FIREFLY-1: A Phase 2, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Pan-RAF Inhibitor DAY101 in Pediatric Patients With RAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced Solid Tumors
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 141
- 试验地点
- 35
- 主要终点
- Arm 1: Overall response rate
研究概览
简要总结
This is a Phase 2, multi center, open-label study to evaluate the safety and efficacy of Type II RAF (tovorafenib) in pediatric participants with low-grade glioma or advanced solid tumors. Qualifying genomic alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories prior to enrollment into any of the arms. The study will consist of a screening period, a treatment period, a long-term extension phase, end of treatment (EOT) visit(s), a safety follow-up visit, and long-term follow-up assessments.
详细描述
The study will consist of the following treatment arms:
Arm 1 (Low-Grade Glioma): Patients aged 6 months to 25 years, inclusive, with recurrent or progressive low-grade glioma harboring a known activating BRAF alteration, including BRAF V600 mutations and KIAA1549:BRAF fusions.
Arm 2 (Low-Grade Glioma Expanded Access): Patients aged 6 months to 25 years, inclusive, with recurrent or progressive low-grade glioma harboring a known or expected to be activating RAF alteration (e.g., BRAF or CRAF/RAF1 fusion or BRAF V600 mutations). Opening of Arm 2 to enrollment will be based on the recommendation of the Data Safety Monitoring Board (DSMB).
Arm 3 (Advanced Solid Tumor): Patients aged 6 months to 25 years, inclusive, with advanced solid tumors harboring a known or expected to be activating RAF fusion (e.g., BRAF or CRAF/RAF1 fusion).
Qualifying genomic alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories prior to enrollment into any of the aforementioned arms.
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
- 6 Months 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Low Grade Glioma & Low-Grade Glioma Extension: a relapsed or progressive LGG with documented known activating BRAF alteration.
- •Advanced Solid Tumor: locally advanced or metastatic solid tumor with documented known or expected to be activating RAF fusion.
- •Participants must have histopathologic verification of malignancy at either original diagnosis or relapse.
- •Must have received at least one line of prior systemic therapy and have documented evidence of radiographic progression.
- •Must have at least 1 measurable lesion as defined by RANO (Arms 1 & 2) or RECIST v1.1 (Arm 3) criteria
排除标准
- •Participant's tumor has additional previously-known activating molecular alterations.
- •Participant has symptoms of without radiographically recurrent or radiographically progressive disease.
- •Known or suspected diagnosis of neurofibromatosis type 1 (NF-1) via genetic testing or current diagnostic criteria.
- •Other inclusion/exclusion criteria as stipulated by protocol may apply
研究组 & 干预措施
Arm 1: Low-Grade Glioma
Participants with recurrent or progressive low-grade glioma will receive 420 milligrams/meters square (mg/m^2) of tovorafenib weekly according to dose rounding guidelines and according to their baseline body surface area (BSA).
干预措施: Tovorafenib (Drug)
Arm 2: Low-Grade Glioma Expanded Access
Participants with recurrent or progressive low-grade glioma will receive 420 mg/m^2 of tovorafenib weekly according to dose rounding guidelines and according to their baseline BSA.
干预措施: Tovorafenib (Drug)
Arm 3: Advanced Solid Tumor
Participants with advanced solid tumors will receive 420 mg/m^2) of tovorafenib weekly according to dose rounding guidelines and according to their baseline BSA.
干预措施: Tovorafenib (Drug)
结局指标
主要结局
Arm 1: Overall response rate
时间窗: Up to 48 months
ORR is defined as percentage of participants with best overall confirmed response of complete response (CR) or partial response (PR) by the Response Assessment in Neuro-Oncology - high-grade glioma (RANO-HGG) criteria.
Arm 2: Number of participants reporting adverse events
时间窗: Up to 48 months
An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Arm 2: Number of participants with clinically significant changes in clinical chemistry parameters
时间窗: Up to 48 months
Arm 2: Number of participants with clinically significant changes in hematology parameters
时间窗: Up to 48 months
Arm 3: Overall response rate
时间窗: Up to 48 months
Determined by the treating investigator and measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or RANO-HGG criteria, as appropriate.
次要结局
- Arm 1 and 3: Number of participants with clinically significant changes in hematology parameters(Up to 48 months)
- Arm 1: Area under the concentration-time curve (AUC) of Tovorafenib(Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1)
- Arm 1: Minimum drug concentration (Cmin)(Cycle 1: Day 1 and Day 15; Cycles 2, 4, 7, 10 and 13: Day 1)
- Arm 1: Change from Baseline QT interval corrected for heart rate by Fridericia's formula (ΔQTcF)(Baseline to 48 months)
- Arm 1: Change from Baseline PR interval (ΔPR)(Baseline to 48 months)
- Arm 1: Change from Baseline QRS interval (ΔQRS)(Baseline to 48 months)
- Arm 1: Change from baseline heart rate (ΔHR)(Baseline to 48 months)
- Arm 1: Change in electrocardiogram (ECG) waveform morphology(Baseline to 48 months)
- Arm 1 and Arm 2: Overall response rate(Up to 48 months)
- Arm 1 and 3: Number of participants reporting adverse events(Up to 48 months)
- Arm 1 and 3: Number of participants with clinically significant changes in clinical chemistry parameters(Up to 48 months)
- Arm 1, Arm 2 and Arm 3: Overall response rate in Pediatric participants(Up to 48 months)
- Arm 1, Arm 2 and Arm 3: duration of progression-free survival (PFS)(Up to 48 months)
- Arm 1, Arm 2 and Arm 3: Duration of response (DOR)(Up to 48 months)
- Arm 1, Arm 2 and Arm 3: Time to response (TTR)(Up to 48 months)
- Arm 1, Arm 2 and Arm 3: Clinical benefit rate (CBR)(Up to 48 months)
- Arm 1 and Arm 2: Duration of overall survival(Up to 48 months)
- Arm 1: Change from baseline in best corrected visual acuity (BCVA) outcomes(Baseline to 48 months)
- Arm 1: Changes in molecular analysis of cells obtained from archival tissue(At Screening)