Evaluation of Asciminib in Combination with ATP-Competing BCR-ABL1 Inhibitors for Achieving Deep Molecular Response in Newly Diagnosed Chronic Myeloid Leukemia

Trial ID: 2024-516212-24-00
Protocol: FASCINATION
Sponsor: Friedrich-Schiller-Universitaet Jena

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Diseases & Conditions

Chronic myeloid leukaemia

Objectives

The primary objective of this study is to evaluate the **achievement of deep molecular response (MR4)** in patients with newly diagnosed **Chronic Myeloid Leukemia (CML)** in the chronic phase. This is achieved through the combination of ATP-competing BCR-ABL1 inhibitors with **asciminib**. The deep molecular response is a critical endpoint in CML treatment, as it indicates a significant reduction in disease burden and is associated with improved long-term outcomes. The study aims to determine the efficacy of this combination therapy in achieving MR4, which is a key marker of treatment success in CML management.

Participants

The clinical trial focuses on patients diagnosed with **Chronic Myeloid Leukemia** (CML), specifically those with cytogenetic confirmation of the Philadelphia chromosome (Ph+). The study population includes both male and female participants aged 18 years and older, with no upper age limit specified. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not specify the total number of participants, as the sponsor has not provided this information. The selection criteria include normal serum levels of potassium, magnesium, and total calcium, with allowances for correction through supplements. Additionally, participants must have serum lipase, AST, ALT, alkaline phosphatase, total bilirubin, and serum creatinine levels within specified limits, with certain exceptions for conditions related to leukemia or known Gilbert disease. The trial population is selected based on these health parameters, and the study does not impose specific lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **asciminib** in combination with ATP competing BCR-ABL1 inhibitors for the treatment of **Chronic Myeloid Leukemia** (CML) in the chronic phase. This is a Phase 4, randomized, double-blind, controlled trial with an estimated duration from July 23, 2019, to January 30, 2027. The primary objective is to achieve a deep molecular response (MR4) in newly diagnosed CML patients. The primary endpoint is the rate of MR4 at month 12. Participants will be administered a maximum daily dose of 80 mg of asciminib orally, with a maximum treatment period of 21 days per cycle.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility is confirmed based on criteria such as cytogenetic confirmation of the Ph+ chromosome, serum lipase levels, and ECOG performance status. Following the screening, participants will undergo regular follow-up visits to monitor their response to the treatment and any adverse effects. The end-of-study visit will assess the overall treatment efficacy and safety. The expected length of participant involvement is approximately 7.5 years, from recruitment to the end of the study.

Participants may be terminated early from the study if they experience significant adverse effects, fail to comply with the study protocol, or withdraw consent. The trial is not classified as low intervention, and it is categorized as a therapeutic confirmatory clinical trial. The study aims to provide valuable insights into the treatment of CML, contributing to the optimization of therapeutic strategies for this condition.

Treatment

The clinical trial involves the use of **Asciminib**, an experimental medication, as part of a treatment regimen for patients with chronic phase chronic myeloid leukemia (CML). **Asciminib** is classified under the ATC code L01EA06 and is administered in an oral pharmaceutical form, designated as PHF00082MIG. The maximum daily dose of **Asciminib** is 80 mg, with the same amount being the maximum total dose allowed per day. The treatment period for **Asciminib** is set at a maximum of 21 days. The medication is not formulated specifically for pediatric use and is categorized as a chemical medicinal product. The primary objective of the trial is to achieve a deep molecular response (MR4) in newly diagnosed CML patients through the combination of ATP-competing BCR-ABL1 inhibitors with **Asciminib**.

Efficacy

Efficacy in the clinical trial titled "Frontline Asciminib combination in chronic phase CML" will be assessed primarily through the achievement of a deep molecular response, specifically **MR4**, in patients with newly diagnosed chronic phase chronic myeloid leukemia (CML). The primary endpoint for evaluating efficacy is the rate of MR4 at month 12. This endpoint will be measured using appropriate molecular diagnostic techniques to assess the level of BCR-ABL1 transcripts in patients. The trial aims to determine the effectiveness of combining ATP-competing BCR-ABL1 inhibitors with asciminib in achieving this molecular response. Data collection and analysis will be conducted at specified intervals, with the primary focus on the 12-month mark to evaluate the rate of MR4. The trial is designed as a phase 4 therapeutic confirmatory clinical trial, ensuring rigorous assessment of the treatment's efficacy in the target population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients with diagnosis of CP‐CML with cytogenetic confirmation of the Ph+ chromosome [t(9;22)(q34;q11)]
Ph‐negative cases or patients with variant translocations who are BCR‐ABL1 positive in multiplex PCR will be also considered eligible
ECOG performance status of ≤2
Age ≥ 18 years old (no upper age limit is given)
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
Serum lipase ≤1.5 x ULN
Written informed consent prior to any study procedures being performed

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Exclusion Criteria

Allogeneic stem cell transplantation
Known impaired cardiac function, including any of the following: o Congenital long QT syndrome o History of or presence of clinically significant ventricular or atrial tachyarrhythmia o QTc >450 ms on screening ECG o Myocardial infarction within 12 months prior to starting therapy o History of clinically significant/ symptomatic bradycardia o Family history of idiopathic sudden death
Patients with resting QTcF ≥450 msec (male) or ≥460 msec (female) at pretreatment, or inability to determine the QTcF interval
Patients with uncorrected hypokalemia or hypomagnesemia
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)
History of acute or chronic pancreatitis
Concomitant medications known to be strong inducers or inhibitors of the CYP450 isoenzyme CYP3A4
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)
Known serious hypersensitivity reactions to asciminib, imatinib, nilotinib or dasatinib
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