Metformin in Children With Relapsed or Refractory Solid Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Trial of Dose Escalation of Metformin in Combination With Vincristine, Irinotecan, and Temozolomide in Children With Relapsed or Refractory Solid Tumors

Conditions
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Solid Tumors, Primary Brain Tumors

Intervention / Treatment
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* Drug: Vincristine
* Drug: Irinotecan
* Drug: Temozolomide
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin in Combination with VIT<br>Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT). | Drug: Vincristine<br>* Vincristine (VCR) = 1.5 mg/m^2/day (maximum dose 2 mg), days 1 and 8, administered as intravenous (IV) bolus over 1-5 minutes<br>* Other names: Vincristine sulfate;Drug: Irinotecan<br>* Irinotecan (IRN) = 50 mg/m^2/day, days 1-5, IV over 60 minutes<br>* Other names: IRN;Drug: Temozolomide<br>* Temozolomide (TEM) = 50 mg/m^2/day by mouth (PO) Days 1-5<br>* Other names: TEM;Drug: Metformin<br>* Metformin (MET) = dose as per dose escalation, divided twice a day (BID), PO continuously for the 21 day cycle.<br>* Other names: MET;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | To determine the maximum tolerated dose (MTD) of metformin when given in conjunction with VIT in children with refractory and relapsed solid tumors. | Average of 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Antitumor Activity | To evaluate the antitumor activity of the addition of metformin to VIT. | Average of 3 Months | 
| Pharmacokinetics | To describe the pharmacokinetics of metformin in children with relapsed malignancies receiving VIT combination chemotherapy. | Average of 3 Months | 
| Pharmacodynamics | To define the pharmacodynamics of metformin. | Average of 3 Months | 
| Metformin Concentrations | To determine tissue and tumor metformin concentrations in patients undergoing resection. | Average of 3 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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central nervous system (CNS), malignancy, relapsed, refractory, pediatric, recurrent