E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resectable, Stage IIIB to IVM1a Melanoma |
Melanoma reseclable en estadio IIIB a IVM1a |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053571 |
E.1.2 | Term | 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 estimate the treatment effect of neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on recurrence-free survival (RFS). |
Estimar el efecto del tratamiento neoadyuvante con talimogene laherparepvec más cirugía en comparación con solo cirugía en la supervivencia libre de recurrencia (SLR). |
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E.2.2 | Secondary objectives of the trial |
To estimate the effect of: - neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on 2-year, 3-year, and 5-year RFS - neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on rate of histopathological tumor-free margin (R0) surgical resection neoadjuvant talimogene laherparepvec on rate of pathological complete response (pCR) - neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on local recurrence-free survival (LRFS) and distant metastases-free survival (DMFS) - neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone on 2-year, 3-year, 5-year, and overall survival (OS) To estimate response to neoadjuvant talimogene laherparepvec overall and separately in injected and uninjected lesions during treatment (arm 1 only) To evaluate the safety of neoadjuvant talimogene laherparepvec plus surgery compared to surgery alone |
Estimar el efecto de: -tratamiento neoadyuvante con talimogene laherparepvec más cirugía en comparación con solo cirugía en la SLR a los 2 años, 3 años y 5 años. - tratamiento neoadyuvante con talimogene laherparepvec más cirugía en comparación con solo cirugía en la tasa de resección quirúrgica con margen libre de tumor en el examen histopatológico (R0) y en la tasa de respuesta completa patológica (RCp). - tratamiento neoadyuvante con talimogene laherparepvec más cirugía en comparación con solo cirugía en la supervivencia libre de recurrencia local (SLRL) y la supervivencia libre de metástasis distantes (SLMD); en la supervivencia global (SG) y en la supervivencia a los 2 años, 3 años y 5 años. - tratamiento neoadyuvante con talimogene laherparepvec en conjunto y por separado en lesiones inyectadas y no inyectadas durante el tratamiento(solo el grupo 1). -Evaluar la seguridad del tratamiento neoadyuvante con talimogene laherparepvec más cirugía en comparación con solo cirugía. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male or female >= 18 years of age with histologically confirmed diagnosis of stage IIIB, IIIC or IVM1a melanoma eligible for complete surgical resection. Prior systemic, regional and radiation anticancer therapies for melanoma must have been completed at least 3 months prior to randomization. Subject must have measurable disease and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (>= 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of >= 10 mm. Also, subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and must have a serum lactate dehydrogenase (LDH) <= 1.0 X upper limit of normal and adequate hematologic, hepatic, renal, and coagulation organ function. |
Hombres o mujeres de >= 18 años de edad con diagnóstico histológico confirmado de melanoma en estadio IIIB, IIIC o IVM1a elegibles para una resección quirúrgica completa. Los tratamientos anticancerígenos sistémicos, regionales y radioterápicos para el melanoma se deben haber completado al menos 3 meses antes de la aleatorización. El sujeto debe tener enfermedad medible y debe ser candidato para el tratamiento intralesional con al menos una lesión melanomatosa cutánea, subcutánea o nodular inyectable (diámetro más largo >= 10 mm) o con múltiples lesiones inyectables cuyo diámetro más largo en conjunto sea >= 10 mm. Asimismo, el sujeto debe tener un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1, una lactato deshidrogenasa (LDH) sérica <= 1,0 X límite superior de la normalidad y función orgánica hematológica, hepática, renal y de coagulación adecuadas. |
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E.4 | Principal exclusion criteria |
Subject must not have primary ocular or mucosal melanoma, or history or evidence of melanoma associated with immunodeficiency states (eg, hereditary immune deficiency, organ transplant, or leukemia). Subject must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, or other symptomatic autoimmune disease. Subject must not have evidence of clinically significant immunosuppression or active herpetic skin lesions or prior complications of herpes simplex type 1 (HSV-1) infection (eg, herpetic keratitis or encephalitis) and must not require intermittent or chronic systemic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use. Subject known to have acute or chronic active hepatitis B, hepatitis C, or human immunodeficiency virus infection will also be excluded. Subject must not have been treated previously with talimogene laherparepvec or tumor vaccine. |
El sujeto no debe tener melanoma ocular o mucoso primario ni antecedentes o evidencia de melanoma asociado a estados de inmunodeficiencia (p. ej., deficiencia inmune hereditaria, trasplante de órganos o leucemia). El sujeto no debe tener antecedentes o evidencia de neumonitis autoinmune sintomática, glomerulonefritis, vasculitis u otra enfermedad autoinmune sintomática. El sujeto no debe presentar evidencia de inmunosupresión clínicamente significativa o lesiones cutáneas herpéticas activas o complicaciones anteriores de infección por virus del herpes simple tipo 1 (VHS-1) (por ejemplo, queratitis o encefalitis herpética) y no debe requerir tratamiento sistémico intermitente o crónico con un fármaco antiherpético (por ejemplo, aciclovir), aparte del uso tópico intermitente. También se excluirán aquellos sujetos de los que se sepa que tengan hepatitis B activa aguda o crónica, hepatitis C, o infección por el virus de la inmunodeficiencia humana. El sujeto no debe haber sido tratado previamente con talimogene laherparepvec ni vacunas tumorales. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Recurrence-free survival (RFS) |
supervivencia libre de recurrencia (SLR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analyses for RFS will occur at the later time of either the occurrence of approximately 64 events (local or distant recurrence of melanoma or death) or approximately 2 years after end of randomization. The final analyses will occur approximately 5 years after end of randomization. |
El análisis principal de la SLR tendrá lugar como muy tarde cuando se hayan producido aproximadamente 64 acontecimientos (recurrencia local o distante del melanoma o muerte) o hayan transcurrido aproximadamente 2 años desde el final de la aleatorización.El análisis final ocurrirá aproximadamente 5 años tras el final de la aleatorización. |
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E.5.2 | Secondary end point(s) |
2-year, 3-year, and 5-year RFS Rate of histopathology tumor-free margin (R0) surgical resection Rate of pCR LRFS DMFS 2-year, 3-year and 5-year, and overall survival Overall tumor response and tumor response in injected and uninjected lesions Subject incidence of treatment-emergent and treatment-related adverse events |
-SLR a los 2 años, 3 años y 5 años. -Tasa de resección quirúrgica con margen libre de tumor en el examen histopatológico (R0). -Tasa de RCp. -SLRL. -SLMD. -Supervivencia global y supervivencia a los 2 años, 3 años y 5 años. -Respuesta tumoral global y respuesta tumoral en lesiones inyectadas y no inyectadas (solo el grupo 1). -Incidencia en los sujetos de acontecimientos adversos que aparecen durante el tratamiento y los relacionados con el tratamiento. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for certain secondary endpoints will be performed using the data from the second interim analysis. The final analyses will occur approximately 5 years after end of randomization. |
El análisis principal de ciertas variables secundarias se realizará utilizando los datos del segundo análisis intermedio. Los análisis finales se realizarán aproximadamente 5 años después del fin de la aleatorización. |
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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 | 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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Russian Federation |
United States |
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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 time when the last subject is assessed or receives an intervention for evaluation in the study. The end of trial will occur when the last subject has had the opportunity to complete the long-term follow-up. |
El momento en que el último sujeto se evalúa o recibe una intervención para la evaluación en el estudio. El fin del ensayo tendrá lugar cuando el último sujeto haya tenido la oportunidad de completar el seguimiento a largo plazo. |
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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 | 7 |
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 | 7 |
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 |