A Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Participants With Advanced Urothelial Cancer and Selected Fibroblast Growth Factor Receptor (FGFR) Gene Aberrations

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy of erdafitinib versus chemotherapy or pembrolizumab in participants with advanced urothelial cancer harboring selected fibroblast growth factor receptor (FGFR) aberrations who have progressed after 1 or 2 prior treatments, at least 1 of which includes an anti-programmed death ligand 1(PD-[L]1) agent (cohort 1) or 1 prior treatment not containing an anti-PD-(L) 1 agent (cohort 2).

Detailed Description
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A study of erdafitinib versus standard of care, consisting of chemotherapy (docetaxel or vinflunine) or anti-PD-(L) 1 agent pembrolizumab, in participants with advanced urothelial cancer and selected FGFR aberrations who have progressed on or after 1 or 2 prior treatments, at least 1 of which includes an anti-PD-(L) 1 agent (cohort 1) or 1 prior treatment not containing an anti-PD-(L) 1 agent (cohort 2). It will consist of screening, treatment phase (from randomization until disease progression, intolerable toxicity, withdrawal of consent or decision by investigator to discontinue treatment, post-treatment follow-up (from end-of-treatment to participants death, withdraws consent, lost to follow-up study completion for the respective cohort, whichever comes first). The study will have long term extension (LTE) period after clinical cutoff date is achieved for final analysis of each cohort and participants eligible in the opinion of the investigator, will continue to benefit from the study intervention. Efficacy, pharmacokinetics, biomarkers, patient reported outcomes, medical resource utilization and safety will be assessed.

Official Title
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A Phase 3 Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Subjects With Advanced Urothelial Cancer and Selected FGFR Gene Aberrations

Conditions
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Urothelial Cancer

