Seguridad y Eficacia de Asciminib en Pacientes Pediátricos y Adultos Jóvenes con Leucemia Linfoblástica Aguda (LLA) Filadelfia Positiva (Ph+) o de Clase ABL Ph-like Recaída/Refractaria (r/r)
Estudio abierto de fase I/II para evaluar la seguridad y eficacia de Asciminib con quimioterapia seguido de Asciminib más Blinatumomab en niños, adolescentes y adultos jóvenes con ALL recidivante o refractaria BCR::ABL1 positiva (Filadelfia positiva, Ph+) o similar a BCR::ABL1 (similar a Ph)
Multi-center, open-label, single arm study of asciminib in participants aged ≥1 year to ≤30 years old with r/r Ph+ or ABL-class Ph-like ALL. This study will have 2 parts: Part 1 dose escalation and Part 2 dose expansion. Part 1 dose escalation will enroll participants aged ≥1 year to ≤30 years to determine the recommended phase 2 dose (RP2D) of asciminib when administered with low intensity chemotherapy. Part 2 dose expansion will enroll participants aged ≥1 year to ≤30 years to evaluate safety, tolerability, and efficacy of asciminib at the RP2D with the treatment regimen.
Descripción general del estudio
Estado
Condiciones
Descripción detallada
This is a single arm phase I/II multicenter study to assess the safety and efficacy of asciminib at the RP2D in combination with low intensity chemotherapy (debulking induction) followed by asciminib plus blinatumomab (consolidation) in pediatric and young adult participants with r/r Ph+ ALL (inclusive of participants with T315I mutation).
The aim of the study design is to explore a novel treatment regimen which is expected to be more tolerable than the high intensity chemotherapy backbone-based regimens.
This study will consist of a 2-part design:
Part 1 dose escalation using a Bayesian Optimal Interval (BOIN) statistical design, and after determination of RP2D Part 2 dose expansion.
Participants will only enroll in either Part 1 or Part 2, and not both.
Both Part 1 and Part 2 (dose escalation and dose expansion) will have the following phases:
- Core Study Treatment Phase
- Survival Follow up Phase
Participants with known T315I mutation will not participate in Part 1 or Part 2. They will be part of a separate cohort.
The core study treatment phase will consist of 3 cycles of therapy: cycle 1 asciminib with low intensity chemotherapy (debulking induction), followed by cycle 2 (blinatumomab-block 1 with asciminib) and cycle 3 (blinatumomab-block 2 with asciminib).
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 2
- Fase 1
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Novartis Pharmaceuticals
- Número de teléfono: 1-888-669-6682
- Correo electrónico: novartis.email@novartis.com
Copia de seguridad de contactos de estudio
- Nombre: Novartis Pharmaceuticals
- Número de teléfono: +41613241111
Ubicaciones de estudio
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New South Wales
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Sydney, New South Wales, Australia, 2031
- Reclutamiento
- Novartis Investigative Site
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Queensland
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Brisbane, Queensland, Australia, 4101
- Reclutamiento
- Novartis Investigative Site
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Victoria
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Melbourne, Victoria, Australia, 3004
- Reclutamiento
- Novartis Investigative Site
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Seoul, Corea del Sur, 03080
- Reclutamiento
- Novartis Investigative Site
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Seoul, Corea del Sur, 06591
- Reclutamiento
- Novartis Investigative Site
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Marseille, Francia, 13885
- Reclutamiento
- Novartis Investigative Site
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Ramat Gan, Israel, 5265601
- Reclutamiento
- Novartis Investigative Site
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Utrecht, Países Bajos, 3584 CS
- Reclutamiento
- Novartis Investigative Site
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Taipei, Taiwán, 10002
- Reclutamiento
- Novartis Investigative Site
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
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Evidence of Ph+ ALL or ABL1 or ABL2 fusion Ph-like ALL, inclusive of participants with ABL1 T315I mutation
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Participants with CNS1, CNS2, CNS3a, or CNS3b at screening
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Active B-Cell ALL at screening defined by MFC or IG/TCR PCR of ALL blasts >0.01% in participants with either:
- Primary refractory disease (>0.01% ALL blasts present at the end of consolidation) OR
- Relapsed ALL with evidence of involvement of BM with ALL (MFC or IG/TCR PCR >0.01%) after at least one line of therapy
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Documented history of CD19 expressing B-cell ALL (in peripheral blood or bone marrow by flow cytometry).
