A Study of Erdafitinib in Participants With Metastatic or Locally Advanced Urothelial Cancer

Study Overview
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Brief Summary
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The purpose of this study is to: (a) characterize the safety and tolerability of and to identify the recommended Phase 2 dose (RP2D) and schedule for erdafitinib in combination with cetrelimab, and for erdafitinib in combination with cetrelimab and platinum (cisplatin and carboplatin) chemotherapy and; (b) to evaluate the safety and clinical activity of erdafitinib alone and in combination with cetrelimab in cisplatin-ineligible participants with metastatic or locally advanced urothelial cancer (UC) with select fibroblast growth factor receptor (FGFR) gene alterations and no prior systemic therapy for metastatic disease.

Detailed Description
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This open-label (all people know identity of intervention) and multicenter (when more than one hospital or medical school team work on a medical research study) study to establish the recommended phase 2 dose (RP2D) for erdafitinib and cetrelimab and/or platinum (cisplatin or carboplatin) chemotherapy, and to evaluate the safety of erdafitinib in combination with cetrelimab and platinum chemotherapy in Phase 1b and to evaluate the safety and efficacy of the RP2D of erdafitinib plus cetrelimab versus erdafitinib in Phase 2 in participants with advanced urothelial cancer with select fibroblast growth factor receptor (FGFR) gene alterations. Participants enrolled in Phase 1b erdafitinib + cetrelimab cohort may have received any number of lines of prior therapy, and participants enrolled in Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort will have had no prior systemic therapy for metastatic disease and participants enrolled in Phase 2 will have had no prior systemic therapy for metastatic disease and will be cis-ineligible. Part 1 (Phase 1b: Dose Escalation) will identify safety and RP2Ds of erdafitinib + cetrelimab and erdafitinib + cetrelimab + platinum (cisplatin or carboplatin) chemotherapy, and Part 2 (Phase 2: Dose Expansion) will evaluate erdafitinib monotherapy and the RP2D regimen of the erdafitinib + cetrelimab combination to further characterize safety and clinical activity. The study will be conducted in 3 phases: screening phase, treatment phase, and follow-up phase. Study evaluations include efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, biomarkers, and safety.

Official Title
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A Phase 1b-2 Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Various Regimens of Erdafitinib in Subjects With Metastatic or Locally Advanced Urothelial Cancer

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: Erdafitinib
* Drug: Cetrelimab
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic demonstration of transitional cell carcinoma of the urothelium. Variant urothelial carcinoma histologies such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable Metastatic or locally advanced urothelial cancer Must have measurable disease by radiological imaging according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) at baseline Prior systemic therapy for metastatic urothelial cancer: (a) For Phase 1b erdafitinib + cetrelimab cohort: Any number of lines of prior therapy; (b) For Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort: No prior systemic therapy for metastatic disease; and renal function for participants must have a creatinine clearance (CrCl) greater than (>) 30 milliliter per minute (mL/min) to receive carboplatin and >60 mL/min to receive cisplatin as calculated by Cockcroft Gault and (c) Phase 2: No prior systemic therapy for metastatic disease and cisplatin-ineligible based on: ECOG PS 0-1 and at least one of the following criteria: Renal function defined as creatinine clearance (CrCl) less than (˂) 60 mL/min as calculated by Cockcroft-Gault; Grade 2 or higher peripheral neuropathy per NCI-CTCAE version 5.0; Grade 2 or higher hearing loss per NCI-CTCAE version 5.0 OR ECOG PS 2 Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade of: (a) Phase 1b erdafitinib + cetrelimab cohort: ECOG 0-2; (b) Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort: ECOG 0-1 for cisplatin and 0-2 for carboplatin (c) Phase 2: ECOG 0-2 Exclusion Criteria: Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to Cycle 1 Day 1. For Phase 1b, participants who have received the following prior antitumor therapy: received nitrosoureas and mitomycin C within 6 weeks Phase 1b erdafitinib + cetrelimab cohort: Chemotherapy within 3 weeks of Cycle 1 Day 1; Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort and Phase 2: Prior neoadjuvant/adjuvant chemotherapy is allowed if the last dose was given >12 months prior to recurrent disease progression and did not result in drug-related toxicity leading to treatment discontinuation Prior anti-programmed death receptor-1 (PD-1), anti-programmed death ligand-1 (PD-L1), or anti-programmed death ligand-2 (PD-L2) therapy. Prior neoadjuvant/adjuvant checkpoint inhibitor therapy is allowed if the last dose was given more than (>)12 months prior to recurrent disease progression and did not result in drug-related toxicity leading to treatment discontinuation. PD-1 for non-muscle invasive bladder cancer is also allowed Active malignancies requiring concurrent therapy other than urothelial cancer Symptomatic central nervous system metastases

