transfusiones de sangre, factor estimulante de colonias de granulocitos o transfusiones de plaquetas con regularidad.
14.Pacientes que necesiten transfusiones de sangre, factor estimulante de colonias de granulocitos o transfusiones de plaquetas con regularidad.
15.Hospitalización por obstrucción del intestino en los 3 meses anteriores a la aleatorización.
16.Presencia de cualquier otra afección que pudiera aumentar el riesgo asociado con la participación en el estudio o que pudiera interferir en la interpretación de los resultados del estudio y que, en opinión del investigador, hiciera que la paciente no fuera apta para inscribirse en el estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease progression according to RECIST Version 1.1 as assessed by the Investigator, or death from any cause |
| Progresion de la enfermedad evaluada por el investigador conforme a la version 1.1 de RECIST, o muerte por cualquier causa |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first event of disease progression, assessment will be carried out every 8 weeks |
| El primer acontecimiento de progression de la enfermedad, la evaluacion se hara cada 8 semanas. |
|
| E.5.2 | Secondary end point(s) |
1).To compare efficacy of rucaparib versus chemotherapy as measured by overall survival (OS)
2).To compare efficacy of rucaparib versus chemotherapy as measured by ORR using RECIST Version 1.1 by investigator assessment
3).To compare efficacy of rucaparib versus chemotherapy as measured by DOR by investigator assessment
4).To compare efficacy of rucaparib versus chemotherapy as measured by ORR using RECIST Version 1.1 by investigator assessment and Gynecologic Cancer InterGroup (GCIG) cancer antigen 125 (CA-125) response criteria
5).To evaluate patient-reported outcome (PRO) for rucaparib versus chemotherapy as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 and ovarian cancer module QLQ-OV28
6).To evaluate the safety and tolerability of rucaparib versus chemotherapy. |
1. Comparar la eficacia de rucaparib frente a quimioterapia en términos de supervivencia total (ST).
2. Comparar la eficacia de rucaparib frente a la quimioterapia en términos del IRG empleando la versión 1.1 de RECIST y mediante la evaluación del investigador.
3. Comparar la eficacia de rucaparib frente a la quimioterapia en términos de DdR conforme a la evaluación del investigador.
4. Comparar la eficacia de rucaparib frente a la quimioterapia en términos de DdR empleando la versión 1.1 de RECIST, conforme a la evaluación del investigador y los criterios de respuesta de CA-125 del Gynecologic Cancer InterGroup (GCIG).
5. Evaluar los resultados comunicados por la paciente (RCP) para rucaparib frente a la quimioterapia, conforme a la evaluación del cuestionario sobre calidad de vida (EORTC QLQ) C30 de la Asociación europea para la investigación y tratamiento del cáncer y módulo QLQ OV28 para el cáncer ovárico de la EORCT
6. Evaluar la seguridad terapéutica y la tolerabilidad del rucaparib frente a la quimioterapia. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Patients will be followed for 28 days after last dose, long-term follow-up assessments every 12 weeks until death, withdrawal of consent or study closure
2) RECIST at screening, at end of every 8 weeks relative to Cycle 1 Day 1 until radiologically confirmed disease progression by RECIST, as assessed by investigator, or death
3) DOR will be summarized & analyzed using the same methodology described for primary endpoint
4) At screening & end of every 8 weeks relative to Cycle 1 Day 1 after randomization.
5) PRO’s will be completed by patients at screening, Day 1 of treatment, treatment discontinuation & 28-day safety follow-up
6) Changes from baseline will be analyzed for each post-baseline visit & for final visit for each subscale & total score |
1.Se realizará un seguimiento de las pacientes para evaluar la seguridad y la eficacia durante los 28 días siguientes a la última dosis , habrá evaluaciones de seguimiento a largo plazo cada 12 semanas hasta que se produuzca muerte, retirada del consentimieto o cierre del studio.
2.RECIST en la seleccion, al final de cada 8 semanas en relacion al Ciclo 1 dia 1 hasta confirmacion radiologica de progression por RECIST, conforme a la evaluacion del investigador o muerte |
|
| 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 | 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) | 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 | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Brazil |
| Canada |
| Czech Republic |
| Hungary |
| Israel |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| Ukraine |
| 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
|
| The trial will close when the required number of PFS events has been observed and sufficient follow-up for OS events has occurred. |
| El Estudio se cerrará cuando el numero de PFS ha sido observado y un numero suficiente de Follo-up hayan ocurrido. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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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