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

Helsinn Healthcare SA

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Conditions

Advanced Solid Tumor CNS Tumor Recurrent WHO Grade II Glioma

Interventions

InfigratinibDRUG

Hard gelatin capsules for oral use

Eligibility

Sex: ALLMin age: 3 Years

Medical Language ↔ Plain English

Inclusion Criteria: Phase 1b: * Subject must be ≥ 3 to \<18 years of age at the Screening visit. * Confirmed diagnosis of one of the following: 1. 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 2. Histologically/cytologically confirmed CNS tumor (other than LGG). 3. 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.

Locations (10)

Lucile Packard Children's Hospital at Stanford University Medical Center

Palo Alto, California, United States

Children's National Hospital - Brain Tumor Institute

Washington D.C., District of Columbia, United States

Nicklaus Children's Hospital

Miami, Florida, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Up to 24 months

Secondary Outcomes

Phase 1b Pharmacokinetics (PK): Cmax

The maximum observed plasma concentration after drug administration (defined as the 2-hour post-dose concentration)

Time frame: Up to 24 months

Phase 1b Pharmacokinetics (PK): AUC

Area under the plasma concentration-time curve

Time frame: Up to 24 months

Phase 1b Pharmacokinetics (PK): T1/2

Apparent terminal Half-Life

Time frame: Up to 24 months

Phase 1b Pharmacokinetics (PK): Tmax

Peak time

Time frame: Up to 24 months

Phase 1b Pharmacokinetics (PK): CL/F

Apparent clearance Day1

Time frame: Up to 24 months

Data from ClinicalTrials.gov

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Memorial Sloan Kettering Cancer Center

New York, New York, United States

Duke Cancer Institute (DCI) - The Preston Robert Tisch Brain Tumor Center

Durham, North Carolina, United States

UPCM - Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Alberta - Stollery Children's Hospital (SCH)

Edmonton, Alberta, Canada

McMaster Children's Hospital (MCH)

Hamilton, Ontario, Canada

University of Toronto - The Hospital for Sick Children (SickKids)

Toronto, Ontario, Canada

Universitaetsklinikum Heidelberg (UKHD) - Zentrum fuer Kinder- und Jugendmedizin - Klinik Kinderheilkunde III

Heidelberg, Baden-Wurttemberg, Germany

Phase 1b Pharmacokinetics (PK): Vz/F

Apparent volume of distribution

Time frame: 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.

Time frame: 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.

Time frame: Up to 24 months

Phase 1b Objective Response Rate (ORR) assessed by Investigator

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Up to 24 months

Phase 2 Duration of Response (DOR) assessed by blinded independent central review (BICR)

Time frame: Up to 24 months

Phase 2 Time to Response (TTR) assessed by blinded independent central review (BICR)

Time frame: Up to 24 months

Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR)

Time frame: 6 months from treatment initiation

Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR)

Time frame: 12 months from treatment initiation

Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR)

Time frame: 24 months from treatment initiation

Post-treatment termination Phase 2 Progression Free survival (PFS) assessed by blinded independent central review (BICR)

Time frame: 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.

Time frame: 12 months

Phase 2 Overall Survival (OS)

Time frame: 24 months

Phase 2 Best Overall Response (BOR) assessed by blinded independent central review (BICR)

Time frame: Up to 24 months

Phase 2 Disease Control Rate (DCR) assessed by blinded independent central review (BICR)

Time frame: Up to 24 months

Phase 2 Best change in tumor size assessed by blinded independent central review (BICR)

Time frame: Up to 24 months

Phase 2 Best Overall Response (BOR) assessed by Investigator

Time frame: Up to 24 months

Phase 2 Disease Control Rate (DCR) assessed by Investigator

Time frame: Up to 24 months

Phase 2 Objective Response Rate (ORR) assessed by Investigator

Time frame: Up to 24 months

Phase 2 Duration of Response (DOR) assessed by Investigator

Time frame: Up to 24 months

Phase 2 Time to Response (TTR) assessed by Investigator

Time frame: Up to 24 months

Phase 2 Progression Free Survival (PFS) assessed by Investigator

Time frame: Up to 24 months

Phase 2 Best change in tumor size assessed by Investigator

Time frame: Up to 24 months

Post-treatment termination Phase 2 Progression Free Survival (PFS) assessed by Investigator

Time frame: 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.

Time frame: Up to 30 days after treatment termination

Phase 2 Incidence/severity of Adverse Events (AEs)

Time frame: 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.

Time frame: Up to 30 days after treatment termination

Phase 2 Incidence/severity of Serious Adverse Events (SAEs)

Time frame: Up to 30 days after treatment termination