A Phase 1 Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Selumetinib, a Selective Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor, in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
概览
- 阶段
- 1 期
- 干预措施
- Selumetinib
- 疾病 / 适应症
- Neurofibromatosis 1
- 发起方
- AstraZeneca
- 入组人数
- 32
- 试验地点
- 2
- 主要终点
- Terminal half-life (t1/2) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas
- 状态
- 进行中（未招募）
- 最后更新
- 3个月前
概览
简要总结
A Phase 1 Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Selumetinib, a Selective Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor, in Chinese Paediatric and Adult Subjects with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN).
详细描述
Paediatric and adult patients with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN) will be evaluated in the screening visit to confirm eligibility. Approximately 16 paediatric and 16 adult qualified patients will receive oral selumetinib 25 mg/m\^2 twice a day (approximately every 12 hours) continuously until disease progression or unacceptable drug-related toxicity, whichever occurs first. Once a patient has discontinued the study treatment then the patient will be followed for specified period for safety assessment
研究者
入排标准
入选标准
- •Paediatric cohort: Chinese subjects ≥3 years and \<18 years of age
- •Adult cohort: Chinese subjects ≥18 years of age at the time of study enrollment
- •Subjects must be diagnosed with (i) NF1 as per NIH Consensus Development Conference Statement and（ii) PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. (iii) inoperable PN
- •Subjects must have at least one measurable typical or nodular PN
- •Absolute neutrophil count ≥1.5×10\^9/L, haemoglobin ≥9g/dL, and platelet count ≥100×10\^9/L. Subject must be without growth factor support and platelet transfusion support 7 days before the screening assessment.
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2×upper limit of normal (ULN), total bilirubin ≤1.5×ULN except in the case of subjects with documented Gilbert's disease (≤2.5×ULN).
排除标准
- •Evidence of malignant peripheral nerve sheath tumour.
- •Clinically significant cardiovascular disease
- •Prior malignancy (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject had been disease free for ≥2 years or which would not have limited survival to \<2 years) or other cancer requiring treatment with chemotherapy or radiation therapy.
- •Subjects with the following ophthalmological findings/conditions:
- •Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion; Intraocular pressure \>21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP); Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study physician; Any other significant abnormality on ophthalmic examination that would make the subject unsuitable for enrolment into the study, as assessed by the investigator.
研究组 & 干预措施
Selumetinib
All eligible subjects will first receive a single oral dose of selumetinib 25 mg/m\^2. Then, selumetinib 25 mg/m\^2 oral twice daily will be administered continuously until disease progression or unacceptable drug-related toxicity, whichever occurs first.
干预措施: Selumetinib
结局指标
主要结局
Terminal half-life (t1/2) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas
时间窗: From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
t1/2 after single dose and multiple doses administration
Area under the concentration-time curve from zero to the last measurable concentration (AUC0-t) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas
时间窗: From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
AUC0-t after single dose and multiple doses administration
Adverse events
时间窗: For paediatric cohort: from signing the informed consent form until up to 3 years after last subject dosed; For adult cohort: from signing the informed consent form until up to 2 years+30 days after last subject dosed.
* Occurrence/frequency. * Relationship to IP as assessed by investigator. * Common Terminology Criteria for Adverse Events (CTCAE) grade. * Seriousness. * Death. * Adverse events leading to discontinuation of IP. * Adverse events of special interest.
Maximum plasma concentration (Cmax) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas
时间窗: From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Cmax after single dose and multiple doses administration
次要结局
- Measures of pain via FLACC scale(First patient first dose until up to 2 years after last subject dosed)
- objective response rate (ORR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas(First patient first dose until up to 2 years after last subject dosed)
- time to progression (TTP) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas(First patient first dose until up to 2 years after last subject dosed)
- Measures of Physical function via Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire(First patient first dose until up to 2 years after last subject dosed)
- duration of response (DoR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas(First patient first dose until up to 2 years after last subject dosed)
- time to response (TTR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas(First patient first dose until up to 2 years after last subject dosed)
- Measures of pain via PII(First patient first dose until up to 2 years after last subject dosed)
- Measures health-related quality of life (HRQoL) via PedsQL (paediatric cohort, self-and parent-reported)(First patient first dose until up to 2 years after last subject dosed)
- progression-free survival (PFS) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas(First patient first dose until up to 2 years after last subject dosed)
- Measures of pain via NRS-11(First patient first dose until up to 2 years after last subject dosed)
- Measures of pain via Faces Pain Scale (revised)(First patient first dose until up to 2 years after last subject dosed)
- Measures health-related quality of life (HRQoL) via EORTC QLQ-C30 (adult cohort)(First patient first dose until up to 2 years after last subject dosed)
- Measures health-related quality of life (HRQoL) via PlexiQoL (adult cohort)(First patient first dose until up to 2 years after last subject dosed)
- Measures of pain via Pain Medication Survey(First patient first dose until up to 2 years after last subject dosed)