Testing SIROLIMUS in Beta-thalassemia Transfusion Dependent Patients (THALA-RAP) (THALA-RAP)

Inclusion Criteria:

• Patients over 18 years of age;
• Patients able to understand the informed consent and to sign it before any study procedure;
• Patients with β0/β0 and β+/β0 thalassaemia genotype;
• Documented diagnosis of major or intermediate thalassemia transfusion-dependent (number of transfusions not less than 8 over the past 12 months before selection);
• On regular transfusion since at least 6 years;
• Splenectomy performed at least 60 days before selection or spleen largest dimensions < 20 cm as detected by abdominal echography;
• Female participants who are surgically sterilised/hysterectomised or post-menopausal for longer than 2 years or female participants of childbearing potential using and/or willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or using any other method considered sufficiently reliable by the investigator in individual cases. Patients must be counselled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of sirolimus;
• Patient willing to follow all the study requirements and perform all the study visits and to cooperate with the investigator;
• Patient followed by the same clinical site since at least 6 months.

Note that patients will be treated with oral sirolimus only in the case their Erythroid Precursor Cells (ErPCs) are responsive to the in vitro treatment with sirolimus according to laboratory-specific definition (≥ 20% increase of HbF in comparison with samples not treated with sirolimus);

Exclusion Criteria:

• Patient treated with hydroxyurea at selection visit or in the last 6 months;
• Ongoing treatment with drugs possibly affecting sirolimus actions;
• Documented aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x Upper Limit of Normal (ULN) at selection;
• Documented Platelet count <150.000/microliter and >1.000.000/microliter at selection;
• Heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher;
• Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg;
• Significant arrhythmia requiring treatment,
• Corrected QT interval> 450 msec on selection ECG;
• Ejection fraction <50% by echocardiogram, multiple gated acquisition scan or cardiac magnetic resonance;
• Myocardial infarction within 6 months prior to selection;
• Positivity for human immunodeficiency virus (HIV) antibody, active hepatitis B (HBV) or hepatitis C (HCV) as demonstrated by the presence of hepatitis B surface antigen (HBsAg) and a positive HCV-RNA test, HBcAb and HBV-DNA positivity
• White blood cell [WBC] count <3000 cells per μL and/or Granulocytes <1500/mm3;
• Total cholesterol > 240 mg/dl;
• Triglycerides > 200 mg/dl;
• Proteinuria with urinary protein >1g/24 hrs;
• Current participation in another trial with an investigational drug or experimental device, or inclusion in another trial with an investigational drug or experimental device within the preceding month;
• Major surgery (including splenectomy) within 60 days before selection (patients must have fully recovered from any previous surgery);
• Iron chelation therapy changed in the last 3 months prior to selection (note that Deferiprone is not accepted as a chelation therapy drug in this study while Desferrioxamine and Deferasirox are tolerated at stable dose);
• Current treatment with macrolide antibiotics (clarithromycin);
• Pregnant or lactating women;
• History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the experimental drug;
• Treatment with live vaccines within 90 days preceding the selection;
• Subject with history or current malignancies (solid tumours and haematological malignancies) or presence of masses/tumour detected by ultrasound at selection;
• Subject with any significant medical condition and/or laboratory abnormality considered by the investigator as not adequately controlled at the time of selection.