A Phase 1/2 Study of Mirdametinib and Vinblastine for Newly Diagnosed or Previously Untreated Patients With Pediatric Low-grade Glioma and Activation of the MAPK Pathway
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 9
- 主要终点
- Determine maximum tolerated dose of Mirdametinib plus Vinblastine.
研究概览
简要总结
This is a 3-part open-label study (feasibility phase, treatment phase and follow-up phase) of orally administered mirdametinib in combination with intravenous vinblastine chemotherapy in patients with PLGG with activation of MAPK pathway.
Feasibility Phase:
The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination will be assessed using a modified Rolling-6 design.
Treatment Phase:
Patients will receive mirdametinib twice daily (continuously) at a fixed dose (2mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles. If adverse events occur, two dose reductions are allowed.
Follow-up Phase:
Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS.
详细描述
This is a phase 1/2, open label, interventional clinical trial that will study the response rate of newly diagnosed pediatric low-grade glioma (PLGG) to oral administration of mirdametinib in combination with weekly vinblastine. Patients meeting all inclusion criteria for a given study group will receive mirdametinib twice daily (continuous) at a fixed dose (2 mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles.
The lead-in feasibility phase will be conducted to establish the maximum tolerated/recommended phase 2 dose (MTD/RP2D) of vinblastine in combination with mirdametinib combination using a modified Rolling-6 design. The established RP2D for mirdametinib (2 mg/m2 po BID up to 4 mg BID) will be used on this study. Mirdametinib will be administered on a continuous dosing schedule and de-escalated as necessary to an intermittent (3 weeks on, 1 week off) dosing schedule. Vinblastine will be escalated (or de-escalated) as necessary. Since these classes of agents do not have overlapping toxicities, the starting dose (i.e., Dose Level 0) for vinblastine is 4 mg/m2/week, which is 20% lower than the recommended single agent dose of vinblastine of 5 mg/m2/week. Dose Level 1 for vinblastine is 5 mg/m2/week and Dose Level -1 for vinblastine is 3 mg/m2/week.
Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS. A total of 50 patients will be recruited as part of this clinical study.
Patients aged between 2 and 25 years old will be eligible, in order to include a maximum of patients affected by glioma. This study includes PLGG patients with neurofibromatosis type 1 (NF1) with a KIAA1549-BRAF fusion and patients with activation of the MAPK pathway with the exception of patients with a BRAFV600E mutation.
Response to treatment will be evaluated using the modified Response Assessment in Pediatric Neuro-Oncology (RAPNO), Response Assessment in Pediatric Neuro-Oncology (RANO) 1. Evaluation of quality of life will be measured using the Pediatric Quality of Life inventory (PedsQL) (Generic/Brain tumor modules).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed written informed consent prior to study participation.
- •Study activities compliance: must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast enhanced MRI.
- •Aged ≥ 2 years to ≤ 25 years when starting mirdametinib.
- •BSA ≥ 0,40m2
- •Diagnosis:
- •Participants must have PLGG with NF1 gene mutation (based on clinical NIH criteria, germline NF1 mutation or molecular analysis of the tumor) or PLGG with KIAA1549-BRAF fusion (based on molecular analysis of the tumor) or PLGG with evidence of MAPK pathway alteration with the exception of patients with BRAF V600E mutation (based on molecular analysis of the tumor).
- •Tumor tissue is required (at minimum, paraffin-embedded tissue block and additionally fresh frozen tissue [if available]). Patients with NF1 and Low Grade Glioma (LGG) can still be enrolled without tissue if no surgery or biopsy was conducted.
- •Baseline MRI.
- •Life expectancy greater than 6 months.
- •Lansky/Karnofsky score ≥
- •Normal organ and marrow function (see study protocol for specifics).
- •Female and male patients of fertile age must agree to use highly effective contraceptive measures.
- •Must be able to ingest by mouth and retain entirely the administered medication. Mirdametinib can not be administered via nasogastric tube or gastrostomy tube.
排除标准
- •Patients who are receiving other investigational agents.
- •Cardiac: QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 49%.
- •Patients who have any other malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
- •Tumor with BRAF V600E mutation.
- •Patients who received previous systemic or radiotherapy treatment.
- •Other severe and uncontrollable medical disease
- •Blood pressure higher than 95th percentile for patient's age, height and gender.
- •Increased risk of serious retinopathy and retinal vein occlusion.
- •Known diagnosis of human immunodeficiency virus infection, hepatitis B or C.
- •Previous major surgery within 2 weeks.
- •History of allergic reactions to compounds of similar chemical or biological composition to mirdametinib.
- •Pregnant or breastfeeding.
研究组 & 干预措施
Mirdametinib + IV Vinblastine
Patients will receive oral mirdametinib twice daily (continuous) at a fixed dose (2mg/m2 PO BID, rounded to the nearest 1mg, up to a maximum of 4 mg BID) for a total of 13 cycles. Each cycle will last 28 days.
干预措施: Mirdametinib (Drug)
结局指标
主要结局
Determine maximum tolerated dose of Mirdametinib plus Vinblastine.
时间窗: 3 years
The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination using a modified Rolling-6 design.
Determine the objective response rate of mirdametinib plus vinblastine for PLGG with Mitogen-activated Protein Kinase (MAPK) pathway activation in treatment naïve patients.
时间窗: 5 years
The proportion of patients with complete (CR), major (MaR), partial (PR) and minor response (MiR) as the best response on study based on RAPNO criteria. Response = MiR+PR+MaR+CR
次要结局
- Determine neurological changes in patients during active treatment and after completion of therapy.(5 years)
- Evaluate the quality of life during treatment.(5 years)
- Efficacy outcome measures: Overall Survival.(Up to 3 years following completion of treatment.)
- Efficacy outcome measures: Progression-Free Survival.(Up to 3 years following completion of treatment.)
- Efficacy outcome measures: Time to Progression.(Up to 3 years following completion of treatment.)
- Efficacy outcome measures: Objective Response Rate.(Up to 3 years following completion of treatment.)
- Determine the safety and tolerability of the combination of mirdametinib plus vinblastine.(5 years)
研究者
Dr Perreault
Principal Investigator
St. Justine's Hospital