Infigratinib in Subjects With GC or GEJ With FGFR2 Amplification or Other Solid Tumors With Other FGFR Alterations

Study Overview
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Brief Summary
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Infigratinib is an oral drug which selectively binds to fibroblast growth factor receptor (FGFR) 1-3. This is a multicenter, open-label, single arm phase IIa study to evaluate the efficacy and safety of Infigratinib in subjects with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with FGFR2 genetic amplification or other advanced solid tumors with other FGFR genetic alternations who have failed in 2nd line or above treatment. This trial includes 2 cohorts (i.e., baskets) with above mentioned indications.

Detailed Description
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The subject will go through 4 periods, including Pre-screen period, screening period, treatment period and follow up period. Pre-screening period (up to 28 days) For cohort 1, subject sign pre-screening ICF( Inform consent ), subject will do tumor biopsy or provide FFPE samples before prescreening for FGFR2-amp detection by FISH from the central laboratory. If the result is positive, subjects can go through the main screening stage, otherwise participants will be considered a prescreen failure. subjects can go through the main screening stage, otherwise participants will be considered a prescreen failure. Screening period ( All cohorts; up to 28 days): Subjects who had positive genetic result could sign main ICF for all the screening examinations and establish study baseline documents. Only the eligible participants could enter the next treatment period. Treatment period: Eligible subjects will be orally administered Infigratinib (125mg, QD) for 3 weeks on, 1-week off in each 28-day cycle until the occurrence of unacceptable toxicity, disease progression, withdrawing informed consent, death, contact lost, starting a new anticancer therapy, etc (whichever occurs first). During this period, subjects will be routinely assessed efficacy status by radiographic check at W9/W17/W25/W33 . After that, subjects will be evaluated every 12 weeks until disease progression. The safety assessment will be performed at cycle 1- 4; Follow up period: Once a treatment discontinuation happens, subjects should return to the hospital within 30 days to receive a complete safety examination. Subjects with treatment discontinuation or disease progression should directly enter the follow-up period, visit approximately every 3 months for survival status reporting until withdrawing informed consent, death, contact lost, starting a new anti-cancer therapy, etc. (whichever occurs first).

Official Title
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A Phase IIa of Infigratinib in Subjects With Locally Advanced or Metastatic Gastric Cancer or Gastroesophageal Junction Adenocarcinoma With FGFR2 Amplification or Other Advanced Solid Tumors With Other FGFR Alterations

Conditions
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Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, Solid Tumor

Intervention / Treatment
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* Drug: Infigratinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort 1 : 1) histologically or cytologically confirmed locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. 2) failed 2nd line or above therapy with locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. 3) willing to do tumor biopsy for FGFR2 gene amplification via FISH test at central lab Cohort 2: 1) Histologically or cytologically confirmed locally advanced or metastatic solid tumors other than CHOL and UC. 2) Subjects must have failed established standard medical anti-cancer therapies for a diagnosed tumor or have been intolerant to such therapy, or no standard therapy, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds.(3) Previous documented proof of FGFR1, FGFR2 ,or FGFR3 fusions/rearrangements and activating mutations (FISH/NGS/PCR results could be accepted) presented by local laboratory or central laboratory. [Except Cohort 1GC, or GEJ patients with FGFR2 amplification] Measurable disease by RECIST v1.1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Exclusion Criteria: To be eligible for the study, subjects must not meet any of the following criteria: History of other primary malignancies within 3 years except adequately treated in situ carcinoma of the cervix or nonmelanoma carcinoma of the skin or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the study. Previous or current treatment of a mitogen-activated protein kinase (MAPK-MEK) or selective FGFR inhibitor. Any known hypersensitivity to Infigratinib or its excipients. Subjects with symptomatic central nervous system metastasis. History and/or current evidence of extensive tissue calcification. Amylase or lipase >2.0 × ULN. Abnormal calcium or phosphorus, or calcium-phosphorus product ≥55 mg2/dL2. Current evidence of endocrine alterations of calcium/phosphate homeostasis. Current evidence of corneal or retinal disorder/keratopathy. Currently receiving or planning to receive treatment with agents or foods that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration during this study. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) with FGFR2 amplification<br>Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off (every 4 weeks as one treatment cycle). | Drug: Infigratinib<br>* Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off.<br>* Other names: BGJ398;|
| Experimental: Advanced Solid tumors[Exclude GC/GEJ Arm and CHOL,UC]with FGFR1-3 fusions/rearrangements/mutations<br>Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off (every 4 weeks as one treatment cycle). | Drug: Infigratinib<br>* Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off.<br>* Other names: BGJ398;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Defined as the proportion of subjects with confirmed responses of CR or PR; Tumor response status will be assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Approximately 12 months after dosed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | Defined as from the first evaluation as CR or PR to the first evaluation as PD or death of any cause (percent of subjects with ≥6 months, ≥9 months, and ≥12 months DOR will be reported). | Approximately 12 months after dosed | 
| Disease Control Rate (DCR) | Defined as the proportion of subjects whose best overall response is confirmed to be CR or PR or SD (RECIST v1.1). | Approximately 12 months after dosed | 
| Best Overall Response (BOR) | Defined as best response recorded from the start of the study treatment until the disease progression/recurrence | Approximately 12 months after dosed | 
| Progression-free survival (PFS) | Defined as the time from the first date of treatment to the date of progression determined by investigator or death due to any cause. | Approximately 12 months after dosed | 
| Overall Survival (OS) | Defined as the time from the first date of treatment until date of death. | Approximately 24 months after dosed | 
| Incidence of Adverse Events | The incidence of adverse events is defined as the proportion of the patients, who have adverse event(s) since the time of main informed consent. | Approximately 24 months | 
| Incidence of Serious Adverse Events | The incidence of serious adverse events is defined as the proportion of the patients, who have serious adverse event(s) since the time of main informed consent. | Approximately 24 months | 
| Incidence of Laboratory Abnormalities | Incidence of abnormal laboratory is defined as the proportion of patients who have abnormal laboratory value since the time of main informed consent. | Approximately 24 months | 
| Maximum plasma concentration (Cmax) | To characterize the pharmacokinetic parameter Maximum plasma concentration (Cmax) of Infigratinib following oral administration of Infigratinib in patients | Approximately 5 months. | 
| Area under the plasma concentration versus time curve (AUC) | To characterize the pharmacokinetic parameter Area under the plasma concentration versus time curve (AUC) of Infigratinib following oral administration of Infigratinib in patients. | Approximately 5 months. | 
| Apparent total plasma clearance (CL/F) | To characterize the pharmacokinetic parameter Apparent total plasma clearance (CL/F) of Infigratinib following oral administration of Infigratinib in patients. | Approximately 5 months. | 
| Terminal elimination half-life (t1/2) | To characterize the pharmacokinetic parameter Terminal elimination half-life (t1/2) of Infigratinib following oral administration of Infigratinib in patients. | Approximately 5 months. | 
| Accumulation ratio (Racc) | To characterize the pharmacokinetic parameter Accumulation ratio (Racc) of Infigratinib following oral administration of Infigratinib in patients. | Approximately 5 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer, Receptors, Fibroblast Growth Factor, Gastroesophageal Junction, Solid tumor