An Efficacy and Safety Study of Erdafitinib (JNJ-42756493) in Participants With Urothelial Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the objective response rate (complete response [CR]+ partial response [PR]) of the selected dose regimen in participants with metastatic or surgically unresectable urothelial cancers that harbor specific FGFR genomic alterations.

Detailed Description
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This is a multicenter, open-label study (participants will know the identity of study drugs administered) to evaluate the efficacy and safety of erdafitinib in participants with urothelial cancer. The study comprises a 30-days Screening Phase, a Treatment Phase comprised of 28-day treatment cycles that will continue until disease progression or unacceptable toxicity occurs in a long-term extension (LTE) phase, and a post-treatment Follow-up Phase that will extend from the End-of-Treatment Visit until the participant has died, withdraws consent, is lost to follow-up, or the end of the study, whichever comes first. The end of study is defined as the date when all participants have completed the study treatment (Regimens 1 to 3) and all participants enrolled under the drug-drug interaction (DDI) substudy are no longer receiving treatment with erdafitinib. The purpose of DDI sub-study is to evaluate the interaction of repeated doses of erdafitinib with a sensitive cytochrome 450 (CYP) 3A substrate (midazolam) and with an organic cation transporter 2 (OCT2) probe substrate (metformin). Safety will be monitored throughout the study.

Official Title
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A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two Different Dose Regimens of a Pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects With Metastatic or Surgically Unresectable Urothelial Cancer With FGFR Genomic Alterations

Conditions
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Urothelial Cancer

Intervention / Treatment
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* Drug: Erdafitinib
* Drug: Midazolam
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have histologic demonstration of metastatic or surgically unresectable urothelial cancer. Minor components of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable Must have measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) at baseline Must have an Eastern Cooperative Oncology Group (ECOG) performance status score 0, 1, or 2 Must have adequate bone marrow, liver, and renal function as described in protocol Negative pregnancy test (urine or serum beta human chorionic gonadotropin [b-hCG]) at Screening for women of child bearing potential who are sexually active Must have shown disease progression according to RECIST, version 1.1, following prior chemotherapy for metastatic or surgically unresectable urothelial cancer. Participants who received neoadjuvant or adjuvant chemotherapy and showed disease recurrence or progression according to RECIST, version 1.1, within 12 months of the last dose are considered to have received chemotherapy in the metastatic setting. These participants will be referred to as chemo-refractory participants. (Participants who have shown disease progression according to RECIST, version 1.1 following prior treatment with anti-Programmed death-ligand 1 (anti PDL1/PD1) antibodies are also eligible) For DDI substudy Disease progression following prior chemotherapy for metastatic or surgically unresectable urothelial cancer. Participants who received neoadjuvant or adjuvant chemotherapy and showed disease recurrence or progression within 12 months of the last dose are considered to have received chemotherapy in the metastatic setting Exclusion Criteria: Received chemotherapy, targeted therapies, definitive radiotherapy, or treatment with an investigational anticancer agent within 2 weeks (in the case of nitrosoureas and mitomycin C, within 6 weeks; in the case of immunotherapy, within 4 weeks) before the first administration of study drug. Localized palliative radiation therapy (but should not include radiation to target lesions) and ongoing bisphosphonates and denosumab, are permitted Has persistent phosphate level greater than upper limit of normal (ULN) during screening (within 14 days of treatment and prior to Cycle 1 Day 1) and despite medical management Has a history of or current uncontrolled cardiovascular disease Females who are pregnant, breast-feeding, or planning to become pregnant within 3 months after the last dose of study drug and males ho plan to father a child while enrolled in this study or within 5 months after the last dose of study drug Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, or Grade 1 neuropathy)

