NCT02650401进行中（未招募）1 期
A Phase 1/2, Open-Label, Dose-Escalation And Expansion Study Of Entrectinib (Rxdx-101) In Pediatrics With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 69
- 试验地点
- 41
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Disease status:
- •Phase 1 portion (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1
- •Phase 2 portion:
- •Part B: Participants must have measurable or evaluable disease, as defined by RANO
- •Part C (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale
- •Part D: Participants must have measurable or evaluable disease, as defined by RECIST v1.1
- •Part E (closed): Participants must have measurable or evaluable disease, as defined by RECIST v1.1 ± Curie Scale or RANO
- •Tumor type:
- •Phase 1 portion:
- •* Part A: Relapsed or refractory extracranial solid tumors
- •Phase 2 portion
- •Part B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method
- •Part D: Extracranial solid tumors (including NB) with NTRK1/2/3 or ROS1 gene fusions; gene fusions are defined as those predicted to translate into a fusion protein with a functional TRKA/B/C or ROS1 kinase domain, without a concomitant second oncodriver as determined by a nucleic acid-based diagnostic testing method
- •Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
- •Archival tumor tissue from diagnosis or, preferably, at relapse
- •Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks
- •Prior therapy: Participants must have a disease that is locally advanced, metastatic, or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options for solid tumors and primary CNS tumors that are neurotrophic tyrosine receptor kinase (NTRK) or ROS1 fusion-positive
- •Participants must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment
- •Adequate organ and neurologic function
- •Females of childbearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Agreement to remain abstinent or use use combined contraceptive methods prior to study entry, for the duration of study participation and in the following 90 days after discontinuation of study treatment.
- •For male participants with a female partner of childbearing potential or a pregnant female partner: Agreement to remain abstinent or use a condom during the treatment period and for at least 3 months after the last dose of study drug
排除标准
- •Receiving other experimental therapy
- •Known congenital long QT syndrome
- •History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening
- •Known active infections
- •Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia
- •Receiving Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of first dose.
- •Prior treatment with approved or investigational TRK or ROS1 inhibitors
- •Known hypersensitivity to entrectinib or any of the other excipients of the investigational medicinal product
- •Patients with NB with bone marrow space-only disease
- •Incomplete recovery from acute effects of any surgery prior to treatment.
- •Active gastrointestinal disease or other malabsorption syndromes that would impact drug absorption.
- •Other severe acute or chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation, drug administration or may interfere with the interpretation of study results.
研究组 & 干预措施
CNS tumors harboring- NTRK1/2/3, ROS1, ALK
Active Comparator
Arm closed for further enrollment
molecular alterations, including gene fusions
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
Neuroblastoma
Active Comparator
Arm closed for further enrollment
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
Any participant unable to swallow capsules
Active Comparator
Arm closed for further enrollment
Any participant who otherwise meet all other eligibility criteria
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
Expansion: CNS tumors harboring NTRK1/2/3, ROS1
Active Comparator
gene fusions
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
Expansion: Extracranial solid tumors harboring NTRK1/2/3, ROS1
Active Comparator
NTRK 1,2,3 and ROS1 fusions
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
Extracranial solid tumors harboring NTRK1/2/3,
Active Comparator
Arm closed for further enrollment
ROS1, ALK non-gene fusion molecular alterations
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
Non-neuroblastoma, extracranial solid tumors
Active Comparator
Arm closed for further enrollment
harboring - NTRK1/2/3, ROS1, ALK gene fusions
Oral entrectinib (RXDX-101)
干预措施: Entrectinib (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: Approximately 6 months
Assessed by National Cancer Institute Common Terminology for Adverse Events Criteria (NCI CTCAE v4.03)
Recommended Phase 2 Dose (RP2D) Of Minitablets/F15 Formulation In Pediatric Participants Unable To Swallow Intact Capsules
时间窗: Approximately 6 months
Assessed by NCI CTCAE v4.03
Cohort B: Objective Response Rate (ORR)
时间窗: Approximately 6 months
Assessed by RANO per the BICR
Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric Participants Able To Swallow Intact Capsules
时间窗: Approximately 6 months
Assessed by NCI CTCAE v4.03
Recommended Phase 2 Dose (RP2D) of F1 Formulation In Pediatric Participants Able To Swallow Intact Capsules
