E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Platinum-resistant or refractory, high-grade serous ovarian cancer with no germline BRCA mutation |
Cáncer ovárico seroso de alto grado sin mutación germinal de BRCA, refractario o resistente al platino. |
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E.1.1.1 | Medical condition in easily understood language |
High-grade serous ovarian cancer without hereditary BRCA mutation that did not respond to prior platinum-based chemotherapy or recurred within six months after such therapy |
Cáncer de ovario seroso de alto grado sin mutación hereditaria de BRCA que no respondió a la quimioterapia previa a base de platino o recidivó dentro de los seis meses posteriores a dicha terapia |
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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 |
Primary objective: To determine whether treatment with alpelisib in combination with olaparib prolongs PFS compared to single agent cytotoxic chemotherapy |
Objetivo principal: Determinar si el tratamiento con alpelisib en combinación con olaparib prolonga la SLP, comparado con la quimioterapia citotóxica de un solo fármaco. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objective: To determine whether treatment with alpelisib in combination with olaparib prolongs OS compared to single agent cytotoxic chemotherapy
Secondary objectives: 1. To assess safety and tolerability of alpelisib in combination with olaparib
2. To evaluate alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy with respect to time to deterioration of ECOG (Eastern Cooperative Oncology Group) performance status
3. To assess additional efficacy parameters
4. To characterize alpelisib when administered in combination with olaparib
5. To evaluate patient reported-outcomes of alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy |
Objetivo secundario clave: Determinar si el tratamiento con alpelisib en combinación con olaparib prolonga la SLP, comparado con la quimioterapia citotóxica de un solo fármaco,
Objetivos secundarios:
1. Evaluar la seguridad y tolerabilidad de alpelisib en combinación con olaparib
2. Evaluar alpelisib en combinación con olaparib, comparado con la quimioterapia citotóxica de un solo fármaco, respecto al tiempo hasta el deterioro del estado funcional del Grupo Cooperativo Oncológico del Este (ECOG).
3. Evaluar los parámetros adicionales de eficacia.
4.Caracterizar alpelisib administrado en combinación con olaparib.
5. Evaluar los resultados comunicados por la paciente respecto a alpelisib en combinación con olaparib, comparado con la quimioterapia citotóxica de un solo fármaco. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125.
Participant has no germline BRCA1/2 mutation as determined by an FDA-approved assay.
Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions (Wilson et al 2016). The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry.
Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment.
Participant has adequate bone marrow and organ function. |
Participantes con diagnóstico histológicamente confirmado de cáncer ovárico seroso o endometrioide de alto grado, cáncer de trompas de Falopio o cáncer peritoneal primario.
Enfermedad medible, es decir, al menos una lesión medible según RECIST 1.1 (una lesión en un lugar previamente irradiado solo se podrá considerar una lesión diana en caso de existir signos claros de progresión desde la irradiación).
Si no presenta una enfermedad medible, la enfermedad deberá ser evaluable mediante los criterios del Gynecologic Cancer Intergroup (GCIG) para CA-125.
Participantes sin mutación germinal de BRCA1/2 determinada por un análisis aprobado por la FDA.
Participantes con un estado funcional del Grupo Cooperativo Oncológico del Este (ECOG) de 0 o 1.
Participantes con enfermedad resistente a platino (progresión entre uno y seis meses después de completar el tratamiento basado en platino) o refractaria a platino (progresión durante el tratamiento o durante las 4 semanas posteriores a la última dosis), en la que el tratamiento basado en platino no es una opción, según las definiciones del 5th Ovarian Cancer Consensus Conference del GCIG (Wilson et al., 2016). La pauta de quimioterapia basada en platino no tiene que ser necesariamente la última pauta que haya recibido la participante antes de entrar en el estudio.
Participantes que hayan recibido al menos una pero no más de tres pautas de tratamiento sistémico previo y para quienes la quimioterapia de un solo fármaco sea apropiada como siguiente línea de tratamiento.
Participantes con una función adecuada de la médula ósea y los órganos. |
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E.4 | Principal exclusion criteria |
Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor. Participant is concurrently using other anti-cancer therapy.
Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease.
Participant has had surgery within 14 days prior to starting study drug or has not recovered from major side effects.
Participant has not recovered from all toxicities related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade </=1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study.
Participants with liver impairment and Child Pugh score B or C
Participant has received radiotherapy </= 4 weeks or limited field radiation for palliation </= 2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related side effects of such therapy (with the exception of alopecia).
Participant has a known hypersensitivity to any of the study drugs or excipients. |
Participantes que hayan recibido tratamiento previo con un inhibidor de PI3K, mTOR o AKT.
Participantes que estén recibiendo otro tratamiento concomitante contra el cáncer.
Participantes con una obstrucción del intestino delgado o grueso o con otra alteración de la función gastrointestinal (GI) o enfermedad GI.
Participantes que se hayan sometido a una cirugía durante los 14 días anteriores al inicio del fármaco del estudio o que no se hayan recuperado de efectos secundarios importantes.
Participantes que no se hayan recuperado de todas las toxicidades relacionadas con tratamientos antineoplásicos previos hasta los valores basales o a un grado </=1 de los CTCAE versión 4.03 del NCI. Una excepción a este criterio son las participantes con alopecia de cualquier grado, que podrán entrar en el estudio.
Participantes con deterioro hepático y puntuaciones B o C de Child-Pugh.
Participantes que hayan recibido radioterapia </=4 semanas o radioterapia paliativa de campo limitado </=2 semanas antes de la aleatorización y cuyos efectos secundarios de dicho tratamiento no se hayan recuperado hasta los valores basales, grado 1 o inferior (salvo alopecia).
Participantes con hipersensibilidad conocida a cualquiera de los fármacos del estudio o sus excipientes. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival based on blinded independent review committe assessment using RECIST 1.1 criteria |
Supervivencia libre de progresión basada en la evaluación de un comité de revisión independiente ciego utilizando los criterios RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Futility analysis based on progression-free survival: approximately after 90 progression-free survival events (first documented progression or death due to any cause), approximately 14 months after randomization of the first subject
Final analysis for progression-free survival: approximately after 224 progression-free survival events, approximately 22 months after randomization of the first subject |
Análisis de futilidad basado en la supervivencia libre de progresión: aproximadamente después de 90 eventos de supervivencia libre de progresión (primera progresión documentada o muerte por cualquier causa), aproximadamente 14 meses después de la aleatorización del primer sujeto
Análisis final para la supervivencia libre de progresión: aproximadamente después de 224 eventos de supervivencia libre de progresión, aproximadamente 22 meses después de la aleatorización del primer sujeto |
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E.5.2 | Secondary end point(s) |
Key secondary endpoint: To determine whether treatment with alpelisib in combination with olaparib prolongs OS compared to single agent cytotoxic chemotherapy in participants with platinum-resistant or refractory, gBRCAnm HGSOC
Secondary endpoints: To assess safety and tolerability of alpelisib in combination with olaparib with administered to participants with platinum-resistant or refractory gBRCAnm HGSOC. To Evaluate alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy in participants with platinum-resistant or refractory, gBRCAnm HGSOC with respect to time to deterioration of ECOG performance status. To assess additional efficacy parameter, such as ORR, CBR, DOR and TTR based on BIRC assessment using RECIST 1.1. To characterize alpelisib when administered in combination with olaparib in participants with platinum- resistant or refractory gBRCAnm HGSOC. To evaluate patient report outcomes of alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy in participants with platinum-resistant or refractory, gBRCAnm HGSOC. |
Variable secundaria clave: Determinar si el tratamiento con alpelisib en combinación con olaparib prolonga la OS comparado con el tratamiento con quimioterapia citotóxica de un solo fármaco en participantes con cáncer ovárico seroso de alto grado sin mutación germinal de BRCA y refractario o resistente al platino.
Variables secundarias: Evaluar la seguridad y tolerabilidad de alpelisib en combinación con olaparib administrado en participantes con COSAG sin mutación germinal de BRCA y refractario o resistente al platino. Evaluar alpelisib en combinación con olaparib, comparado con la quimioterapia citotóxica de un solo fármaco, en participantes con COSAG sin mutación germinal de BRCA y refractario o resistente al platino respecto al tiempo hasta el deterioro del estado funcional del Grupo Cooperativo Oncológico del Este (ECOG). Evaluar los parámetros adicionales de eficacia como ORR, CBR, DOR y TTR basando en la evaluación de un comité de revisión independiente ciego utilizando los criterios RECIST 1.1. Caracterizar alpelisib administrado en combinación con olaparib en pacientes con COSAG sin mutación germinal de BRCA y refractario o resistente al platino. Evaluar los resultados comunicados por la paciente respecto a alpelisib en combinación con olaparib, comparado con la quimioterapia citotóxica de un solo fármaco, en participantes adultas con COSAG sin mutación germinal de BRCA y refractario o resistente al platino. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary endpoint: OS will only be tested if final analysis of PFS is statistically significant.
• The time point for the first OS interim analysis will be at the time of final PFS analysis after approximately 50% of deaths (126 deaths) are expected to have been recorded in the clinical database.
• If OS is not statistically significant at the first interim analysis, the second OS analysis will be planned after approximately 75% of deaths (189 deaths) have been recorded in the clinical database (approximately 31 months after randomization of the first subject). If OS is not statistically significant at this stage, a final analysis is planned at the time approximately 252 deaths have been recorded (approximately 44 months after randomization of the first subject). |
Variable secundaria clave: la OS solo se evaluará si el análisis principal de la SLP es estadísticamente significativo.
- El momento para el primer análisis intermedio de OS será el momento del análisis final de la SLP después de que se espera que aproximadamente el 50% de las muertes (126 muertes) se hayan registrado en la base de datos clínica. |
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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 | 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 | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Brazil |
Canada |
China |
India |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Russian Federation |
Singapore |
Taiwan |
Turkey |
United States |
Austria |
Belgium |
Denmark |
Finland |
France |
Germany |
Italy |
Netherlands |
Portugal |
Slovakia |
Spain |
United Kingdom |
Czechia |
Argentina |
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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
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Study completion is defined as when the last subject finishes their safety and efficacy follow-up periods (as applicable) and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
pending |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 21 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 3 |