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erdafitinib (8 milligram)<br>Prior to interim analysis 1 (IA1), there were 2 treatment regimens: Regimen 1 (10 milligram [mg] once daily, 7 days on/7 days off); and Regimen 2 (6 mg once daily for 28 days). Following IA1, Regimen 1 is closed for further enrollment and starting dose of Regimen 2 is increased to 8 mg once daily for 28 days on a 28-day cycle (referred to as Regimen 3). Participants who enrolled in DDI substudy will receive pretreatment with single doses of midazolam (Day -2) and metformin (Day -1). Participants enrolled in DDI substudy will receive 8 mg erdafitinib treatment from Day 1 to Day 15, single doses of midazolam 2.5 mg (Day 13) and metformin 1000 mg (Day 14) and erdafitinib treatment will continued until disease progression. Participants who completed the DDI substudy and continue to benefit from erdafitinib treatment, will continue to receive erdafitinib in long-term extension (LTE) phase. | Drug: Erdafitinib<br>* 8 mg orally once daily for 28 days on a 28 day cycle.<br>* Other names: JNJ-42756493;Drug: Midazolam<br>* Participants who enrolled in DDI substudy will receive pretreatment with single dose of midazolam on Day -2 and single dose of midazolam on Day 13.<br>Drug: Metformin<br>* Participants who enrolled in DDI substudy will receive pretreatment with single dose of metformin on Day -1 and single dose of metformin on Day 14.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Study: Percentage of Participants With Best (Overall) Objective Response | Percentage of participants with best (overall) objective response were reported. Best objective response is defined as the best (overall) objective response a participants achieved during the study in the order of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), where CR and PR were confirmed as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. As per RECIST version 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in the short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responders are participants with BOR of CR or PR. | From Cycle 1 Day 1 up to 6 years 2 months | 
| Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone or in Combination With Erdafitinib | Cmax is the maximum observed plasma concentration of midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose | 
| Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib | Cmax is the maximum observed plasma concentration of 1-OH-Midazolam (midazolam metabolite) alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Metformin Alone or in Combination With Erdafitinib | Cmax is the maximum observed plasma concentration of metformin alone or in combination with erdafitinib | Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Midazolam Alone or in Combination With Erdafitinib | Tmax is the time to reach the maximum observed plasma concentration of midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib | Tmax is the time to reach the maximum observed plasma concentration of 1-OH-Midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Metformin Alone or in Combination With Erdafitinib | Tmax is the time to reach maximum observed plasma concentration of metformin alone or in combination with erdafitinib | Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC[0-last]) of Midazolam Alone or in Combination With Erdafitinib | AUC(0-last) is the area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration of midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC[0-last]) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib | AUC(0-last) is the area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration of 1-OH-Midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC[0-last]) of Metformin Alone or in Combination With Erdafitinib | AUC(0-last) is the area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration of metformin alone or in combination with erdafitinib. | Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Infinite Time (AUC[0-Infinity]) of Midazolam Alone or in Combination With Erdafitinib | AUC(0-Infinity) is the area under the plasma concentration versus time curve from time 0 to the infinite time of midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Infinite Time (AUC[0-Infinity]) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib | AUC(0-Infinity) is the area under the plasma concentration versus time curve from time 0 to the infinite time of 1-OH-Midazolam alone or in combination with erdafitinib. | Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) | 
| Drug-Drug Interaction (DDI) Substudy: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Infinite Time (AUC[0-Infinity]) of Metformin Alone or in Combination With Erdafitinib | AUC(0-Infinity) is the area under the plasma concentration versus time curve from time 0 to the infinite time of metformin alone or in combination with erdafitinib | Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Study: Progression-free Survival (PFS) | Progression-free survival is defined as the duration from the date of the first dose of study drug until the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death due to any cause, whichever occurs first, regardless of the use of subsequent anticancer therapy. As per RECIST version 1.1, CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must had reduction in the short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From screening up to 6 years 2 months | 
| Main Study: Duration of Response (DoR) | DOR is defined as the time (in months) from the date of first observation of response (PR or CR) to the date of the first observation of progression or date of death, whatever the cause based on the RECIST version 1.1. CR: disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis <10 mm. PR: at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From screening up to 6 years 2 months | 
| Main Study: Overall Survival | Overall survival is defined as the time from the date of first dose of study drug to the date of the participant's death from any cause. | From screening up to 6 years 2 months | 
| Main Study: Percentage of Participants With Treatment-emergent Adverse Event (TEAEs) | Percentage of participants with TEAEs were reported. 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. TEAEs are those events that occurred from first dose date through 30 days after last dose date, or day before subsequent anticancer therapy, whichever occurs first. | From Day 1 up to 6 years 2 months | 
| Main Study: Plasma Concentration of Erdafitinib at 2 Hours (C2h) | C2h is the plasma concentration of erdafitinib at 2 hours. | Cycle 1 Days 1 and 21: Pre-dose up to 2 hours post-dose (each cycle length=28 days) | 
| Main Study: Plasma Concentration of Erdafitinib at 4 Hours (C4h) | C4h is the plasma concentration of erdafitinib at 4 hours. | Cycle 1 Days 1 and 21: Pre-dose up to 4 hours post-dose (each cycle length=28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial Cancer, JNJ-42756493, Erdafitinib, Tyrosine Kinase Inhibitor