A Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in Participants Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC)

• ClinicalTrials.gov Identifier: NCT04172675
• Recruitment Status: Recruiting
• First Posted: November 21, 2019
• Last Update Posted: May 6, 2023
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: November 20, 2019
• First Posted Date: November 21, 2019
• Last Update Posted Date: May 6, 2023
• Actual Study Start Date: February 28, 2020
• Estimated Primary Completion Date: March 29, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 20, 2019)

Recurrence-Free Survival (RFS) [ Time Frame: Up to 4 years ]

RFS is defined as the time from the date of randomization until the date of the reappearance of high-risk disease, or death, whichever is reported first.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 9, 2021)

• Time to Disease Worsening [ Time Frame: Up to 4 years ]
  Time from the date of randomization to the date of first documented evidence of cystectomy, change in therapy indicative of more advanced disease (including systemic chemotherapy or radiotherapy). Participants who are free of disease worsening and alive or have unknown status will be censored at the last tumor assessment.
• Time to Progression [ Time Frame: Up to 4 years ]
  Time from the date of randomization until the date of first documented evidence of any of progression or death. Participants who are progression -free and alive or have unknown status will be censored at the date of the last tumor assessment.
• Disease-Specific Survival [ Time Frame: Up to 4 years ]
  The time from the date of randomization to the date of the participant's death resulting from bladder cancer. Participants who are alive or have unknown vital status will be censored at the date the participant was last known to be alive. Participants whose death result from causes other than bladder cancer will be censored at their death dates.
• Overall Survival [ Time Frame: Up to 4 years ]
  The time from the date of randomization to the date of the participant's death resulting from any cause. Participants who are alive or have unknown vital status will be censored at the date the participant was last known to be alive.
• Recurrence-Free Survival [ Time Frame: Months 6, 12, and 24 ]
  RFS is defined as the time from the date of randomization until the date of the reappearance of high-risk disease, or death, whichever is reported first. Participants who are recurrence-free and alive or have unknown status will be censored at the last tumor assessment.
• Recurrence-Free Survival 2 (RFS2) [ Time Frame: Up to 4 years ]
  RFS2 is defined as the time from the date of randomization until the date of the reappearance of high-risk disease on the first subsequent non-surgical anticancer treatment, or death, whichever is reported first.
• RFS by Central Histopathologic Review [ Time Frame: Up to 4 years ]
  RFS will be assessed by central histopathologic review. RFS is defined as the time from the date of randomization until the date of the reappearance of high-risk disease, or death, whichever is reported first.
• Plasma Concentration of Erdafitinib [ Time Frame: Cycle 1 Day 14, Cycle 2 Day 1 (each cycle is of 28 days) ]
  Plasma concentration of erdafitinib will be reported.
• Number of Participants with Adverse events [ Time Frame: Up to 4 years ]
  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
• Change from Baseline in Patient's Global Impression of Severity (of cancer) (PGIS) [ Time Frame: Baseline up to 4 years ]
  PGIS is single-item questionnaires to evaluate patient's global impression of severity.
• Change from Baseline in Patient's Global Impression of Change (of cancer) (PGIC) [ Time Frame: Baseline, Cycle 2 Day 1 and end of treatment (up to 2 years) (each cycle is of 28 days) ]
  PGIC is single-item questionnaires to evaluate a patient's global impression of change of cancer.
• Change from Baseline in European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire (EORTC QLQ) -C30 [ Time Frame: Baseline up to 4 years ]
  EORTC QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies.
• Change from Baseline in EORTC QLQ- Non-Muscle-Invasive Bladder Cancer (NMIBC) 24 [ Time Frame: Baseline up to 4 years ]
  EORTC QLQ-NMIBC24 is a 24-item questionnaire for evaluating the HRQoL of participants with superficial (non-muscle-invasive) bladder cancer. The questionnaire is designed to supplement the QLQ-C30.
• Change from Baseline in EuroQol European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) [ Time Frame: Baseline up to 4 years ]
  EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression.

