E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High Risk Chronic Lymphocytic Leukemia |
Leucemia linfocítica crónica de alto riesgo |
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E.1.1.1 | Medical condition in easily understood language |
High Risk Chronic Lymphocytic Leukemia |
Leucemia linfocítica crónica de alto riesgo |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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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 check the efficacy of acalabrutinib in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy |
Evaluar la eficacia de acalabrutinib en sujetos con LLC recidivante/resistente que no toleran el tratamiento con ibrutinib. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of acalabrutinib in subjects with relapsed/refractory CLL who are intolerant of ibrutinib therapy EXPLORATORY OBJECTIVES: - To determine the effect of acalabrutinib on peripheral blood B cells, T cells, NK cells, and MDSCs. - To evaluate potential predictive biomarkers and mechanisms of resistance for the disease. |
Evaluar la seguridad y la tolerabilidad de acalabrutinib en sujetos con LLC recidivante/resistente que no toleran el tratamiento con ibrutinib. OBJETIVOS EXPLORATORIOS: - Determinar el efecto de acalabrutinib en linfocitos B, linfocitos T, linfocitos citolíticos naturales y CSOM en sangre periférica. - Evaluar posibles biomarcadores predictivos y mecanismos de resistencia para la enfermedad. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1-Prior diagnosis of CLL that meets published diagnostic criteria (Hallek 2008) 2-Must have received ? 1 prior therapy for CLL and not be appropriate for treatment or retreatment with purine analogue-based therapy 3-Intolerant of ibrutinib, defined as the subject has discontinued ibrutinib therapy due to Grade 3 or 4 AEs that persisted in spite of optimal supportive care measures OR patients who had Grade 2 AEs related to ibrutinib therapy, in spite of optimal supportive care measures, that persisted for ? 2 weeks or that recurred ? 2 times whether dose was reduced or discontinued. 4-ECOG performance status of ? 2 |
1-Diagnóstico previo de LLC que cumple los criterios de diagnóstico publicados (Hallek 2008) 2-Debe haber recibido ? 1 tratamiento previo para la LLC y no ser adecuado para el tratamiento o la repetición del tratamiento con análogos de la purina 3-Intolerancia al ibrutinib, lo que se define como que el sujeto ha discontinuado el tratamiento con ibrutinib debido a AA de grado 3 o 4 que persistieron a pesar del tratamiento sintomático óptimo, O BIEN pacientes que presentaron AA de grado 2 relacionados con ibrutinib, a pesar del tratamiento sintomático óptimo, que persistieron durante ? 2 semanas o que reaparecieron ? 2 veces, aunque se redujera o discontinuara la dosis. 4-Estado funcional ECOG ? 2. |
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E.4 | Principal exclusion criteria |
1-Ongoing Grade 3 or 4 AE attributed to ibrutinib therapy. Note: Patients may be eligible for enrollment once the ibrutinib-related AE improves to Grade ? 2. 2-Treatment with systemic anticancer therapy for CLL is prohibited between discontinuation of ibrutinib and enrollment on this trial. 3-Prior exposure to a BCL-2 inhibitor (eg, ABT-199). 4-Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the subject has been disease free for ? 2 years. |
1-AA de grado 3 o 4 en curso atribuidos al tratamiento con ibrutinib. Nota: Los pacientes pueden ser elegibles para la inclusión una vez que el AA relacionado con ibrutinib mejore hasta un grado ? 2. 2-Está prohibido el tratamiento con antineoplásicos sistémicos para la LLC entre el momento de la discontinuación de la administración de ibrutinib y la inclusión en este ensayo. 3-Exposición previa a un inhibidor de BCL-2 (como ABT-199). 4-Neoplasia maligna previa (distinta de la LLC), a excepción de carcinoma basocelular o carcinoma espinocelular, cáncer localizado u otro tipo de cáncer adecuadamente tratado del que el sujeto haya estado libre durante ? 2 años . |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy will be evaluated based on the IWCLL 2008 criteria. The primary efficacy endpoint is Overall Response Rate (ORR) assessed by the investigators at the end of treatment. |
La eficacia se evaluará sobre la base de los criterios del IWCLL 2008. El criterio principal de valoración de la eficacia es la Tasa de Respuesta Global (TRG) evaluada por los investigadores al finalizar el tratamiento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
See section above. |
Ver sección anterior. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are: - Duration of Response (DOR) - Progression-Free Survival (PFS) - Time to Next Treatment (TTNT) - Overall Survival (OS)
The safety of acalabrutinib will be characterized by laboratory assessments performed throughout the study and the type, frequency, severity, and attribution of AEs, or AEs leading to discontinuation of study treatment.
The exploratory objectives will be evaluated through pharmacodynamic and biomarker parameters. The occupancy of Btk by acalabrutinib will be measured in PBMCs with the aid of a biotin-tagged acalabrutinib analogue probe. The effect of acalabrutinib on B cells, NK cells (CD56+), T cells (CD3+, CD4+, CD8+ levels), and MDSCs (HLA-DR- CD14+CD11b+ CD33+ levels) will also be evaluated. Genotyping for Btk, p53, and PLC? mutations will be performed. |
Los criterios secundarios de valoración de la eficacia son: - Duración de la respuesta (DDR) - Supervivencia sin progresión (SSP) - Tiempo hasta el siguiente tratamiento (THST) - Supervivencia Global (SG)
La seguridad de acalabrutinib se describirá por medio de análisis de laboratorio realizados a lo largo del estudio y el tipo, la frecuencia, la intensidad y la atribución de los AA, o los AA que conducen a la discontinuación del tratamiento del estudio.
Los objetivos exploratorios se evaluarán mediante parámetros farmacodinámicos y de biomarcadores. La ocupación de Btk por parte de acalabrutinib se medirá en CMSP con ayuda de una sonda de análogo de acalabrutinib marcado con biotina. También se evaluará el efecto de acalabrutinib sobre los linfocitos B, los linfocitos citolíticos naturales (NK) (CD56+), linfocitos T (concentraciones de CD3+, CD4+, CD8+), y CSOM (concentraciones de HLA-DR-, CD14+, CD11b+, CD33+). Se llevará a cabo la genotipificación de las mutaciones de Btk, p53 y PLC?. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See section above. |
Ver sección anterior. |
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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 | 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) | 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 | 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.8.3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Belgium |
France |
Israel |
Spain |
United Kingdom |
United States |
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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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The end of trial is defined as the point when the last subject enrolled completes end of Cycle 36 or withdraws for any reason and completes the 30-day SFU visit (if applicable), whichever occurs first. |
El final del ensayo se define como el punto en el que el último sujeto incluido completa el ciclo 36 o se retira por cualquier razón y finaliza la visita de SS de los 30 días (si procede), lo que ocurra antes. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |