A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 9
- 主要终点
- Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
研究概览
简要总结
This phase I trial is studying the side effects and best dose of GDC-0449 in treating young patients with medulloblastoma that is recurrent or did not respond to previous treatment. GDC-0449 may be effective in treating young patients with medulloblastoma.
详细描述
PRIMARY OBJECTIVE:
I. To investigate the safety and pharmacokinetics of a daily dose of hedgehog antagonist GDC-0449 using the available formulation in pediatric patients with recurrent or refractory medulloblastoma.
SECONDARY OBJECTIVES:
I. To document and describe toxicities associated with this drug in these patients.
II. To characterize the pharmacokinetics of this drug in these patients. III. To document preliminary antitumor activity of this drug in these patients. IV. To document pathologic and genomic methods to identify CNS tumors with activation of the PTCH/SHH pathway.
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
- 3 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed medulloblastoma, including posterior fossa primitive neuroectodermal tumor (PNET)
- •Recurrent, progressive, or refractory to standard therapy
- •No known curative therapy exists
- •Neurological deficits allowed provided they are stable for ≥ 1 week prior to study entry
- •No atypical teratoid/rhabdoid tumor or supratentorial PNET
- •Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)
- •ANC ≥ 1,000/μL*
- •Platelet count ≥ 100,000/μL (transfusion independent)*
- •Hemoglobin ≥ 8.0 g/dL (RBC transfusion allowed)*
- •Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age as follows:
- •≤ 0.8 mg/dL (for patients ≤ 5 years of age)
- •≤ 1.0 mg/dL (for patients 6 to 10 years of age)
- •≤ 1.2 mg/dL (for patients 11 to 15 years of age)
- •≤ 1.5 mg/dL (for patients > 15 years of age)
- •Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
- •ALT/AST ≤ 2.5 times ULN for age
- •Serum albumin ≥ 2.5 g/dL
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile female patients must use 2 effective methods of contraception during and for 12 months following study treatment
- •Fertile male patients must use effective barrier contraception during and for 12 months following study treatment
- •Body surface area > 0.67 m^2 and ≤ 2.5 m^2
- •Able to swallow capsules
- •No malabsorption syndrome or other condition that would interfere with enteral absorption
- •No history of congestive heart failure
- •No history of ventricular arrhythmia requiring medication
- •No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation
- •No clinically important history of liver disease, including viral hepatitis or cirrhosis
- •No concurrent clinically significant unrelated systemic illness (e.g., serious infection) or significant cardiac, pulmonary, hepatic, or other organ dysfunction that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results
- •NOTE: * In the absence of bone marrow involvement
- •Recovered from prior treatment-related toxicity
- •At least 3 months since prior craniospinal radiotherapy (at doses ≥ 23 Gy)
- •At least 8 weeks since prior local radiotherapy to primary tumor
- •At least 2 weeks since prior focal radiotherapy to symptomatic metastatic sites
- •More than 4 weeks since prior myelosuppressive chemotherapy or immunotherapy (6 weeks for nitrosoureas)
- •More than 1 week since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin)
- •No other concurrent anticancer or investigational drug therapy
- •Concurrent dexamethasone allowed provided dosage is stable or decreasing for ≥ 1 week prior to study entry
排除标准
- 未提供
研究组 & 干预措施
Arm I
Patients receive oral hedgehog antagonist GDC-0449 once daily on days 1 and 4-28 in course 1 and on days 1-28 in all subsequent courses. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for pharmacokinetic studies. Archival tumor tissue samples are collected and analyzed for the expression of genes that activate the SHH (e.g., Gli1, Gli2, SFRP1, ATOH1, and PTCH2) or WNT (e.g., DKK2 and DKK4) cell signal pathways by in situ hybridization and reverse transcriptase real time-PCR.
干预措施: vismodegib (Drug)
Arm I
Patients receive oral hedgehog antagonist GDC-0449 once daily on days 1 and 4-28 in course 1 and on days 1-28 in all subsequent courses. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for pharmacokinetic studies. Archival tumor tissue samples are collected and analyzed for the expression of genes that activate the SHH (e.g., Gli1, Gli2, SFRP1, ATOH1, and PTCH2) or WNT (e.g., DKK2 and DKK4) cell signal pathways by in situ hybridization and reverse transcriptase real time-PCR.
干预措施: laboratory biomarker analysis (Other)
Arm I
Patients receive oral hedgehog antagonist GDC-0449 once daily on days 1 and 4-28 in course 1 and on days 1-28 in all subsequent courses. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for pharmacokinetic studies. Archival tumor tissue samples are collected and analyzed for the expression of genes that activate the SHH (e.g., Gli1, Gli2, SFRP1, ATOH1, and PTCH2) or WNT (e.g., DKK2 and DKK4) cell signal pathways by in situ hybridization and reverse transcriptase real time-PCR.
干预措施: pharmacological study (Other)
结局指标
主要结局
Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
时间窗: 21 days
95% confidence interval estimates for 2 doses compared.
Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life
时间窗: Up to 3 months after completion of study treatment
We will study two BSA defined strata.
次要结局
- Tumor responses(Up to 30 days after completion of study treatment)
- Progression-free survival(Up to 30 days after completion of study treatment)