| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| pediatric patients with newly diagnosed Ph+ chronic myelogenous leukemia (CML) in chronic phase (CP) or with Ph+ CML in CP or accelerated phase (AP) resistant or intolerant to either imatinib or dasatinib |
| pacientes pediátricos con leucemia mieloide crónica (LMC) Ph+ en fase crónica (FC) de nuevo diagnóstico o con LMC Ph+ en FC o fase acelerada (FA), resistente o intolerante a imatinib o a dasatinib |
|
| E.1.1.1 | Medical condition in easily understood language |
| Study of efficacy and safety of nilotinib in pediatric CML patients |
| Estudio de eficacia y seguridad de nilotinib en pacientes pediátricos con LMC |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054352 |
| E.1.2 | Term | Chronic phase chronic myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 assess efficacy of nilotinib in pediatric patients with Ph+ CML CP resistant or intolerant to either imatinib or dasatinib.
?To assess efficacy of nilotinib in pediatric patients with Ph+ CML AP resistant or intolerant to either imatinib or dasatinib.
?To assess efficacy of nilotinib in pediatric patients with newly diagnosed Ph+ CML CP. |
? Evaluar la eficacia de nilotinib en pacientes pediátricos con LMC Ph+ en FC resistente o intolerante a imatinib o a dasatinib
? Evaluar la eficacia de nilotinib en pacientes pediátricos con LMC Ph+ en FA resistente o intolerante a imatinib o a dasatinib
? Evaluar la eficacia de nilotinib en pacientes pediátricos con LMC Ph+ en FC de diagnóstico reciente. |
|
| E.2.2 | Secondary objectives of the trial |
?To characterize efficacy in pediatric patients with Ph+ CML.
?To further characterize PK in pediatric patients with Ph+ CML.
?To identify emerging signs of resistance to nilotinib.
?To describe acceptability of the study drug formulation.
?To further characterize safety and tolerability of nilotinib in pediatric patients with Ph+ CML. |
? Caracterizar la eficacia en pacientes pediátricos con LMC Ph+.
? Caracterizar mejor la PK en pacientes pediátricos con LMC Ph+.
? Identificar signos emergentes de resistencia a nilotinib.
? Describir la aceptabilidad de la formulación de la medicación del estudio.
? Caracterizar mejor la seguridad y tolerabilidad de nilotinib en pacientes pediátricos con LMC Ph+. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1.Male or female patients from 1 year of age to less than 18 years of age at study entry.
2.Patients must have the diagnosis of newly diagnosed and untreated Ph+ CML CP or Ph+ CML CP or AP resistant or intolerant to either imatinib or dasatinib
3.Performance status: Karnofsky ? 50% for patients > 10 years of age, and Lansky ? 50 for patients ? 10 years of age.
4.Patients must have adequate renal, hepatic and pancreatic function
5.Patients must have potassium, magnesium, phosphorus and total calcium values ? LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.
Written informed consent must be obtained prior to any screening procedures. |
Los pacientes elegibles para inclusión en este estudio deberán cumplir todos los criterios siguientes:
1.Pacientes varones y mujeres de 1 años de edad hasta menos de 18 años de edad al inicio del estudio
2.Los pacientes deberán tener diagnosticada LMC Ph+ no tratada o de diagnóstico reciente o LMC Ph+ en FC o FA resistente o intolerante a imatinib o a dasatinib
3.Estado funcional: Karnofsky ? 50% para pacientes > 10 años de edad, y Lansky ? 50 para pacientes ? 10 años de edad
4.Los pacientes deberán presentar función pancreática, renal y hepática adecuada
5.Los pacientes deberán presentar valores de potasio, magnesio, fósforo y calcio total ? LIN (límite inferior de normalidad) o corregidos hasta dentro de los límites de normalidad con suplementos antes de la primera dosis de la medicación del estudio.
El consentimiento informado por escrito deberá obtenerse antes de cualquier procedimiento de selección. |
|
| E.4 | Principal exclusion criteria |
1.Female patients of childbearing potential who do not agree to abstinence or, if sexually active, do not agree to the use of contraception as defined in Section 7.2.2.5.5.
2.Patients actively receiving therapy with strong CYP3A4 inhibitors or inducers and the treatment cannot be either discontinued or switched to a different medication at least 14 days prior to starting study drug.
3.Patients who are currently receiving treatment with any medications that have a known risk or possible risk to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
4.Acute or chronic liver, pancreatic or severe renal disease considered unrelated to CML.
