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)

Phase 2Not Yet RecruitingNCT07387926

Novartis Pharmaceuticals50 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 1 YearMax age: 30 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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: 1. Primary refractory disease (\>0.01% ALL blasts present at the end of consolidation) OR 2. 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: 1. ALT ≤ 5x upper limit of normal (ULN) for age 2. 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 3. 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 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.

Outcomes

Primary Outcomes

Part 1 Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) occurring during cycle 1 (debulking induction)

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.

Time frame: During Cycle 1 (Cycle 1 = 28 days)

Part 1 Dose Escalation: Incidence and severity of adverse events (AEs) during cycle 1 (debulking induction)

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.

Time frame: 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)

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.

Time frame: End of Cycle 1 (Cycle 1 = 28 days)

Secondary Outcomes

Complete remission (CR) rate

Percentage of participants who had a CR

Time frame: End of Cycle 2 and Cycle 3 (Cycle 2 & 3 = 42 days)

Overall response rate (ORR)

Percentage of participants who had CR and/or complete remission with incomplete blood count recovery (CRi)

Time frame: 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

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).

Time frame: 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

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).

Time frame: 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

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).

Time frame: 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

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).

Time frame: 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)

The period from when a participant is in remission until they have relapse or death due to any reason.

Time frame: 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)

The duration of time from treatment initiation until the participant's death due to any reason.

Time frame: 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

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

Time frame: Cycle 1, Day 8 (Cycle 1 = 28 days)

PK parameter of asciminib at steady state: Cmax

Maximum concentration-the peak (highest) plasma drug concentration observed after administration

Time frame: Cycle 1, Day 8 (Cycle 1 = 28 days)

PK parameter of asciminib at steady state: Tmax

The time it takes to reach the Cmax after drug administration

Time frame: Cycle 1, Day 8 (Cycle 1 = 28 days)

PK parameter of asciminib at steady state: Ctrough

Trough concentration- lowest drug concentration observed, typically right before the next dose is administered (steady-state condition)

Time frame: Cycle 1, Day 8 (Cycle 1 = 28 days); Cycle 2, Day 22 (Cycle 2 = 42 days); Cycle 3, Day 22 (Cycle 3 = 42 days)

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)

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts