| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Melanoma stage IIIB-IVM1a |
| Melanoma estadío IIIB-IVM1a |
|
| E.1.1.1 | Medical condition in easily understood language |
| Melanoma (most serious type of skin cancer) in stage IIIB (cancer present in skin cells and in lymphatic ganglia) to IVM1a (cutaneous metastases, subcutaneous and ganglionic at distance) |
| Melanoma (cáncer de piel más grave) estadio IIIB (cáncer presente en células de la piel y en ganglios linfáticos) a IVM1a (metástasis cutáneas, subcutáneas y ganglionares a distancia |
|
| 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 |
| Explore the correlation/predictive role of lesion vascularization (measured by Doppler sonography) and clinical response in subjects with stage IIIB-IVM1a treated with T-VEC. |
| Explorar la correlación/predictiva de la vascularización de las lesiones (medidas con sonografía Doppler) y la respuesta clínica en pacientes Melanoma estadio IIIB-IVM1a tratados con T-VEC. |
|
| E.2.2 | Secondary objectives of the trial |
Overall response rates
Overall survival
Progression free-survival |
Tasa de respuesta global
Supervivencia global
Supervivencia libre de progresión |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Subject has provided informed consent prior to initiation of any study-specific
activities/procedures
-Male or female age ≥ 18 years.
-Histologically confirmed diagnosis of malignant melanoma.
-Subjects with unresected stage IIIB to IVM1a melanoma
-Candidate for intralesional therapy defined as:
- at least 1 injectable cutaneous, subcutaneous or nodal melanoma lesion ≥ 10 mm in longest
diameter or, multiple injectable melanoma lesions which in aggregate have a longest diameter of
≥ 10mm and measurable by sonography and positive Doppler signal.
-Measurable disease defined as one or more of the following:
- at least 1 melanoma lesion that can be accurately and serially measured in at least 2 dimensions
and for which the greatest diameter is ≥ 10 mm as measured by contrast enhanced or spiral
computed tomography (CT) scan for nodal/soft tissue disease(including lymph nodes)
- at least 1 ≥ 10 mm superficial cutaneous or subcutaneous melanoma lesion as measured by
calipers
- at least 1 ≥ 10 mm superficial cutaneous or subcutaneous melanoma lesion as measured by
ultrasound
- multiple superficial melanoma lesions which in aggregate have a total diameter of ≥ 10mm
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Serum LDH levels ≤ upper limit of normal (ULN) within 28 days prior to enrollment.
- Adequate organ function determined within 28 days prior to enrollment, defined as:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3
- Platelet count ≥ 100,000/mm3
- Hemoglobin ≥ 8 g/dL without need for hematopoietic growth factor or transfusion support
- Serum creatinine ≤ 1.5 x ULN
- Serum bilirubin ≤ 1.5 x ULN
- Aspartate amino transferase (AST) ≤ 2.5 x ULN
- Alanine amino transferase (ALT) ≤ 2.5 x ULN
- Alkaline phosphatase ≤ 2.5 x ULN
- Serum albumin ≥ 2.5 g/dL
- Coagulation
- International normalization ratio (INR) or prothrombin time (PT) £ 1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.
· PTT or aPTT £ 1.5 x ULN, unless the subject is receiving anticoagulant therapy as long as PT and
PTT/aPTT is within therapeutic range of intended use of anticoagulants.
-Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required |
- Edad ≥ 18 años.
- Diagnóstico histológicamente confirmado de melanoma maligno.
- Sujetos con melanoma en estadio IIIB no resecado a IVM1a
- Candidato para terapia intralesional definido como:
- al menos 1 lesión inyectable de melanoma cutáneo, subcutáneo o ganglionar ≥ 10 mm en el
diámetro mayor o múltiples lesiones inyectables de melanoma que en conjunto tienen un
diámetro mayor de ≥ 10 mm medibles por ecografía y señal Doppler positiva.
