| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| relapsed, refractory, incurable teratoma |
| Teratoma recurrente/refractario con progresión reciente |
|
| E.1.1.1 | Medical condition in easily understood language |
| relapsed, refractory, incurable teratoma |
| Teratoma recurrente/refractario con progresión reciente |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| To assess the efficacy of LEE011 compared to placebo in patients with relapsed/refractory teratoma with recent progression |
| Evaluar la eficacia de LEE011 comparado con placebo en pacientes con teratoma recurrente/refractario con progresión reciente |
|
| E.2.2 | Secondary objectives of the trial |
1.To assess other measures of efficacy of LEE011 compared with placebo
2.To assess safety and tolerability of LEE011 compared with placebo |
1. Evaluar otras medidas de eficacia de LEE011 en comparación con placebo.
2. Evaluar la seguridad y tolerabilidad de LEE011 en comparación con placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age greater than or equal to 15 years old at time of informed consent.
2.Diagnosis of teratoma for which no additional standard surgical or medical therapy exists
3.Availability of an archival tumor biopsy specimen (collected at diagnosis or progression) with accompanying pathology report
Patients without an archival tumor sample may be permitted to participate after discussion between Novartis and the investigator
4.Patients must have completed at least 1 prior line of chemotherapy for germ cell tumor
5.If malignant transformation is present then chemotherapy appropriate for malignant transformation histology must have been given
6. Radiographic progression, defined by RECIST v.1.1, after the last cancer treatment and within 12 weeks prior to enrollment, compared with scans within 1 year of enrollment.
7.Measurable or evaluable extra-cranial disease as defined by RECIST v.1.1
8.Patients must have ECOG performance status of 0-1
Other criteria may apply. |
1.Edad mayor o igual a 15 años de edad en el momento del consentimiento informado.
2.Diagnóstico de teratoma para el que no existe terapia quirúrgica o médica estándar adicional.
3.Disponibilidad de una muestra de tumor de archivo o de nueva obtención (obtenida en el diagnóstico o progresión) con el informe patológico acompañante. A los pacientes sin una muestra de tumor de archivo se les puede permitir participar tras discusión entre Novartis y el investigador
4.Los pacientes deben haber completado al menos 1 línea previa de quimioterapia para tumor de células germinales.
5.Si hay presencia de transformación maligna entonces debe haberse administrado quimioterapia apropiada para histología de transformación maligna.
6.Progresión radiológica definida mediante RECIST v1.1, después del último tratamiento del cáncer y durante las 12 semanas previas a la inclusión, comparada con imágenes en el plazo de 1 año de la inclusión.
7.Enfermedad extra-craneal medible o evaluable como se define en RECIST v1.1.
8.Los pacientes deben tener un estado de actividad ECOG de 0-1. |
|
| E.4 | Principal exclusion criteria |
1.CNS disease unless radiation therapy and/or surgery has been completed and serial evaluation by CT (with contrast enhancement) or MRI over a minimum of 3 months demonstrates stable disease. Patient must be asymptomatic and without need for treatment with systemic corticosteroids or anti-epileptic medications
2.Malignant germ cell tumors other than that being treated in this study, including tumors with elements of mixed histology such as embryonal carcinoma, choriocarcinoma, yolk sac tumor or seminoma
3.Concurrent malignancy other than teratoma or malignancy within 3 years of randomization, with the exception of adequately treated basal or squamous cell carcinoma of the skin, curatively resected cervical cancer or curatively resected carcinoma in situ of any type
4.Prior treatment with any CDK4/6 inhibitor therapy
5.Any concurrent severe and/or uncontrolled medical condition that, in the investigator?s judgment serves as a contraindication to patient participation (e.g., chronic pancreatitis, active hepatitis, viral hepatitis or known HIV positivity. Baseline HIV screening is not required
6.Patients who have not recovered to ? CTCAE grade 1 from the acute toxic effects (except for alopecia) of all prior chemotherapy, immunotherapy, or radiotherapy
7.Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
8.Impaired cardiac function or any clinically significant cardiac disease, including any of the following
?Left ventricular ejection fraction (LVEF) < 45% or less than the institution?s lower limit of normal as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO)
?Congenital long QT syndrome or family history of unexpected sudden cardiac death
?QT corrected with Fredericia?s (QTcF) QTcF >450 msec for males and >470 msec for females on screening ECG
?Clinically significant heart disease such as CHF requiring treatment (NYH grade ? 2), unstable angina pectoris or myocardial infarction within the past 3 months. Any other clinically significant heart disease such as unstable arrhythmia, resting bradycardia, right bundle branch block, bifascicular block, or any heart disease that requires the use of a cardiac pacemaker ? 3 months prior to starting study drug
