| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Uveal Melanoma |
| Melanoma uveal |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer which starts and spreads from the pigmented cells of the eye |
| Cancer que empieza y se dispersa desde las células pigmentadas del ojo |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025650 |
| E.1.2 | Term | Malignant melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to compare the OS in patients treated with IMCgp100 monotherapy versus Investigator’s Choice in HLA-A*0201 positive patients with advanced UM with no prior treatment in the metastatic setting. |
| El objetivo principal es comparar la SG de los pacientes tratados con monoterapia de IMCgp100 frente a la elección del investigador en pacientes con HLA-A*0201 positivo con MMU avanzado sin tratamiento previo en situación de metástasis. |
|
| E.2.2 | Secondary objectives of the trial |
• To characterize the safety and tolerability of IMCgp100 in the intra-patient dose escalation regimen
• To characterize the PK profile of single-agent IMCgp100 in the intra-patient dose escalation regimen
• To assess the ORR comparing IMCgp100 and Investigator’s Choice using RECIST v1.1 response criteria
• To assess the anti-tumor efficacy of IMCgp100 with the parameters of ORR, PFS, duration of response (DOR), and disease control rate (DCR)
• To evaluate the treatment and disease impact to HRQoL in patients treated with IMCgp100 versus patients treated with Investigator’s Choice. HRQoL will be assessed using 2 established patient reported outcome instruments:
o EQ-5D,5L to enable an assessment of health status compared to population norms
o QLQ-C30 to provide an insight into domains of cancer-specific patient health
• To evaluate the incidence of anti-IMCgp100 antibody formation following multiple infusions of IMCgp100 in the intra-patient dose escalation regimen |
•Caracterizar la seguridad y la tolerabilidad de IMCgp100 en el régimen de aumento intrapaciente de la dosis
•Caracterizar el perfil FC de la monoterapia con IMCgp100 en el régimen de aumento intrapaciente de la dosis
•Evaluar TRO entre IMCgp100 y la elección del investigador usando la versión 1.1 de RECIST
•Evaluar la eficacia antineoplásica de IMCgp100 con los parámetros de TRO, SSP,DdR y TCE
•Evaluar el tratamiento y el impacto en la CdVRs tratados con IMCgp100 frente a los pacientes tratados con la elección del investigador. La CdVRS se evaluará usando :
oEl cuestionario EuroQol de 5 dimensiones:
oEl cuestionario QLC-C30 de la EORTC para aportar información acerca de la salud de pacientes con un tipo específico de cáncer
•Evaluar la incidencia de la formación de anticuerpos anti-IMCgp100 tras varias infusiones de IMCgp100 en el régimen de aumento intrapaciente de la dosis |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Male or female patients age ≥ 18 years of age at the time of informed consent
2. Ability to provide and understand written informed consent prior to any study procedures
3. Histologically or cytologically confirmed metastatic UM
4. Must meet the following criteria related to prior treatment:
• No prior systemic therapy in the metastatic or advanced setting including chemotherapy, immunotherapy, or targeted therapy
• No prior local, liver-directed therapy including chemotherapy, radiotherapy, radiofrequency ablation (RFA), or embolization
• Prior surgical resection of oligometastatic liver disease is allowed
• Prior neoadjuvant or adjuvant therapy is allowed provided administered in the curative setting in patients with localized disease. Patients may not be re-treated with Investigator’s Choice therapy that was administered as adjuvant or neo-adjuvant treatment
5. HLA-A*0201 positive by central assay
6. Life expectancy of > 3 months as estimated by the investigator
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at Screening
8. Patients must have measurable disease according to RECIST v.1.1 criteria
9. All other relevant medical conditions must be well-managed and stable, in the opinion of the
investigator, for at least 28 days prior to first administration of study drug |
1.Hombres y mujeres de ≥ 18 años en el momento de la firma del consentimiento informado
2.Capacidad para otorgar y comprender el consentimiento informado escrito antes de que se lleve a cabo cualquier procedimiento del estudio
3.MMU metastásico, confirmado histológica o citológicamente
