A Phase I/II, 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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 25
- 试验地点
- 6
- 主要终点
- 1. Dose limiting toxicity DLT during the first cycle (28 days) in pediatric patients with relapsed or refractory solid tumors using the F1 formulation (and subsequently using F06, minitablets). The RP2D will be determined from DLT derived from clinical and laboratory observations in the first treatment cycle according to the NCI CTCAE v4.03 that is related to entrectinib)
研究概览
简要总结
To determine the maximum tolerated dose (MTD), or recommended Phase 2 dose (RP2D), of F1 entrectinib formulation in pediatric patients with relapsed or refractory solid tumors (Cohort A). To confirm RP2D of F06 entrectinib formulation in pediatric patients able to swallow intact capsules and in patients dosed via feeding tube (nasogastric tube or gastric tube). To confirm RP2D of minitablet formulation in pediatric patients unable to swallow intact capsules. To evaluate efficacy of entrectinib as assessed by objective response rate (ORR) in the efficacy evaluable patients from Phase II dose expansion (Cohorts B and D) harboring NTRK1/2/3 or ROS1 gene fusions. Responses will be evaluated with use of the Response Assessment in Neuro-Oncology Criteria (RANO) for primary CNS tumors and RECIST v1.1 in patients with extracranial solid tumors, as assessed by blinded independent central review (BICR)
研究设计
- 研究类型
- Interventional
- 分配方式
- Not Applicable
- 主要目的
- Phase II (Dose Expansion)
- 盲法
- None
入排标准
- 年龄范围
- 0 years 至 17 years（0-17 Years）
- 接受健康志愿者
- 是
入选标准
- •Sex and age: male or female aged from birth to age < 18 years
- •Disease status: Phase 1 portion (closed): Patients must have measurable or evaluable disease Phase 2 portion: Cohort B: Patients must have measurable or evaluable disease as defined by RANO Cohort C (closed) and D: Patients must have measurable or evaluable disease as defined per RECIST v1.1±Curie Scale Cohort D: Patients must have measurable or evaluable disease, Cohort E (closed): Patients must have measurable or evaluable disease and be assessed according to tumor type as defined per RECIST v1.1±Curie Scale or RANO
- •Tumor types included below harboring NTRK1/2/3 or ROS1 gene fusions as determined locally by an appropriately validated assay performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently-accredited diagnostic laboratory, or centrally by a Foundation Medicine Clinical Trial Assay or the alternative, approved central laboratory for that region: Phase 1 portion: Cohort A: Relapsed or refractory extracranial solid tumors Phase 2 portion: Cohort B: Primary brain tumors with NTRK1/2/3 or ROS1 gene fusions Cohort D: Extracranial solid tumors with NTRK1/2/3 or ROS1 gene fusions
- •Histologic/molecular diagnosis of malignancy at diagnosis or the time of relapse
- •For patients enrolled via local molecular testing, an archival tumor tissue from diagnosis or, preferably, from relapsed disease is required to be submitted for independent central testing at Foundation Medicine, Inc. laboratory or the alternative, approved central assay laboratory for that region
- •Performance status: Lansky or Karnofsky score ≥ 60% and minimum life expectancy of at least 4 weeks
排除标准
- •Current participation in another therapeutic clinical trial
- •Known congenital long QT syndrome
- •History of recent (3 months) symptomatic congestive heart failure or ejection fraction ≤50% at screening
- •Known active infections (bacterial, fungal, or viral)
- •All Phase 2 patients: Prior treatment with approved or investigational tyrosine receptor kinase inhibitor (TRK) or ROS1 inhibitors
- •Incomplete recovery from acute effects of any surgery prior to treatment
结局指标
主要结局
1. Dose limiting toxicity DLT during the first cycle (28 days) in pediatric patients with relapsed or refractory solid tumors using the F1 formulation (and subsequently using F06, minitablets). The RP2D will be determined from DLT derived from clinical and laboratory observations in the first treatment cycle according to the NCI CTCAE v4.03 that is related to entrectinib)
1. Dose limiting toxicity DLT during the first cycle (28 days) in pediatric patients with relapsed or refractory solid tumors using the F1 formulation (and subsequently using F06, minitablets). The RP2D will be determined from DLT derived from clinical and laboratory observations in the first treatment cycle according to the NCI CTCAE v4.03 that is related to entrectinib)
2. Objective response rate as assessed by the BICR will be evaluated in the efficacy evaluable population from the Phase II dose expansion cohorts (Cohort B and D)
2. Objective response rate as assessed by the BICR will be evaluated in the efficacy evaluable population from the Phase II dose expansion cohorts (Cohort B and D)
次要结局
- 10. Assessment of growth (weight, height), puberty (Tanner), neurological function and neurocognitive function of patients on treatment
- 1. Incidence and severity of adverse events, laboratory and electrocardiogram (ECG) abnormalities
- 2. Maximal plasma concentration (Cmax) of entrectinib (F1, F06 given intact, F06 administered via feeding tube, and minitablets)
- 3. Time of maximal plasma concentration (Tmax) of entrectinib (F1, F06 given intact, F06 administered via feeding tube, and minitablets)
- 4. Area under the plasma concentration vs. time curve (AUC) of entrectinib (F1, F06 given intact, F06 administered via feeding tube, and minitablets)
- 5. ORR in the efficacy evaluable and safety evaluable populations
- 6. DOR and TTR as assessed by BICR and the investigator in the efficacy evaluable and safety evaluable populations:
- 7. ORR, TTR, DOR in the efficacy evaluable and safety evaluable populations as assessed by BICR and the investigator with use of RECIST v1.1, RANO, and the Curie scale, as applicable
- 8. CBR and PFS in the efficacy evaluable and safety evaluable populations as assessed by BICR and investigator with use of RECIST v1.1, RANO, and the Curie scale, as applicable
- 9. OS in the efficacy evaluable and safety evaluable populations
- 11. Acceptability and palatability assessment for F06 capsules and minitablets formulation
研究者
Trial Information System - TISL
Scientific
F. Hoffmann-La Roche AG