Clinical trial NCT04265651: Study of Infigratinib in Children With Achondroplasia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Achondroplasia
Keywords: Skeletal dysplasia
Endochondral ossification
ACH
Shortened proximal limbs
Fibroblast growth factor receptor 3
FGFR3
Endochondral bone formation
Short-limb disproportionate dwarfism
dwarfism
Bone disease
Bone diseases, developmental
Musculoskeletal diseases
Osteochondrodysplasia
Genetic diseases, inborn
Inborn
Lead sponsor: QED Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2020-02-11
Enrollment: 84
Sex: ALL
Minimum age (years): 3
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Signed informed consent by participant or parent(s) or legally authorized representative (LAR) and signed informed assent by the participant (when applicable).
2. Diagnosis of ACH, documented clinically and confirmed by genetic testing.
3. At least a 6-month period of growth assessment in the PROPEL study (Protocol QBGJ398-001) before study entry.
4. Ambulatory and able to stand without assistance
5. Able to swallow oral medication.

Exclusion Criteria:

1. Hypochondroplasia or short stature condition other than ACH.
2. In females, having had their menarche.
3. Height \< -2 or \> +2 standard deviations for age and sex based on reference tables on growth in children with ACH.
4. Significant concurrent disease or condition that, in the view of the Investigator and/or Sponsor, would confound assessment of efficacy or safety of infigratinib.
5. Current evidence of corneal or retinal disorder/keratopathy.
6. History of malignancy.
7. Currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration.
8. 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.
9. Treatment with a C-type natriuretic peptide (CNP) analog, fibroblast growth factor (FGF) ligand trap, or treatment targeting FGFR inhibition at any time.
10. Regular long-term treatment (\>3 weeks) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma is acceptable).
11. Treatment with any other investigational product or investigational medical device for the treatment of ACH or short stature.
12. Previous limb-lengthening surgery or guided growth surgery.
13. Fracture within 12 months of screening.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events (TEAEs) that lead to dose decrease or discontinuation
timeFrame: Up to 18 months
measure: Change from baseline in annualized height velocity
timeFrame: Up to 18 months
measure: PK parameters of infigratinib (Cmax- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (Clast- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (Tmax- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (AUC24- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (T1/2- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (AUCinf- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (CL/F- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (Vz/F- PK substudy only)
timeFrame: 21 days
measure: PK parameters of infigratinib (Racc- PK substudy only)
timeFrame: 21 days
Secondary outcomes:
measure: Incidence of adverse events (AEs) and serious adverse events (SAEs) as a measure of safety and tolerability
timeFrame: Up to 18 months
measure: Absolute height velocity (annualized to cm/year), expressed numerically and as Z-score in relation to ACH and non-ACH tables
timeFrame: Up to 18 months
measure: Absolute and change from baseline in weight (kg)
timeFrame: Up to 18 months
measure: Absolute and change from baseline in sitting height (cm)
timeFrame: Up to 18 months
measure: Absolute and change from baseline in head circumference (cm)
timeFrame: Up to 18 months
measure: Absolute and change from baseline in upper and lower arm length (cm)
timeFrame: Up to 18 months
measure: Absolute and change from baseline in thigh length (cm)
timeFrame: Up to 18 months
measure: Absolute and change from baseline in knee height (cm)
timeFrame: Up to 18 months
measure: Absolute and change from baseline in arm span (cm)
timeFrame: Up to 18 months
measure: Pharmacokinetic profile of infigratinib by assessment of maximum concentration (Cmax)
timeFrame: Up to 18 months
measure: Pharmacokinetic profile of infigratinib by assessment of time-to-maximum concentration (Tmax)
timeFrame: Up to 18 months
measure: Changes in pharmacodynamic parameters by assessing collagen X marker
timeFrame: Up to 18 months
Other outcomes:
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Wilmington
country: United States
facility: Nemours Alfred I. Dupont Hospital for Children
state: Delaware
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Parkville
country: Australia
facility: Murdoch Children's Hospital
state: Victoria
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Lyon
country: France
facility: Hopital Femme Mere Enfant
city: Paris
country: France
facility: Hopital Necker-Enfants Malades
city: Toulouse
country: France
facility: Hopital des Enfants
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Vitoria-Gasteiz
country: Spain
facility: Vithas Hospital San José
state: Álava
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol and Weston NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: London
country: United Kingdom
facility: Evelina London Children's Hospital
city: Manchester
country: United Kingdom
facility: Manchester University Children's Hospital
Study officials:
affiliation: QED Therapeutics
name: QED Therapeutics VP, Clinical Development
role: STUDY_DIRECTOR
References:
citation: Savarirayan R, De Bergua JM, Arundel P, McDevitt H, Cormier-Daire V, Saraff V, Skae M, Delgado B, Leiva-Gea A, Santos-Simarro F, Salles JP, Nicolino M, Rossi M, Kannu P, Bober MB, Phillips J 3rd, Saal H, Harmatz P, Burren C, Gotway G, Cho T, Muslimova E, Weng R, Rogoff D, Hoover-Fong J, Irving M. Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies. Ther Adv Musculoskelet Dis. 2022 Mar 21;14:1759720X221084848. doi: 10.1177/1759720X221084848. eCollection 2022.