| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non small cell lung cancer |
| Cánce de pulmón no microcítico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer |
| Cáncer de pulmón |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029515 |
| E.1.2 | Term | Non-small cell lung cancer recurrent |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy and safety of X-396 vs. crizotinib in patients with ALK-positive NSCLC that have received up to 1 prior chemotherapy regimen
and no prior ALK tyrosine kinase inhibitor (TKI). |
| Evaluar la eficacia y la seguridad de X-396 frente a crizotinib en pacientes con CPNM positivo para ALK que han recibido al menos una pauta de quimioterapia previa y ningún inhibidor de la actividad tirosina-cinasa ALK (TKI) anteriormente. |
|
| E.2.2 | Secondary objectives of the trial |
| To obtain additional pharmacokinetic (PK) data on X-396 from sparse PK sampling from patients at selected sites. |
| Obtener datos adicionales sobre la farmacocinética (PK) de X-396 a partir del muestreo de PK disperso de pacientes en centros seleccionados |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana IHC assay. Patients may have received up to 1 prior chemotherapy regimen, which may also include maintenance therapy.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 2.
3. Life expectancy of at least 12 weeks.
4. Ability to swallow and retain oral medication.
5. Adequate organ system function, defined as follows:
a. Absolute neutrophil count (ANC) > or = 1.5 x 109/L
b. Platelets > or =100 x 109/L
c. Hemoglobin > or =9 g/dL (> or =90 g/L)
d. Total bilirubin < or =1.5 times the upper limit of normal (ULN)
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or =2.5 x ULN if no liver involvement or < or =5 x ULN with liver involvement.
f. Creatinine < or =1.5 x ULN. If >1.5 x ULN, patient may still be eligible if calculated creatinine clearance > or =50 mL/min (0.83 mL/s) as calculated by the Cockcroft-Gault method.
6. Brain metastases allowed if asymptomatic at study baseline. Patients with untreated brain metastases must not be on corticosteroids. If patients have
neurological symptoms or signs due to CNS metastases, patients need to complete whole brain radiation or focal treatment at least 14 days before start of study treatment and be asymptomatic on stable or decreasing doses of corticosteroids at baseline.
7. Men willing to use adequate contraceptive measures.
8. Women who are not of child-bearing potential, and women of child-bearing potential who agree to use adequate contraceptive measures and who have
a negative serum or urine pregnancy test within 1 week prior to initial trial treatment.
9. Patients must be > or = 18 years of age.
10. Patients must have measurable disease per RECIST v. 1.1.
11. Patients must be ALK-positive by IHC. Testing will be done centrally;
however, patients will be allowed to enroll based on local results (positive by FISH or IHC), if available.
12. Willingness and ability to comply with the trial and follow-up procedures.
13. Ability to understand the nature of this trial and give written informed consent. |
1. Diagnóstico confirmado histológicamente o citológicamente de CPNM avanzado o recurrente (estadio IIIB no sensible a tratamiento multimodal) o metastásico (estadio IV) positivo para ALK, evaluado mediante ensayo de IHQ de Ventana. Pacientes que pueden haber recibido hasta una pauta de quimioterapia previa, que también puede incluir tratamiento de mantenimiento.
2. Puntuación del estado funcional (EF) de 0 a 2 del Eastern Cooperative Oncology Group (ECOG).
3. Esperanza de vida de al menos 12 semanas.
4. Capacidad de tragar y retener la medicación oral.
5. Función orgánica aceptable, definida como:
a. Recuento absoluto de neutrófilos (RAN) > o = 1,5 × 109/l
b. Plaquetas > o = 100 × 109/l
c. Hemoglobina > o =9 g/dl (> o = 90 g/l)
d. Bilirrubina total ≤1,5 veces el límite superior de normalidad (LSN)
e. Alanina-aminotransferasa (ALT) y aspartato-aminotransferasa (AST) < o = 2,5 × LSN si no existe afectación hepática o < o = 5 × LSN si existe afectación hepática.
f. Creatinina < o = 1,5 × LSN. Si > 1,5 × LSN, el paciente todavía puede ser apto si el aclaramiento de creatinina calculado es > o = 50 ml/min (0,83 ml/s), según el cálculo mediante el método de Cockcroft-Gault.
6. Puede haber metástasis cerebrales si son asintomáticas al inicio del estudio. Los pacientes con metástasis cerebrales no tratadas no pueden estar recibiendo corticosteroides. Si los pacientes tienen síntomas o signos neurológicos debido a metástasis en el SNC, deben haber completado la radioterapia de todo el cerebro o un tratamiento focal al menos 14 días antes del inicio del tratamiento del estudio y estar asintomáticos en dosis de corticosteroides estables o que se vayan reduciendo gradualmente al inicio del estudio.
7. Varones dispuestos a utilizar métodos anticonceptivos aceptables.
8. Mujeres que no tengan capacidad reproductora y mujeres con capacidad reproductora que estén dispuestas a utilizar métodos anticonceptivos aceptables y que obtengan un resultado negativo en una prueba de embarazo en suero u orina realizada una semana antes del tratamiento inicial del estudio.
9. Los pacientes deben ser > o =18 años.
10. Los pacientes deben tener enfermedad mensurable mediante los criterios RECIST v. 1.1.
11. Los pacientes deben presentar positividad para ALK según análisis IHQ. Las pruebas se llevarán a cabo de forma centralizada; no obstante, se podrá ir incluyendo a los pacientes según los resultados locales (positividad según FISH o IHQ), si procede.
12. Voluntad y capacidad para cumplir con los procedimientos del ensayo y del seguimiento.
13. Capacidad para comprender la naturaleza de este estudio y proporcionar el consentimiento informado por escrito. |
|
| E.4 | Principal exclusion criteria |
1. Patients that have previously received an ALK TKI, and patients currently receiving cancer therapy (i.e., other targeted therapies, chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization).
2. Use of an investigational drug within 21 days prior to the first dose of study drug. Note that to be eligible, any drug-related toxicity should have recovered to Grade 1 or less, with the exception of alopecia.
3. Any chemotherapy within 4 weeks, or major surgery or radiotherapy within the last 14 days.
4. Patients with primary CNS tumors and leptomeningeal disease are ineligible.
5. Patients with a previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, or any cancer that is considered to be cured and have no impact on PFS and OS for the current NSCLC).
6. Concomitant use of drugs with a risk of causing Torsades de Pointes within 14 days prior to starting study drug.
7. Concomitant use of herbal medications. These should be stopped prior to study entry.
8. Patients receiving strong CYP3A inhibitors or inducers.
9. Women who are pregnant or breastfeeding.
10. Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of study medications.
11. Clinically significant cardiovascular disease including:
a. QTcF interval > o = 450 ms, symptomatic bradycardia <45 beats per minute or other significant ECG abnormalities in the investigator’s opinion.
b. Clinically uncontrolled hypertension in the investigator’s opinion (e.g., blood pressure >160/100 mmHg; note that isolated elevated readings considered to not be indicative of uncontrolled hypertension are allowed).
The following within 6 months prior to Cycle 1 Day 1:
a. Congestive heart failure (New York Heart Class III or IV).
b. Arrhythmia or conduction abnormality requiring medication. Note: patients with atrial fibrillation/flutter controlled by medication and arrhythmias controlled by pacemakers are eligible.
c. Severe/unstable angina, coronary artery/peripheral bypass graft, or myocardial infarction.
d. Cerebrovascular accident or transient ischemia.
12. Patients who are immunosuppressed (including known HIV infection), have a serious active infection at the time of treatment, have interstitial lung disease/pneumonitis, or have any serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. Patients with controlled hepatitis C, in the investigator’s opinion, are allowed. Patients with known hepatitis B must be HBeAg and HB viral DNA negative for enrollment. Note that, because of the high prevalence, all patients in the Asia-Pacific region (except Australia, New Zealand, and Japan) must be tested and, if HBsAg positive, must be HBeAg and HB viral DNA negative for enrollment.
13. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
14. Concurrent condition that in the investigator’s opinion would jeopardize compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the patient to be enrolled.
15. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol. |
1. Pacientes que hayan recibido anteriormente un TKI ALK y pacientes que actualmente estén recibiendo un tratamiento oncológico (es decir, otros tratamientos dirigidos, quimioterapia, radioterapia, inmunoterapia, tratamiento biológico, hormonoterapia, cirugía y/o embolización del tumor).
2. Uso de un fármaco en investigación en el transcurso de los 21 días anteriores a la primera dosis del fármaco del estudio. Tenga en cuenta que para ser apto, el paciente debe haberse recuperado de cualquier toxicidad relacionada con el fármaco hasta el grado 1 o menor, con la excepción de la alopecia.
3. Cualquier tratamiento quimioterápico recibido en las 4 últimas semanas, o cirugía mayor o radioterapia realizada en los últimos 14 días.
4. Los pacientes con tumores primarios del SNC y enfermedad leptomeníngea no son aptos.
5. Pacientes que han tenido cáncer en los últimos 3 años (excepto carcinoma cutáneo basocelular tratado con intención curativa, carcinoma in situ del cuello del útero o cualquier tipo de cáncer que se considere curado y no afecte a la SSP y la SG para el CPNM actual).
6. Uso concomitante de fármacos con riesgo de causar torsades de pointes durante el transcurso de los 14 días previos de inicio del fármaco del estudio.
7. Uso concomitante de fitoterápicos. Su uso debe suspenderse antes de entrar en el estudio.
8. Pacientes que reciban inhibidores o inductores potentes de la isoenzima CYP3A.
9. Mujeres embarazadas o en periodo de lactancia.
10. Presencia de enfermedad gastrointestinal (GI) activa u otra enfermedad que pueda interferir significativamente en la absorción, distribución, metabolismo o excreción de los fármacos del estudio.
11. Enfermedad cardiovascular clínicamente significativa, tales como:
a. Intervalo QTcF > o = 450 ms, bradicardia sintomática <45 latidos por minuto u otras anomalías significativas en el ECG en opinión del investigador.
b. Hipertensión no controlada clínicamente en opinión del investigador (p. ej., presión arterial >160/100 mm Hg; tenga en cuenta que las lecturas elevadas aisladas que no se consideren indicativas de hipertensión no controlada están permitidas).
Los criterios siguientes en las 6 semanas previas al día 1 del ciclo 1:
a. Insuficiencia cardíaca congestiva (clase III o IV según la New York Heart Association).
b. Arritmia o alteración de la conducción que requiera medicación. Nota: Los pacientes con fibrilación/aleteo auricular controlado con medicación y arritmias controladas con marcapasos son aptos.
c. Angina grave/inestable, injerto de derivación periférica/de la arteria coronaria o infarto de miocardio.
d. Accidente cerebrovascular o isquemia transitoria.
12.Pacientes que estén inmunodeprimidos (incluida infección por el VIH conocida), tengan una infección activa grave en el momento del tratamiento, presenten enfermedad pulmonar intersticial/neumonía o sufran alguna enfermedad subyacente grave que podría afectar a la capacidad del paciente para recibir el tratamiento del protocolo. Se permiten pacientes con hepatitis C controlada, en opinión del investigador. Los pacientes con hepatitis B confirmada deben obtener un resultado negativo para ADN del virus de la hepatitis B y HBeAg para que se les pueda incluir. Tenga en cuenta que, debido a la alta prevalencia, todos los pacientes de la región Asia-Pacífico (excepto Australia, Nueva Zelanda y Japón) deben ser evaluados y, si son HBsAg positivos, deben tener un resultado negativo para el ADN del virus de la hepatitis B y HBeAg para la inclusión.
13. Circunstancias psicológicas, familiares, sociológicas o geográficas que no permitan el cumplimiento del protocolo.
14. Afección concurrente que, en opinión del investigador, podría poner en peligro el cumplimiento del protocolo o supondría un riesgo excesivo asociado a la participación en el estudio que haría que fuera inadecuado incluir al paciente.
15. Incapacidad o poca voluntad para cumplir con los procedimientos del estudio y/o de seguimiento indicados en el protocolo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) as assessed by independent radiology review based on RECIST v. 1.1 criteria. |
| Supervivencia sin progresión (SSP) evaluada según una revisión radiológica independiente basada en los criterios RECIST v. 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The final analysis (primary analysis) will be performed after 305 PFS events have been observed. |
| El análisis final (analisis primario) se realizará tras 305 eventos de SSP |
|
| E.5.2 | Secondary end point(s) |
| Overall survival, objective response rate (based on independent radiology review), PFS based on investigator assessment, ORR (based on investigator assessment), time to response (based on investigator assessment and independent radiology review), duration of response (based on investigator assessment and independent radiology review), CNS response rate (based on investigator assessment and independent radiology review), time to CNS progression. |
| Supervivencia global, tasa de respuesta objetiva (basada en una revisión radiológica independiente), SSP (basada en la evaluación del investigador), TRG (basada en la evaluación del investigador), tiempo transcurrido hasta la respuesta (basado en la evaluación del investigador y la revisión radiológica independiente), duración de la respuesta (basada en la evaluación del investigador y la revisión radiológica independiente), tasa de respuesta del SNC (basada en la evaluación del investigador y la revisión radiológica independiente) y tiempo transcurrido hasta la progresión en el SNC. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analysis (secondary efficacy endpoint analysis) will be performed after 305 PFS events have been observed. |
| El análisis final (analisis secundario de la variable de eficacia) se realizará tras 305 eventos de SSP |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Latvia |
| Netherlands |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Switzerland |
| Turkey |
| 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
|
| LVLS |
| Ultima 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 | 4 |
| 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 | 4 |
| 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 |
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