Phase 1 Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 53
- 试验地点
- 10
- 主要终点
- Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 2
研究概览
简要总结
This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma (DIPG). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stratum 1 treats patients with DIPG that has returned or gotten worse (progressed). Stratum 2 treats patients with DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) that has not yet gotten worse.
详细描述
Description
This is a multicenter, phase 1 trial of Panobinostat (LBH589) for children with diffuse intrinsic pontine glioma tumors.
Panobinostat is a pan-HDAC inhibitor of Class I, II and IV histone deacetylases (HDACs) involved in the deacetylation of histone and non-histone cellular proteins. Panobinostat inhibits purified total cellular histone deacetylase activity (IC50 = 0.03 uM) and activities of most HDAC isoforms (IC50 <10nM). In addition, panobinostat induces expression of the cell-cycle control genes including CDKN1A (p21), and selectively inhibits the proliferation of a variety of tumor cells compared to normal cells. It has been extensively profiled for its in vitro and in vivo pharmacological activity on a variety of tumor cell lines and tumor xenograft mice models.
Based on the in vitro and in vivo activity of panobinostat in preclinical models using DIPG cell cultures and orthotopic xenograft model systems, and the potentially important role of histone deacetylases and histone 3 K27M mutations in relation to pontine malignancies, the investigators are conducting a Phase 1 study of panobinostat in children with recurrent/progressive DIPG.
The primary objectives of the study are to (1) describe the toxicity profile and define the dose-limiting toxicities of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) taken every other week; (2) estimate the maximum tolerated dose and/or the recommended Phase 2 dose of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) taken every other week; and (3) evaluate and characterize the plasma pharmacokinetics of panobinostat in children with recurrent/progressive DIPG, or with non-progressed DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) taken every other week.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Treatment (STRATUM 1)
Patients with recurrent/progressive DIPG will be enrolled at the time of progression. All patients will take the study drug panobinostat (LBH589).
干预措施: LBH589 (Drug)
Treatment (STRATUM 2)
Patients with non-progressed DIPG or H3K27M+ Thalamic DMG will be enrolled. All patients will take the study drug panobinostat (LBH589).
干预措施: LBH589 (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 2
时间窗: 4 weeks
The MTD of panobinostat was defined as the dose at which the continual reassessment method (CRM) estimated that 25% of patients were expected to experience DLTs. For Stratum 2, non-progressed DIPG or H3K27M+ thalamic diffuse malignant glioma (DMG) patients who completed conventional radiation treatment were eligible. All patients enrolled on this stratum had DIPG tumors and were treated with the "3 times/week, every other week" schedule (1 course = 28 days).
Volume of Distribution (Vd)
时间窗: Up to day 3
Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Volume of distribution (Vd) was estimated using a noncompartmental method.
Maximum Tolerated Dose (MTD) of Panobinostat in Stratum 1
时间窗: 4 weeks
The MTD of panobinostat was defined as the dose at which the continual reassessment method (CRM) estimated that 25% of patients were expected to experience DLTs. Stratum 1 consisted of recurrent or progressive diffuse intrinsic pontine glioma (DIPG) patients who were treated with the "3 times/week, three weeks on, one week off" schedule (1 course = 28 days).
Half-life (t1/2)
时间窗: Up to day 3
Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Half-life (t1/2) was estimated using a noncompartmental method.
Clearance (CL/F)
时间窗: Up to day 3
Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Clearance (CL/F) was estimated using a noncompartmental method.
Area Under the Curve (AUC)
时间窗: Up to day 3
Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. The area under the curve (AUC) was estimated using a noncompartmental method and calculated from time of dosing to the last measurable concentration.
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
时间窗: 4 weeks
DLTs were defined as adverse events that were at least possibly related to panobinostat that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding, grade 3 thrombocytopenia that occurs twice within a treatment course, myelosuppression that causes greater than a 14-day delay between treatment courses, grade 4 neutropenia, grade 3 or 4 febrile neutropenia. Non-hematologic DLTs included any grade 3 or greater non-hematologic toxicities with a few exclusions (such as grade 3 nausea/vomiting that is responsive to antiemetics and that resolves to grade 2 or lower within 5 days, etc.), any grade 2 non-hematological toxicity that persists for more than 7 days and is considered sufficiently medically significant or sufficiently intolerable by patients, and any panobinostat-related non-hematological toxicity that results in a delay of treatment \> 14 days between treatment courses.
Elimination Rate (Kel)
时间窗: Up to day 3
Plasma samples for pharmacokinetic (PK) analysis were drawn at pre-dose and at 0.5, 1, 2, 4, 8 (±1), 24 (±4) hours after the first dose of panobinostat, as well as prior to the second dose on Course 1 Day 3. Elimination rate (Kel) was estimated using a noncompartmental method.
次要结局
- Percentage of Patients With H3F3A K27M Mutation Detected in Blood Samples(Blood samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1.)
- Percentage of Patients With H3F3A K27M Mutation Detected in Urine Samples(Urine samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1.)
- Progression-free Survival (PFS) in Stratum 2(From date on treatment until date of PD or death due to any cause or date of last follow-up)
- Overall Survival (OS) in Stratum 2(From date on treatment until date of death due to any cause or date of last follow-up)
- Percentage of Patients With Hist1H3B K27M Mutation Detected in Blood Samples(Blood samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1.)
- Progression-free Survival (PFS) in Stratum 1(From date on treatment until date of PD or death due to any cause or date of last follow-up)
- Overall Survival (OS) in Stratum 1(From date on treatment until date of death due to any cause or date of last follow-up)
- Percentage of Patients With Hist1H3B K27M Mutation Detected in Urine Samples(Urine samples were collected for cell-free DNA based assay at Course 1 Day 1 (C1D1), C2D1, C4D1, and C6D1.)