Original Secondary Outcome Measures (submitted: November 20, 2019)

• Time to Progression [ Time Frame: Up to 4 years ]
  Time from the date of randomization until the date of first documented evidence of any of progression or death. Participants who are progression -free and alive or have unknown status will be censored at the date of the last tumor assessment.
• Time to Disease Worsening [ Time Frame: Up to 4 years ]
  Time from the date of randomization to the date of first documented evidence of change in therapy indicative of more advanced disease. Participants who are free of disease worsening and alive or have unknown status will be censored at the last tumor assessment.
• Disease-Specific Survival [ Time Frame: Up to 4 years ]
  The time from the date of randomization to the date of the participant's death resulting from bladder cancer. Participants who are alive or have unknown vital status will be censored at the date the participant was last known to be alive. Participants whose death result from causes other than bladder cancer will be censored at their death dates.
• Overall Survival [ Time Frame: Up to 4 years ]
  The time from the date of randomization to the date of the participant's death resulting from any cause. Participants who are alive or have unknown vital status will be censored at the date the participant was last known to be alive.
• Recurrence-Free Survival [ Time Frame: Months 6, 12, and 24 ]
  RFS is defined as the time from the date of randomization until the date of the reappearance of high-risk disease, or death, whichever is reported first. Participants who are recurrence-free and alive or have unknown status will be censored at the last tumor assessment.
• Recurrence-Free Survival 2 (RFS2) [ Time Frame: Up to 4 years ]
  RFS2 is defined as the time from the date of randomization until the date of the reappearance of high-risk disease on the first subsequent non-surgical anticancer treatment, or death, whichever is reported first.
• RFS by Central Histopathologic Review [ Time Frame: Up to 4 years ]
  RFS will be assessed by central histopathologic review. RFS is defined as the time from the date of randomization until the date of the reappearance of high-risk disease, or death, whichever is reported first.
• Plasma Concentration of Erdafitinib [ Time Frame: Cycle 1 Day 14, Cycle 2 Day 1 (each cycle is of 28 days) ]
  Plasma concentration of erdafitinib will be reported.
• Number of Participants with Adverse events [ Time Frame: Up to 4 years ]
  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
• Change from Baseline in Patient's Global Impression of Severity (of cancer) (PGIS) [ Time Frame: Baseline up to 4 years ]
  PGIS is single-item questionnaires to evaluate patient's global impression of severity.
• Change from Baseline in Patient's Global Impression of Change (of cancer) (PGIC) [ Time Frame: Baseline, Cycle 2 Day 1 and end of treatment (up to 2 years) (each cycle is of 28 days) ]
  PGIC is single-item questionnaires to evaluate a patient's global impression of change of cancer.
• Change from Baseline in European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire (EORTC QLQ) -C30 [ Time Frame: Baseline up to 4 years ]
  EORTC QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies.
• Change from Baseline in EORTC QLQ- Non-Muscle-Invasive Bladder Cancer (NMIBC) 24 [ Time Frame: Baseline up to 4 years ]
  EORTC QLQ-NMIBC24 is a 24-item questionnaire for evaluating the HRQoL of participants with superficial (non-muscle-invasive) bladder cancer. The questionnaire is designed to supplement the QLQ-C30.
• Change from Baseline in EuroQol European Quality of Life - 5 Dimensions-5 Levels (EQ-5D-5L) [ Time Frame: Baseline up to 4 years ]
  EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression.
• Maximum Observed Analyte Concentration (Cmax) of Midazolam and its Metabolite (1-OH-Midazolam) [ Time Frame: Predose, Cycle 1 Day 13 (each cycle is of 28 days) ]
  Cmax is the maximum observed analyte concentration.
• Time to Reach Maximum Observed Analyte Concentration (Tmax) Midazolam and its Metabolite (1-OH-Midazolam) [ Time Frame: Predose, Cycle 1 Day 13 (each cycle is of 28 days) ]
  Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
• Area Under the Analyte Concentration Versus time Curve (AUC) from Time Zero to the Time of Last Measurable Analyte Concentration of Midazolam and its Metabolite (1-OH-Midazolam) [ Time Frame: Predose, Cycle 1 Day 13 (each cycle is of 28 days) ]
  AUClast defined as time zero to the time of the last measurable (non-below quantification limit [BQL]) analyte concentration.
• Area Under the Analyte Concentration Versus time Curve (AUC) from Time Zero to Infinite Time of Midazolam and its Metabolite (1-OH-Midazolam) [ Time Frame: Predose, Cycle 1 Day 13 (each cycle is of 28 days) ]
  AUCinfinity is defined as time zero to infinite time.
• Maximum Observed Plasma Concentration (Cmax) of Metformin [ Time Frame: Predose, Cycle 1 Day 14 (each cycle is of 28 days) ]
  Cmax is the maximum observed analyte concentration.
• Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin [ Time Frame: Predose, Cycle 1 Day 14 (each cycle is of 28 days) ]
  Tmax is defined as actual sampling time to reach maximum observed plasma concentration.
• Area Under the Analyte Concentration Versus time Curve (AUC) from Time Zero to the Time of Last Measurable of Metformin [ Time Frame: Predose, Cycle 1 Day 14 (each cycle is of 28 days) ]
  AUClast defined as time zero to the time of the last measurable (non-below quantification limit [BQL]) analyte concentration
• Area Under the Analyte Concentration Versus time Curve (AUC) from Time Zero to Infinite Time of Metformin [ Time Frame: Predose, Cycle 1 Day 14 (each cycle is of 28 days) ]
  AUCinfinity is defined as time zero to infinite time.

