Ponatinib in CML Patients in Chronic Phase

Study Overview
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Brief Summary
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The goal of this retrospective observational study is to evaluate any possible association between plasma concentrations of ponatinib and its pharmacodynamics (efficacy/tolerability) in patients affected by chronic myeloid leukemia in chronic phase (CML-CP). In particular, the aims of the study will be: primary aim: to investigate the relationships (if any) between plasma concentrations and activity/toxicity of ponatinib in a population of CML-CP patients enrolled in several Italian hematological centers; secondary aim: to set up an algorithm aimed at helping physicians to improve drug dosing based on several variables (i.e., plasma drug concentrations, tolerability, molecular response to therapy). The study will enroll CML-CP patients who were exposed to ponatinib as second, third or fourth line of chemotherapy.

Detailed Description
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The study protocol is a non-interventional, retrospective observational study which involves the collection of data from medical records relating to the plasma dosages of ponatinib performed as per clinical practice, all carried out at the pharmacokinetics laboratory of the U.O. Clinical Pharmacology and Pharmacogenetics of AOUP. These data will be collected in CRF and will be correlated to efficacy data (extent of molecular response) and toxicity of ponatinib (haematological, extra-haematological adverse events, together with adverse event severity). Real-life experience (dosage adjustments made by clinicians based on plasma dosage) will be used to propose an algorithm that can help in choosing the correct dosage of ponatinib. Classical statistical analyses (for descriptive and comparison aims) will be used according to their appropriateness. Moreover, factors affecting the pharmacokinetics of ponatinib will be investigated by nonlinear mixed effect modeling adopting the MONOLIX 2021R2 suite. Final model will be used as parte of the dosing algorithm. Notably, all clinical and laboratory data will be anonymized to protect patients' privacy, and harvested in a database that will be used to perform pharmacometric and statistical analyses.

Official Title
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Ponatinib in cHronic myelOid LEukemia patieNts In Chronic phaSe: the PHOENICS Protocol

Conditions
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Chronic Myeloid Leukemia, Chronic Phase

Intervention / Treatment
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* Diagnostic Test: Therapeutic drug monitoring
* Diagnostic Test: Molecular Response


Participation Criteria
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Eligibility Criteria
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Patients will be enrolled according the following inclusion criteria: Subjects ≥18 years old affected by CML Patients being treated with ponatinib at a dose of 45, 30 or 15 mg/day for more than 14 days Patients who have provided informed consent to the study Exclusion criteria: Subjects <18 years old Patients who did not provide an informed consent to the study The co-administration of drugs other than ponatinib will not be considered an exclusion criterium, but all of the drugs will be registered (together with daily doses and duration of treatment) as possible factors of ponatinib PK variability.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: Therapeutic drug monitoring|At each follow up visit, plasma concentrations of ponatinib will be measured and compared with therapeutic range (according to a lower concentration equal to 21 nM)|
|Diagnostic Test: Molecular Response|BCR-ABl transcript levels will be assessed to evaluate molecular response to ponatinib|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ponatinib plasma concentrations | Plasma concentrations of ponatinib included in the therapeutic range (i.e., >21 nM) | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Molecular response | Plasma levels of BCR-ABl transcript | Up to 2 year | 
| Occurrence of adverse events/adverse drug reactions | Adverse events/Adverse drug reactions observed and registered during ponatinib administration | Up to 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic myeloid leukemia, chronic phase, Ponatinib, Therapeutic drug monitoring, Efficacy, Tolerability