A Phase I/II Study of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, NSC# 724772) in Children With Refractory Solid Tumors or Refractory Leukemias
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 25
- 主要终点
- Number of Patients With Treatment-related Adverse Events
研究概览
简要总结
This phase I/II trial is studying the side effects and best dose of sorafenib in treating young patients with relapsed or refractory solid tumors or leukemia. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.
详细描述
PRIMARY OBJECTIVES:
I. Determine the maximum-tolerated dose (MTD) and recommended phase II dose of sorafenib in pediatric patients with relapsed or refractory solid tumors.
II. Determine whether pediatric patients with relapsed or refractory leukemia can tolerate the MTD of sorafenib for solid tumors.
III. Determine the tolerability, active N-oxide metabolite, pharmacodynamics, and activity of sorafenib a the MTD in a subset of patients with acute myeloid leukemia (AML) and FLT3-ITD mutation.
IV. Determine the toxicities of this drug in these patients. V. Determine the pharmacokinetics of this drug in these patients.
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
- 2 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of 1 of the following:
- •Histologically confirmed malignant solid tumor at original diagnosis or relapse
- •Measurable or evaluable disease by CT scan or MRI
- •Histologically confirmed leukemia, including 1 of the following:
- •Acute lymphoblastic leukemia (ALL)
- •Greater than 25% blasts in the bone marrow (M3 bone marrow)
- •Acute myeloid leukemia (AML)
- •Greater than 25% blasts in the bone marrow (M3 bone marrow)
- •AML and FLT3-ITD mutation
- •Patients must have ? 5% blasts in the bone marrow
- •Active extramedullary disease (except leptomeningeal disease) allowed
- •Juvenile myelomonocytic leukemia (JMML) meeting the following criteria:
- •Peripheral blood monocytosis > 1,000/mm^3
- •Blasts (including promonocytes) are < 20% of the WBCs in the blood and of the nucleated bone marrow cells
- •No Philadelphia chromosome (Ph) or BCR/ABL fusion gene
- •Has ? 2 of the following additional diagnostic criteria:
- •Hemoglobin F increased for age
- •Immature granulocytes in the peripheral blood
- •WBC > 10,000/mm^3
- •Clonal chromosomal abnormality (e.g., may be monosomy 7)
- •Sargramostim (GM-CSF) hypersensitivity of myeloid progenitors in vitro
- •Chronic myelogenous leukemia (CML) in blast crisis
- •Greater than 25% blasts in the bone marrow (M3 bone marrow)
- •Patients with Ph-positive CML must be refractory to imatinib mesylate
- •Relapsed or refractory disease
- •Patients with acute promyelocytic leukemia (APL) must be refractory to treatment with tretinoin and arsenic trioxide
- •Standard curative therapies or therapies proven to prolong survival with an acceptable quality of life do not exist
- •Active extramedullary disease, except active leptomeningeal leukemia, allowed
- •No brain tumors or known brain metastases
- •Karnofsky performance status (PS) 50-100% (for patients > 10 years of age)
- •Lansky PS 50-100% (for patients ? 10 years of age)
- •Patients with solid tumors must have adequate bone marrow function, as defined by the following:
- •Absolute neutrophil count ? 1,000/mm^3
- •Platelet count ? 75,000/mm^3 (transfusion independent)
- •Hemoglobin ? 8.0 g/dL (red blood cell [RBC] transfusions allowed)
- •Patients with leukemia may have abnormal blood counts but must meet the following criteria:
- •Platelet count ? 20,000/mm^3 (platelet transfusions allowed)
- •Hemoglobin ? 8.0 g/L (RBC transfusions allowed)
- •Patients with acute myeloid leukemia and FLT3-ITD mutation
- •Platelet count ? 20,000/mm^3
- •Lipase and amylase normal
- •Creatinine clearance or radioisotope glomerular filtration rate ? 70 mL/min OR creatinine normal based on age as follows:
- •No greater than 0.8 mg/dL (for patients 5 years of age and under)
- •No greater than 1.0 mg/dL (for patients 6-10 years of age)
- •No greater than 1.2 mg/dL (for patients 11-15 years of age)
- •No greater than 1.5 mg/dL (for patients over 15 years of age)
- •Patients with solid tumors must meet the following criteria:
- •Bilirubin normal for age
- •ALT normal for age (for the purpose of this study, the upper limit of normal [ULN] for ALT is 45 ?/L)
- •Serum albumin ? 2 g/dL
- 另有 43 项未显示
排除标准
- 未提供
研究组 & 干预措施
Treatment (sorafenib tosylate)
Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (sorafenib tosylate)
Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Treatment (sorafenib tosylate)
Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Sorafenib Tosylate (Drug)
结局指标
主要结局
Number of Patients With Treatment-related Adverse Events
时间窗: Up to 2 years
Number of patients with treatment-related adverse events stratified by dose level through study completion.
Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level
时间窗: Up to 2 years
Number of patients with treatment-related dose limiting toxicities in later cycles, as defined by study protocol, stratified by dose level.
Volume of Distribution at Steady State (Vss) of Sorafenib
时间窗: 8 hours post dose on day 1 of cycle 1
Volume of distribution at steady state (Vss) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors, leukemia, or AML and FLT3-ITD mutation.
Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level
时间窗: Up to 28 days
Number of patients with treatment-related dose limiting toxicities in cycle 1, as defined by study protocol, stratified by dose level.
Maximum Serum Concentration (Cmax) of Sorafenib
时间窗: 8 hours post dose on day 1 of cycle 1
Maximum serum concentration (Cmax) of Sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Half-life of Sorafenib
时间窗: 8 hours post dose on day 1 of cycle 1
Half-life of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib
时间窗: 8 hours post dose on day 1 of cycle 1
Area under the plasma concentration versus time curve (AUC) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Clearance (Cl) of Sorafenib
时间窗: 8 hours post dose on day 1 of cycle 1
Clearance of Sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
次要结局
- Number of Patients With DEMRI(Up to 2 years)
- Number of Patients Who Respond Using RECIST Criteria(Up to 2 years)
- Leukemia Mutations(1 week prior to enrollment)
- Plasma Inhibitory Activity (PIA)(1 week prior to enrollment and then every 28 days)
- Mean Concentration of VEGF2(28 days)
- Pharmacodynamics (PD) Blood Flow Part C(1 week prior to enrollment, then every 28 days)