Metformin as Maintenance Therapy in Patients With Bone Sarcoma and High Risk of Relapse

MATERIALS & METHODS The study is divided in two groups

• Group 1-Localized osteosarcoma that have reported a post neoadjuvant chemotherapy primary tumor necrosis ≤ 60% Metformin will be administrated for 3 years maximum or until progression disease or if G3 or G4 toxicity is verified.

37 patients as total population are necessary to evaluate a 3 yrs increase of EFS from 35% ( historical data Tsuda Y ) to 60%,

• Group 2 Osteosarcoma and Ewing sarcoma patients in Complete Remission after the first relapse.Metformin will be administrated for 3 years or until progression .

The Event Free Survival of this second group will be calculated at 1 yr with the aim of an increase of EFS from 20%(historical data) to 45%

STATISTICAL ANALYSIS AND SAMPLE SIZE Sample size was calculated by the Expected Total Study Length minimization criteria to ensure a potency parameter of 80 % and point if there is a benefit in use Metformin compared to the historical control.

EFS will be estimated by Kaplan-Meier and the standard error will be used to calculate the interim analysis Z-factor as well as the final statistical analysis.

The final statistical analysis will be performed

• Group 1 after 3 years after last patient enrollment
• Group 2 at 1 year from the last patient enrollment : EFS at 1 year

OBJECTIVE

• Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control.
• Evaluate Metformin's toxicity as maintenance therapy.

Inclusion criteria

• Non metastatic osteosarcoma patients with necrosis ≤ 60 % in the end of post-operatory chemotherapy treatment (within 45 days.from the end of chemotherapy treatment).
• Osteosarcoma or Ewing sarcoma patients free from the disease after first relapse (within 45 days.from the local surgery or 45 days from the end of chemotherapy treatment).
• ≥ 14 years.
• Patient should not be participating in other clinical study.
• Patients should be able to swallow.
• Screening up to 30 days from the end of chemotherapy treatment or relapse.
• Start therapy up to 30 days from the screening.
• Normal renal function (creatinine <1,3 mg/L, clearance creatinine ≥ 70 ml/min) end liver function (total serum bilirubina <1,2 mg/dL, except Gilbert syndrome patients), AST e ALT <1,8 times the normal range value

Exclusion criteria

• Type B diabetic patient
• Metastatic patients
• Patients with acute metabolic acidosis (lactic acidosis, diabetic ketoacidosis).
• Patients with renal insufficiency (GFR < 70 ml/min).
• Patients with acute conditions that could cause kidney alterations as dehydration, severe infection and shock.
• Patients with hepatic insufficiency as acute alcohol intoxication and alcoholism.
• Patients with medical conditions that could cause tissue hypoxia: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
• Patient who does not meet the inclusion criteria
• Pregnant and breastfeeding patients, or young women at childbearing age who cannot exclude the state of pregnancy (possibly excluded by serum pregnancy test (BhCG test), in accordance with the recommendations of the CTFG.