Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies (FLORENCE)

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies: a Randomized, Double Blind, Phase III Study Versus Allopurinol

The purpose of this study is to determine whether febuxostat is superior to allopurinol in the prevention of tumor lysis syndrome (TLS) in patients with hematological malignancies at intermediate or high risk of TLS (according to Cairo-Bishop classification) who undergo chemotherapy

This study is designed as a randomised, double-blind, active-controlled, parallel-group study to be conducted in approximately 80 sites. Approximately 340 male or female patients aged 18 or older suffering from hematologic malignancies (de novo patients or relapsing patients) at intermediate to high risk of TLS and scheduled for receiving the first cycle of cytotoxic chemotherapy, regardless of the line of treatment, will be randomized in this study. Eligible patients (as per screening visit) will be randomly allocated in a 1:1 ratio to Febuxostat or Allopurinol. The double-blind treatment period starts two days prior to the planned beginning of chemotherapy and continues for 7 to 9 consecutive days, according to Investigator judgment and on the basis of the actual duration of chemotherapy regimen administered to the patient. Along the study treatment, uric acid levels, creatinine levels, Laboratory TLS/Clinical TLS and Adverse Events represent the major clinical findings to be monitored on a daily basis. Overall the study encompasses 10 to 11 planned visits at site, including screening, randomisation, on treatment and final follow up visits.

Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)

Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)

Assessment of treatment responder rate, where treatment response is defined as the maintenance of sUA ≤ 7.5 mg/dL from Day 3 to Day 8

Assessment of LTLS, from Day 3 to Day 8. According to Cairo-Bishop definition LTLS is defined by the presence of 2 or more laboratory abnormalities including: a 25% increase or levels above normal for serum uric acid, potassium, and phosphate or a 25% decrease or levels below normal for calcium.

Assessment of CTLS, from Day 3 to Day 8. According to Cairo-Bishop definition, CTLS is defined by the presence of LTLS in addition to 1 or more of the following significant clinical complications: renal insufficiency, cardiac arrhythmias, sudden death and seizures. The grade of CTLS is defined by the maximal grade of the clinical manifestation

Inclusion Criteria: Patients scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment, because of hematologic malignancies at intermediate or high risk of TLS (according to the TLS risk stratification, Cairo M et al, British Journal of Haematology, 2010)candidate to Allopurinol treatment or have no access to Rasburicase Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 Life expectancy > 1 month Exclusion Criteria: Patients known to be hypersensitive to Febuxostat or Allopurinol or to any of the components of the formulations Patients with sUA levels ≥ 10 mg/dL at randomization Patients receiving Febuxostat, Allopurinol or any other urate lowering therapy (e.g. Rasburicase, probenecid) within 30 days prior to randomization Patients with severe renal and/or hepatic insufficiency Patients with diagnosis of LTLS or CTLS at randomization

Spina M, Nagy Z, Ribera JM, Federico M, Aurer I, Jordan K, Borsaru G, Pristupa AS, Bosi A, Grosicki S, Glushko NL, Ristic D, Jakucs J, Montesinos P, Mayer J, Rego EM, Baldini S, Scartoni S, Capriati A, Maggi CA, Simonelli C; FLORENCE Study Group. FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk. Ann Oncol. 2015 Oct;26(10):2155-61. doi: 10.1093/annonc/mdv317. Epub 2015 Jul 27.