Panobinostat in Combination With Idarubicin and Cytarabine in Patients Aged 65 Years or Older With Newly Diagnosed Acute Myeloblastic Leukaemia (AML) (PANOBIDARA)

Inclusion Criteria:

• The patient should, in the investigator's opinion, be able to meet all clinical trial requirements.
• The patient should have voluntarily give the informed consent before performing any study test that is not part of the regular care of the patients.
• Age > 65 years.
• The patient should be diagnosed with AML according to the standard criteria of the World Health Organisation (WHO) (see Appendix 8).
• The patient should not have received any prior treatment for AML.
• The patient should have a performance status measured by the ECOG scale <= 2 .

• The patient should have the following laboratory values prior to the start of the treatment:

  • Aspartate transaminase (AST): ≤ 2.5 x the upper normal ranges.
  • Alanine transaminase (ALT): ≤ 2.5 x the upper normal ranges.
  • Total bilirubin: ≤ 1.5 x the upper normal ranges.
  • Alkaline phosphatase: ≤ 2.5 x the upper normal ranges.
  • Serum creatinine ≤ 2 mg/dl.
  • Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution. Note: Electrolytes (supplemental therapy) should be given to correct values that are <LLN. Post-correction values must not be deemed to be a clinically significant abnormality prior to patients being dosed.
• Left ventricular ejection fraction measured by echocardiography ≥ 50%

Exclusion Criteria:

• Patients previously receiving treatment with histone deacetylase inhibitors (HDACi).
• Patient will need valproic acid for any medical condition during the study or within 5 days prior to the first panobinostat dose.
• Promyelocytic AML (M3).
• Secondary AML or previous history of MDS.
• Male patients whose sexual partners are women of a fertile age and do not use contraceptive.
• Known brain or leptomeningeal involvement.
• Presence of any limitation affecting the ability of the patient to comply with the treatment.
• Patients receiving any investigational agent in the 30 days prior to inclusion.
• Patient carrier of human immunodeficiency virus (HIV), hepatitis B virus surface antigen or active infection by hepatitis C virus.

• Presence of heart disorders or clinically significant heart diseases, including any of the following:

  • Congenital QT prolongation "long QT syndrome").
  • History or presence of sustained ventricular tachyarrhythmia (patients with a history of atrial arrhythmia are acceptable, but this must be discussed with the sponsor prior to inclusion).
  • Any history of ventricular fibrillation or "torsade de pointes".
  • Bradycardia defined as HR < 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm.
  • Screening ECG with QTc > 450 msec.
  • Right bundle branch block + left anterior hemiblock (bifascicular block).
  • Patients with acute myocardial infarction or unstable angina ≤ 6 months before the start of the investigational drug.
  • Any clinically significant heart disease (e.g., NYHA grades III or IV, or baseline LVEF <45%, uncontrolled hypertension, or history of poor compliance of antihypertensive treatment).
• Gastrointestinal disease making panobinostat absorption significantly difficult.
• Diarrhea > grade 1 according to CTCAE criteria, version 3.0.
• Any serious or uncontrolled medical condition (e.g., uncontrolled diabetes, or active or uncontrolled infection), including laboratory disorders that could involve unacceptable risks or affect protocol compliance.
• Concomitant administration of drugs with a relative risk of increasing the QT interval or inducing "torsade de pointes" if this treatment cannot be discontinued or replaced by another prior to the start of the test drug.
• Patient has active bleeding diathesis or is currently being treated with therapeutic doses of sodium warfarin (Coumadin®) or other vitamin K active agents Note: mini-dose of Coumadin® (e.g., 1 mg/day) or anti-coagulants given to maintain intravenous line patency, as well as unfractionated or low molecular weight heparin therapy is permitted
• Patients undergoing major surgery in the four weeks prior to the start of the study treatment or not recovering from the treatment adverse events.
• Patients with a history of malignancies in the past five years. Basal cell carcinoma, skin epithelioma and carcinoma of the cervix in situ are excluded.