A Phase I Trial of Dose Escalation of Metformin in Combination With Vincristine, Irinotecan, and Temozolomide in Children With Relapsed or Refractory Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 14
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Metformin in Combination with VIT
Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT).
干预措施: Vincristine (Drug)
Metformin in Combination with VIT
Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT).
干预措施: Irinotecan (Drug)
Metformin in Combination with VIT
Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT).
干预措施: Temozolomide (Drug)
Metformin in Combination with VIT
Participants will receive metformin in combination with vincristine, irinotecan and temozolomide (VIT).
干预措施: Metformin (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: Average of 3 Months
To determine the maximum tolerated dose (MTD) of metformin when given in conjunction with VIT in children with refractory and relapsed solid tumors.
次要结局
- Number of Participants with Antitumor Activity(Average of 3 Months)
- Pharmacokinetics(Average of 3 Months)
- Pharmacodynamics(Average of 3 Months)
- Metformin Concentrations(Average of 3 Months)