Intervention / Treatment
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* Drug: Erdafitinib
* Drug: Vinflunine
* Drug: Docetaxel
* Drug: Pembrolizumab
* Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic demonstration of transitional cell carcinoma of the urothelium. Minor components ( less than [<] 50 percent [%] overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable Metastatic or surgically unresectable urothelial cancer Documented progression of disease, defined as any progression that requires a change in treatment, prior to randomization Cohort 1: Prior treatment with an anti-PD-(L) 1 agent as monotherapy or as combination therapy; no more than 2 prior lines of systemic treatment. Cohort 2: No prior treatment with an anti-PD-(L) 1 agent; only 1 line of prior systemic treatment. Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose are considered to have received systemic therapy in the metastatic setting. A woman of childbearing potential who is sexually active must have a negative pregnancy test (beta human chorionic gonadotropin [beta hCG]) at Screening (urine or serum) Participants must meet appropriate molecular eligibility criteria Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2 Adequate bone marrow, liver, and renal function Exclusion Criteria: Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to randomization Active malignancies (that is, requiring treatment change in the last 24 months). The only allowed exceptions are: urothelial cancer, skin cancer treated within the last 24 months that is considered completely cured, localized prostate cancer with a gleason score of 6 (treated within the last 24 months or untreated and under surveillance) and localized prostate cancer with a gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence. Symptomatic central nervous system metastases Received prior fibroblast growth factor receptor (FGFR) inhibitor treatment Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade. History of uncontrolled cardiovascular disease Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Arm 1A): Erdafitinib<br>Participants will be screened based on Fibroblast Growth Factor Receptor Inhibitor Clinical Trial Assay (FGFRi CTA) to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-programmed cell death protein PD-[L] 1 agent) will swallow erdafitinib tablets orally at a starting dose of 8 milligram (mg), once daily for 21 days in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustment are based on phosphate level and observed toxicity (adverse events [AEs]). Participants who enter in Long-term extension (LTE) phase will continue to receive the erdafitinib tablet as per investigator's decision. | Drug: Erdafitinib<br>* Participants will swallow erdafitinib tablets orally at a starting dose of 8 mg.<br>* Other names: JNJ-42756493;Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)<br>* FGFRi CTA will be used to determine molecular eligibility.<br>|
| Experimental: Cohort 1 (Arm 1B): Vinflunine or Docetaxel<br>Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (treated with prior anti-PD-[L] 1 agent) will receive vinflunine 320 milligram per meter square (mg/m^2) as a 20-minute intravenous infusion once every 3 weeks or docetaxel 75 mg/m^2 as a 1 hour intravenous infusion every 3 weeks. Treatment with either agent (choice of investigator) will be administered until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive Vinflunine or Docetaxel until the participant can commercially receive chemotherapy within the local healthcare system. | Drug: Vinflunine<br>* Participants will receive vinflunine 320 mg/m^2 as a 20-minute intravenous infusion.<br>Drug: Docetaxel<br>* Participants will receive docetaxel 75 mg/m^2 as a 1 hour intravenous infusion.<br>Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)<br>* FGFRi CTA will be used to determine molecular eligibility.<br>|
| Experimental: Cohort 2 (Arm 2A): Erdafitinib<br>Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (no prior treatment with anti-PD-[L] 1 agent) will swallow erdafitinib tablets orally at a starting dose of 8 mg, once daily for 21 days in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on phosphate level and observed toxicity (AEs). Participants who enter in LTE phase will continue to receive the erdafitinib tablet as per investigator's decision. | Drug: Erdafitinib<br>* Participants will swallow erdafitinib tablets orally at a starting dose of 8 mg.<br>* Other names: JNJ-42756493;Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)<br>* FGFRi CTA will be used to determine molecular eligibility.<br>|
| Experimental: Cohort 2 (Arm 2B): Pembrolizumab<br>Participants will be screened based on FGFRi CTA to determine molecular eligibility and participants who meet molecular eligibility criteria will be eligible for full study screening. Participants enrolled in the study (no prior treatment with anti-PD-[L] 1 agent) will receive pembrolizumab 200 mg as a 30-minute intravenous infusion once every 3 weeks, until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment. Dose adjustments are based on observed toxicities. Participants who enter in LTE phase will continue to receive the pembrolizumab until 2 years after the first dose of pembrolizumab (at start of study) or until the participant can commercially receive pembrolizumab within the local healthcare system, whichever comes first. | Drug: Pembrolizumab<br>* Participants will receive pembrolizumab 200 mg as a 30-minute intravenous infusion.<br>Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)<br>* FGFRi CTA will be used to determine molecular eligibility.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is measured from the date of randomization to the date of the participant's death. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant was last known to be alive. | Date of first randomization to the date of participant's death (approximately up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is defined as duration in days from date of randomization to disease progression date (assessed per Response Evaluation Criteria in Solid Tumors Version 1.1 [RECIST v1.1] by investigator) or relapse from CR or death, whichever is reported first. RECIST 1.1, progressive disease is defined as a 20 percent (%) increase in the sum of diameters of all target lesions and a minimum absolute increase of 5 millimeter (mm) in the sum. CR is defined as disappearance of all target lesions, non-target lesions and normalization of tumor marker level. | Date of randomization to the date of disease progression or relapse from complete response (CR) or death, whichever is reported first (approximately up to 3 years) | 
| Overall Response Rate (ORR) | ORR is defined as the proportion of participants who achieve CR (CR; disappearance of all target lesions and disappearance of all non-target lesions and normalization of tumor marker level) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), as assessed per RECIST v1.1 by the investigator. | Approximately up to 3 years | 
| Change from Baseline in Participant-Reported Health Status and Physical Functioning Scales of the Functional Assessment of Cancer Therapy (FACT-Bl) | The FACT-Bl consists of 36 core items, with 5-point Likert response scales, covering 5 primary domains: Physical well-being, social/family well-being, emotional well-being, functional well-being, and bladder symptom subscale. The answer scales range from Not at all (score=0) to very much (score=4) to assess the meaningful significant symptom deterioration. | Baseline up to end of treatment (approximately 3 years) | 
| Time Until Symptom Deterioration (Subset of FACT-BI Items) | The FACT-Bl consists of 36 core items, with 5-point Likert response scales, covering 5 primary domains: Physical well-being, social/family well-being, emotional well-being, functional well-being, and bladder symptom subscale. The answer scales range from Not at all (score=0) to very much (score=4) to assess the meaningful significant symptom deterioration. | Baseline up to end of treatment (approximately 3 years) | 
| Change from Baseline in Patient-Global Impression of Severity (PGIS) Score | The PGIS is a single question regarding the participant report of disease severity. Participants will be asked that ''considering all aspects of your bladder cancer symptoms right now, would you say your bladder cancer symptoms are none, mild, moderate, severe, or very severe? The PGIS is an anchor question that will be used to establish the magnitude of meaningful change in this study by assessing disease severity. | Baseline up to end of treatment (approximately 3 years) | 
| Change from Baseline in the Visual Analog Scale (VAS) of the EQ-5D-5L | European Quality of Life 5 Dimensions (EQ-5D) visual analog scale (VAS) is a 20 centimeter (cm) vertical VAS with scores ranging from 0 (worst imaginable health) to 100 (perfect health). A higher score indicates an improvement in health in the Health Status Index. | Baseline up to follow up phase (approximately 3 years) | 
| Change from Baseline in the Utility Scale of the EQ-5D-5L | The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating full health and 0 representing dead. | Baseline up to follow up phase (approximately 3 years) | 
| Duration of Response (DOR) | DOR for responders is defined as duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease (PD) or relapse for participants who experience CR (CR; disappearance of all target lesions and disappearance of all non-target lesions and normalization of tumor marker level) during the study or death. | From the date of initial documentation of a response to date of first documented evidence of progressive disease (or participants relapse who experience CR during the study) or death (approximately up to 3 years) | 
| Number of Participants with Adverse Events (AEs) as a Measure of Safety | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Approximately up to 3 years | 
| Oral Clearance (CL/F) of Erdafitinib | CL/F is the oral clearance; that is clearance based on oral bioavailability of erdafitinib. | Day 14 (Cycle 1), Day 1 (Cycle 2) (each cycle is of 21 days) | 
| Area Under the Plasma Concentration-Time Curve from Time Zero to Time 't' (AUC[0-t]) of Erdafitinib | AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't' of erdafitinib. | Day 14 (Cycle 1), Day 1 (Cycle 2) (each cycle is of 21 days) |