Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Glioblastoma or Other Primary Central Nervous System Tumors Harboring Activating FGFR1-3 Alterations

Study Overview
=================
Brief Summary
-----------------
This is an open-label, monotherapy study of pemigatinib in participants with recurrent glioblastoma (GBM) or other recurrent gliomas, circumscribed astrocytic gliomas, and glioneuronal and neuronal tumors with an activating FGFR1-3 mutation or fusion/rearrangement. This study consists of 2 cohorts, Cohorts A, and B, and will enroll approximately 82 participants into each cohort. Participants will receive pemigatinib 13.5 mg QD on a 2-week on-therapy and 1-week off-therapy schedule as long as they are receiving benefit and have not met any criteria for study withdrawal.

Official Title
-----------------
A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Glioblastoma or Other Primary Central Nervous System Tumors Harboring Activating FGFR1-3 Alterations (FIGHT-209)

Conditions
-----------------
Glioblastoma, Adult-type Diffuse Gliomas

Intervention / Treatment
-----------------
* Drug: Pemigatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological, cytological, or molecular confirmation of recurrent GBM or other glioma, circumscribed astrocytic glioma, or glioneuronalor neuronal tumors that has recurred. Radiographically measurable disease. . -Karnofsky performance status ≥ 60. Life expectancy ≥ 12 weeks. Documentation of an actionable FGFR1-3 gene mutation or fusion/rearrangement from tissue : FGFR1-3 fusions or other rearrangements (FGFR1-3 in-frame fusions, any FGFR2 rearrangement, or FGFR1/3 rearrangement with known partner) or a defined FGFR1-3 activating mutation or in-frame deletion. Only participants with FGFR fusions or rearrangements with an intact kinase domain are eligible. MRI-documented objective progression after prior therapy and must have no therapy available that is likely to provide clinical benefit. Most recent archival tumor specimen must be a tumor block or a minimum of 15 unstained slides from biopsy or resection of primary tumor or metastasis. Willingness to avoid pregnancy or fathering children. Exclusion Criteria: Prior receipt of an FGFR inhibitor. Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of study drug. Participants may have had treatment for an unlimited number of prior relapses but must not have had prior bevacizumab or other VEGF/VEGFR inhibitors (exception: prior bevacizumab is allowed if it was administered for the treatment of radiation necrosis rather than progressive tumor and was stopped at least 12 weeks prior to MRI showing tumor progression). Concurrent anticancer therapy Candidate for potentially curative surgery. Dexamethasone (or equivalent) > 4 mg daily at the time of study registration Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. Diffuse leptomeningeal disease. Radiation therapy administered within 12 weeks before enrollment/first dose of study drug. Known additional malignancy that is progressing or requires active systemic treatment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study consists of 2 cohorts and participants will receive pemigatinib 13.5 mg QD on a 2-week on-therapy and 1-week off-therapy schedule.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: IDH-wild-type GBM<br>Participants with histopathologically proven, WHO Grade 4, IDH-wild-type GBM OR molecular diagnosis of IDH-wild-type, diffuse astrocytic glioma with molecular features of Grade 4 GBM that are recurrent, harboring FGFR1-3 fusions/or other rearrangements, or with a defined FGFR1-3 mutation or in-frame deletion. | Drug: Pemigatinib<br>* 13.5mg tablet taken every morning (unless otherwise directed) for 2 weeks and then 1 week off.<br>* Other names: NCB054828;|
| Experimental: Cohort B: Other gliomas other than GBM<br>Participants with other histopathologically proven gliomas other than GBM, circumscribed astrocytic gliomas, and glioneuronal and neuronal tumors that are recurrent, harboring FGFR1-3 fusions/or other rearrangements or with a defined FGFR1-3 activating mutation or in-frame deletion | Drug: Pemigatinib<br>* 13.5mg tablet taken every morning (unless otherwise directed) for 2 weeks and then 1 week off.<br>* Other names: NCB054828;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Overall Response Rate (ORR) | Defined as the proportion of participants in Cohort A who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Assessment in Neuro-Oncology (RANO) as determined by an Independent Central Radiology (ICR). | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort B : ORR | Defined as the proportion of participants who achieve a CR or PR based on RANO. Response will be determined by an ICR review. | up to 3 months | 
| Cohorts A and B combined: ORR | Defined as the proportion of participants in Cohorts A and B who achieve a BOR of CR or PR based on RANO as determined by an ICR. | Up to 3 months | 
| Cohorts A and B: Disease Control Rate (DCR) | Defined as the proportion of participants who achieve a CR, PR, or SD as assessed by ICR in cohorts A and B respectively | Up to 3 months | 
| Cohorts A and B: Progression-Free Survival (PFS) | Defined as the time from first dose until progressive disease (according to RANO and assessed by an ICR) or death (whichever occurs first) in cohorts A and B, respectively | Up to 3 months | 
| Cohorts A and B: Overall Survival (OS) | Defined as the time from first dose of study drug to death due to any cause in cohorts A and B respectively | Up to 3 months | 
| Safety and tolerability | Safety and tolerability in each cohort, assessed by monitoring the frequency and severity of AEs according to NCICTCAE v5.0. | Up to 3 months | 
| Cohorts A and B : Duration Of Response (DOR) | Defined as the time from first assessment of Complete Response (CR) or Partial Response (PR) until progressive disease (according to RANO and assessed by an ICR), or death (whichever occurs first) in cohorts A and B, respectively | up to 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
glioblastoma, GBM, adult-type diffuse gliomas, gliomas, oligodendroglioma, FGFR1-3 Alteration, FGFR1-3 fusions, FGFR1-3 rearrangements, Central nervous system tumor, isocitrate dehydrogenase, IDH-mutant astocytoma, IDH-wild-type GBM, glioneuronal, neuronal, circumscribed astrocytic glioma