Investigating the role of targeted therapy Sorafenib - the Fms-like tyrosine kinase 3 (FLT3) inhibitor, in combination with intensive chemotherapy, for previously untreated adult patients with Acute Myeloid Leukaemia (AML) with FLT3 mutations. A Phase II randomised placebo-controlled multi-centre study

The study will screen newly diagnosed AML patients aged 15-65 for the presence of the FLT3-ITD mutation. Based on power calculations, 99 patients with FLT3-ITD will be randomized 2:1 to receive Sorafenib or placebo on days 4-10 of induction (1-2 x 28 day cycles), days 4-10 of consolidation (2 x 28 day cycles) and then for 12 months as maintenance therapy. Patients with suspected AML (WHO 2008 classification) will be consented for standard preliminary study procedures, including centralized cytogenetics review, molecular testing, tissue banking and the commencement of standard induction chemotherapy. Patients with acute promyelocytic leukaemia (APML) will be excluded. All patients will receive the following INDUCTION chemotherapy regimens: Age 15-55 (HiDAC-3) CYTARABNE 3 g/m2 IV over 2-4 hours twice daily (bd) days 1,3,5,7. Patients with a serum creatinine greater than ULN prior to therapy should receive cytarabine at 1 g/m2 IV over 2-4 hours bd days 1,3,5,7. IDARUBICIN 12 mg/m2 IV days 1-3 Age 56-65 (7+3) CYTARABINE 100mg/m2 IV continuous infusion on days 1-7 IDARUBICIN 12 mg/m2 IV days 1-3 FLT3-ITD identification Patients will be assessed for molecular eligibility prior to commencement of Sorafenib via a network of molecular centres located throughout Australia and New Zealand. These centres will undergo a regular quality assessment program conducted in association with the Australian Leukaemia and Lymphoma Group (ALLG) laboratory sciences committee. On day 4 of induction chemotherapy, patients with FLT3-ITD positive AML (allelic mutant: wild-type ratio = 0.05), will be randomized 2:1 by the ALLG biostatistical and coordinating centre (BaCT) to commence taking the FLT3 inhibitor Sorafenib or placebo. Sorafenib administration Patients allocated Sorafenib will be given 400 mg twice daily (bd) orally from day 4 to day 10, inclusive (14 doses), after starting induction chemotherapy. If the first dose of Sorafenib is given late in the afternoon on day 4, the final dose may be given on the morning of day 11. A bone marrow assessment will occur on day 28 to assess response. Those achieving CR/CRi/CRp will receive CONSOLIDATION chemotherapy. Age 15-55 (IcE) IDARUBICIN 9 mg/m2 IV days 1,2 CYTARABINE 100 mg/m2 days 1-5 IVI ETOPOSIDE 75 mg/m2 IV days 1-5 Age 56-65 (HiDAC-2) CYTARABINE 1000 mg/m2 IV over 2-4 hours bd days 1,3,5 IDARUBICIN 12 mg/m2 IV days 1,2 Those randomized to Sorafenib during induction will receive for consolidation: Sorafenib 400 mg bd from day 4 to day 10, inclusive (14 doses) Maintenance therapy Patients with FLT3-ITD positive AML who received Sorafenib during induction and consolidation will also receive Sorafenib as maintenance therapy, commencing day 42 after day 1 of the last round of consolidation chemotherapy, or up to day 60 if recovery of neutrophils to 1.0 x 109/L and platelets to 75 x 109/L is delayed. Sorafenib will be given at a dose of 400 mg bd for a total maintenance period of 12 months. Patients allocated to receive placebo will continue to do so in a double-blinded manner. The tablet cores contain Sorafenib tosylate (BAY 54-9085) and the excipients croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulphate and magnesium stearate. The film-coat consists of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and red iron oxide. The tablets have a red colour in appearance, a weight of 350mg, and a 10mm round shape.