a) For participants who received anti-CD19 targeted therapy (e.g CD19 CAR T cells or blinatumomab), CD19 expressing B-cell ALL must be documented after anti-CD19 therapy completion prior to cycle 1 day 1
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Adequate hepatic and renal function (local laboratory analysis) as defined:
- ALT ≤ 5x upper limit of normal (ULN) for age
- Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x ULN) for age, except for participants with Gilbert's syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
- Estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula in participants ≥ 18 years, OR radioisotope GFR ≥50 mL/min/1.73 m^2, OR creatinine based on age and sex for participants < 18 years old
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Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left ventricular ejection fraction of ≥50% by ECHO
Exclusion Criteria:
- Participants with >3 relapses of ALL
- Extramedullary disease (non-CNS and/or isolated CNS disease)
- Participants with CNS3c (Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome))
- Cardiac or cardiac repolarization abnormality, including but not limited to clinically significant cardiac arrhythmias, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or other clinically significant heart disease (e.g., congestive heart failure, etc.)
- 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.
Other protocol defined inclusion/exclusion criteria may apply.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Single Arm
Asciminib Adult formulation group: escalating doses evaluated Asciminib Pediatric formulation group: dose is based on body weight; dose level being evaluated will be converted into a mg/kg daily dose. For known T315I mutation: Fixed asciminib dose twice daily or the pediatric formulation dose equivalent twice daily. |
oral, administered daily (twice daily for participants with known T315I mutation); Cycles 1, 2, 3
Otros nombres:
oral, administered daily (twice daily for participants with known T315I mutation); Cycles 1, 2, 3
Otros nombres:
Fixed doses, oral (preferred) or intravenous (IV) twice daily; Cycle 1, Days 1 - 14; (Cycle 1 = 28 days) Fixed doses, IV, weekly; Cycle 1 Dosing based on bone marrow disease burden and weight. Continuous IV infusion; Cycles 2, 3 Intrathecal Intrathecal Intrathecal Intrathecal |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Part 1 Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) occurring during cycle 1 (debulking induction)
Periodo de tiempo: During Cycle 1 (Cycle 1 = 28 days)
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A dose-limiting toxicity (DLT) is defined as an adverse event which starts between Day 1 and Day 28, is suspected by the investigator to be related to asciminib, and meets one of the several criteria. |
During Cycle 1 (Cycle 1 = 28 days)
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Part 1 Dose Escalation: Incidence and severity of adverse events (AEs) during cycle 1 (debulking induction)
Periodo de tiempo: During Cycle 1 (Cycle = 28 days)
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An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
During Cycle 1 (Cycle = 28 days)
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Part 2 Dose Expansion: Percentage of complete response/remission (CR) evaluable participants who achieve CR treated at recommended phase 2 dose (RP2D) (debulking induction)
Periodo de tiempo: End of Cycle 1 (Cycle 1 = 28 days)
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Participants with Complete Response/Remission (CR) will achieve the following: No circulating blasts or extramedullary disease; No lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass/CNS involvement; Marrow <5% blasts (M1) OR < 1% blasts by flow cytometry. If a discrepancy occurs between disease detection methods, the result of the flow cytometry assay will be used to determine CR status; Peripheral blood count recovery; ANC > 1000μL and platelets > 100,000μL. CR evaluable: Participants will be considered CR evaluable for Part 2 if they have relapsed/refractory Ph+ ALL defined as either >1% bone marrow (BM) blasts by MFC or immunoglobulin/T-cell receptor (IG/TCR) PCR, OR > 5% BM blasts by morphologic evaluation at enrollment and are treated at RP2D. |
End of Cycle 1 (Cycle 1 = 28 days)
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Complete remission (CR) rate
Periodo de tiempo: End of Cycle 2 and Cycle 3 (Cycle 2 & 3 = 42 days)
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Percentage of participants who had a CR |
End of Cycle 2 and Cycle 3 (Cycle 2 & 3 = 42 days)
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Overall response rate (ORR)
Periodo de tiempo: At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)
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Percentage of participants who had CR and/or complete remission with incomplete blood count recovery (CRi) |
At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)
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Next generation sequencing (NGS) minimal residual disease (MRD) negative rate
Periodo de tiempo: At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)
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Percentage of participants who have NGS MRD negative CR at and by the end of cycle 1 (debulking induction), cycle 2 and cycle 3 (consolidation). |
At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)
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Multiparametric flow cytometry (MFC) MRD negative CR rate
Periodo de tiempo: At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)
