metformin in children with relapsed or refractory solid tumors

Conditions: Solid Tumors; Primary Brain Tumors

Summary: the purpose of this study is to evaluate the tolerability and safety of escalating doses of metformin on a backbone of vincristine, irinotecan and temozolomide (vit) in children with recurrent and refractory solid tumors.

metformin is an oral anti-diabetes medication that activates amp-activated protein kinase (ampk). recent data from in vitro and in vivo experiments, as well as epidemiologic retrospective analyses, suggest that metformin has anti-cancer activity. vincristine, irinotecan, and temozolomide (vit) is a combination of chemotherapeutic agents that have different mechanisms of action as well as disparate side effect profiles. two recent phase 1 trials have demonstrated that this regimen is safe and well-tolerated in children with relapsed and refractory solid tumors.

Eligibility criteria:
inclusion criteria: * age: patients must be \> 1 year of age and ≤ 18 years of age at time of initiation of protocol therapy. * diagnosis: patients have a histologically or radiographically confirmed relapsed or refractory solid tumor or primary central nervous system (cns) malignancy. * disease status: patients must have radiographically measurable disease. * therapeutic options: patients must have relapsed or refractory cancers for which there is no known curative option or other available therapy proven to prolong survival with an acceptable quality of life. * performance level: karnofsky ≥ 50% for patients older than 16 years old, and lansky ≥ 50 for patients 1-16 years old. * prior therapy: patients may have received prior therapy including vincristine, irinotecan, or temozolomide. patients may not have previously been treated with combination therapy of irinotecan and temozolomide. * patients must be fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. * myelosuppressive chemotherapy: patients must not have received myelosuppressive chemotherapy within 3 weeks of starting protocol therapy, or a minimum of six weeks must have elapsed since prior nitrosurea chemotherapy. * hematopoietic growth factor: at least 7 days must have elapsed since the last administration of filgrastim, or 14 days since administration of pegfilgrastim. * biologic (anti-neoplastic agent): at least 7 must have elapsed since the last administration of any biologic agent. * radiation therapy (xrt): at least 14 days since the last dose of local palliative radiation therapy. greater than 6 months must have elapsed since the last day of treatment if given total body irradiation, craniospinal irradiation. * autologous or allogenic stem cell transplant: complete resolution of graft versus host disease and no current need for immunosuppressive medication. greater than 3 months must have elapsed since engraftment and no longer requiring transfusion of platelets or injection of colony stimulating factors. * organ function requirements * bone marrow function: peripheral absolute neutrophil count (anc) ≥ 1000/μl; platelet count ≥ 100,000/μl (no platelet transfusion within 7 days prior to obtaining laboratory result); hemoglobin ≥ 8.0 gm/dl * adequate renal function: creatinine clearance or glomerular filtration rate ≥ 70ml/min/1.73m\^2 * adequate liver function: total bilirubin ≤ 1.5x upper limit of normal (uln) for age; alanine transaminase (alt) ≤ 5x uln; serum albumin ≥ 2gm/dl * informed consent: all patients ≥ 18 years of age must sign a written informed consent. for patients \< 18 years old, the patient's parents or legal guardians must sign a written informed consent, unless the patient is an emancipated minor. childhood assent, when age appropriate as per institutional guidelines, should be signed by the participating patient. exclusion criteria: * significant organ dysfunction, not meeting inclusion criteria. * pregnancy or breast-feeding woman will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. * concomitant medications: * growth factor: growth factors that support platelet or white cell number of function must not have been administered within the past 7 days. * steroids: patients with cns tumors who have not been on a stable or decreasing dose of dexamethasone for the past 7 days. * investigational drugs: patients who are currently receiving another investigational drug. * anti-cancer agents: patients who are currently receiving other anti-cancer agents. * medication allergy: allergy or intolerance to agents on this protocol: vincristine, irinotecan, temozolomide, or metformin; allergy to cephalosporins. * infection: patients who have uncontrolled infection, positive blood cultures within the past 48 hours, or receiving treatment for clostridium difficile infection.

Keywords: central nervous system (cns) malignancy relapsed refractory pediatric recurrent