E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Uveal Melanoma |
Melanoma uveal metastásico |
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E.1.1.1 | Medical condition in easily understood language |
Uveal melanoma |
Melanoma uveal metastásico |
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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 |
Phase Ib: Estimate the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the AEB071 and MEK162 combination in patients with metastatic uveal melanoma
Phase II: Assess the preliminary evidence for anti-tumor activity at the RP2D for AEB071 and MEK162 and at the RP2D for MEK162 alone |
Fase Ib: Determinar la DMT y la DRF2 de la combinación de AEB071 y MEK162 en pacientes con melanoma uveal metastásico. Fase II: Evaluar la evidencia preliminar de la actividad antitumoral a la DRF2 de AEB071 y MEK162 y a la DRF2 de MEK162 en monoterapia. |
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E.2.2 | Secondary objectives of the trial |
Phase Ib/II: Further characterize the safety and tolerability of the combination of AEB071 and MEK162, including acute and chronic toxicities Phase Ib: To assess the preliminary anti-tumor activity of the combination of AEB071 and MEK162 To characterize the PK profiles of AEB071 and MEK162, as well as evaluate their active metabolites Phase II: Evaluate and compare the preliminary anti-tumor activity at the RP2D for AEB071 and MEK162 and at 45 mg BID of MEK162 alone |
Fase Ib/II: Caracterizar mejor la seguridad y tolerabilidad de la combinación de AEB071 y MEK162, incluyendo toxicidades agudas y crónicas Fase Ib: Evaluar la actividad antitumoral preliminar de la combinación de AEB071 y MEK162 Caracterizar los perfiles de PK de AEB071 y MEK162, así como evaluar sus metabolitos activos. Fase II: Evaluar y comparar la actividad antitumoral preliminar a la DRF2 de AEB071 y MEK162 y a 45 mg BID de MEK162 en monoterapia |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written informed consent - Male and female patients aged 18 years or older - A history of uveal (ocular) melanoma with biopsy-confirmed metastatic disease - Consent to providing 3 tumor biopsy samples throughout the course of the study - Presence of measurable disease - A WHO performance status of less than or equal to 1 Other inclusion criteria apply |
- Pacientes varones y mujeres con ? 18 años de edad - Antecedentes de un melanoma uveal (ocular) con enfermedad metastásica confirmada con biopsia -Consentimiento para una biopsia del tumor en la visita basal, el día 15 del ciclo 1 (D15C1) y en el momento de la progresión de la enfermedad - Presencia de enfermedad medible según los RECIST v1.1 (en circunstancias excepcionales, Novartis puede permitir que un paciente, que no presente enfermedad medible, participe en la parte de la fase Ib, pero esto queda a discreción únicamente de Novartis) - Un estado funcional de la OMS de ? 1. |
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E.4 | Principal exclusion criteria |
- Presence of CNS lesions (stable lesions may be acceptable) - Previous or concurrent malignancy, other than basal cell or squamous cell carcinoma of the skin: in situ carcinoma of the cervix, without evidence of recurrence for at least 3 years; a primary malignancy completely resected and no evidence of recurrence for at least 3 years - Adverse event from prior chemotherapy, radiotherapy or surgery that has not recovered to CTCAE v4.03 Grade 1 or less, except for alopecia/sensory peripheral neuropathy, which must be less than Grade 2 - History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or any predisposing factor to CSR/RVO - History of retinal degenerative disease - Impaired cardiac function or clinically significant cardiac disease - Impaired GI function or disease that could interfere with the absorption of AEB071 and/or MEK162 - Treatment with medicines or herbal supplements that are known inhibitors or inducers of CYP3A4/5 and cannot be withdrawn prior to study treatment - Females of child-bearing potential who are unwilling or unable to use highly effective means of contraception - Males who are unwilling or unable to use a condom during sexual intercourse - Prior exposure to a MEK or PKC inhibitor Other inclusion/exclusion criteria apply |
