Phase 2, Open-Label, Dose-Escalation and Dose-Expansion Study of Infigratinib, an FGFR 1-3-Selective Tyrosine Kinase Inhibitor, in Children With Achondroplasia: PROPEL 2
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 84
- 试验地点
- 19
- 主要终点
- Change from baseline in annualized height velocity
研究概览
简要总结
This is a Phase 2, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, and efficacy of infigratinib, a fibroblast growth factor receptor (FGFR) 1-3-selective tyrosine kinase inhibitor, in children 3 to 11 years of age with Achondroplasia (ACH) who previously participated in the PROPEL study (Protocol QBGJ398-001) for at least 6 months. The study includes dose escalation with extended treatment, and dose expansion. The study also includes a PK Substudy to fully characterize the pharmacokinetics of infigratinib in children with ACH.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent by participant or parent(s) or legally authorized representative (LAR) and signed informed assent by the participant (when applicable).
- •Diagnosis of ACH, documented clinically and confirmed by genetic testing.
- •At least a 6-month period of growth assessment in the PROPEL study (Protocol QBGJ398-001) before study entry.
- •Ambulatory and able to stand without assistance
- •Able to swallow oral medication.
排除标准
- •Hypochondroplasia or short stature condition other than ACH.
- •In females, having had their menarche.
- •Height < -2 or > +2 standard deviations for age and sex based on reference tables on growth in children with ACH.
- •Significant concurrent disease or condition that, in the view of the Investigator and/or Sponsor, would confound assessment of efficacy or safety of infigratinib.
- •Current evidence of corneal or retinal disorder/keratopathy.
- •History of malignancy.
- •Currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration.
- •Treatment with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the previous 6 months or long-term treatment (>3 months) at any time.
- •Treatment with a C-type natriuretic peptide (CNP) analog, fibroblast growth factor (FGF) ligand trap, or treatment targeting FGFR inhibition at any time.
- •Regular long-term treatment (>3 weeks) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma is acceptable).
- •Treatment with any other investigational product or investigational medical device for the treatment of ACH or short stature.
- •Previous limb-lengthening surgery or guided growth surgery.
- •Fracture within 12 months of screening.
研究组 & 干预措施
Infigratinib 0.016 mg/kg
Dose Escalation:
Infigratinib is provided as minitablets in 2 strengths: 0.1 mg and 1 mg for daily oral administration. The dose and number of minitablets/day will be calculated based on individual participant weight. Doses will be adjusted based on weight changes approximately every 3 months.
干预措施: Infigratinib 0.016 mg/kg (Drug)
Infigratinib 0.032 mg/kg
Dose Escalation and PK substudy:
Infigratinib is provided as minitablets in 2 strengths: 0.1 mg and 1 mg for daily oral administration. The dose and number of minitablets/day will be calculated based on individual participant weight. Doses will be adjusted based on weight changes approximately every 3 months.
干预措施: Infigratinib 0.032 mg/kg (Drug)
Infigratinib 0.064 mg/kg
Dose Escalation and PK substudy:
Infigratinib is provided as minitablets in 2 strengths: 0.1 mg and 1 mg for daily oral administration. The dose and number of minitablets/day will be calculated based on individual participant weight. Doses will be adjusted based on weight changes approximately every 3 months.
干预措施: Infigratinib 0.064 mg/kg (Drug)
Infigratinib 0.128 mg/kg
Dose Escalation and PK substudy:
Infigratinib is provided as minitablets in 2 strengths: 0.1 mg and 1 mg for daily oral administration. The dose and number of minitablets/day will be calculated based on individual participant weight. Doses will be adjusted based on weight changes approximately every 3 months.
干预措施: Infigratinib 0.128 mg/kg (Drug)
Infigratinib 0.25 mg/kg
Dose Escalation and PK substudy:
Infigratinib is provided as minitablets in 2 strengths: 0.1 mg and 1 mg for daily oral administration. The dose and number of minitablets/day will be calculated based on individual participant weight. Doses will be adjusted based on weight changes approximately every 3 months.
Dose Expansion:
Upon identification of the recommended dose from all cohorts analyzed, an expansion cohort of 20 subjects may begin enrollment to further determine safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of the selected dose.
干预措施: Infigratinib 0.25 mg/kg (Drug)
结局指标
主要结局
Change from baseline in annualized height velocity
时间窗: Up to 18 months
Incidence of treatment-emergent adverse events (TEAEs) that lead to dose decrease or discontinuation
时间窗: Up to 18 months
PK parameters of infigratinib (Clast- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (Racc- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (Tmax- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (Vz/F- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (Cmax- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (AUCinf- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (AUC24- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (T1/2- PK substudy only)
时间窗: 21 days
PK parameters of infigratinib (CL/F- PK substudy only)
时间窗: 21 days
次要结局
- Incidence of adverse events (AEs) and serious adverse events (SAEs) as a measure of safety and tolerability(Up to 18 months)
- Absolute height velocity (annualized to cm/year), expressed numerically and as Z-score in relation to ACH and non-ACH tables(Up to 18 months)
- Absolute and change from baseline in weight (kg)(Up to 18 months)
- Absolute and change from baseline in sitting height (cm)(Up to 18 months)
- Absolute and change from baseline in head circumference (cm)(Up to 18 months)
- Absolute and change from baseline in upper and lower arm length (cm)(Up to 18 months)
- Absolute and change from baseline in thigh length (cm)(Up to 18 months)
- Absolute and change from baseline in knee height (cm)(Up to 18 months)
- Absolute and change from baseline in arm span (cm)(Up to 18 months)
- Pharmacokinetic profile of infigratinib by assessment of maximum concentration (Cmax)(Up to 18 months)
- Pharmacokinetic profile of infigratinib by assessment of time-to-maximum concentration (Tmax)(Up to 18 months)
- Changes in pharmacodynamic parameters by assessing collagen X marker(Up to 18 months)