E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable/Metastatic Stage IIIB-IVM1d Melanoma |
melanoma en estadio IIIB a IVM1d irresecable/metastásico |
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E.1.1.1 | Medical condition in easily understood language |
A type of cancer that develops from the pigment-containing cells known as melanocytes |
Un tipo de cáncer que se desarrolla a partir de las células que producen el pigmento conocidas como melanocitos |
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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 | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate the efficacy of Talimogene laherparepvec in combination with pembrolizumab as assessed by ORR in subjects with unresectable/metastatic stage IIIB-IVM1d melanoma who have progressed on prior anti-PD-1 therapy |
Evaluar la eficacia de talimogén laherparepvec en combinación con pembrolizumab, valorada mediante la TRO, en sujetos con melanoma en estadio IIIB a IVM1d irresecable/metastásico que han progresado con el tratamiento previo basado en anti-PD-1. |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of talimogene laherparepvec in combination with pembrolizumab, as assessed by: o CRR, best overall response, (BOR) durable response rate, (DRR) duration of response, (DOR) and disease control rate, (DCR) o ORR using modified irRC-RECIST o Progression free survival (PFS) o Overall survival (OS) -To evaluate the safety of talimogene laherparepvec in combination with pembrolizumab as assessed by incidence of treatment-emergent and treatment-related adverse events, and abnormal laboratory tests in patients who have progressed on prior anti-PD-1 therapy -To evaluate time to subsequent anti-cancer therapy |
- Evaluar la eficacia de talimogén laherparepvec en combinación con pembrolizumab según: o La TRC, la mejor respuesta global (MRG), la tasa de respuesta duradera (TRD), la duración de la respuesta (DR) y la tasa de control de la enfermedad (TCE). o La TRO según los criterios irRC-RECIST modificados. o La supervivencia libre de progresión (SLP). o La supervivencia global (SG). - Evaluar la seguridad de talimogén laherparepvec en combinación con pembrolizumab mediante la incidencia de acontecimientos adversos que aparecen durante el tratamiento y relacionados con el tratamiento y pruebas de laboratorio anómalas en pacientes que han progresado con el tratamiento previo basado en anti-PD-1. - Evaluar el tiempo hasta el tratamiento anticanceroso posterior. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
This study will enroll subjects -who are male or female age > 18 years at the time of informed consent -with histologically confirmed diagnosis of melanoma (unresectable or metastatic stage IIIB, IIIC, IIID, IVM1a, IVM1b, IVM1c, or IVM1d melanoma). - Subjects with stage IVM1d and up to 3 cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife therapy, with no evidence of progression and not requiring steroids for at least 2 months prior to enrollment. -Subjects must have measurable disease and be a candidate for intralesional therapy. -Subjects must have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 -Adequate hematologic, hepatic, renal, and coagulation function. - Subject must also have received prior anti-PD-1 therapy for at least 2 to 3 consecutive cycles within an 8 week period and have disease progression as defined by RECIST v1.1 criteria. |
Este estudio incluirá los sujetos: -Hombre o mujer de edad ≥ 18 años en el momento de proporcionar el consentimiento informado -Diagnóstico de melanoma confirmado histológicamente (melanoma irresecable o metastásico de estadio IIIB, IIIC, IIID, IVM1a, IVM1b, IVM1c o IVM1d). -Sujetos en estadio IVM1d y con hasta 3 metástasis cerebrales, siempre que todas las lesiones se hayan tratado adecuadamente con radioterapia estereotáctica, craneotomía o terapia con bisturí de rayos gamma, sin evidencia de progresión ni necesidad de esteroides durante al menos los 2 meses previos a la inclusión. -Los sujetos deben tener una enfermedad medible y ser candidatos para recibir tratamiento intralesional. -Los sujetos deben presentar un estado funcional del Eastern Cooperative Oncology Group (EF ECOG) de 0 o 1 -Funciones hematológica, hepática, renal y coagulante adecuadas. -El sujeto también debe haber recibido tratamiento previo anti-PD-1 durante al menos 2 o 3 ciclos consecutivos en un período de 8 semanas y presentar progresión de la enfermedad según la definición de los criterios RECIST v. 1.1. |
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E.4 | Principal exclusion criteria |
-Subjects must not have clinically active cerebral melanoma metastases and/or carcinomatous meningitis. -Subjects must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia), or history of other malignancy within the past 3 years with the exceptions noted in Section 6.2 of the protocol. -Subjects must not have been previously treated with talimogene laherparepvec, any other oncolytic viruses, or tumor vaccine (unless administered in the adjuvant setting). -Subjects must not have a history or evidence of symptomatic autoimmune glomerulonephritis, vasculitis, or other symptomatic autoimmune disease, or active autoimmune disease or syndrome that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. -Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. -Subjects must not have active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use. |
-Los sujetos no deben tener metástasis melanomatosas cerebrales clínicamente activas y/o meningitis carcinomatosa. -Los sujetos no deben tener melanoma uveal o mucoso primario, antecedentes ni evidencia de melanoma asociado a estados de inmunodeficiencia (p. ej., inmunodeficiencia hereditaria, trasplante de órganos o leucemia) ni antecedentes de otros tumores malignos en los últimos 3 años, con las excepciones que se indican en el apartado 6.2. -Los sujetos no pueden haber recibido tratamiento previo con talimogén laherparepvec, virus oncolíticos o vacunas tumorales (salvo administración en el contexto adyuvante). -Los sujetos no deben presentar antecedentes ni evidencia de glomerulonefritis autoinmunitaria sintomática, vasculitis u otra enfermedad autoinmunitaria sintomática, ni de enfermedad o síndrome autoinmunitario activo que haya requerido tratamiento sistémico en los 2 últimos años (es decir, uso de agentes modificadores de la enfermedad, corticosteroides o fármacos inmunosupresores), excepto vitiligo o asma/atopia infantil resuelta. -El tratamiento sustitutivo (p. ej., tiroxina, insulina, o tratamiento sustitutivo fisiológico con corticosteroides para la insuficiencia suprarrenal o pituitaria, etc.) no se considera una forma de tratamiento sistémico. -Los sujetos no deben presentar lesiones cutáneas herpéticas activas ni complicaciones anteriores de infección herpética (p. ej., queratitis o encefalitis herpética) y no deben requerir tratamiento intermitente o crónico con un fármaco antiherpético (p. ej., aciclovir), aparte del uso tópico intermitente. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR (complete response [CR]+partial response [PR]) (by investigator assessment using modified Response Evaluation Criteria in Solid Tumor [RECIST v1.1]) |
TRO (respuesta completa [RC] + respuesta parcial [RP]) (según la evaluación del investigador con los criterios de evaluación de la respuesta en tumores sólidos modificados [RECIST v. 1.1]) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Efficacy analysis will be performed on the Full Analysis Set (FAS) defined as all enrolled subjects who received at least 1 dose of talimogene laherparepvec and at least 1 dose of pembrolizumab in combination |
- Se realizará un análisis de la eficacia en el grupo de análisis completo (GAC), definido como todos los sujetos incluidos que hayan recibido al menos 1 dosis de talimogén laherparepvec y al menos 1 dosis de pembrolizumab en combinación |
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E.5.2 | Secondary end point(s) |
- CRR, BOR, DRR, DOR, and DCR, (investigator assessment using modified RECIST v1.1 and modified irRC-RECIST) and iORR using modified irRC-RECIST by investigator assessment -PFS (by investigator assessment using modified RECIST v1.1 and modified irRC-RECIST) -OS -Incidence of treatment-emergent and treatment-related adverse events (all adverse events, grade ≥ 3 adverse events, serious adverse events, fatal adverse events, adverse events defined as events of interest), and abnormal laboratory tests -Time to subsequent anti-cancer therapy |
- La TRC, la MRG, la TRD, la DR y la TCE (evaluación del investigador con los criterios RECIST v. 1.1 modificados y los irRC-RECIST modificados) y la TROi según la evaluación del investigador con los criterios irRC-RECIST modificados. - La SLP (según la evaluación del investigador con los criterios RECIST v. 1.1 modificados y los irRC-RECIST modificados). - La SG. - Incidencia de acontecimientos adversos que aparecen durante el tratamiento y relacionados con el tratamiento (todos los acontecimientos adversos, acontecimientos adversos de grado ≥ 3, acontecimientos adversos graves, acontecimientos adversos mortales y acontecimientos adversos definidos como acontecimientos de interés) y pruebas de laboratorio anómalas. - Tiempo hasta el tratamiento anticanceroso posterior. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Efficacy analysis will be performed on the Full Analysis Set (FAS) defined as all enrolled subjects who received at least 1 dose of talimogene laherparepvec and at least 1 dose of pembrolizumab in combination - The Safety Analysis Set (SAS), defined as all enrolled subjects who received at least 1 dose of talimogene laherparepvec or pembrolizumab, will be used in the analysis of the safety endpoints. |
- Se realizará un análisis de la eficacia en el grupo de análisis completo (GAC), definido como todos los sujetos incluidos que hayan recibido al menos 1 dosis de talimogén laherparepvec y al menos 1 dosis de pembrolizumab en combinación - En el grupo de análisis de la seguridad (GAS), definido como todos los sujetos incluidos que hayan recibido al menos 1 dosis de talimogén laherparepvec o pembrolizumab, se realizará análisis de la seguridad. |
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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 | No |
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) | 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 | No |
E.8.1.1 | Randomised | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 38 |
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 |
Finland |
France |
Germany |
Greece |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of study date is defined as the date when the last subject across all sites is assessed or receives an intervention for evaluation in the study (ie, last subject last visit), following any additional parts in the study (eg, long-term follow-up), as applicable. |
La fecha de fin de ensayo se define como la fecha cuando el último sujeto del último centro se evalúa o recibe una intervención para la evaluación en el estudio (ej. último sujeto última visita), siguiendo cualquier parte adicional del estudio (ej. seguimiento a largo plazo), según proceda. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
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 |