Study of Infigratinib in Children With Achondroplasia

Sponsor

QED Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04265651

Collaborator

(none)

Enrollment

Locations

Arms

45.7

Anticipated Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Achondroplasia	Drug: Infigratinib 0.016 mg/kg Drug: Infigratinib 0.032 mg/kg Drug: Infigratinib 0.064 mg/kg Drug: Infigratinib 0.128 mg/kg	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

78 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 10, 2020

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Infigratinib 0.016 mg/kg Initial cohort dose of infigratinib at the protocol-specified starting dose, with subsequent cohort escalations based on protocol-specific criteria. Infigratinib tablets to be administered by mouth.
Experimental: 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.	Drug: Infigratinib 0.032 mg/kg Subsequent cohort dose escalation based on protocol-specific criteria. Infigratinib tablets to be administered by mouth.
Experimental: 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.	Drug: Infigratinib 0.064 mg/kg Subsequent cohort dose escalation based on protocol-specific criteria. Infigratinib tablets to be administered by mouth.
Experimental: 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. 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.	Drug: Infigratinib 0.128 mg/kg Subsequent cohort dose escalation based on protocol-specific criteria. Infigratinib tablets to be administered by mouth.

Outcome Measures

Primary Outcome Measures

Incidence of treatment-emergent adverse events (TEAEs) that lead to dose decrease or discontinuation [Up to 18 months]
Change from baseline in annualized height velocity [Up to 18 months]
PK parameters of infigratinib (Cmax- PK substudy only) [21 days]
PK parameters of infigratinib (Clast- PK substudy only) [21 days]
PK parameters of infigratinib (Tmax- PK substudy only) [21 days]
PK parameters of infigratinib (AUC24- PK substudy only) [21 days]
PK parameters of infigratinib (T1/2- PK substudy only) [21 days]
PK parameters of infigratinib (AUCinf- PK substudy only) [21 days]
PK parameters of infigratinib (CL/F- PK substudy only) [21 days]
PK parameters of infigratinib (Vz/F- PK substudy only) [21 days]
PK parameters of infigratinib (Racc- PK substudy only) [21 days]

Secondary Outcome Measures

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]
Changes in pharmacodynamic parameters by assessing serum type 1 collagen c-telopeptide [Up to 18 months]
Changes in pharmacodynamic parameters by assessing procollagen type 1 N-telopeptide [Up to 18 months]
Changes in pharmacodynamic parameters by assessing bone-specific alkaline phosphatase [Up to 18 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Years to 11 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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 6 months of screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Benoiff Children's Hospital	Oakland	California	United States	94618
2	Nemours Alfred I. Dupont Hospital for Children	Wilmington	Delaware	United States	19803
3	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
4	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
5	Murdoch Children's Hosptial	Parkville	Victoria	Australia	3052
6	Stollery Children's Hosptial	Edmonton	Alberta	Canada	T6G 2H7
7	Hopital Femme Mere Enfant	Lyon		France
8	Hopital Necker-Enfants Malades	Paris		France
9	Hopital des Enfants	Toulouse		France
10	Hosptial Universitario La Paz	Madrid		Spain	24086
11	Hospital Universitario Virgen de la Victoria	Málaga		Spain
12	Vithas Hospital San José	Vitoria-Gasteiz	Álava	Spain	01012
13	Sheffield Children's Hospital	Sheffield	England	United Kingdom	S10 2TH
14	Birmingham Children's Hospital	Birmingham		United Kingdom
15	University Hospitals Bristol and Weston NHS Foundation Trust	Bristol		United Kingdom	BS1 3NU
16	Queen Elizabeth University Hospital	Glasgow		United Kingdom
17	Evelina London Children's Hospital	London		United Kingdom
18	Manchester University Children's Hospital	Manchester		United Kingdom