Extension Study of Infigratinib in Children With Achondroplasia (ACH)

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, multicenter, open-label, extension (OLE) study to evaluate the long-term safety, tolerability, and efficacy of infigratinib, an FGFR 1-3-selective tyrosine kinase inhibitor, in subjects with ACH who previously completed a QED-sponsored interventional study, and potentially in additional subjects who are naïve to infigratinib treatment. Quality of Life assessments for this subject population will also be evaluated. Treatment-naïve subjects must have at least a 6-month period of growth assessment in the PROPEL study (Protocol QBGJ398 001) and will be enrolled in this OLE study only after a dose to be explored further is identified in Phase 2 Study QBGJ398-201.

Official Title
-----------------
Phase 2, Open-Label, Long-Term, Extension (OLE) Study of Infigratinib, an FGFR 1-3-Selective Tyrosine Kinase Inhibitor, in Children With Achondroplasia: PROPEL OLE

Conditions
-----------------
Achondroplasia

Intervention / Treatment
-----------------
* Drug: Infigratinib
* Drug: Infigratinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Rollover Subjects Inclusion Criteria: Pediatric subjects with ACH who have completed study activities in a previous QED-sponsored interventional study with infigratinib. Subjects and parent(s) or legally authorized representatives (LARs) are willing and able to comply with study visits and study procedures. Subjects are able to swallow oral medication. In girls ≥10 years of age or girls of any age who have experienced menarche, having a negative pregnancy test. If sexually active, subject must be willing to use a highly effective method of contraception while taking study drug and for 1 month after the last dose of study drug. The PI, or a person designated by the PI, will obtain written informed consent from each subject's LAR and the subject's assent, when applicable, before any study-specific activity is performed. Rollover Subjects Exclusion Criteria: Subject has concurrent circumstance, disease, or condition that, in the view of the PI and/or sponsor, would interfere with study participation or safety evaluations. Subjects who developed a medical condition that will require the initiation of treatment with a prohibited medication. Subjects prematurely discontinued a prior QED-sponsored interventional study with infigratinib Subjects that have reached final height or near final height. Key Inclusion Criteria for Treatment Naïve Subjects Subject must be 3 to <18 years of age at screening and have growth potential. Subjects who have a diagnosis of ACH, documented clinically and confirmed by genetic testing. Subjects have at least a 6-month period of growth assessment in the PROPEL study (Protocol QBGJ398 001) before study entry. In girls ≥10 years of age or girls of any age who have experienced menarche, having a negative pregnancy test. If sexually active, subject must be willing to use a highly effective method of contraception while taking study drug and for 1 month after the last dose of study drug. The PI, or a person designated by the PI, will obtain written informed consent from each subject's LAR and the subject's assent, when applicable, before any study-specific activity is performed. Key Exclusion Criteria for Treatment Naïve Subjects Subjects who have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia, psychosocial short stature). Subjects who have significant concurrent disease or condition that, in the view of the PI and/or sponsor, would represent an increased risk to the subject or would interfere with study participation or safety evaluations. Subjects who have a history of malignancy. Subjects who are currently receiving treatment with agents that are known strong inducers or inhibitors of cytochrome P450 (CYP) 3A4. Subjects who have received treatment with growth hormone, insulin-like growth factor 1 (IGF 1), anabolic steroids or any investigational or approved drug for the treatment of ACH in the previous 6 months. Subjects who have significant abnormality in screening laboratory results. Subjects who have had a fracture within 12 months of screening.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Rollover subjects<br>Children who have completed QED-sponsored interventional study with infigratinib | Drug: Infigratinib<br>* Infigratinib minitablets to be administered by mouth. In subjects that completed a prior study with infigratinib, the starting dose will be the same as the last dose received in the prior interventional study with infigratinib. Infigratinib dose may be adjusted to the dose identified from the dose escalation portion of the Phase 2 study (PROPEL 2).<br>|
| Experimental: Arm 2: Treatment naïve subjects<br>Children naïve to infigratinib | Drug: Infigratinib<br>* Infigratinib minitablets to be administered by mouth. Starting dose for the subjects naive to infigratinib will be the one identified during QBGJ398-201 (PROPEL 2).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (TEAE) and serious TEAE |  | 10 years | 
| Changes over time in height Z-score in relation to ACH and non-ACH growth charts |  | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes over time in absolute height velocity, expressed as height velocity z-score in relation to ACH and non ACH growth chart |  | 10 years | 
| Changes over time in body proportions |  | 10 years | 
| Changes over time in weight z-score |  | 10 years | 
| Changes overtime in BMI |  | 10 years | 
| Age of puberty onset and time to Tanner stage ≥4 |  | 10 years | 
| Changes over time in number of episodes of otitis media per year |  | 10 years | 
| Changes over time in number of episodes and/or severity of sleep apnea |  | 10 years | 
| Changes over time in range of motion (hip, knee and elbow) |  | 10 years | 
| Changes over time in skeletal abnormalities of the lower extremities and spine |  | 10 years | 
| Changes in health-related qQuality of life [HRQoL] as assessed by Pediatric Quality of Life Inventory (PedsQL) and Quality of Life in Short Stature Youth questionnaire (QoLISSY) |  | 10 years | 
| Changes in overall body pain as assessed by Numeric Rating Scale for pain (Pain-NRS) |  | 10 years | 
| Changes in functional abilities as evaluated by Functional Independence Measure for Children (WeeFIM) |  | 10 years | 
| Changes in cognitive functions assessed by age-appropriate computerized tests |  | 10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Skeletal dysplasia, Endochondral ossification, Achondroplasia (ACH), Quality of life in achondroplasia, Fibroblast growth factor receptor 3, FGFR3, Endochondral bone formation, Short-limb disproportionate dwarfism, dwarfism, Bone disease, Functionality in achondroplasia, Musculoskeletal diseases, Osteochondrodysplasia, Genetic diseases, Long - term treatment, Growth, Average growth velocity