Evaluation of Pioglitazone and Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myelogenous Leukemia Post-TKI Discontinuation Failure

The primary objective of this study is to assess the **safety** and pharmacokinetics of the combination of pioglitazone and tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) who experience a loss of major molecular response (MMR) following a TKI discontinuation. Additionally, for patients who are included and eligible to discontinue, the study aims to evaluate survival without loss of MMR over a 12-month period following a subsequent TKI discontinuation. This is clinically relevant as it addresses the challenge of maintaining MMR in CML patients after TKI therapy cessation, potentially improving long-term disease management and patient outcomes.

The clinical trial involves participants diagnosed with **chronic phase chronic myelogenous leukaemia** (CML) who have experienced a loss of major molecular response (MMR) following a tyrosine kinase inhibitor (TKI) discontinuation. The study population includes both male and female subjects, aged over 18 years, who are not considered part of a vulnerable population. Participants must have been previously treated with imatinib, dasatinib, nilotinib, or bosutinib for more than two years from the last discontinuation. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants are required to have a serum bilirubin level of less than 1.5 times the upper limit of normal values and AST (SGOT)/ALT (SGPT) levels of less than 2.5 times the upper limit of normal values. Females of childbearing potential must agree to use medically approved contraceptive measures during and for three months after the treatment period, while males must agree to similar contraceptive measures. All participants must provide signed informed consent and be able and willing to comply with study visits and procedures.

The clinical trial is designed to evaluate the **safety** and pharmacokinetics of a combination therapy involving **pioglitazone** and tyrosine kinase inhibitors (TKIs) in patients with **chronic myeloid leukemia** (CML) who have experienced a loss of major molecular response (MMR) following a TKI discontinuation. This is a Phase IV, randomized, double-blind, controlled trial. The trial aims to assess the proportion of subjects maintaining MMR over a 12-month period after discontinuation of the combination therapy. The trial is expected to run until December 2029, with recruitment having started in December 2016.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous treatment history, and laboratory values. Following the screening, participants will be randomized to receive the study medication. Regular follow-up visits will occur monthly for the first six months, quarterly for the next six months, and bi-annually thereafter, to monitor safety and efficacy through blood tests and adverse event reporting. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is approximately two years, with conditions for early termination including significant adverse events, withdrawal of consent, or failure to comply with study procedures. Participants are required to adhere to contraceptive measures during and for three months following the treatment period. The study will utilize **Actos 30 mg tablets** administered orally, with a maximum daily dose of 45 mg and a total treatment period of up to six months. The trial is conducted under the authorization of relevant regulatory bodies, ensuring compliance with ethical standards and scientific rigor.

The clinical trial involves the administration of **Actos 30 mg tablets**, which contain the active substance **pioglitazone**. Pioglitazone is a chemical compound classified under the ATC code A10BG03. The pharmaceutical form of the medication is a tablet, and it is administered orally. The maximum daily dose of pioglitazone is 45 mg, with a total maximum dose of 7200 mg over the course of the treatment. The treatment period is limited to a maximum of six months. The medication is manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH and is authorized for use in the European Union under the marketing authorization number EU/1/00/150/027.

In this study, the experimental treatment with pioglitazone is combined with **Tyrosine Kinase Inhibitors (TKIs)** in patients with Chronic Myeloid Leukemia (CML) who have experienced a loss of major molecular response (MMR) following a TKI discontinuation. The objective is to assess the safety and pharmacokinetics of this combination therapy. The study aims to evaluate survival without loss of MMR over a 12-month period following a subsequent TKI discontinuation. The trial does not involve any additional non-experimental treatments such as placebo or comparator treatments. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed by determining the proportion of subjects with **Chronic Myeloid Leukemia (CML)** who maintain Major Molecular Response (MMR) over a 12-month period following the discontinuation of Pioglitazone (PIO) and Tyrosine Kinase Inhibitors (TKIs). The primary efficacy endpoint involves the use of blood quantitative reverse transcription polymerase chain reaction (qRT-PCR) for BCR-ABL1, which will be obtained monthly for the first six months, quarterly for the following six months, and bi-annually in the second year, in accordance with the center's policy. This method allows for the precise monitoring of molecular response levels in patients, providing a robust measure of the treatment's efficacy in maintaining MMR after the discontinuation of the therapeutic agents.