?Patients who are currently receiving medications with known risk of prolonging the QT interval or inducing Torsades de Pointes and are unable to discontinue or switch to an alternate medication
9.Concomitant therapy that precludes enrollment
?Systemic antineoplastic therapy or any experimental therapy within 3 weeks before the first dose of study drug (6 weeks for prior nitrosoureas, bevacizumab, or mitomycin C)
?Systemic corticosteroids within 2 weeks prior to starting study drug. Note: Corticosteroids are permitted for use as single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
10.Major surgery within 2 weeks prior to planned start of study drug or patient has not recovered from major side effects of the surgery
11.Received radiotherapy ? 4 weeks or limited field radiation for palliation ? 2 weeks prior to randomization, or patient has not recovered to ? CTCAE grade 1 related toxicity
12.Requirement for treatment with any of the prohibited medications including strong CYP3A inhibitors, strong CYP3A inducers, CYP3A substrates with a narrow therapeutic index, and medications with strong risk of QT prolongation
13.Have any of the following out-of-range laboratory values
?Absolute neutrophil count < 1.5× 10^9/L
?Platelet count < 100 × 10^9/L
?Hemoglobin <9.0 g/dL
?Potassium unless correctable by oral supplementation
?Calcium (corrected for serum albumin) unless correctable by oral supplementation
?Magnesium within normal limits for the institution unless correctable by oral supplementation
?Serum creatinine ?1.5 × ULN
?Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) > 3 × ULN for age; for patients with liver metastases ? 5 × ULN for age.
?Total serum bilirubin >1.5 x ULN; or total bilirubin ?3.0 × ULN with direct bilirubin within normal range in patients with well documented Gilbert?s Syndrome
?INR ?1.5
other criteria may apply |
1.Enfermedad del SNC a menos que se haya completado la radioterapia y/o cirugía y la evaluación serial mediante TC (con aumento de contraste) o RM durante un mínimo de 2 meses demuestre enfermedad estable. Los pacientes deben ser asintomáticos y sin necesidad de tratamiento con corticosteroides sistémicos o medicamentos anti-epilépticos
2.Tumores de células germinales malignos aparte de los tratados en este estudio, incluyendo tumores con elementos de histología mixta como carcinoma embrionario, coriocarcinoma, tumor de saco vitelino o seminoma
3.Otra neoplasia concurrente aparte de teratoma o neoplasia en los 3 años de la aleatorización, a excepción de carcinoma de piel de células escamosa basales adecuadamente tratado, cáncer cervical resecado con intención curativa o carcinoma in situ de cualquier tipo resecado con intención curativa
4.Tratamiento previo con alguna terapia inhibidora de CDK4/6
5.Cualquier condición médica concurrente grave y/o no controlada que, a criterio del investigador sirve como contraindicación a la participación del paciente (p.e., pancreatitis crónica, hepatitis activa, hepatitis viral o positividad conocida a VIH). No es necesaria la determinación basal de VIH
6.Pacientes que no se hayan recuperado a ? grado 1 CTCAE de los efectos tóxicos agudos (excepto alopecia) de toda quimioterapia, inmunoterapia, o radioterapia previa
7.Función gastrointestinal (GI) alterada o enfermedad GI que puede alterar significativamente la absorción de los fármacos del estudio (p.e., enfermedades ulcerosas, náuseas no controladas, vómitos, diarrea, síndrome de malabsorción, o resección del intestino delgado)
8.Alteración de la función cardiaca o enfermedad cardiaca clínicamente significativa, incluyendo cualquiera de las siguientes
>Fracción de eyección ventricular izquierda (FEVI) < 45% o menos del límite inferior de normalidad del centro determinado mediante adquisición de conducto múltiple (MUGA) o ecocardiograma (ECO)
>Síndrome de QT largo congénito o historia familiar de muerte cardiaca súbita inesperada
>QT corregido mediante Fridericia (QTcF) QTcF > 450 mseg para hombres y > 470 mseg para mujeres en el ECG de selección
>Enfermedad cardiaca clínicamente significativa como ICC que precisa tratamiento (grado mayor o igual a 2 NYH), angina pectoris inestable o infarto de miocardio en los últimos 3 meses. Cualquier otra enfermedad cardiaca significativa como arritmia inestable, bradicardia en reposo, bloqueo de rama derecha, bloqueo bifascicular, o cualquier enfermedad cardiaca que precise el uso de marcapasos cardiaco ? 3 meses antes de iniciar el fármaco del estudio
>Pacientes que están actualmente recibiendo medicaciones con riesgo conocido de prolongación del intervalo QT o de inducir Torsades de Pointes y no pueden retirarla o cambiar a una medicación alternativa
9.Terapia concomitante que impide la inclusión
>Terapia antineoplásica sistémica o cualquier terapia experimental en las 3 semanas anteriores a la primera dosis del fármaco del estudio (6 semanas para nitrosoureas, bevacizumab o mitomicina C previas)
>Corticosteroides sistémicos en las 2 semanas previas al inicio del fármaco del estudio. Nota: Los corticosteroides están permitidos para usar como dosis únicas, aplicaciones tópicas (p.e., para erupción), sprays inhalados (p.e., para enfermedades respiratorias obstructivas), gotas para los ojos o inyecciones locales (p.e., intra-articular)
10.Cirugía mayor en las 2 semanas previas al inicio previsto del fármaco del estudio o el paciente no se ha recuperado de los efectos secundarios importantes de la cirugía
11.Radioterapia recibida ? 4 semanas o radiación paliativa de campo limitado ? 2 semanas antes de la aleatorización, o el paciente no se ha recuperado a ? grado 1 CTCAE de toxicidad relacionada
12.Necesidad de tratamiento con alguna de las medicaciones prohibidas incluyendo inhibidores fuertes de CYP3A, inductores fuertes de CYP3A, sustratos de CYP3A con un estrecho índice terapéutico, y medicaciones con fuerte riesgo de prolongación QT
13.Tener cualquiera de los siguientes valores de laboratorio fuera de rango
>Recuento de neutrófilos absoluto < 1,5 x 109/L
>Recuento de plaquetas < 100 x 109/L
>Hemoglobina < 9,0 g/dL
>Potasio a menos que se puedan corregir mediante suplemento oral
>Calcio (corregido para albumina sérica) a menos que se pueda corregir mediante suplemento oral
>Magnesio a menos que se pueda corregir mediante suplemento oral
>Creatinina en suero mayor o igual a 1,5 x LSN
>Alanina aminotransferasa (AST) y aspartato aminotransferasa (ALT) > 3 x LSN para la edad; para pacientes con metástasis hepática mayor o igual a 5 LSN para la edad
>Bilirrubina total en suero > 1,5 x LSN; o bilirrubina total mayor o igual a 3,0 x LSN con bilirrubina directa en el rango normal en pacientes con Síndrome de Gilbert bien documentado INR mayor o igual a 1,5 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) as per RECIST v1.1 (by local investigator assessment) |
| Supervivencia Sin Progresión (PFS) según RECIST v1.1 (por evaluación del investigador local) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| -Evaluated after at least 25 and approximately 62 PFS events have been documented for the interim analysis and primary CSR, respectively. |
| Evaluados después de al menos 25 y aproximadamente 62 eventos de PFS que se hayan documentado para el análisis intermedio y respectivamente CSR primario |
|
| E.5.2 | Secondary end point(s) |
1. Best Overall Response (BOR),Overall response rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1, Overall Survival (OS) and OS rate.
2. Incidence and severity of adverse events and serious adverse events, changes in laboratory values, and electrocardiograms will be used to assess the safety as per CTCAE v.4.03. Dose interruptions and changes will be used to assess the tolerability. |
1.Mejor Respuesta Global (BOR), tasa de respuesta global (TRG) y Tasa de Control de la Enfermedad (DCR) a los 4 meses según RECIST v1.1, Supervivencia Global (SG), y tasa de SG a los 12 meses.
2.La incidencia y severidad de acontecimientos adversos y acontecimientos adversos graves, cambios en los valores de laboratorio, electrocardiogramas, y constantes vitales se utilizarán para evaluar la seguridad según CTCAE v4.01. Las interrupciones y cambios de dosis se utilizarán para evaluar la tolerabilidad. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| -All secondary endpoints will be evaluated after at least 25 and approximately 62 PFS events have been documented for the interim analysis and primary CSR, respectively. |
| Todos los criterios de valoración secundarios serán evaluados después de al menos 25 y aproximadamente 62 eventos de PFS que se hayan documentado para el análisis intermedio y respectivamente CSR primario |
|
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | Yes |
| 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 |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| The study data will be analyzed and a primary clinical study report will be written based on all patients? data at the time when there are approx. 62 PFS events for the primary efficacy analysis, or if the study is terminated early. Additional data for patients continuing on study or in survival follow-up past the data cutoff date for the primary CSR will be reported in a final CSR once the treatment period, safety follow-up, disease follow-up and survival follow-ups have ended for all patients |
| La data del EC se analizará y el CSR inicial se redactará en base a los datos de todos los pac.cuando haya aprox.62 acontecimientos de PFS para el análisis de eficacia principal,o si el ECfinaliza prematuramente.Los datos adici.de pac.que continúen en el EC o en seguimiento de supervivencia, se notificarán en un CSR final una vez haya final.el periodo de trata.,y los periodos de seguimiento de seguridad,seguimiento de progresión de la enfermedad y seguimiento de supervivencia,para todos los pac. |
|
| 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 | 6 |
| 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 | 6 |
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