Testing the Anti-cancer Drug Erdafitinib for Brain Cancers That Have Returned or Progressed Following Treatment

Study Overview
=================
Brief Summary
-----------------
This phase II trial tests how well erdafitinib works in controlling IDH-wild type (WT) gliomas with FGFR-TACC gene fusion that have returned or that have grown, spread, or gotten worse (progressed). Erdafitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein that signals tumor cells to multiply. This may help keep tumor cells from growing and may kill them. Giving erdafitinib may help to slow the growth of or to shrink tumor cells in patients with recurrent or progressive IDH-wild type gliomas with FGFR-TACC gene fusion.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To assess the preliminary anti-tumor activity of erdafitinib in patients with recurrent or progressive IDH-WT glioma with FGFR-TACC gene fusion as measured by the best response at any time during treatment in terms of objective response rate (ORR). SECONDARY OBJECTIVES: I. To determine the safety and tolerability of erdafitinib in patients with recurrent or progressive IDH-WT glioma with FGFR-TACC gene fusion. II. To assess the overall survival (OS) of erdafitinib in patients with recurrent or progressive IDH-WT glioma with FGFR-TACC gene fusion. III. To assess the progression free survival (PFS) at 6 months of patient with IDH-WT glioma with FGFR-TACC gene fusion treated with erdafitinib. OUTLINE: This is a dose-escalation study of erdafitinib followed by a dose-expansion study. Patients receive erdafitinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI), optical coherence tomography (OCT), and collection of blood samples throughout the trial. After study completion, patients are followed up every 3 months for 2 years.

Official Title
-----------------
A Phase 2 Study of Erdafitinib in Patients With Recurrent or Progressive IDH-Wild Type Glioma With an FGFR-TACC Gene Fusion

Conditions
-----------------
Recurrent Glioblastoma, IDH-Wildtype, Recurrent WHO Grade 2 Glioma, Recurrent WHO Grade 3 Glioma

Intervention / Treatment
-----------------
* Procedure: Biospecimen Collection
* Drug: Erdafitinib
* Procedure: Magnetic Resonance Imaging
* Procedure: Optical Coherence Tomography


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient must be >= 18 years of age Patient must have histologically confirmed IDH-WT gliomas (grade 2-4) as per World Health Organization (WHO) 2016 or 2021 classification Tumor tissue should be positive for FGFR-TACC gene fusion as per any local next generation sequencing (NGS) (Clinical Laboratory Improvement Act [CLIA]-approved) assay described in background section The disease should be recurrent or progressive glioma after initial anti-tumor treatment with at least 1 line of treatment including surgical resection, radiation therapy and/or chemotherapy. For patients with WHO grade 3 or 4 glioma and progressive disease < 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria: New enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line) If there is unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas. i.e., > 70% tumor cell nuclei in areas), high or progressive increase in Ki-67 proliferation index compared with prior biopsy, or evidence for histologic progression or increased anaplasia in tumor). For patients with WHO grade 3 or 4 glioma and progressive disease >= 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria: New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids Increase by >= 25% in the sum of the products of perpendicular diameters between the first post-radiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 weeks or later on stable or increasing doses of corticosteroids For patients receiving antiangiogenic therapy, significant increase in T2/FLAIR non-enhancing lesion may also be considered progressive disease. The increased T2/FLAIR must have occurred with the patient on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy and not be a result of comorbid events (e.g., effects of radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects). For patients with WHO grade 2 glioma progression is defined by any one of the following: Development of new lesions or increase of enhancement (radiological evidence of malignant transformation) A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not attributable to radiation effect or to comorbid events There must be measurable disease (enhancing or non-enhancing as per Response Assessment in Neuro-Oncology [RANO] or RANO-low-grade glioma [LGG] criteria), as evaluated on pre-treatment MRI Patient understands the procedures and investigational nature of the study drug and agrees to comply with study requirements by providing written informed consent Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%) Absolute neutrophil count >= 1000/uL Hemoglobin > 8 g/dL (Patients are allowed to be transfused to this level) Platelets >= 100 x 10^9/L Serum total bilirubin =< 1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or disease involvement following approval by the medical monitor Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN Creatinine clearance > 30 mL/min (patients with mild or moderate renal impairment) based on the Cockroft-Gault glomerular filtration rate (GFR) estimation Patient must have normal serum phosphate level as per local laboratory parameters. (Medical management allowed) Patient must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or chemotherapy treatment with temozolomide Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients should be New York Heart Association Functional Classification class 2B or better The effects of erdafitinib on the developing human fetus are unknown. For this reason and because FGFR inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and one month after completion of erdafitinib administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and one month after completion of erdafitinib administration Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants Exclusion Criteria: Patients who are receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to erdafitinib Patients requiring any medications or substances that are moderate CYP2C9 inducers and strong CYP3A4 inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product Patients with uncontrolled intercurrent illness Pregnant women are excluded from this study because erdafitinib is an FGFR inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with erdafitinib, breastfeeding should be discontinued if the mother is treated with erdafitinib Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade Corrected QT interval (QTc) prolongation as confirmed by electrocardiography (ECG) at screening (Fridericia; QTc > 480 milliseconds) Patients who have previously received FGFR inhibitors

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

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (erdafitinib)<br>Patients receive erdafitinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, OCT, and collection of blood samples throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Drug: Erdafitinib<br>* Given PO<br>* Other names: JNJ-42756493;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Optical Coherence Tomography<br>* Undergo OCT<br>* Other names: Optical Coherence Tomography (OCT);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Defined as the proportion of patients with either complete response or partial response as per Response Assessment in Neuro-Oncology (RANO) criteria. The response rate will be estimated along with the corresponding 95% confidence interval using the binomial exact method. Univariable and multivariable logistic regression models will be used to estimate the associations between study covariates and response status. Odds ratios (ORs) and corresponding 95% confidence intervals and p-values will be reported. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Analyzed based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. | Up to 28 days | 
| Incidence of adverse events (AEs) and serious AEs | Analyzed based on NCI CTCAE version 5.0. | Up to 2 years | 
| Progression-free survival (PFS) | PFS is defined as the elapsed time between the date of enrollment and the date of progression or date of death from any cause. Alive patients without progression will be censored at the last date of follow-up. Kaplan-Meier method will be used to estimate survival rates for pre-specified time points along with 95% confidence intervals. Hazard ratios (HRs) will be estimated using Cox proportional hazards regression model to examine the associations of study covariates with time-to-event outcomes along with corresponding 95% confidence intervals and p-values if these are estimable. | Time between date of enrollment and date of progression or date of death from any cause, assessed at 6 months | 
| Overall survival (OS) | Kaplan-Meier method will be used to estimate survival rates for pre-specified time points along with 95% confidence intervals. Hazard ratios (HRs) will be estimated using Cox proportional hazards regression model to examine the associations of study covariates with time-to-event outcomes along with corresponding 95% confidence intervals and p-values if these are estimable. | Time between the date of enrollment and date of death from any cause, censored at the last date of follow-up, assessed up to 2 years |