5.History of pancreatitis within 12 months of starting study drug or past medical history of chronic pancreatitis.
6.Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, uncontrolled infection)
7.Impaired cardiac function
8.Patients with a known T315I mutation in BCR-ABL.
9.Previous treatment with more than one TKI for imatinib or dasatinib resistant/intolerant Ph+ CML patients. Previous treatment with any TKI for newly diagnosed Ph+ CML patients.
10.Patients who have received myelosuppressive chemotherapy less than 3 weeks prior to first dose of study drug.
11.Patients who have not recovered from all acute toxicities from all prior myelosuppressive chemotherapy prior to starting study drug.
12.Patients who have received hematopoietic growth factors within 7 days of starting study drug.
13.Patients who have received Pegfilgrastim (Neulasta®) within 14 days of starting study drug.
14.In case of Stem Cell Transplant (SCT) or Rescue without total body irradiation (TBI): Evidence of active graft vs. host disease and < 3 months since SCT.
15.In case of radiation therapy: less than 2 weeks if local palliative, less than 3 months after total body irradiation (TBI), or craniospinal radiation therapy or if at least 50% radiation of pelvis; less than 6 weeks after other substantial BM radiation.
16.Patients with known Hepatitis B, Hepatitis C, or HIV infection.
17.Patients who, in the opinion of the investigator, are unlikely to comply with the protocol or safety monitoring requirements.
18.Patients who are breast feeding
19.Patients who have a known hypersensitivity to the active ingredient or any of the excipients including lactose. |
Los pacientes elegibles para este estudio no deberán cumplir ninguno de los siguientes criterios:
1.Pacientes mujeres físicamente fértiles que no accedan a practicar abstinencia o, si son sexualmente activas, no accedan a utilizar un método anticonceptivo definido en el Apartado 7.2.2.5.5.
2.Pacientes que reciban activamente terapia con inhibidores o inductores potentes de CYP3A4 y que el tratamiento no pueda ser suspendido o cambiado por una medicación distinta por lo menos 14 días antes de iniciar la medicación del estudio.
3.Pacientes que estén recibiendo actualmente tratamiento con alguna medicación que tenga un riesgo conocido o posible riesgo de prolongar el intervalo QT y que el tratamiento no pueda ser suspendido o cambiado por una medicación distinta antes de iniciar la medicación del estudio. En http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm puede hallarse una lista de compuestos que prolongan el QT.
4.Enfermedad hepática, pancreática o renal severa crónica o aguda considerada no relacionada con la LMC
5.Antecedentes de pancreatitis dentro de los 12 meses de iniciar la medicación del estudio o historial clínico previo de pancreatitis crónica.
6.Enfermedad clínica concurrente incontrolada y/o severa que, a criterio del investigador, pudiese causar riesgos de seguridad inaceptables o comprometer el cumplimiento con el protocolo (por ejemplo, diabetes incontrolada, infección incontrolada)
7.Deterioro de la función cardíaca
8.Pacientes con una mutación T315I conocida en BCR-ABL.
9.Tratamiento previo con más de un ITK para pacientes con LMC Ph+ intolerante/resistente a imatinib o dasatinib. Tratamiento previo con algún ITK para pacientes con LMC Ph+ de diagnóstico reciente.
10.Pacientes que hayan recibido quimioterapia mielosupresora menos de 3 semanas antes de la primera dosis de la medicación del estudio.
11.Pacientes que no se hayan recuperado de todas las toxicidades agudas de toda la quimioterapia mielosupresora previa antes de iniciar la medicación del estudio.
12.Pacientes que hayan recibido factores de crecimiento hematopoyético dentro de los 7 días del inicio de la medicación del estudio.
13.Pacientes que hayan recibido Pegfilgrastim (Neulasta®) dentro de los 14 días del inicio de la medicación del estudio.
14.En caso de trasplante de células madre (SCT) o rescate sin irradiación corporal total (TBI): Evidencia de enfermedad de injerto contra huésped activa y < 3 meses desde el SCT.
15.En caso de radioterapia: menos de 2 semanas si paliativa local, menos de 3 meses después de irradiación corporal total (TBI) o radioterapia craneoespinal o si por lo menos radiación del 50% de la pelvis; menos de 6 semanas después de otra radiación sustancial de la MO.
16.Pacientes con infección conocida por virus de la hepatitis B, hepatitis C o VIH.
17.Pacientes que, a criterio del investigador, sea improbable que cumplan con los requisitos del protocolo o con los de monitorización de la seguridad.
18.Pacientes en periodo de lactancia.
