A Phase I Trial of Indoximod and Temozolomide-Based Therapy for Children With Progressive Primary Brain Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 81
- 试验地点
- 5
- 主要终点
- Incidence of regimen limiting toxicities (RLTs)
研究概览
简要总结
This is a first-in-children phase 1 trial using indoximod, an inhibitor of the immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO), in combination with temozolomide-based therapy to treat pediatric brain tumors. Using a preclinical glioblastoma model, it was recently shown that adding IDO-blocking drugs to temozolomide plus radiation significantly enhanced survival by driving a vigorous, tumordirected inflammatory response. This data provided the rationale for the companion adult phase 1 trial using indoximod (IND#120813) plus temozolomide to treat adults with glioblastoma, which is currently open (NCT02052648). The goal of this pediatric study is to bring IDO-based immunotherapy into the clinic for children with brain tumors. This study will provide a foundation for future pediatric trials testing indoximod combined with radiation and temozolomide in the up-front setting for patients with newly diagnosed central nervous system tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Group 1 (CLOSED)
Core Regimen: Dose-escalation of indoximod, in combination with temozolomide, for pediatric patients with progressive brain tumors.
Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Indoximod (Drug)
Group 1 (CLOSED)
Core Regimen: Dose-escalation of indoximod, in combination with temozolomide, for pediatric patients with progressive brain tumors.
Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Temozolomide (Drug)
Group 2 (CLOSED)
Expansion cohorts: Indoximod therapy at the pediatric recommended phase 2 dose (RP2D) determined by Group 1, in combination with temozolomide.
Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Indoximod (Drug)
Group 2 (CLOSED)
Expansion cohorts: Indoximod therapy at the pediatric recommended phase 2 dose (RP2D) determined by Group 1, in combination with temozolomide.
Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Temozolomide (Drug)
Group 3 (CLOSED)
Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors.
Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Indoximod (Drug)
Group 3 (CLOSED)
Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors.
Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Temozolomide (Drug)
Group 3 (CLOSED)
Dose-escalation of indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with progressive brain tumors.
Indoximod will be administered in escalating doses. Initial dosing will be 12.8 mg/kg/dose BID with escalation planned to 22.4 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Conformal Radiation (Radiation)
Group 3b
Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG).
Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Indoximod (Drug)
Group 3b
Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG).
Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Temozolomide (Drug)
Group 3b
Indoximod, in combination with up-front conformal radiation therapy, for pediatric patients with newly diagnosed treatment-naive diffuse intrinsic pontine glioma (DIPG).
Indoximod will be administered at the RP2D of 19.2 mg/kg/dose BID.
Temozolomide to be given at 200 mg/m^2 x 5 days
干预措施: Conformal Radiation (Radiation)
Group 4
Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide.
Indoximod will be administered at 32 mg/kg/dose divided twice daily.
Cyclophosphamide to be given at 2.5 mg/kg/dose daily
Etoposide to be given at 50 mg/m2/dose daily
干预措施: Indoximod (Drug)
Group 4
Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide.
Indoximod will be administered at 32 mg/kg/dose divided twice daily.
Cyclophosphamide to be given at 2.5 mg/kg/dose daily
Etoposide to be given at 50 mg/m2/dose daily
干预措施: Cyclophosphamide (Drug)
Group 4
Continued access to indoximod in combination with low-dose oral cyclophosphamide and etoposide for patients with progressive disease after treatment with indoximod plus temozolomide.
Indoximod will be administered at 32 mg/kg/dose divided twice daily.
Cyclophosphamide to be given at 2.5 mg/kg/dose daily
Etoposide to be given at 50 mg/m2/dose daily
干预措施: Etoposide (Drug)
结局指标
主要结局
Incidence of regimen limiting toxicities (RLTs)
时间窗: First 35 days of treatment
To estimate the RP2D of indoximod combined with conformal radiation
Objective Response Rate
时间窗: Up to three years
To assess preliminary evidence of efficacy of indoximod and temozolomide using COG brain tumor measurement criteria.
Safety and tolerability assessed by development of AEs and laboratory parameters of indoximod in combination with cyclophosphamide and etoposide.
时间窗: Up to three years
In patients who initially achieve prolonged stable disease or better with Indoximod plus temozolomide but then develop progressive disease
次要结局
- Progression Free Survival (PFS)(Up to three years)
- Overall Survival(Start of study until end of follow-up, up to five years)
- Safety and Tolerability of Indoximod combined with Temozolomide as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.(Continuous during study until 30 days after study treatment is complete.)
- Pharmacokinetics: Serum concentrations (Cmax/Steady State)(First 48 hours of treatment)
- Time to Progression(Start of study until disease progression follow-up, up to three years)
- Safety and Feasibility of Indoximod combined with conformal radiation as assessed by incidence and severity of adverse events, dose interruptions and dose reductions.(Continuous during study until 30 days after study treatment is complete.)