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 (THOR)

• ClinicalTrials.gov Identifier: NCT03390504
• Recruitment Status: Active, not recruiting
• First Posted: January 4, 2018
• Last Update Posted: April 25, 2024
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: December 20, 2017
• First Posted Date: January 4, 2018
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: March 23, 2018
• Estimated Primary Completion Date: September 11, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2018)

Overall Survival (OS) [ Time Frame: Date of first randomization to the date of participant's death (approximately up to 3 years) ]

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: April 23, 2021)

• Progression-free Survival (PFS) [ Time Frame: 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) ]
  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.
• Overall Response Rate (ORR) [ Time Frame: Approximately up to 3 years ]
  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.
• Change from Baseline in Participant-Reported Health Status and Physical Functioning Scales of the Functional Assessment of Cancer Therapy (FACT-Bl) [ Time Frame: Baseline up to end of treatment (approximately 3 years) ]
  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.
• Time Until Symptom Deterioration (Subset of FACT-BI Items) [ Time Frame: Baseline up to end of treatment (approximately 3 years) ]
  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.
• Change from Baseline in Patient-Global Impression of Severity (PGIS) Score [ Time Frame: Baseline up to end of treatment (approximately 3 years) ]
  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.
• Change from Baseline in the Visual Analog Scale (VAS) of the EQ-5D-5L [ Time Frame: Baseline up to follow up phase (approximately 3 years) ]
  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.
• Change from Baseline in the Utility Scale of the EQ-5D-5L [ Time Frame: Baseline up to follow up phase (approximately 3 years) ]
  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.
• Duration of Response (DOR) [ Time Frame: 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) ]
  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.
• Number of Participants with Adverse Events (AEs) as a Measure of Safety [ Time Frame: Approximately up to 3 years ]
  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.
• Oral Clearance (CL/F) of Erdafitinib [ Time Frame: Day 14 (Cycle 1), Day 1 (Cycle 2) (each cycle is of 21 days) ]
  CL/F is the oral clearance; that is clearance based on oral bioavailability of erdafitinib.
• Area Under the Plasma Concentration-Time Curve from Time Zero to Time 't' (AUC[0-t]) of Erdafitinib [ Time Frame: Day 14 (Cycle 1), Day 1 (Cycle 2) (each cycle is of 21 days) ]
  AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't' of erdafitinib.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: A Phase 3 Study of Erdafitinib Compared With Vinflunine or Docetaxel or Pembrolizumab in Subjects With Advanced Urothelial Cancer and Selected FGFR Gene Aberrations
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urothelial Cancer

Intervention

• Drug: Erdafitinib
  Participants will swallow erdafitinib tablets orally at a starting dose of 8 mg.
  Other Name: JNJ-42756493
• Drug: Vinflunine
  Participants will receive vinflunine 320 mg/m^2 as a 20-minute intravenous infusion.
• Drug: Docetaxel
  Participants will receive docetaxel 75 mg/m^2 as a 1 hour intravenous infusion.
• Drug: Pembrolizumab
  Participants will receive pembrolizumab 200 mg as a 30-minute intravenous infusion.
• Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)
  FGFRi CTA will be used to determine molecular eligibility.

Study Arms

• Experimental: Cohort 1 (Arm 1A): Erdafitinib
  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.
  Interventions:

  • Drug: Erdafitinib
  • Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)
• Experimental: Cohort 1 (Arm 1B): Vinflunine or Docetaxel
  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.
  Interventions:

  • Drug: Vinflunine
  • Drug: Docetaxel
  • Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)
• Experimental: Cohort 2 (Arm 2A): Erdafitinib
  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.
  Interventions:

  • Drug: Erdafitinib
  • Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)
• Experimental: Cohort 2 (Arm 2B): Pembrolizumab
  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.
  Interventions:

  • Drug: Pembrolizumab
  • Device: Fibroblast Growth Factor Receptor inhibitor Clinical Trial Assay (FGFRi CTA)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 10, 2023): 629
• Original Enrollment: Not Provided
• Estimated Study Completion Date: November 1, 2026
• Estimated Primary Completion Date: September 11, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Czechia, Denmark, India, Lebanon, Thailand

Administrative Information

• NCT Number: NCT03390504
• Other Study ID Numbers: CR108401; 2017-002932-18 ( EudraCT Number ); 42756493BLC3001 ( Other Identifier: Janssen Research & Development, LLC ); 2023-509329-32-00 ( Registry Identifier: EUCT number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: [Redacted]
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: [Redacted]
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: April 2024