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Percentage of participants who have MFC MRD negative CR at and by the end of cycle 1 (debulking induction), cycle 2 and cycle 3 (consolidation). |
At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)
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Overall MRD negative response (MRD negative CR and/or CRi rate) by NGS
Periodo de tiempo: at and by the end of cycle 1 (debulking induction) (Cycle 1 = 28 days), cycle 2, and cycle 3 (consolidation) (each cycle = 42 days)
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Overall MRD negative response is the percentage of participants who have NGS MRD negative complete response (CR) and complete response incomplete blood count recovery (CRi). |
at and by the end of cycle 1 (debulking induction) (Cycle 1 = 28 days), cycle 2, and cycle 3 (consolidation) (each cycle = 42 days)
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Overall MRD negative response (MRD negative CR and/or CRi rate) by MFC
Periodo de tiempo: at and by the end of cycle 1 (Cycle 1 = 28 days) (debulking induction), cycle 2, cycle 3 (consolidation) (each cycle = 42 days)
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Overall MRD negative response is the percentage of participants who have MFC MRD negative complete response (CR) and complete response incomplete blood count recovery (CRi). |
at and by the end of cycle 1 (Cycle 1 = 28 days) (debulking induction), cycle 2, cycle 3 (consolidation) (each cycle = 42 days)
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Disease Free Survival (DFS)
Periodo de tiempo: End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years)
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The period from when a participant is in remission until they have relapse or death due to any reason. |
End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years)
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Overall survival (OS)
Periodo de tiempo: End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years)
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The duration of time from treatment initiation until the participant's death due to any reason. |
End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years)
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Pharmacokinetic (PK) parameter of asciminib at steady state: AUClast
Periodo de tiempo: Cycle 1, Day 8 (Cycle 1 = 28 days)
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Area Under the Curve to the Last Measurable Concentration-represents the total drug exposure (area under the plasma concentration-time curve) from the time of administration until the last measurable concentration |
Cycle 1, Day 8 (Cycle 1 = 28 days)
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PK parameter of asciminib at steady state: Cmax
Periodo de tiempo: Cycle 1, Day 8 (Cycle 1 = 28 days)
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Maximum concentration-the peak (highest) plasma drug concentration observed after administration |
Cycle 1, Day 8 (Cycle 1 = 28 days)
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PK parameter of asciminib at steady state: Tmax
Periodo de tiempo: Cycle 1, Day 8 (Cycle 1 = 28 days)
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The time it takes to reach the Cmax after drug administration |
Cycle 1, Day 8 (Cycle 1 = 28 days)
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PK parameter of asciminib at steady state: Ctrough
Periodo de tiempo: Cycle 1, Day 8 (Cycle 1 = 28 days); Cycle 2, Day 22 (Cycle 2 = 42 days); Cycle 3, Day 22 (Cycle 3 = 42 days)
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Trough concentration- lowest drug concentration observed, typically right before the next dose is administered (steady-state condition) |
Cycle 1, Day 8 (Cycle 1 = 28 days); Cycle 2, Day 22 (Cycle 2 = 42 days); Cycle 3, Day 22 (Cycle 3 = 42 days)
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Director de estudio: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Neoplasias
- Enfermedades del sistema inmunológico
- Neoplasias por tipo histológico
- Enfermedades hematológicas
- Enfermedades linfáticas
- Trastornos linfoproliferativos
- Trastornos inmunoproliferativos
- Leucemia Linfoide
- Leucemia
- Enfermedades hemic y linfáticas
- Leucemia-linfoma linfoblástico de células precursoras
- Hormonas
- Hormonas, sustitutos hormonales y antagonistas hormonales
- Compuestos heterocíclicos, 1 anillo
- Compuestos heterocíclicos
- Compuestos heterocíclicos, 2 anillos
- Compuestos heterocíclicos, anillo fusionado
- Ácidos nucleicos, nucleótidos y nucleósidos
- Alcaloides
- Compuestos policíclicos
- Indoles
- Citidina
- Nucleósidos de pirimidina
- Pirimidinas
- Espierra
- Embarazos
- Esteroides
- Compuestos de anillo fusionado
- Esteroides, fluorado
- Nucleósidos
- Pterins
- Pteridinas
- Esparrazadienetrioles
- Alcaloides de Vinca
- Alcaloides de triptamina de secologanina
- Alcaloides de indol
- Indolizidinas
- Indolizinas
- Arabinonucleósidos
- Aminopterina
- Embarazadas
- Embarazo
- 11-hidroxicorticosteroides
- Hidroxicorticosteroides
- Hormonas de la corteza suprarrenal
- 17-hidroxicorticosteroides
- Dexametasona
- Metotrexato
- Prednisolona
- Citarabina
- Vincristina
- Hidrocortisona
- blinatumomab
- asciminib
Otros números de identificación del estudio
- CABL001L12101
- 2025-522019-40 (Número EudraCT)
- 2025 (Subvención/contrato del NIH de EE. UU.)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
Tipo de información de apoyo para compartir IPD
- PROTOCOLO DE ESTUDIO
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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