Evaluation of Treatment-Free Remission in Chronic Myeloid Leukemia Patients Following Second Discontinuation of Dasatinib Therapy

The primary objective of this study is the **assessment of treatment-free remission** in patients with **chronic myeloid leukemia** (CML) after a second attempt at discontinuing tyrosine kinase inhibitor (TKI) therapy. This is particularly relevant for patients who experienced a relapse in the EURO-SKI study or under similar conditions. The clinical significance lies in determining the feasibility of maintaining major molecular remission (MMR) without continuous TKI treatment, which could potentially reduce long-term medication burden and associated side effects. Patients eligible for this study must have undergone at least three years of TKI treatment, with the last two years involving dasatinib, and must have achieved MR4 for at least one year.

Secondary objectives include:

• Identification of clinical and biological factors correlating with the persistence of MMR or better after stopping TKI a second time.
• Estimation of overall progression-free survival.
• Time to re-achievement of MR4 after restarting therapy following a second molecular relapse.
• Assessment of the incidence of any adverse events, such as treatment-related musculoskeletal adverse events, that arise after stopping TKI treatment a second time.

The clinical trial involves participants diagnosed with **chronic myeloid leukemia** (CML) who are undergoing treatment with tyrosine kinase inhibitors (TKIs). The study population includes both male and female subjects aged 18 years and older. Participants are required to have been treated with TKIs for at least one year after a failed prior attempt to discontinue TKI treatment, either within the EURO-SKI study or under similar conditions. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Participants must have a confirmed typical BCR/ABL1 transcript at diagnosis or later during the disease course. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria focus on individuals who have been in molecular response 4 (MR4) for at least one year and have received at least three years of TKI treatment, with the last two years being dasatinib, to assess treatment-free remission.

The clinical trial is designed to evaluate the **treatment-free remission** in patients with **chronic myeloid leukemia** (CML) who have previously failed an initial attempt to discontinue tyrosine kinase inhibitor (TKI) therapy. This is a multicenter, prospective trial with a randomized, double-blind, controlled design. The trial is set to run from December 20, 2016, to December 31, 2026, with an estimated duration of 10 years. Participants will be involved in the study for a maximum treatment period of 36 months, during which they will receive **dasatinib** in the form of film-coated tablets, administered orally.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (18 years or older), previous TKI treatment duration, and molecular response status. Following the screening, participants will undergo regular follow-up visits to monitor their molecular response and overall health status. The primary endpoint is the proportion of patients maintaining major molecular remission (MMR) at 6 and 12 months after the second discontinuation of TKI therapy. Secondary endpoints include the number of patients who re-achieve stable MR4, overall and progression-free survival, and the occurrence of adverse events related to the second TKI stop.

The end-of-study visit will assess the long-term outcomes of the second TKI discontinuation attempt. Participants may be terminated early from the study if they experience a loss of MMR, defined as BCR-ABL1>0.1% on the International Scale at one time point, or if they encounter significant adverse events. The trial aims to provide insights into the clinical and biological factors that correlate with the persistence of MMR or better after the second TKI stop, contributing valuable data to the management of CML.

The clinical trial involves the administration of **dasatinib**, marketed under the name SPRYCEL, in two different dosages: 20 mg and 50 mg film-coated tablets. Dasatinib is a chemical substance with the active ingredient identified by the synonyms BMS354825 and N-(2-CHLORO-6-METHYLPHENYL)-2-((6-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL)-2-METHYL-4-PYRIMIDINYL)AMINO)-5-THIAZOLECARBOXAMIDE. The pharmaceutical form of the medication is a film-coated tablet, and it is administered orally. The maximum daily dose for dasatinib is 100 mg, with a total maximum dose of 109,500 mg over a treatment period of up to 36 months. The medication is produced by BRISTOL-MYERS SQUIBB PHARMA EEIG and is authorized for use in the country coded as IS.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on assessing the persistence of major molecular remission in patients with chronic myeloid leukemia after a second attempt to discontinue tyrosine kinase inhibitor (TKI) treatment. Participants must have received at least three years of TKI treatment, with the last two years involving dasatinib, and must have been in MR4 for at least one year. Compliance with the dosing schedule and administration route is monitored to ensure adherence to the trial protocol.

The efficacy of the clinical trial titled "Persistence of major molecular remission in chronic myeloid leukemia after a second stop of TKI treatment in patients who failed an initial stop attempt: a multicenter prospective trial. DASTOP2 TRIAL" will be assessed through both primary and secondary endpoints. The primary endpoint is the proportion of patients maintaining **major molecular remission (MMR)** at 6 and 12 months after discontinuing tyrosine kinase inhibitor (TKI) treatment for the second time. MMR is defined as a BCR-ABL1 level greater than 0.1% on the International Scale (IS) at one time point.

Secondary endpoints include the number of patients who re-achieved stable MR4 and were offered study participation, overall and progression-free survival, and the occurrence of a restart of TKI without prior molecular relapse. Additionally, clinical and biological factors correlating with the persistence of MMR or better after the second TKI stop will be evaluated. These factors include BCR-ABL level before the second stop, Sokal score, gender, duration and type of TKI treatment, duration of the first TKI stop, and immunological biomarkers. The time to re-achievement of MR4 after the second loss of MMR and adverse events related to the second TKI stop, along with clinical and biological factors correlated to the development of these adverse events, will also be assessed.