Safety and Efficacy of Asciminib in Pediatrics and Young Adults With Relapse/Refractory (r/r) Philadelphia Positive (Ph+) or ABL-class Ph-like Acute Lymphoblastic Leukemia (ALL)

Официальное название

Open-label, Phase I/II Study to Evaluate Safety and Efficacy of Asciminib With Chemotherapy Followed by Asciminib Plus Blinatumomab in Pediatric, Adolescent, and Young Adults With Relapsed or Refractory BCR::ABL1-positive (Philadelphia Positive, Ph+) or BCR::ABL1-like (Ph-like) ALL

Обзор

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.

Подробное описание

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).

Вмешательства

• Препарат Asciminib Adult formulation
  oral, administered daily (twice daily for participants with known T315I mutation); Cycles 1, 2, 3
• Препарат Asciminib Pediatric formulation
  oral, administered daily (twice daily for participants with known T315I mutation); Cycles 1, 2, 3
• Препарат Dexamethasone
  Fixed doses, oral (preferred) or intravenous (IV) twice daily; Cycle 1, Days 1 - 14; (Cycle 1 = 28 days)
• Препарат Vincristine
  Fixed doses, IV, weekly; Cycle 1
• Препарат Blinatumomab
  Dosing based on bone marrow disease burden and weight. Continuous IV infusion; Cycles 2, 3
• Препарат Methotrexate (intrathecal)
  Intrathecal
• Препарат Cytarabine (intrathecal)
  Intrathecal
• Препарат Hydrocortisone (intrathecal)
  Intrathecal
• Препарат Prednisolone (intrathecal)
  Intrathecal

Первичные конечные точки

• Part 1 Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) occurring during cycle 1 (debulking induction) [Срок оценки: During Cycle 1 (Cycle 1 = 28 days)]
• Part 1 Dose Escalation: Incidence and severity of adverse events (AEs) during cycle 1 (debulking induction) [Срок оценки: During Cycle 1 (Cycle = 28 days)]
• Part 2 Dose Expansion: Percentage of complete response/remission (CR) evaluable participants who achieve CR treated at recommended phase 2 dose (RP2D) (debulking induction) [Срок оценки: End of Cycle 1 (Cycle 1 = 28 days)]

Вторичные конечные точки (12)

• Complete remission (CR) rate [Срок оценки: End of Cycle 2 and Cycle 3 (Cycle 2 & 3 = 42 days)]
• Overall response rate (ORR) [Срок оценки: At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)]
• Next generation sequencing (NGS) minimal residual disease (MRD) negative rate [Срок оценки: At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)]
• Multiparametric flow cytometry (MFC) MRD negative CR rate [Срок оценки: At and by the end of Cycle 1 (Cycle 1 = 28 days), Cycle 2, and Cycle 3 (Cycle 2 & 3 = 42 days)]
• Overall MRD negative response (MRD negative CR and/or CRi rate) by NGS [Срок оценки: at and by the end of cycle 1 (debulking induction) (Cycle 1 = 28 days), cycle 2, and cycle 3 (consolidation) (each cycle = 42 days)]
• Overall MRD negative response (MRD negative CR and/or CRi rate) by MFC [Срок оценки: at and by the end of cycle 1 (Cycle 1 = 28 days) (debulking induction), cycle 2, cycle 3 (consolidation) (each cycle = 42 days)]
• Disease Free Survival (DFS) [Срок оценки: End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years)]
• Overall survival (OS) [Срок оценки: End of Cycle 3 (Cycle 3 = 42 days) in Part 2 of the study and at the end of study (EOS = approx. 3 years)]
• Pharmacokinetic (PK) parameter of asciminib at steady state: AUClast [Срок оценки: Cycle 1, Day 8 (Cycle 1 = 28 days)]
• PK parameter of asciminib at steady state: Cmax [Срок оценки: Cycle 1, Day 8 (Cycle 1 = 28 days)]
• PK parameter of asciminib at steady state: Tmax [Срок оценки: Cycle 1, Day 8 (Cycle 1 = 28 days)]
• PK parameter of asciminib at steady state: Ctrough [Срок оценки: Cycle 1, Day 8 (Cycle 1 = 28 days); Cycle 2, Day 22 (Cycle 2 = 42 days); Cycle 3, Day 22 (Cycle 3 = 42 days)]

Критерии участия

Критерии включения

• Evidence of Ph+ ALL or ABL1 or ABL2 fusion Ph-like ALL, inclusive of participants with ABL1 T315I mutation
• Participants with CNS1, CNS2, CNS3a, or CNS3b at screening
• 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
• 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

• 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
• Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left ventricular ejection fraction of ≥50% by ECHO

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Израиль · 1 центр

• Novartis Investigative Site — Ramat Gan

Идентификаторы

NCT: NCT07387926 · CABL001L12101 · 2025-522019-40

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