- Enfermedad medible definida como uno o más de los siguientes:
- al menos 1 lesión de melanoma que puede medirse de manera precisa y en serie en al menos 2
dimensiones y para la cual el mayor diámetro es ≥ 10mm medido por medio de contraste o
tomografía computarizada (TC) en espiral para detectar la enfermedad de los tejidos nodales /
blandos (incluido nódulos linfáticos)
- al menos 1 lesión cutánea o subcutánea superficial de melanoma ≥ 10mm medida con regla.
- al menos una lesión cutánea o subcutánea superficial de melanoma ≥ 10mm medida por
ultrasonido
- Múltiples lesiones superficiales de melanoma que en conjunto tengan un diámetro total de ≥
10mm.
-Eastern Cooperative Oncology Group (ECOG) performance status 0 o 1
-Niveles séricos de LDH ≤ límite superior de normalidad (ULN) dentro de los 28 días anteriores a la inclusión.
-Función orgánica adecuada determinada dentro de los 28 días anteriores a la inclusión, definida como:
- Recuento absoluto de neutrófilos (ANC) ≥ 1500 / mm3
- Recuento de plaquetas ≥ 100,000 / mm3
- Hemoglobina ≥ 8 g / dL sin necesidad de factor de crecimiento hematopoyético o soporte de
transfusión
- Creatinina sérica ≤ 1.5 x ULN
- Bilirrubina sérica ≤ 1.5 x ULN
- Aspartato amino transferasa (AST) ≤ 2.5 x ULN
- Alanina amino transferasa (ALT) ≤ 2.5 x ULN
- Fosfatasa alcalina ≤ 2,5 x ULN
- Albúmina sérica ≥ 2.5 g / dL
- Coagulación:
- - Relación de normalización internacional (INR) o tiempo de protrombina (PT) £ 1.5 x ULN, a
menos que el sujeto reciba terapia anticoagulante, en cuyo caso el tiempo de PT y el tiempo de
tromboplastina parcial (PTT) / PTT activado (aPTT) deben estar dentro del rango terapéutico
previsto para el uso de anticoagulantes.
- PTT o aPTT £ 1.5 x ULN, a menos que el sujeto reciba terapia anticoagulante siempre que el PT y
el PTT / aPTT estén dentro del rango terapéutico del uso previsto de los anticoagulantes.
-Las mujeres en edad fértil deben tener una prueba de embarazo negativa en orina o suero dentro
de las 72 horas previas a la inscripción. Si la prueba de orina es positiva o no se puede confirmar como negativa, se requerirá una prueba de embarazo en suero. |
|
| E.4 | Principal exclusion criteria |
-Primary ocular or mucosal melanoma
-Known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids >10 mg/day of prednisone or equivalent. The exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability.
-History or evidence of active autoimmune disease that requires systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
-Evidence of clinically significant immunosuppression such as the following: primary immunodeficiency state such as Severe Combined Immunodeficiency Disease receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment.
-Concurrent opportunistic infection.
-Patients with allergy to contrast
-Subject has known sensitivity to talimogene laherparepvec or any of its components to be administered during dosing.
-Patients with a history of any ischemic event will be excluded
-Known to have acute or chronic active hepatitis B infection
-known to have acute of chronic active hepatitis C infection
-known to have human immunodeficiency virus (HIV) infection
-Active herpetic skin lesions or prior complications of HSV-1 infection (eg, herpetic keratitis or encephalitis)
-Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
-Previous treatment with talimogene laherparepvec or any other oncolytic virus.
-Prior therapy with tumor vaccine.
-Received live vaccine within 28 days prior to enrollment.
-Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec.
-Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of talimogene laherparepvec.
-Sexually active subjects and their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with talimogene laherparepvec.
-Subjects who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or infants under the age of 3 months, during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec.
-Prior immunosuppressive, chemotherapy, radiotherapy (in which the field encompassed a planned injection site), biological cancer therapy, or major surgery within 28 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 28 days prior to enrollment. Adjuvant hormonal therapy is allowed if appropriate for planned study.
-Prior radiotherapy in which the field does not overlap the injection sites or non-immunosuppressive targeted therapy within 14 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 14 days prior to enrollment
-Currently receiving treatment with another investigational device or drug study, or < 28 days since ending treatment with another investigational device or drug study(s).
-Other investigational procedures while participating in this study are excluded.