19.Pacientes con hipersensibilidad conocida al ingrediente activo o a cualquiera de los excipientes incluyendo lactosa. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Rate of MCyR by 12 months
Rate of complete hematological response (CHR) by 3 months
?Rate of MMR by 12 months by PCR analysis. MMR is defined as ? 0.1% BCR-ABL/control gene % by international scale, measured by RQ-PCR which is equivalent to ? 3 log reduction of BCR-ABL transcript from standardized
?Rate of MCyR by 12 months |
Tasa de RCM a los 12 meses
Tasa de respuesta hematológica completa (RHC) a los 3 meses
Tasa de RMM a los 2 meses con análisis por PCR. La RMM se define como % de BCR-ABL/gen control ? 0.1% en escala internacional, medido con RQ-PCR que es equivalente a una reducción de ? 3 logaritmos de los tránscritos BCR-ABL comparado con el basal estandarizado
Tasa de RCM a los 12 meses |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
?12 months
?12 months
? 3 months |
?12 meses
?12 meses
? 3 meses |
|
| E.5.2 | Secondary end point(s) |
?Time to response, duration of response, time to disease progression, overall survival
?Rate of MCyR and CCyR in newly diagnosed Ph+ CML CP and in Ph+ CML CP AP patients resistant/intolerant to either imatinib or dasatinib by 6, 12* and 24 months
?Rate of MMR by 3, 6, 9, 12* and 24 months in newly diagnosed Ph+ CML CP and Ph+ CML CP and AP patients resistant/intolerant to either imatinib or dasatinib
?Rate of CHR by 3*, 6, 9, 12 and 24 in newly diagnosed Ph+ CML CP and in Ph+ CML CP and AP patients resistant/intolerant to either imatinib or dasatinib
?Population PK parameters of nilotinib
?Pharmacodynamics (BCR-ABL transcript levels determined with standard protocols in peripheral blood and bone marrow) |
?Tiempo hasta la respuesta, duración de la respuesta, tiempo hasta la progresión, supervivencia global
?Tasa de RCM y de RCC en pacientes con LMC Ph+ en FC de diagnóstico reciente y en pacientes con LMC Ph+ en FC y FA resistente/intolerante a imatinib o a dasatinib a los 6, 12* y 24 meses.
?Tasa de RMM a los 3, 6, 9, 12* y 24 meses en pacientes con LMC Ph+ en FC de diagnóstico reciente y en pacientes con LMC Ph+ en FC y FA resistente/intolerante a imatinib o a dasatinib
?Tasa de RHC a los 3*, 6, 9, 12 y 24 meses en pacientes con LMC Ph+ en FC de diagnóstico reciente y en pacientes con LMC Ph+ en FC y FA resistente/intolerante a imatinib o a dasatinib
?Parámetros PK de la población de nilotinib
?Farmacodinamia (niveles de tránscritos de BCR-ABL determinado con protocolos estándares en médula ósea y sangre periférica) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
?1, 3, 6, 9, 12 months
? up to 24 months
? up to 24 months
? up to 24 months or date of last contact in follow-up
?up to 24 months
?up to 24 months
? up to 24 months |
?1, 3, 6, 9, 12 meses
? a los 24 meses
? a los 24 meses
? a los 24 meses o el último follow-up
? a los 24 meses
? a los 24 meses
? a los 24 meses |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| acceptability of study drug formulation (including palatability) |
| aceptabilidad de la formulación de fármaco del estudio (incluyendo palatabilidad) |
|
| 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 | 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 | 3 |
| 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 | 22 |
| 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 |
| Canada |
| France |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Russian Federation |
| Spain |
| Thailand |
| Turkey |
| 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
|
All patients will be treated with nilotinib in the study for a total of 24
cycles of 28 days, after this patients will be given the opportunity to
participate in the long-term extension study.The end of the
CAMN107A2203 study occurs once the last patient still on treatment
has EoT assessment or study evaluation completion assessment (either
early discontinuation or elects not to enroll in long-term extension
study). |
El final del estudio CAMN107A2203 ocurrirá cuando el último paciente que aún esté en tratamiento:
?complete la evaluación de final de tratamiento del estudio (EoT) en caso de que el paciente elija participar en el estudio de extensión a largo plazo o
?complete la evaluación de finalización de evaluación del estudio en caso de que el paciente sea retirado prematuramente o complete 24 ciclos de tratamiento pero elija no participar en el estudio de extensión a largo plazo. |
|
| 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 | 3 |
| 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 | 3 |
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