- La presencia de lesiones metastásicas del SNC - Antecedentes de enfermedad maligna secundaria previa o actual (excepto carcinoma del cuello del útero o carcinoma cutáneo de células basales localizado tratado de forma adecuada o cualquier otra enfermedad maligna tratada curativamente que no haya sido tratada ni haya recurrido en los últimos 3 años) - Antecedentes o evidencia actual de retinopatía serosa central (RSC) u oclusión venosa retiniana (OVR), evaluado con un examen oftalmológico en la visita basal -Deterioro de la función cardíaca o enfermedad cardíaca clínicamente significativa, por ejemplo, LVEF < 50%, determinado con MUGA o ETT. - Creatinina sérica >1,5 x LSN 1 -Tratamiento con inductores o inhibidores potentes (medicamentos y suplementos vegetales) del citocromo P450 3A4/5 (CYP3A4/5), o sustratos de CYP3A4/5 con riesgo de prolongación del QT que no se pueden suspender al menos 7 semividas (o 14 días, si no se conoce la semivida) antes del tratamiento con el fármaco del estudio1 -Exposición previa a inhibidores de MEK o de PKC (es decir, los pacientes tratados en la fase I no serán aptos para la fase II) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: Dose limiting toxicity (DLT)
Phase II: Objective Response Rate (ORR) |
Fase I: La toxicidad limitante de dosis
Fase II: Tasa de respuesta objetiva |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: Up to 28 days of treatment with AEB071 and MEK162
Phase II: From first dose cycle 1, day 1 (C1D1) to time to progression up to 18 months from Last Patient First Visit (LPFV) |
Fase I: Hasta 28 días de tratamiento con AEB071 y MEK162
Fase II: Desde la primera dosis del primer ciclo del día 1 hasta el tiempo de progresión de hasta 18 meses de la primera visita del último paciente (LPFV) |
|
E.5.2 | Secondary end point(s) |
a) Phase Ib: Disease control rate (DCR) b) Phase II: Disease control rate (DCR) c) Duration of Response d) Best Overall Response e) Progression free survival f) Overall survival g) Safety and tolerability of AEB071 and MEK162 h) Blood concentrations of AEB071, MEK162 and their active metabolites (Phase Ib) |
a) Fase Ib: Tasa de control de la enfermedad (DCR) b) Fase II: Tasa de control de la enfermedad (DCR) c) Duración de la respuesta d) Mejor respuesta global e) Supervivencia libre de progresión f) Supervivencia global g) Seguridad y tolerabilidad de AEB071 y MEK162 h) Concentraciones sanguíneas de AEB071, MEK162 y sus metabolitos activos (Fase Ib) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Phase Ib: From first dose cycle 1 day 1 (C1D1) to time to progression up to 18 months from Last Patient First Visit (LPFV) b) Phase II: At 4 months of treatment c) From first dose (C1D1) to time to progression up to 18 months from LPFV d) From first dose (C1D1) to time to progression up to 18 months from LPFV e) From first dose (C1D1) to time to progression up to 18 months from LPFV f) From LPFV to death or lost to follow-up up to 18 months from LPFV g) From consent to 30-days post-end-of-treatment h) up to 28 days |
a) Fase Ib: De la primera dosis del primer ciclo, día 1 (C1D1) hasta el tiempo de progresión de hasta 18 meses desde la primera visita del último paciente (LPFV) b) Fase II: A los 4 meses de tratamiento c) A partir de la primera dosis (C1D1) para el tiempo de progresión de hasta 18 meses a partir de LPFV d) De la primera dosis (C1D1) para el tiempo de progresión de hasta 18 meses a partir de LPFV e) De la primera dosis (C1D1) para el tiempo de progresión de hasta 18 meses a partir de LPFV f) De LPFV a la muerte o la pérdida durante el seguimiento hasta 18 meses a partir de LPFV g) De acuerdo a 30 días después de la final de su tratamiento h) hasta 28 días |
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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 | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
France |
Germany |
Italy |
Netherlands |
Norway |
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
|
End of study will be upon confirmation of the last patient?s death (for overall survival) or that the patient has been lost to follow-up. |
El estudio finalizará cuando se confirme la muerte del último paciente (para la supervivencia global) o se haya perdido el seguimiento de dicho paciente. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |