E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with chronic myeloid leukemia with complete molecular response can stop tyrosine kinase inhibitors under close monitoring |
Pacientes con leucemia mieloide cronica con respuesta molecular completa pueden interrumpir los inhibidores de tirosina quinasa bajo estrecha vigilancia |
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E.1.1.1 | Medical condition in easily understood language |
Trial estimating the impact of stopping tyrosine kinase inhibitors in chronic myeloid leukemia; patients in complete molecular response with CML are requested to stop therapy under close monitoring |
Los ensayos evaluan el impacto de interrumpir los TKI en la leucemia mieloide cronica. Los pacientes con respuesta molecular completa con CML interrumpen el tratamiento bajo estrecha supervision |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009016 |
E.1.2 | Term | Chronic myeloid leukemia in remission |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Evaluation of molecular relapse-free survival after stopping TKI (survival without molecular relapse defined by BCR-ABL1 > 0.1% on the IS at one time point (loss of major molecular response, MMR) |
Evaluación del intervalo libre de recaida después de retirar los inhibidores tirosina cinasa (ITC) en pacientes con leucemia mieloide crónica en respuesta molecular grado 4 (CMR4). |
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E.2.2 | Secondary objectives of the trial |
1- Identification of clinical and biological factors affecting the persistence of complete molecular remission and MMR after stopping TKI (e.g. level of CMR before treatment stop, risk score, duration of TKI treatment, type of TKI pretreatment) 2- Estimation of overall and progression free survival, and probabilities of a restart of TKI treatment without prior molecular relapse 3- Patient reported QoL and symptom burden over time 4- Evaluation of medico-economic impact of stopping TKI 5- Estimating the number of patients in CMR (CMR4 and CMR4.5) who would be eligible for stopping TKI therapy 6- Time to recovery of CMR4 after restart of therapy following molecular relapse |
1- Identificar factores clínicos y biológicos que afecten a la persistencia de remisión molecular y respuesta molecular mayor después de suspender los ITC. 2- Estimación de la supervivencia libre de progresión y global y las probabilidades de reiniciar los ITC sin recaída molecular previa. 3- Evaluar los cuestionarios de calidad de vida y síntomas a lo largo del estudio. 4- Evaluación médico-económica del impacto de suspender los ITC. 5- Estimar el número de pacientes en CMR (CMR4 y CMR5) que podrían ser elegibles para suspender el tratamiento con ITC. 6- Tiempo para recuperar la CMR4 tras reiniciar el tratamiento después de la recaída molecular. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Nordic mmunology substudy (substudy 5 in protocol) |
Subestudio inmunologico nordico (5 subestudios en protocolo) |
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E.3 | Principal inclusion criteria |
- CML in CP under treatment with TKI in first line or in second line because of toxicity to first line TKI or with TKI in combination - Duration of TKI treatment before enrolment at least 3 years - At least complete molecular remission CMR4 (either (i) detectable disease <=0.01% BCR-ABL IS or (ii) undetectable disease in cDNA with >=10,000 ABL or >=24,000 GUS transcripts) for at least one year; at least three PCR-results with CMR4 within the last year (± 2 months) before study entry and no PCR-results > 0.01% during the same period - Before inclusion confirmation of CMR4 through a EUTOS-CMR laboratory - Baseline data and documentation on treatment before study entry available - Both sexes but fertile women only if using effective contraceptive - Health insurance coverage - 18 years or older - Known baseline data at diagnosis, EURO-Score |
- Pacientes con LMC en fase crónica en tratamiento con ITC en primera línea o segunda por toxicidad a la primera línea o con ITC en combinación. - Duración del tratamiento previamente a la inclusión de al menos 3 años. - Al menos remisión molecular completa CMR4 (enfermedad no detectable <=0,01% BCR-ABL IS o enfermedad indetectable en cDNA con >=10,000 ABL o >=24,000 GUS tránscritos) por al menos un año; al menos 3 resultados de PCR con CMR4 y al menos un año (± 2 meses) antes de entrar en el estudio y ningún resultado de PCR > 0,01% durante el mismo periodo. - Antes de la inclusión confirmar la CMR4 a través de un análisis en el laboratorio EUTOS-CMR. - Los datos basales y la documentación sobre el tratamiento deben estar disponible antes del estudio. - Ambos sexos y mujeres fértiles solo si usan métodos contraceptivos. - Cobertura de un seguro de salud. - Mayores de 18 años - Tener los datos basales al diagnóstico para calcular el EURO-Score. |
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E.4 | Principal exclusion criteria |
- Under 18 years old - Hospitalized patients without ability to give informed consent - Adults under law protection or without ability to consent - Previous or planned allogeneic stem cell transplantation |
- Menores de 18 años. - Pacientes sin la capacidad de firmar el consentimiento informado. - Adultos bajo la protección de la ley sin capacidad para consentir. - Trasplante alogénico de células madre hematopoyéticas previo o planeado. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Evaluation of molecular relapse-free survival after stopping TKI (survival without molecular relapse defined by BCR-ABL1 ratio > 0.1% on the IS at one time point (loss of major molecular response, MMR) |
Evaluar la supervivencia libre de recaída molecular después de suspender los ITC (supervivencia sin recaída molecular definida como BCR/ABL1 > 0,1% en escala IS en un momento temporal (pérdida de respuesta molecular mayor RMM). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 200 patients with follow-up of at least 6 months |
Despues de 200 pacientes con seguimiento de al menos 6 meses |
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E.5.2 | Secondary end point(s) |
? Overall and progression-free survival and the probabilities of a restart of TKI without prior molecular relapse ? Clinical and biological profile of complete and major molecular remission persistence ? Saved treatment costs / country from the time off TKI therapy considering also the more frequent PCR monitoring ? Patient reported QoL and symptom burden over time ? Registering patients in confirmed CMR4 and CMR4.5 ? Analysing the time to recovery of CMR4 after loss of MMR |
? Supervivencia global y libre de progresión y la probabilidad de reiniciar los ITC sin RMM previa. ? Perfil clínico y biológico de los enfermos con respuesta molecular mayor y persistencia de la remisión. ? Ahorro de costes por tratamiento por país desde el tiempo de retirada del ITC considerando la monitorización más frecuente. ? Calidad de vida QoL y síntomas durante todo el estudio. ? Registro de pacientes con CMR4 y CMR 4,5. ? Analizar el tiempo para recuperar la CMR4 después de perder la RMM. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At interim analysis as described above |
En un análisis intermedio como se describe anteriormente |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | 1 |
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 | 45 |
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 |
Russian Federation |
Switzerland |
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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
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In case of hematological relapse or progression to accelerated or blastic phase, the sponsor must be contacted within 24h and the Data Safety Monitoring Board (DSMB) will decide on continuation of the study. Inclusion of patients in the trial will be stopped until then. Criteria to stop the study at interim analysis: According to published study results, if the number of progressions exceeds 2%, the study will be stopped (2). |
En caso de recaída hematológica o progresión a la fase acelerada o blástica, el promotor debe ser informado dentro de 24 h y el comite de control de seguridad de datos (DSMB) decidirá sobre la continuación del estudio. La inclusión de pacientes en el ensayo se detendrá hasta entonces.De acuerdo con los resultados publicados, si el número de progresiones supera el 2%, se detendrá el estudio |
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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 | 5 |
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 | 5 |
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 |