A PHASE 1/2 STUDY OF RO4929097, AN ORAL SMALL MOLECULE INHIBITOR OF GAMMA-SECRETASE, IN CHILDREN WITH RELAPSED/REFRACTORY SOLID OR CNS TUMORS, LYMPHOMA, OR T-CELL LEUKEMIA
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 129
- 试验地点
- 12
- 主要终点
- Maximum tolerated dose (MTD) of RO4929097 determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0)
研究概览
简要总结
This phase I/II clinical trial is studying the side effects and best dose of gamma-secretase inhibitor RO4929097 and to see how well it works in treating young patients with relapsed or refractory solid tumors, CNS tumors, lymphoma, or T-cell leukemia. Gamma-secretase inhibitor RO4929097 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVES:
I. To estimate the maximum-tolerated dose (MTD) and recommend a phase II dose of gamma-secretase inhibitor RO4929097 administered orally to children with relapsed or refractory solid tumors or lymphoma on two schedules: once daily orally on a 3-day on/4-day off weekly schedule (schedule A) or once daily for 5 consecutive days weekly schedule (schedule B).
II. To define and describe the toxicities of this drug administered on these schedules to children with relapsed or refractory solid tumors, lymphoma, or T-cell leukemia.
III. To estimate the MTD and recommended phase II dose of gamma-secretase inhibitor RO4929097 administered with dexamethasone.
IV. To define and describe the toxicities of gamma-secretase inhibitor RO4929097 administered with dexamethasone.
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 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed malignancy (at diagnosis or relapse)
- •Biopsy not required for intrinsic brain stem tumors or optic pathway gliomas
- •No B-cell precursor acute lymphoblastic lymphoma (ALL) or acute myeloid leukemia
- •No T-cell leukemia with CNS3 disease
- •Measurable or evaluable disease
- •Current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
- •Neurologic deficits in patients with CNS tumors must have been relatively stable for 1 week
- •No active CNS leukemia
- •Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) or Lansky PS 50-100% (for patients ≤ 16 years of age)
- •Patients who are unable to walk because of paralysis,but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the PS
- •Patients with solid tumors without bone marrow involvement must meet the following criteria:
- •Peripheral ANC ≥ 1,000/mm^3
- •Platelet count ≥ 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within the past 7 days)
- •Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
- •Patients with known bone marrow metastatic disease must meet the above criteria and must not be known to be refractory to red cell or platelet transfusion
- •Patients with leukemia must meet the following criteria:
- •Platelet count ≥ 20,000/mm^3 (may receive platelet transfusions)
- •Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
- •Must not be known to be refractory to RBC or platelet transfusions
- •Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age/gender as follows:
- •≤ 0.6 mg/dL (patients 1 to < 2 years)
- •≤ 0.8 mg/dL (patients 2 to < 6 years)
- •≤ 1 mg/dL (patients 6 to < 10 years)
- •≤ 1.2 mg/dL (patients 10 to < 13 years)
- •≤ 1.4 mg/dL (female patients ≥ 13 years)
- •≤ 1.5 mg/dL (male patients 13 to < 16 years)
- •≤ 1.7 mg/dL (male patients ≥ 16 years)
- •Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal (ULN) for age
- •ALT ≤ 110 U/L (for the purpose of this study, the ULN for ALT is 45 U/L)
- •Serum albumin ≥ 2 g/dL
- •No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia defined as < lower limit of normal despite adequate electrolyte supplementation
- •Baseline QTc < 450 msec
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective double-method contraception (i.e., one highly effective method and one additional effective method) for ≥ 4 weeks before, during, and for ≥ 12 months after completion of study treatment
- •Female patients may not donate ova during or after study treatment
- •Able to comply with the safety monitoring requirements of the study, in the opinion of the investigator
- •Able to swallow tablets and capsules
- •No known malabsorption syndrome or other condition that would interfere with intestinal absorption
- •No known serological positivity for hepatitis A, B, or C, no known history of liver disease, and no other forms of hepatitis or cirrhosis
- •No known HIV positivity
- •No uncontrolled infection
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or dexamethasone
- •Patients may not donate blood during or for ≥ 12 months after completion of study treatment
- •No hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia that is uncontrolled despite adequate electrolyte supplementation
- •No prior gamma-secretase inhibitor RO4929097
- •Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
- •More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) (for patients with solid tumors, CNS tumors, or lymphomas)
- •Patients with T-cell leukemia must meet the following criteria:
- •Patients who relapsed on standard ALL maintenance chemotherapy must not have received maintenance chemotherapy within the past 3 days
- 另有 17 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm I
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive concurrent oral dexamethasone twice daily on the days of gamma-secretase inhibitor RO4929097 administration.
Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097 in combination with dexamethasone using one of the studied schedules.
干预措施: gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Drug)
Arm I
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive concurrent oral dexamethasone twice daily on the days of gamma-secretase inhibitor RO4929097 administration.
Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097 in combination with dexamethasone using one of the studied schedules.
干预措施: diagnostic laboratory biomarker analysis (Other)
Arm I
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive concurrent oral dexamethasone twice daily on the days of gamma-secretase inhibitor RO4929097 administration.
Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097 in combination with dexamethasone using one of the studied schedules.
干预措施: pharmacological study (Other)
Arm I
GROUP A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
GROUP B: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive concurrent oral dexamethasone twice daily on the days of gamma-secretase inhibitor RO4929097 administration.
Once the MTD or recommended phase II dose of RO4929097 plus dexamethasone in children with solid tumors, including CNS tumors, or lymphoma has been identified, this dose is used for patients with relapsed-refractory T-ALL (phase 2 portion of the study) to evaluate RO4929097 in combination with dexamethasone using one of the studied schedules.
干预措施: dexamethasone (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) of RO4929097 determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0)
时间窗: 28 days
MTD of RO4929097 administered with dexamethasone determined according to DLTs graded using CTCAE v4.0
时间窗: 28 days
次要结局
- Antitumor activity of RO4929097 with or without dexamethasone assessed by Response Evaluation Criteria for Solid Tumors (RECIST)(Up to 30 days)