-Known to have acute or chronic active hepatitis B infection.
- Known to have acute or chronic active hepatitis C infection.
- Known to have human immunodeficiency virus (HIV) infection.
- History of other malignancy within the past 5 years with the following exceptions:
• Adequately treated non melanoma skin cancer without evidence of disease at the time of
enrollment
• Adequately treated cervical carcinoma in situ without evidence of disease at the time of
enrollment
• Adequately treated breast ductal carcinoma in situ without evidence of disease at the time of
enrollment
• Prostatic intraepithelial neoplasia without evidence of prostate cancer at the time of enrollment. |
-Melanoma ocular o mucoso primario
-Antecedentes o evidencia de neumonitis autoinmune sintomática, glomerulonefritis, vasculitis u otra enfermedad autoinmune sintomática que requiera tratamiento sistémico.
-Pacientes con alergia al contraste.
-Se excluirá a los pacientes con antecedentes de cualquier evento isquémico.
-Evidencia de inmunosupresión por cualquier motivo, como los siguientes:
Medicamentos esteroides orales o sistémicos crónicos a una dosis de> 10 mg /día de prednisona
o equivalente (esteroides con baja absorción sistémica (p. Ej., Hexacetonida de triamcinolona)
inyectados en un espacio articular son permitidos) otros signos o síntomas de supresión clínica
del sistema inmunitario .
Estado de inmunodeficiencia primaria tal como enfermedad de inmunodeficiencia combinada
severa
-Infección aguda o crónica por hepatitis B activa.
-Infección aguda o crónica de hepatitis C
-Infección por el virus de la inmunodeficiencia humana (VIH)
-Lesiones cutáneas herpéticas activas o complicaciones previas de la infección por HSV-1 (p. Ej., Queratitis herpética o encefalitis)
-Requiere tratamiento sistémico intermitente o crónico (intravenoso u oral) con un fármaco antiherpético (por ejemplo, aciclovir), distinto del uso tópico intermitente
-Tratamiento previo con talimogene laherparepvec.
-El sujeto tiene sensibilidad conocida al talimogene laherparepvec o cualquiera de sus componentes para ser administrados durante la dosificación
-Los sujetos sexualmente activos y sus parejas no están dispuestos a usar condón masculino o femenino de látex para evitar la posible transmisión viral durante el contacto sexual durante el tratamiento y dentro de los 30 días posteriores al tratamiento con talimogene laherparepvec.
-Mujeres embarazadas o lactantes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the relationship between the vascularization within the node and skin lesions (quantified by Doppler ultrasound) and the clinical response measured by WHO/RECIST 1.1 criteria to T-VEC treatment from the baseline to the end of the follow-up. |
| Relación entre la vascularización dentro del nódulo y las lesiones cutáneas (cuantificadas por ecografía Doppler) y la respuesta clínica medida por los criterios WHO/RECIST 1.1 al tratamiento con T-VEC desde el inicio hasta el final del seguimiento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the baseline to the end of the follow-up.
The end of the study trial will be triggered when the last recruited patient completed the final study visit |
Desde el inicio hasta el final del seguimiento.
El final del ensayo será cuando el último paciente reclutado haya completado la visita final del estudio |
|
| E.5.2 | Secondary end point(s) |
Overall response rate in patients treated with T-VEC measured by WHO/RECIST criteria
Overall survival rate in patients treated with T-VEC measured by WHO/RECIST criteria
Progression free-survival in patients treated with T-VEC measured by WHO/RECIST criteria |
Tasa de respuesta global en pacientes tratados con T-VEC medido por los criterios WHO/RECIST
Tasa de supervivencia global en pacientes tratados con T-VEC. medido por los criterios WHO/RECIST
Supervivencia libre de enfermedad en pacientes tratados con T-VEC medido por los criterios WHO/RECIST |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall response rate at the end of treatment.
Overall survival rate at the end of follow-up.
Progression free-survival at the end of follow-up |
Tasa de respuesta global: al final del tratamiento.
Tasa de supervivencia global: al final del seguimiento.
Supervivencia libre de enfermedad: al final del seguimiento. |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| LVLS |
| última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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