4.Se deben cumplir los siguientes criterios relacionados con el tratamiento previo:
•No haber recibido tratamiento sistémico previo en situación de enfermedad avanzada o con metástasis, incluidos quimioterapia, inmunoterapia o tratamiento dirigido
•No haber recibido terapia hepática local previa, incluidas quimioterapia, radioterapia, ablación por radiofrecuencia (RFA) o embolización
•Se permite la resección quirúrgica de la hepatopatía oligometastásica
•Se permite el tratamiento pre o posquirúrgico previo siempre que se administre en el contexto curativo en pacientes con neoplasia localizada. No se puede volver a tratar a los pacientes con un tratamiento de elección del investigador que ya se hubiese administrado como tratamiento pre y/o posquirúrgico
5.HLA-A*0201 positivos mediante análisis central
6.Esperanza de vida de > 3 meses a juicio del investigador
7.Grado de actividad de 0 a 1 según el Grupo Cooperativo de Oncología del Este (ECOG) en la selección
8.Los pacientes deben tener una neoplasia medible según la versión 1.1 de los criterios RECIST
9.Las demás afecciones médicas pertinentes deben estar bien tratadas y estables, a juicio del investigador, durante al menos los 28 días previos a la primera administración del fármaco del estudio |
|
| E.4 | Principal exclusion criteria |
1.Patient with any out-of-range lab. values defined as:
•Serum creatinine > 1.5 × upper limit of normal (ULN) &/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
•Total bilirubin > 1.5 × ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN
•Alanine aminotransferase > 3 × ULN
•Aspartate aminotransferase > 3 × ULN
•Absolute neutrophil count < 1.0 × 10^9/L
•Absolute lymphocyte count < 0.5 × 10^9/L
•Platelet count < 75 × 10^9/L
•Hemoglobin < 8 g/dL
•Potassium, magnesium, corrected calcium or phosphate abnormality of NCI CTCAE (v4.03) > grade 1
2.History of severe hypersensitivity reactions (eg, anaphylaxis) to other
biologic drugs or monoclonal antibodies
3.Clinically significant cardiac disease or impaired cardiac function,
including any of the following:
•Clinically significant &/or uncontrolled heart disease such as congestive heart failure (NYHA grade = 2), uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment
•QTcF > 470 msec on screening ECG or congenital long QT syndrome
•Acute myocardial infarction or unstable angina pectoris < 6 months
prior to Screening
4.Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require doses of corticosteroids within the prior 3 weeks to study Day 1. Patients with brain metastases are eligible if lesions have been treated with localized therapy and there is no evidence of progression for at least 4 weeks by MRI prior to the first dose of study drug
5.Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug 6.Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated
7.Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary
unless clinically indicated or the patient has a history of HBV or HCV infection
8.Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type
9.Any medical condition that would, in the investigator's or Sponsor's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
10.Patients receiving systemic steroid therapy or any other systemic immunosuppressive medication at any dose level, as these may interfere with the mechanism of action of study treatment. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable
11.History of adrenal insufficiency
12.History of interstitial lung disease
13.History of pneumonitis that required corticosteroid treatment or current pneumonitis
14.History of colitis or inflammatory bowel disease
15.Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary)
16.Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass
17.Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF) = 2 weeks prior to start of study drug. An erythroidstimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is not red blood cell transfusion dependent
18.Pregnant, likely to become pregnant, or lactating women (where pregnancyis defined as the state of a female after conception and until the termination of gestation)
19.Women of child-bearing potential who are sexually active with a nonsterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment, and must agree to continue using such precautions for 6 months after the final dose of investigational product; Cessation of birth control after this point should be discussed with a responsible physician.
