Study With Infigratinib in Subjects With Advanced Solid and CNS Tumors or Recurrent or Progressive Low-Grade Glioma With Selected FGFR1-3 Alterations

Study Overview
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Brief Summary
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The phase 1b study is aimed at determining the pediatric recommended phase 2 dose (RP2D) of Infigratinib. The phase 2 study will evaluate efficacy and safety of infigratinib.

Detailed Description
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Phase 1b: Pediatric subjects with advanced solid and CNS tumors or recurrent or progressive Low-Grade Glioma with selected FGFR1-3 alterations will follow a standard dose escalation, in 3 dose levels, to determine the pediatric recommended Phase 2 dose (RP2D) and to assess the safety. Dose escalation decisions will be assessed through three dose level cohorts. Phase 2: To evaluate the efficacy and safety in Pediatric and adult subjects with LGG with selected FGFR1-3 alterations (including subjects who received infigratinib at the RP2D).

Official Title
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A Phase 1b/2, Multicenter, Open-Label Study of Oral Infigratinib in Pediatric Subjects With Advanced Solid and Central Nervous System (CNS) Tumors (Phase 1b) and in Subjects With Recurrent or Progressive Low-Grade Gliomas Harboring Selected FGFR1, FGFR2, or FGFR3 Alterations (Phase 2)

Conditions
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Advanced Solid Tumor, CNS Tumor, Recurrent WHO Grade II Glioma

Intervention / Treatment
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* Drug: Infigratinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1b: Subject must be ≥ 3 to <18 years of age at the Screening visit. Confirmed diagnosis of one of the following: LGG (WHO Grade I or II glioma) based on histology, molecular, and clinical criteria concordant with the WHO Grading of Tumors of the Central Nervous System, including glial or mixed neuronal-glial tumor Histologically/cytologically confirmed CNS tumor (other than LGG). Histologically/cytologically confirmed advanced solid tumor. Disease is recurrent or progressive after standard therapy (at least 1 prior standard therapy appropriate for tumor type and stage of disease unless available standard therapies are considered inadequate for the subject). Phase 2 at screening: Diagnosis of recurrent or progressive (at least 1 prior standard therapy) LGG (WHO Grade I or II glioma), including glial or mixed neuronal-glial tumor, based on histology, molecular, and clinical criteria concordant with the WHO Grading of Tumors of the Central Nervous System. Age 3 years and older at screening visit. Phase 1b/2 (all subjects) at screening: Able to swallow and retain oral medication. Willing to stop consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges, or products containing juice of these fruits; and have not consumed these within 7 days before the first dose of study drug. Willing and able to comply with scheduled visits, treatment plan, and laboratory tests. Sex and Contraceptive/Barrier Requirements Contraceptive and barrier use as well as pregnancy testing is required as appropriate for the age and sexual activity of pediatric and adult subjects and as required by local regulations. Subjects can be male and female. A legal guardian or caregiver must be able to accurately maintain the pediatric subject's take-home record, including items of general health. Exclusion Criteria: Prior treatment with a FGFR1-3 selective inhibitor. Known serious active infection or any clinically significant systemic illness, which in the Investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the subject's ability to tolerate the study drug. Received anti-convulsant drugs that are strong inducers of CYP3A4 (i.e., carbamazepine, phenobarbital, phenytoin) within 4 weeks before starting study treatment. Currently receiving treatment with agents that are known strong and moderate inducers of CYP3A4 within 4 weeks from start of treatment or inhibitors of CYP3A4 within 1 week from start of treatment, including herbal preparations; medications which increase serum phosphorus and/or calcium concentration; use of a proton-pump inhibitors (e.g., omeprazole) within 4 days prior to start of study therapy or H2 receptor antagonists (e.g., famotidine) within 2 days prior to the start of study therapy. Uncontrollable seizures. Have current evidence of corneal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy; corneal abrasion, inflammation, or ulceration; or keratoconjunctivitis, confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic conditions assessed by the Investigator to pose minimal risk for study participation may be enrolled in the study. Have current evidence of endocrine alterations of calcium/phosphate homeostasis (e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis), unless well controlled. Have a history and/or current evidence of extensive tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, vasculature, myocardium, and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, small renal cyst or stone calcifications, and asymptomatic coronary calcification. Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib (e.g., active ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). Had major surgery within 2 weeks of enrollment or not fully healed from open wound.

