Phase II Study of Asciminib in Chronic‑Phase CML Patients Harboring BCR‑ABL1 T315I Mutation: Molecular Response (MR2) at 12 Months

Trial ID: 2025-523491-23-00
Protocol: ESTIMATION
Sponsor: Friedrich-Schiller-Universitaet Jena

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Diseases & Conditions

Chronic myeloid leukaemia

Objectives

The primary objective is to achieve a reduction of molecular Chronic Myeloid Leukemia BCR::ABL1 levels to MR2, as measured by quantitative PCR at month 12, reflecting a clinically meaningful depth of molecular response in patients harboring the T315I mutation.

Reduction of the size of the T315I‑positive BCR::ABL1 clone.
Rate of MR2 achievement at 12 months stratified by genetic background.
Proportion of patients attaining molecular responses (MR2, MMR, MR4, MR4.5) at 6, 12, 18, and 24 months.
Safety assessment through the collection of adverse events.
Evaluation of progression‑free survival, CML‑related mortality, and overall survival.
Assessment of quality of life using EORTC‑standardized questionnaires.

Participants

The sponsor did not provide the total number of participants. The trial enrolled adult patients of both sexes with Chronic Myeloid Leukemia in the first or second chronic phase following allogeneic stem cell transplantation, confirmed to be BCR::ABL1 positive and to harbor a T315I mutation. Eligibility required age ≥ 18 years (no upper age limit), an ECOG performance status of ≤2, and laboratory values within specified normal ranges, including electrolytes, liver enzymes, bilirubin, and creatinine, with permitted correction of electrolyte abnormalities. Participants were required to provide written informed consent prior to any study procedures. The population comprised patients classified as vulnerable, with no additional lifestyle restrictions such as specific diet or physical‑activity requirements reported in the source data.

Plans and Procedures

The study is a phase 4, therapeutic confirmatory trial evaluating oral asciminib 400 mg once daily in adult patients with Chronic Myeloid Leukemia in first or second chronic phase who harbor a documented T315I mutation. After obtaining written informed consent, eligible participants undergo a screening visit to confirm mutation status, laboratory eligibility criteria, and performance status (ECOG ≤ 2). Baseline assessments are performed on the same day as treatment initiation, followed by scheduled follow‑up visits at months 3, 6, 9, 12, 18, and 24 for molecular monitoring (BCR::ABL1 PCR and NGS), safety labs, and quality‑of‑life questionnaires. The primary endpoint, the proportion of patients achieving MR2 at month 12, is assessed at the 12‑month visit, with additional secondary endpoints evaluated through month 24. The overall participant involvement spans approximately 24 months of treatment plus a final end‑of‑study visit for study closure. Early termination may occur if a participant experiences a treatment‑related serious adverse event, withdraws consent, fails to meet continued eligibility, or demonstrates disease progression requiring alternative therapy.

Treatment

The investigational product is Asciminib, supplied as a film‑coated tablet containing asciminib hydrochloride. The prescribed dose is 400 mg administered orally once daily throughout the treatment period.

No additional experimental agents are included in the protocol. Participants receive standard supportive care as required, but no specific comparator drug or placebo is administered.

Study medication is provided in blister packs and taken at the same time each day. Dosing records are maintained in the electronic case report form, and pill counts are performed at each study visit to assess compliance. Any missed doses are documented and reported according to protocol‑specified procedures.

Efficacy

Efficacy will be evaluated using molecular and clinical endpoints. The primary endpoint is the rate of MR2 at 12 months, defined by BCR::ABL1 transcript levels measured by quantitative PCR. Secondary endpoints include reduction of the T315I‑positive clone size assessed by next‑generation sequencing, the rate of molecular response at 6, 18, and 24 months based on BCR‑ABL1 monitoring, progression‑free survival, CML‑related mortality, overall survival at study completion, and quality‑of‑life assessments.

Quantitative PCR for BCR::ABL1 will be performed at baseline and at month 12 to determine MR2 status. Next‑generation sequencing will be used to quantify the T315I clone at predefined timepoints. Molecular response monitoring will occur at months 6, 18, and 24. Survival outcomes will be tracked throughout the study period until the end of the trial. Quality of life will be measured using a validated patient‑reported outcome instrument at enrolment and at months 3, 6, 9, 12, 18, and 24. All data will be collected according to the study schedule, entered into the trial database, and analyzed using appropriate statistical methods for proportion estimates, time‑to‑event analyses, and longitudinal quality‑of‑life scores.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients with BCR::ABL1 positive CML in first or second chronic phase (i.e. after allogeneic stem cell transplantation) and proven T315I mutation detected by Sanger sequencing or NGS.
Age ≥ 18 years old (no upper age limit is given)
ECOG performance status of ≤2.
Serum levels of potassium, magnesium, total calcium within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]). Correction of electrolytes levels with supplements to fulfil enrolment criteria is allowed.
AST and ALT ≤2.5 x ULN or 5.0 x ULN if considered due to leukemia
Alkaline phosphatase ≤2.5 x ULN unless considered due to leukemia
Total bilirubin ≤1.5 x ULN, except known Gilbert disease
Serum creatinine ≤2 x ULN
Written informed consent prior to any study procedures being performed

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Exclusion Criteria

Pre-treatment with asciminib
Patients who have undergone major surgery ≤2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Patients who are pregnant or breastfeeding or women of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study start. Post-menopausal women must be amenorrheic for at least 12 months in order to be considered of non-childbearing potential.
Male and female patients must agree to employ an effective method of birth control throughout the study and for up to 2 weeks following discontinuation of study drug. (It is required that sexually active men use condom during intercourse while taking the drug and for 2 weeks after stopping treatment and not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Female partners of male patients must be advised to use highly effective methods of contraception.)
Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
Active autoimmune disorder, including autoimmune hepatitis
Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention
Patients unwilling or unable to comply with the protocol.
BCR::ABL1 variants lacking ABL1 exon a2
Known impaired cardiac function, including any of the following: (1)Congenital long QT syndrome; (2)History of or presence of clinically significant ventricular or atrial tachyarrhythmia; (3)QTc >450 msec on screening ECG; (4)Myocardial infarction within 12 months prior to starting therapy
Other clinically significant heart disease (e.g., unstable angina, congestive heart failure)
Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled
Other concurrent uncontrolled medical conditions (e.g., active or uncontrolled infections, acute or chronic liver and renal disease) that could cause unacceptable safety risks or compromise compliance with the protocol
Impaired gastrointestinal function or disease that may alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea, malabsorption syndrome, small bowel resection or gastric by-pass surgery)
Known chronic pancreatitis
Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4
hypersensitivity to the active ingredient asciminib or to any of the other ingredients listed according to the latest version of the SmPC