20.Male patients must be surgically sterile or use double barrier contraception methods from enrollment through treatment and for 6 months following administration of the last dose of study drug |
1.Un paciente con cualquier valor analítico fuera del intervalo, definido como:
•Creatinina en suero > 1,5 × LSN y/o aclaramiento de la creatinina < 50 ml/minuto
•Bilirrubina total > 1,5 × LSN, excepto en el caso de los pacientes con síndrome de Gilbert,
•Alanina-transaminasa > 3 × LSN
•Aspartato-transaminasa > 3 × LSN
•Recuento absoluto de neutrófilos < 1,0 × 109/l
•Recuento absoluto de linfocitos < 0,5 × 109/l
•Recuento plaquetario < 75 × 109/l
•Hemoglobina < 8 g/dl
•Anomalía de grado > 1 en los niveles de potasio, magnesio, calcio corregido o fosfato según NCI CTCAE
2.Antecedentes de reacciones hipersensibles graves a otros biofármacos o anticuerpos monoclonales
3.Afección cardiaca clínicamente significativa o disfunción cardiaca
4.Presencia de metástasis sintomática o sin tratar en el SNC o metástasis en el SNC que haga necesario administrar dosis de corticoesteroides en las 3 semanas previas al día 1 del estudio.
5.Infección activa que exija tratamiento sistémico con antibióticos.
6.Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH).
7.Infección activa por virus de la hepatitis B (VHB) o C (VHC) según el protocolo del centro.
8.Neoplasia maligna, distinta de aquella que se va a tratar en este estudio. Entre las excepciones a esta exclusión se incluyen: neoplasias malignas que hayan sido tratadas curativamente y que no hayan presentado recaída en los 2 años previos al tratamiento del estudio; carcinomas basocelulares o epidermoides totalmente resecados; cualquier neoplasia que se considere de escasa malignidad y que nunca haya necesitado tratamiento; y carcinoma in situ totalmente resecado de cualquier tipo
9.Cualquier afección médica que, a juicio del investigador o el promotor, impida la participación del paciente en el estudio clínico debido a cuestiones relacionadas con la seguridad, el cumplimiento de los procedimientos del estudio clínico o la interpretación de los resultados del estudio
10.Pacientes que reciban tratamiento sistémico con esteroides o cualquier otra medicación inmunosupresora sistémica y con cualquier nivel posológico, ya que estos pueden interferir con el mecanismo de acción del tratamiento del estudio. Los tratamientos locales con esteroides (p. ej., medicamentos óticos, oftálmicos, intraarticulares o inhalados) se consideran aceptables
11.Antecedentes de insuficiencia suprarrenal
12.Antecedentes de enfermedad pulmonar intersticial
13.Antecedentes de neumonitis que exijan tratamiento con corticoesteroides o neumonitis en la actualidad
14.Antecedentes de colitis o enteropatía inflamatoria
15.Cirugía mayor en las dos semanas previas a la primera dosis del fármaco del estudio (no se consideran cirugía mayor y no son excluyentes las intervenciones mínimamente invasivas como broncoscopia, biopsia tumoral, inserción de un dispositivo de acceso a vena central y la inserción de una sonda de alimentación)
16.Radioterapia en las dos semanas previas a la primera dosis del fármaco del estudio, con la excepción de la radioterapia paliativa en un campo limitado, por ejemplo para el tratamiento del dolor óseo o de una masa tumoral focalmente dolorosa
17.Uso de factores de estimulación de las colonias hematopoyéticas (p. ej., FECG, GM-CSF, M-CSF) ≤ 2 semanas antes del inicio del fármaco del estudio. Se permite un agente estimulante de los eritroides, siempre que se haya iniciado al menos 2 semanas antes de la primera dosis del tratamiento del estudio y que el paciente no dependa de transfusiones de eritrocitos
18.Mujeres embarazadas, que probablemente se queden embarazadas o que estén practicando la lactancia materna (se define embarazo como el estado de una mujer tras la concepción y hasta el fin de la gestación)
19.Mujeres potencialmente fértiles que sean sexualmente activas con una pareja masculina no esterilizada, definidas como aquellas mujeres con capacidad fisiológica para quedarse embarazas, salvo que utilicen anticonceptivos altamente eficaces durante el tratamiento del estudio (definido en la sección 6.7). Asimismo, deben comprometerse a seguir aplicando dichas precauciones durante los 6 meses posteriores a la dosis final del producto en investigación; la interrupción de la prevención del embarazo después de este momento debe ser debatida con un médico. En la sección 6.7 se describen los métodos anticonceptivos altamente eficaces
20.Los pacientes varones deber ser quirúrgicamente estériles o utilizar métodos anticonceptivos de doble barrera desde la inclusión, durante el tratamiento y hasta que hayan transcurrido 6 meses desde la administración de la última dosis del fármaco del estudio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is OS, date of death in relation to study enrollment. |
| El objetivo principal es la SG, fecha de fallecimiento en relación a la inclusion en el estudio |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| throughout the whole trial |
| durante todo el ensayo |
|
| E.5.2 | Secondary end point(s) |
1) Tolerability: Dose interruptions, reductions, and dose intensity of all administered agents
2) Serum PK parameters (eg, area under the curve (AUC), Cmax, time of maximum concentration (Tmax), t1/2)
3) Tumor response over time as determined by RECIST v.1.1 response criteria based on blinded independent central review (BICR)
4) Additional measures of efficacy including ORR, PFS, DOR, time to response and DCR (defined at 24 weeks)
5) EQ-5D,5L and EORTC QLQ C30 change from Baseline over time and between treatment strategies
6) Assessments of anti-IMCgp100 antibody formation |
1)Tolerancia: interrupciones de dosis, reducciones e intensidad de dosis de todos los agentes administrados
2)Parámetros FC en suero ( ej. area bajo la curva ( AUC), Cmas, tiempo de maxima concentración (Tmax), t1/2)
3)Respuesta del tumor en el tiempo determinado por RECIST v1.1 basado en una revision central independiente y ciega (BICR)
4)Medidas adicionales de eficacia incluyendo ORR, PFS, DOR, tiempo de respuesta y DCR (definido a las 24 semanas) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) throughout the whole trial
2) see protocol table 7-6
3) Screening, Every 12 weeks from C5D1 until confirmed PD per irRECIST or patient withdrawal. After EOT, during PD follow-up, every 12 weeks until PD per irRECIST or lost to follow-up
4) throughout the whole study
5) C1D1, on D1 of every other cycle to C5D1, every 4th cycle thereafter beginning with C9D1, and EOT. Disease Progression FU and survival FU: every 3M
6) Predose C1D1, C1D8, C2D1, C3D1, C5D1, C7D1, C9D1, C11D1, C13D1, EOT at visit |
1) durante todo el ensayo
2) ver protocol table 7-6
3) selección, cada 12 semanas desde D1C5 hasta confirmación PD por irRECIST o retirada del paciente. Después del fin del studio, durante el seguimiento PD, cada 12 semanas hasta PD por irRECIST o pérdidad de seguimiento
4) durante todo el studio
5)D1C1, en el D1 de cada ciclo hasta el D1C5, cada 4º ciclo tras el principio con D1C9, y fin de studio. Seguimiento de la progresión de la enfermedad(PD) y supervivencia: cada 3 m |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
| Ukraine |
| 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 will be when a minimum of 80% of the patients have completed the follow-up for OS or discontinued the study for any reason, and all patients have completed treatment or post-study access to study drug is established, or if the study is terminated early. |
| El fin de studio sera cuando al menos un mínimo de un 80% de los pacientes haya completado el seguimiento de SG o discontinuado el studio por cualquier razón, y todos los pacientes que hayan completado el tratamiento o el aceso al fármaco se haya establecido, o si el studio se acaba anticipadamente. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
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