时间窗: Approximately 6 months
Assessed by NCI CTCAE v4.03
Recommended Phase 2 Dose (RP2D) of F06 Formulation In Pediatric In Participants Dosed Via Feeding Tube (Nasogastric Tube Or Gastric Tube)
时间窗: Approximately 6 months
Assessed by NCI CTCAE v4.03
Cohort D: ORR
时间窗: Approximately 6 months
Assessed by RECIST v1.1 per the BICR
次要结局
- Maximum observed plasma drug concentration (Cmax) using F1 Formulation(Approximately 24 months)
- AUC at steady state (AUCss) using F1 Formulation(Approximately 24 months)
- Safety and Tolerability - AE, ECG and Labs assessed by NCI CTCAE v4.03(Approximately 24 months)
- Maximum observed plasma drug concentration (Cmax) using minitablets/F15(Approximately 24 months)
- Maximum observed plasma drug concentration (Cmax) using F06 Formulation given intact(Approximately 24 months)
- Maximum observed plasma drug concentration (Cmax) using F06 Formulation administered via feeding tube(Approximately 24 months)
- Time to Cmax, by inspection (Tmax) using F1 Formulation(Approximately 24 months)
- Time to Cmax, by inspection (Tmax) using F06 Formulation given intact(Approximately 24 months)
- Terminal half life (t½) using F06 Formulation given intact(Approximately 24 months)
- Terminal half life (t½) using F06 Formulation administered via feeding tube(Approximately 24 months)
- Cohort A, D, or E: Clinical Benefit Rate (CBR)(Approximately 6 months)
- Cohort B or E: PFS(Approximately 6 months)
- Cohort B or E: DOR(Approximately 6 months)
- Cohort C: DOR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): ORR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): ORR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR(Approximately 6 months)
- Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR(Approximately 6 months)
- Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): DOR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): DOR(Approximately 6 months)
- Time to Cmax, by inspection (Tmax) using F06 Formulation administered via feeding tube(Approximately 24 months)
- Time to Cmax, by inspection (Tmax) using minitablets/F15(Approximately 24 months)
- AUC at steady state (AUCss) using F06 Formulation administered via feeding tube(Approximately 24 months)
- Terminal half life (t½) using F1 Formulation(Approximately 24 months)
- Terminal half life (t½) using minitablets/F15(Approximately 24 months)
- Area under the drug concentration by time curve (AUC) using F1 Formulation(Approximately 24 months)
- Area under the drug concentration by time curve (AUC) using F06 Formulation administered via feeding tube(Approximately 24 months)
- Cohort C: CBR(Approximately 6 months)
- Cohort A, D, or E: ORR(Approximately 6 months)
- Cohort A, D, or E: Time to response (TTR)(Approximately 6 months)
- Cohort B or E: TTR(Approximately 6 months)
- Cohort C: TTR(Approximately 6 months)
- Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): ORR(Approximately 6 months)
- Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): ORR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): ORR(Approximately 6 months)
- AUC at steady state (AUCss) using minitablets/F15(Approximately 24 months)
- Area under the drug concentration by time curve (AUC) using minitablets/F15(Approximately 24 months)
- Cohort A, D, or E: Progression-free Survival (PFS)(Approximately 6 months)
- Cohort C: PFS(Approximately 6 months)
- Cohort A, D, or E: Overall Survival (OS)(Approximately 6 months)
- Cohort C: ORR(Approximately 6 months)
- AUC at steady state (AUCss) using F06 Formulation given intact(Approximately 24 months)
- Cohort B or E: ORR(Approximately 6 months)
- Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): ORR(Approximately 6 months)
- Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): TTR(Approximately 6 months)
- Area under the drug concentration by time curve (AUC) using F06 Formulation given intact(Approximately 24 months)
- Cohort B or E: CBR(Approximately 6 months)
- Cohort B or E: OS(Approximately 6 months)
- Cohort A, D, or E: Duration of Response (DOR)(Approximately 6 months)
- Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): ORR(Approximately 6 months)
- Phase 1/2 Participants with ROS1 gene fusions (Cohort B or E): DOR(Approximately 6 months)
- Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): DOR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): DOR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): DOR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): DOR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort A, D, or E): TTR(Approximately 6 months)
- Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR(Approximately 6 months)
- Phase 2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort D or E): TTR(Approximately 6 months)
- Phase 1/2 Participants with ROS1 gene fusions (Cohort A, D, or E): TTR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 gene fusions (Cohort B or E): TTR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort A, D, or E): TTR(Approximately 6 months)
- Phase 1/2 Participants with NTRK1/2/3 or ROS1 gene fusions (Cohort B or E): TTR(Approximately 6 months)
研究者
研究点 (41)
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