Asciminib

TTDAE is defined as the interval from the date of first study treatment administration to the date of discontinuation of study treatment due to an adverse event (AE). The comparison between the asciminib and nilotinib treatment arms is performed using a cause-specific hazard model, in which discontinuations due to AE are considered the event of interest and discontinuations for reasons other than AE are treated as competing risks. The number of participants who discontinued study treatment due to AE within the specified timeframe is presented in the results table. The formal comparison between treatment arms is performed using a cause-specific hazard model, and the corresponding hazard ratio, confidence interval, and p-value are provided in the Statistical Analysis section. The TTDAE endpoint is event-driven by counting how many participants have experienced treatment discontinuations due to AE.

TTDAE is defined as the interval from the date of first study treatment administration to the date of discontinuation of study treatment due to an adverse event (AE). The comparison between the asciminib and nilotinib treatment arms is performed using a cause-specific hazard model, in which discontinuations due to AE are considered the event of interest and discontinuations for reasons other than AE are treated as competing risks. The number of participants who discontinued study treatment due to AE within the specified timeframe is presented in the results table. The formal comparison between treatment arms is performed using a cause-specific hazard model, and the corresponding hazard ratio, confidence interval, and p-value are provided in the Statistical Analysis section. The TTDAE endpoint is event-driven by counting how many participants have experienced treatment discontinuations due to AE.

Major Molecular Response (MMR) is defined as a significant reduction in the level of BCR::ABL1 transcripts, which are the genetic markers of chronic myeloid leukemia (CML). Specifically, MMR is achieved when there is a ≥ 3.0 log reduction in BCR::ABL1 transcripts compared to a standardized baseline, which corresponds to a BCR::ABL1/ABL1 ratio of ≤ 0.1% on the international scale (IS). The Major Molecular Response (MMR) rate at Week 48 for all patients with no evidence of MMR at baseline refers to the percentage of patients who achieve MMR after 48 weeks of treatment, despite not having MMR at the start.

Adverse events (AEs) and serious adverse events (SAEs) are summarized by cohort. Clinically significant findings for vitals, laboratory values and electrocardiogram (ECG) are reported as adverse events and or serious adverse events as determined by the investigator.

MMR was defined as a ≥ 3.0 log reduction in BCR-ABL1 transcripts compared to the standardized baseline equivalent to ≤ 0.1% BCR-ABL1/ABL% by international scale (IS) as measured by RQ-PCR.

MMR is defined as BCR::ABL1 IS ≤0.1%. MMR is defined as a ≥ 3.0 log reduction in BCR::ABL1 transcripts compared to the standardized baseline equivalent to ≤ 0.1 % BCR::ABL1/ABL % by international scale as measured by RQ-PCR.

Evaluation of asciminib efficacy : proportion of patients with MR2 (BCR::ABL1 IS ≤1%) level of response at 12 months.

MMR is defined as BCR::ABL1IS ≤ 0.1%. A patient will be counted as having achieved MMR at 12 month if he/she meets the MMR criterion at 12 month.

Evaluate the major molecular response rate at 24 weeks in asciminib arm

Safety of administering asciminib in combination with trastuzumab by measuring number of participants with a dose-limiting toxicity at each dose level

Efficacy at maximum tolerated dose (MTD) determined by the number of participants with a complete response (CR) or partial response (PR) as determined by Response Assessment in Neuro-Oncology (RANO) Criteria for Brain Metastases (RANO-BM).

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.

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.

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.

Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).

Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).

Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).

Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).

Goal: identifying the pediatric formulation dose (fed) leading to asciminib exposure comparable to 40 mg BID in adult patients (fasted).

The AUC from time zero to the last measurable concentration sampling time (tlast) (ng\*h/mL)

The AUC from time zero to infinity (ng\*h/mL)

The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (ng/mL)

The total body clearance of drug from the plasma (L/h)

To define the maximum tolerated dose (MTD) of ABL001 for participants with BCR-ABL positive (BCR-ABL+) B-cell acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) in lymphoid blast crisis.

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

To evaluate the pharmacokinetics of a single oral dose of ABL001 in subjects with various degrees of impaired hepatic function (by Child-Pugh classification) relative to healthy subjects

Determine the MTD and/or RDE of ABL001 as single agent in CML and Ph+ ALL, and in combination with either nilotinib or imatinib or dasatinib in CML patients