E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
unresectable pleural or peritoneal malignant mesothelioma |
mesotelioma pleural o peritoneal maligno irresecable |
|
E.1.1.1 | Medical condition in easily understood language |
malignant mesothelioma that is not surgically resectable and that has previously been treated |
mesotelioma maligno que no es resecable y que ha sido tratado previamente |
|
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 | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034670 |
E.1.2 | Term | Peritoneal mesothelioma malignant localised |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10035606 |
E.1.2 | Term | Pleural mesothelioma malignant localised |
E.1.2 | System Organ Class | 100000004864 |
|
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 objective is to compare the overall survival (OS) between the 2 treatment arms (tremelimumab and placebo) in subjects with unresectable malignant mesothelioma. |
El objetivo principal es comparar la supervivencia global (SG) en los 2 grupos de tratamiento (tremelimumab y placebo) en pacientes con mesotelioma maligno irresecable. |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives are: - to estimate and compare durable disease-control rate (DCR), progression-free survival (PFS), overall response rate (ORR) and duration of response, - to evaluate the effect of tremelimumab on patient-reported outcomes (PROs), - to describe the safety and tolerability of tremelimumab in treated subjects, - to evaluate the immunogenicity of tremelimumab - and to describe the pharmacokinetics (PK) of tremelimumab in treated subjects. |
Los objetivos secundarios son: -Calcular y comparar la tasa de control de la enfermedad (TCE) duradero, supervivencia sin progresión (SSP) en los pacientes tratados, tasa de respuesta global (TRG) y duración de la respuesta. -Evaluar el efecto de tremelimumab en los resultados comunicados por los pacientes (CRP). -Describir la seguridad y la tolerabilidad de tremelimumab en los pacientes tratados; -Evaluar la inmunogenia de tremelimumab en los pacientes tratados; -Describir la farmacocinética (FC) de tremelimumab en los pacientes tratados. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria: - Histologically and/or cytologically confirmed pleural or peritoneal malignant mesothelioma. Disease not amenable to curative surgery;
- Age 18 and over at the time of consent;
- ECOG Performance status 0-1;
- Previous receipt of 1-2 prior systemic chemotherapies that included first-line pemetrexed (or anti-folate)-based regimen in combination with platinum agent;
- Recovered from all toxicities associated with prior treatment
- Measurable disease
- Adequate bone marrow, hepatic, and renal function
- Negative screening test results for human immunodeficiency virus (HIV), hepatitis A, B and C.
- Written informed consent and any locally required authorization (eg, HIPAA in the USA, EU Data Privacy Directive authorization in the EU) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations;
- Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product;
- Nonsterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from Day 1 through 90 post last dose. |
Los pacientes deberán cumplir todos los criterios siguientes:
-Mesotelioma maligno pleural o peritoneal confirmado por histología o por citología; Enfermedad que no se puede curar por cirugía;
-Edad de 18 años o más en el momento del consentimiento;
-Estado funcional ECOG de 0 a 1;
-Tratamiento previo con 1 o 2 pautas de quimioterapia sistémica, a base de permetrexed (o un antifolato) combinado con platino en primera línea.
-Haberse recuperado de todos los efectos tóxicos asociados al tratamiento previo,
-Enfermedad mensurable
-Funciones medular, hepática y renal satisfactorias
-Resultado negativo en las pruebas de detección de los virus de la inmunodeficiencia humana (VIH) y de las hepatitis A, B y C.
-El paciente o su representante legal deberán otorgar su consentimiento informado por escrito y cualquier autorización local que sea necesaria (p.ej., la HIPAA en los Estados Unidos, la autorización de la Directiva sobre protección de datos en la UE) antes de someterse a cualquier actuación relacionada con el protocolo, incluidas las evaluaciones de selección;
-Las mujeres en edad fértil que mantengan relaciones sexuales con un varón no esterilizado deberán comprometerse a utilizar un anticonceptivo de gran eficacia desde 28 días antes de recibir la primera dosis del producto en investigación hasta 6 meses después de la última;
-Los varones no esterilizados que mantengan relaciones sexuales con mujeres en edad fértil deberán utilizar un anticonceptivo de gran eficacia desde el día 1 hasta el día 90 después de la última administración. |
|
E.4 | Principal exclusion criteria |
Any of the following would exclude the subject from participation in the study:
- Received any prior monoclonal antibody against CTLA-4, programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PD-L1);
- History of chronic inflammatory or autoimmune disease;
- Active, untreated central nervous system (CNS) metastasis;
- History of other malignancy unless the subject has been disease-free for at least 3 years. Non-invasive cancer history (such as carcinoma in situ [CIS] that has been resected) is allowed;
- Pregnant or breast feeding at time of consent;
- Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol;
- Active or history of diverticulitis. Note that diverticulosis is permitted;
- Active or history of inflammatory bowel disease (eg, colitis, Crohn's), irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active or history of systemic lupus erythematosis or Wegener's granulomatosis;
- History of sarcoidosis syndrome;
- Currently receiving systemic corticosteroids or other immunosuppressive medications;
- Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment;
- The last dose of prior chemotherapy or radiation therapy (with the exception of palliative radiotherapy) was received less than 2 weeks prior to randomization;
- Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results;
- Concurrent enrollment in another clinical study or receipt of an investigational product within the last 4 weeks (participation in the survival follow-up period of a study is not an exclusion criterion);
- Employees of the study site directly involved with the conduct of the study, or immediate family members of any such individuals. |
No podrán participar en el estudio los pacientes que cumplan cualquiera de las siguientes condiciones:
-Pacientes que hayan recibido tratamiento con un anticuerpo monoclonal anti-CTLA-4, con proteína de muerte celular programada 1 (PD1) o con ligando 1 de la proteína de muerte celular programada 1 (PD-L1);
-Antecedentes de enfermedad inflamatoria crónica o autoinmunitaria;
-Metástasis activa y no tratada en el sistema nervioso central (SNC);
-Antecedentes de otros trastornos malignos, salvo que el paciente esté libre de la enfermedad desde al menos 3 años antes; Se permiten los antecedentes de cáncer no invasivo (como carcinoma in situ [CIS] resecado);
-Paciente embarazada o en periodo de lactancia en el momento del consentimiento;
-Cualquier trastorno que le impida al paciente entender o facilitar información y aceptar y cumplir los requisitos de este protocolo;
-Diverticulitis, activa o en el pasado. Obsérvese que se acepta la diverticulosis.
-Enfermedad inflamatoria intestinal (p. ej., colitis, enfermedad de Crohn) activa o en el pasado, enfermedad del intestino irritable, enfermedad celíaca u otras enfermedades digestivas crónicas graves que se asocien a diarrea; Lupus eritematoso sistémico o granulomatosis de Wegener, activas o en el pasado;
-Antecedentes de síndrome de sarcoidosis;
-Pacientes que reciban tratamiento en la actualidad con corticosteroides sistémicos o con otros inmunosupresores;
-Los pacientes no podrán recibir vacunas atenuadas vivas en el mes previo al inicio del tratamiento con tremelimumab;
-Los pacientes no podrán haber recibido quimioterapia ni radioterapia (salvo radioterapia paliativa) en las 2 semanas previas a la aleatorización;
-Cualquier trastorno que, en opinión del investigador, pueda interferir en la evaluación del producto en investigación o en la interpretación de la seguridad del paciente o de los resultados del estudio;
-Reclutamiento concurrente en otro estudio clínico, o haber recibido un producto en investigación en las 4 últimas semanas (la participación en el período de seguimiento de la supervivencia de un estudio no será motivo de exclusión);
-Empleados del centro de estudio que intervengan directamente en el estudio, o sus familiares directos. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is OS which is defined as the time from randomization until death due to any cause. |
El criterio de valoración principal es la SG, que se define como el tiempo que transcurre desde la aleatorización hasta la muerte por cualquier causa. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of OS will be performed after a number of deaths have occurred among the approximately 180 participants randomized. For participants who are alive at the time of the primary analysis or lost to follow-up, OS will be censored on the last date when participants are known to be alive. |
El análisis principal de este criterio de valoración se llevará a cabo cuando se hayan producido un número de fallecimientos en los aproximadamente 180 pacientes aleatorizados. En el caso de los pacientes que sigan vivos en el momento del análisis principal o que se pierdan en el seguimiento, la SG se censará en la última fecha en la que se tenga conocimiento de que aún estaban con vida |
|
E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include PRO as well as durable DCR, PFS, ORR, and duration of response, based on modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural mesothelioma and RECIST criteria v1.1 for peritoneal mesothelioma.
The safety endpoints include adverse events (AEs) and serious adverse events (SAEs) from the time that written informed consent is obtained through 90 days after the last dose of investigational product, changes from baseline in clinical laboratory evaluations, electrocardiograms (ECGs), and vital signs. Adverse events and SAEs will be assessed for severity and relationship to investigational product.
The immunogenic potential of tremelimumab will be analyzed and the pharmacokinetics of tremelimumab will be assessed. |
Los criterios secundarios de valoración de la eficacia son la TCE duradero, la SSP, la puntuación LCSS-Meso, la TRG y la duración de la respuesta, basada en los RECIST modificados para el mesotelioma pleural y en la versión 1.1 de dichos criterios para el mesotelioma peritoneal.
Los criterios de valoración de la seguridad son los acontecimientos adversos (AA) y los acontecimientos adversos graves (AAG) desde el momento de la firma del consentimiento informado por el paciente hasta 90 días después de la administración de la última dosis del producto en investigación, las variaciones desde el inicio en la evaluaciones analíticas, los electrocardiogramas (ECG) y las constantes vitales. Se evaluarán la intensidad de los AA y los AAG y su relación con el producto en investigación.
Se llevará a cabo un análisis del potencial inmunógeno de tremelimumab y se evaluará la farmacocinética de tremelimumab |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of these secondary endpoints will be based on investigator-determined response data |
El análisis de estas variables secundarias se basará en datos de respuesta determinados por el investigador. |
|
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) | 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 | 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) | No |
E.8.2.2 | Placebo | Yes |
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 | 76 |
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 |
Belgium |
Brazil |
Canada |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Sweden |
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 end of the study (?study completion?) is defined as the date when the prespecified number of death events has been reached for the primary endpoint or the date the sponsor stops the study. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |