CompletedPhase 2ACTRN12611001112954

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

Sorafenib in combination with intensive chemotherapy for previously untreated adult FLT3-Internal Tandem Duplication (FLT3-ITD) - positive AML: A Phase II randomised placebo-controlled multi-centre study evaluating two year progression-free survival

Sponsor

Leukaemia Foundation of Australia

Enrollment

102 participants

Start Date

Jan 25, 2013

Study Type

Interventional

Conditions

Previously untreated adult acute myeloid leukaemia (AML) with FLT3-ITD mutation.

Summary

This study aims to determine the safety and efficacy of treatment with the drug Sorafenib, in combination with intensive chemotherapy for adults with previously untreated acute myeloid leukaemia (AML). Who is it for? You may be eligible to join this study if you are aged between 15-65 years and have been diagnosed with AML with FLT3-ITD mutation. You must have received no previous treatment for AML. Trial details All participants in this trial will undergo intensive chemotherapy over a period of minimum twelve months. Participants will be randomly (by chance) allocated to one of two groups. One group will receive the oral drug Sorafenib whilst undergoing chemotherapy and for a period of 12 months afterwards. The other group will receive a placebo (inactive) treatment in conjunction with chemotherapy. Participants will not know which group they are in until completion of the trial. Participants will be assessed at regular timepoints for a period of up to 5 years to determine the safety and clinical benefit of Sorafenib treatment in combination with chemotherapy. Treatment Duration will be a minimum of 1 year. This Phase II study will: Investigate the clinical benefit of frontline Sorafenib in combination with chemotherapy and during maintenance therapy in adult AML Optimise the dosing schedule of Sorafenib based on the kinetics of circulating FLT3 ligand levels after chemotherapy Investigate the clinical benefit of Sorafenib in relation to additional molecular AML lesions Identify pharmacokinetic and pharmacodynamic correlates of response predictive of treatment outcome.

Eligibility

Sex: Both males and femalesMin Age: 15 YearssMax Age: 65 Yearss

Inclusion Criteria11

A morphological diagnosis of AML by WHO 2008 criteria, confirmed by special stains, immunophenotyping and, if available, cytogenetics. All clinico-pathological subtypes will be eligible, except for AML with t(15;17) or variants.
Patients with secondary and therapy related AML are eligible
FLT3-ITD mutation with an allelic mutant:wild-type ratio of = 0.05
Age 15 to 65 years inclusive.
ECOG performance status 0 to 2 inclusive
Absence of serious cardiac, pulmonary, hepatic or renal disease. A serum creatinine <1.5 times the upper limit of normal (ULN) and serum bilirubin < 2.5 times the upper limit of normal, is required for eligibility
Normal left ventricular ejection fraction, according to institutional criteria.
No previous treatment for AML or history of cancer (other than basal cell skin cancer or carcinoma of the cervix in situ, or other localised cancer treated by surgical excision only more than 5 years earlier without evidence of recurrence in the intervening period)
No contraindication to the use of the study drugs
Treatment must be given at an affiliated ALLG centre, with approval of the protocol by the institution’s Human Research Ethics Committee, or equivalent body
Written informed consent must be obtained from each patient prior to registration and start of treatment

Exclusion Criteria9

Clinically active CNS leukaemia
Prior chemotherapy for AML (other than hydroxyurea ceased at least 24 hrs prior)
Known HIV positive
Known active hepatitis B or C, or any other active liver disease
Patients with parenchymal abnormality on screening chest x-ray must have no evidence of pulmonary infection on chest tomography (CT) prior to starting remission induction therapy
Any major surgery or radiation therapy within 4 weeks prior to study entry
Serious concomitant illnesses (for example, pulmonary infiltrate, unstable angina or myocardial infarction or stroke within 3 months prior to study entry, congestive heart failure AHA class 2 or greater, uncontrolled hypertension, uncontrolled diabetes, actively bleeding gastric ulcer, etc.), which in the investigator’s opinion would not make the patient a good candidate for the trial
Pregnant or breastfeeding
Any other known condition (e.g., familial, sociological, or geographical) or behaviour (including substance dependence or abuse, psychological or psychiatric illness), which in the investigator’s opinion would make the patient a poor candidate for the trial.

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Interventions

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.