A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)
概览
- 阶段
- 2 期
- 干预措施
- Alpelisib
- 疾病 / 适应症
- Slow-Flow Vascular Malformation
- 发起方
- Murdoch Childrens Research Institute
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at 48 weeks based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).
- 状态
- 招募中
- 最后更新
- 2个月前
概览
简要总结
Recent studies have demonstrated that growth of vascular malformations can be driven by genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways have been developed and shown to be effective in treating cancer. This study will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants with slow-flow vascular malformations and a gene mutation in one of these signalling pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with fast-flow vascular malformations and a gene mutations in the other signalling pathway (module 2).
详细描述
TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies for patients with vascular malformations. Patients with vascular malformations which are refractory to standard therapies, or in whom standard therapy is not appropriate, are potentially eligible for the clinical trial. Vascular malformations will be classified as slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K) signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed using research protocols or commercial testing assays that are external to this clinical trial. The study consists of individual modules, each evaluating the clinical efficacy of 48 weeks of targeted therapy. The treatment modules are: 1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with slow-flow vascular malformations with an identified causative variant in the PI3K signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period). 2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with fast-flow vascular malformations with an identified causative variant in the MAPK signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period). TARGET-VM will be conducted only in Victoria, Australia.
研究者
入排标准
入选标准
- •Inclusion Criteria:
- •Adult or paediatric patient, 2 years of age or over
- •Patient has a clinical diagnosis of a slow-flow vascular malformation
- •Patient has received standard therapy for the vascular malformation or in which, in the opinion of the investigator, standard therapy is not appropriate
- •\- Note: standard therapy may include treatment with sirolimus. A minimum of 14 days since the last dose of sirolimus is required prior to starting treatment with alpelisib
- •A documented genetic alteration in the PI3K signalling pathway identified by genetic sequencing prior to enrolment in this study
- •Adequate performance status (Eastern Cooperative Oncology Group Performance Status Scale (ECOG) 0-2 in patients ≥ 16 years of age; Lansky \> 50 in patients \< 16 years of age)
- •Patient has a life expectancy ≥ 12 weeks
- •Patient is able to swallow and retain oral medication
- •Adequate haematologic and end-organ function:
排除标准
- •History of hypersensitivity to any drugs or metabolites of PI3K inhibitors or any of the excipients of alpelisib
- •Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment
- •Patient has had a major surgical procedure within 4 weeks prior to enrolment
- •Prior use of an alpha-specific PI3K inhibitor
- •History of pneumonitis or interstitial lung disease
- •Patient is pregnant or lactating at the time of study registration. A pregnancy test is mandated for women of child-bearing potential in the screening period
- •Established diagnosis of type I diabetes mellitus, type II diabetes mellitus requiring anti-hyperglycaemic medication or any participant with HbA1c \> 6.4%
- •Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes
- •Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of treatment:
- •Strong inducers of CYP3A4
研究组 & 干预措施
Module 1: Slow-flow vascular malformations
Slow-flow vascular malformations with identified causative variants in the phosphoinositide 3-kinase (PI3K) signalling pathway will receive alpelisib (provided by Novartis Pharmaceuticals), an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.
干预措施: Alpelisib
Module 2: Fast-flow vascular malformations
Fast-flow vascular malformations with identified causative variants in the RAS-MEK-ERK signalling pathway will receive mirdametinib (provided by SpringWorks Therapeutics, Inc.), an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.
干预措施: Mirdametinib
结局指标
主要结局
The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at 48 weeks based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).
时间窗: At 48 weeks
Vascular malformations present with a range of different symptoms. Therefore, there is no single outcome measure that can capture the effectiveness of a systemic treatment across different patients. Thus for this study, an individualised primary outcome for each patient informed by their symptoms will be used, termed the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM). The study "Outcome Committee" will define an individualised primary outcome for each patient informed by their symptoms and vascular malformation features prior to starting trial treatments. The VM-PSOM endpoint will therefore define a binary outcome for each patients (achieved or failed to reach the threshold improvement in the chosen measure).
次要结局
- The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at the 168-day timepoint based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).(48 weeks, 168-day follow-up)
- Change in symptoms score as recorded on the OVAMA (Outcome measures for VAscular MAlformations) questionnaire.(Time frame: Baseline, 48 weeks)
- The number of participants with an objective response (defined as ≥ 20% reduction from index date in the sum of measurable target lesion volume) by volumetric analysis on MRI.(Baseline, 48 weeks)
- Change in symptoms score as recorded on the OVAMA (Outcome measures for VAscular MAlformations) which is a set of questions developed specifically to measure symptom burden from vascular malformations.(Time frame: 48 weeks, Day 168 follow-up)
- The number of patients who experience adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.(From Baseline to Day 168 follow-up)