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Dose Escalation<br>Two dosing cohorts (erdafitinib and cetrelimab; and erdafitinib, cetrelimab and cisplatin/carboplatin) are explored in Phase 1b of the study. Participants will receive erdafitinib orally followed by cetrelimab intravenously (IV) and carboplatin/cisplatin IV as a part of platinum chemotherapy. The dose levels will be escalated sequentially based on the decisions of the Study Evaluation Team (SET) until the recommended Phase 2 Dose (RP2D) has been identified. | Drug: Erdafitinib<br>* Participants will receive erdafitinib orally.<br>* Other names: JNJ-42756493;Drug: Cetrelimab<br>* Participants will receive cetrelimab by intravenous infusion.<br>* Other names: JNJ-63723283;Drug: Cisplatin<br>* Participants will receive cisplatin by intravenous infusion as a part of platinum chemotherapy.<br>Drug: Carboplatin<br>* Participants will receive carboplatin by intravenous infusion as a part of platinum chemotherapy.<br>|
| Experimental: Phase 2: Dose Expansion<br>The participants will be randomized in a 1:1 manner to receive either erdafitinib alone (orally) or the identified RP2D of Phase 1b for erdafitinib (orally) in combination with cetrelimab (IV). | Drug: Erdafitinib<br>* Participants will receive erdafitinib orally.<br>* Other names: JNJ-42756493;Drug: Cetrelimab<br>* Participants will receive cetrelimab by intravenous infusion.<br>* Other names: JNJ-63723283;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose-Limiting Toxicity (DLTs) | Number of participants with DLTs were reported. The DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE version 5.0) are specific adverse events defined as grade 3 (severe), grade 4 (life-threatening), and grade 5 (death) non-hematological toxicity or hematological toxicity. | Up to 8 weeks | 
| Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Investigator Assessment | ORR is defined as the percentage of participants who achieved confirmed complete response (CR) or confirmed partial response (PR), according to response evaluation criteria in solid tumors (RECIST) version1.1. As per RECIST version 1.1, CR: disappearance of all lesions; all lymph nodes were non-pathological in size and normalization of tumor marker level; PR: greater than or equal to (>=) 30 percent (%) decrease in the sum of the diameters of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of nontarget lesions. | From Day 1 up to 36 months | 
| Phase 2: Number of Participants With Treatment-emergent Adverse Event (TEAEs) | Number of participants with TEAEs were reported. An adverse event is any untoward medical event that occurs in a participant administered an investigational product and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs were defined as adverse events with onset or worsening on or after date of first dose of study treatment. | From Day 1 up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and Phase 2: Plasma Concentration of Erdafitinib |  | Up to 6 years 1 month | 
| Phase 1b and Phase 2: Serum Concentration of Cetrelimab |  | Up to 6 years 1 month | 
| Phase 1b: Plasma Concentration of Platinum (Cisplatin and Carboplatin) Chemotherapy |  | Up to 6 years 1 month | 
| Phase 1b and Phase 2: Number of Participants With Anti-Cetrelimab Antibodies |  | Up to 6 years 1 month | 
| Phase 2: Number of Participants With Serious Adverse Events (SAEs) |  | Up to 6 years 1 month | 
| Phase 2: Number of Participants With Abnormal Laboratory Values |  | Up to 6 years 1 month | 
| Phase 2: Duration of Response (DoR) |  | Up to 6 years 1 month | 
| Phase 2: Time to Response (TTR) |  | Up to 6 years 1 month | 
| Phase 2: Progression-free Survival (PFS) |  | Up to 6 years 1 month | 
| Phase 2: Overall Survival (OS) |  | Up to 6 years 1 month |