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase 1b: Rolling 6 design, 3 cohorts Phase 2: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infigratinib (BGJ398)<br>Generic name: infigratinib. Dosage forms: 18mg and 25mg sprinkle capsules and 25mg, 75mg, 100mg capsules. Phase 1b Three dose levels escalation until RP2D is determined. Phase 2 Pediatric patients: dose defined in the phase 1b (RP2D); Adults: 125 mg. Frequency: once daily for 21 days in each 28-day treatment cycle. Duration: Treatment duration will last up to 26 cycles unless progression, death or unacceptable toxicity occur. | Drug: Infigratinib<br>* Hard gelatin capsules for oral use<br>* Other names: BGJ398;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b Dose Limiting Toxicity (DLT) rate | An adverse event (AE) or abnormal laboratory value that are not clearly due to the underlying disease or extraneous causes, including those AEs and abnormal laboratory values that result in a failure to meet the criteria for re-treatment. | 28 days | 
| Phase 2 Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) | The proportion of subjects who achieve a confirmed complete response (CR), confirmed partial response (PR), or confirmed minor response (MR) for subjects with LGG. For other subjects, ORR is defined as proportion of subjects who achieve a confirmed CR or confirmed PR. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b Pharmacokinetics (PK): Cmax | The maximum observed plasma concentration after drug administration (defined as the 2-hour post-dose concentration) | Up to 24 months | 
| Phase 1b Pharmacokinetics (PK): AUC | Area under the plasma concentration-time curve | Up to 24 months | 
| Phase 1b Pharmacokinetics (PK): T1/2 | Apparent terminal Half-Life | Up to 24 months | 
| Phase 1b Pharmacokinetics (PK): Tmax | Peak time | Up to 24 months | 
| Phase 1b Pharmacokinetics (PK): CL/F | Apparent clearance Day1 | Up to 24 months | 
| Phase 1b Pharmacokinetics (PK): Vz/F | Apparent volume of distribution | Up to 24 months | 
| Phase 1b Best Overall Response (BOR) assessed by Investigator | The best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. | Up to 24 months | 
| Phase 1b Disease Control Rate (DCR) assessed by Investigator | The proportion of subjects with a Best Overall Response (BOR) of complete response (CR), partial response (PR), minor response (MR) or standard deviation (SD) for subjects with LGG. For other subjects, DCR is defined as the proportion of subjects with a BOR of CR, PR or SD. | Up to 24 months | 
| Phase 1b Objective Response Rate (ORR) assessed by Investigator |  | Up to 24 months | 
| Phase 1b Duration of Response (DOR) assessed by Investigator | The time from first documentation of objective response (partial response (PR), complete response (CR), minor response (MR)) to first documentation of PD or death due to any cause, whichever occurs first. | Up to 24 months | 
| Phase 1b Time to Response (TTR) assessed by Investigator | The time from the date of the start of the treatment to the date of the first documented objective response (partial response (PR), complete response (CR), minor response (MR)) which is subsequently confirmed. | Up to 24 months | 
| Phase 1b Progression Free Survival (PFS) assessed by Investigator | The time from the date of the start of treatment to the date of the first documented progression or death due to any cause, whichever is earlier. | Up to 24 months | 
| Post-treatment termination Phase 1b Progression Free Survival (PFS) assessed by Investigator | PFS after treatment termination is the time from the date of treatment interruption for any reason excluding progression disease (PD) to the date of the first documented progression or death due to any cause, whichever is earlier. | After treatment termination up to progression disease (PD), assessed for further 24 months | 
| Phase 1b Best change in tumor size assessed by Investigator | The minimum change from baseline in the sum of diameters of target lesions. | Up to 24 months | 
| Phase 2 Duration of Response (DOR) assessed by blinded independent central review (BICR) |  | Up to 24 months | 
| Phase 2 Time to Response (TTR) assessed by blinded independent central review (BICR) |  | Up to 24 months | 
| Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR) |  | 6 months from treatment initiation | 
| Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR) |  | 12 months from treatment initiation | 
| Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR) |  | 24 months from treatment initiation | 
| Post-treatment termination Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR) |  | After treatment termination up to progression disease (PD), assessed for further 24 months | 
| Phase 2 Overall Survival (OS) | Overall Survival (OS) is defined as the time from the date of start of treatment to the date of death due to any cause. | 12 months | 
| Phase 2 Overall Survival (OS) |  | 24 months | 
| Phase 2 Best Overall Response (BOR) assessed by blinded independent central review (BICR) |  | Up to 24 months | 
| Phase 2 Disease Control Rate (DCR) assessed by blinded independent central review (BICR) |  | Up to 24 months | 
| Phase 2 Best change in tumor size assessed by blinded independent central review (BICR) |  | Up to 24 months | 
| Phase 2 Best Overall Response (BOR) assessed by Investigator |  | Up to 24 months | 
| Phase 2 Disease Control Rate (DCR) assessed by Investigator |  | Up to 24 months | 
| Phase 2 Objective Response Rate (ORR) assessed by Investigator |  | Up to 24 months | 
| Phase 2 Duration of Response (DOR) assessed by Investigator |  | Up to 24 months | 
| Phase 2 Time to Response (TTR) assessed by Investigator |  | Up to 24 months | 
| Phase 2 Progression Free Survival (PFS) assessed by Investigator |  | Up to 24 months | 
| Phase 2 Best change in tumor size assessed by Investigator |  | Up to 24 months | 
| Post-treatment termination Phase 2 Progression Free Survival (PFS) assessed by Investigator |  | After treatment termination up to progression disease (PD), assessed for further 24 months | 
| Phase 1b Incidence/severity of Adverse Events (AEs) | Number of patients who experienced AEs to assess the safety and tolerability of infigratinib in subjects with recurrent or progressive LGG. | Up to 30 days after treatment termination | 
| Phase 2 Incidence/severity of Adverse Events (AEs) |  | Up to 30 days after treatment termination | 
| Phase 1b Incidence/severity of Serious Adverse Events (SAEs) | Number of patients who experienced SAEs to assess the safety and tolerability of infigratinib in subjects with recurrent or progressive LGG. | Up to 30 days after treatment termination | 
| Phase 2 Incidence/severity of Serious Adverse Events (SAEs) |  | Up to 30 days after treatment termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low-Grade Glioma, FGFR1-3 Mutation or fusion/rearrangements, FGFR1-3 Fusion, FGFR1-3 Rearrangements, Advanced Solid Tumor, CNS Tumor