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

Descriptive Information

• Brief Title: A Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in Participants Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC)
• Official Title: A Randomized Phase 2 Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in Subjects Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) and FGFR Mutations or Fusions
• Brief Summary: The purpose of this study is to evaluate recurrence-free survival (RFS) in participants treated with erdafitinib vs Investigator's Choice, for participants with high-risk non-muscle-invasive bladder cancer (NMIBC) who harbor fibroblast growth factor receptor (FGFR) mutations or fusions, and who recurred after bacillus calmette-guerin (BCG) therapy.
• Detailed Description: This study enrolls participants with high risk NMIBC and FGFR mutations or fusions. Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) 1-4 inhibitor with demonstrated clinical activity in participants with solid tumors, including urothelial carcinoma, with alterations in the FGFR pathway. In Cohort 1, participants will be randomized to erdafitinib or to Investigators Choice (intravesical gemcitabine or intravesical MMC/hyperthermic MMC). The study consists of Screening period, Treatment Phase and Follow-up Phase.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urinary Bladder Neoplasms

Intervention

• Drug: Erdafitinib
  Participants will receive erdafitinib orally beginning on Cycle 1 Day 1 until 2 years of treatment have been completed, disease recurrence, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurs first. Each cycle is of 28 days.
  Other Name: JNJ-42756493
• Drug: Investigator Choice (Gemcitabine)
  Investigator's Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly maintenance for at least 6 months.
• Drug: Investigator Choice (Mitomycin C)
  Investigator's Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly maintenance for at least 6 months.

Study Arms

• Experimental: Cohort 1: Erdafitinib
  Participants with high-risk non-muscle-invasive bladder cancer (NMIBC) presenting as papillary tumor only (carcinoma in situ [CIS], absent), with disease recurrence after bacillus Calmette- Guerin (BCG) therapy will receive treatment with erdafitinib.
  Intervention: Drug: Erdafitinib
• Active Comparator: Cohort 1: Investigators Choice
  Participants with high-risk NMIBC presenting as papillary tumor only (CIS, absent), with disease recurrence after BCG therapy will receive the investigator's choice of either intravesical gemcitabine or intravesical mitomycin C (MMC)/hyperthermic MMC. Participants who are randomized to gemcitabine or MMC/hyperthermic MMC in Cohort 1 and demonstrate a recurrence via investigator disease assessment will have the opportunity to cross over to treatment with erdafitinib.
  Interventions:

  • Drug: Investigator Choice (Gemcitabine)
  • Drug: Investigator Choice (Mitomycin C)
• Experimental: Cohort 2
  Participants with high-risk, BCG- unresponsive NMIBC presenting as CIS with or without concurrent papillary tumor will receive treatment with erdafitinib.
  Intervention: Drug: Erdafitinib
• Experimental: Cohort 3
  Marker lesion study in intermediate-risk NMIBC presenting as papillary disease only. All enrolled participants will receive treatment with erdafitinib.
  Intervention: Drug: Erdafitinib

• Publications *: Han MA, Maisch P, Jung JH, Hwang JE, Narayan V, Cleves A, Hwang EC, Dahm P. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane Database Syst Rev. 2021 Jun 14;6(6):CD009294. doi: 10.1002/14651858.CD009294.pub3.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 5, 2022): 105
• Original Estimated Enrollment (submitted: November 20, 2019): 280
• Estimated Study Completion Date: March 29, 2024
• Estimated Primary Completion Date: March 29, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed, recurrent, non-muscle-invasive urothelial carcinoma of the bladder. Variant pathology are allowed
• Tumor with specified fibroblast growth factor receptor (FGFR) mutations or fusions
• Bacillus Calmette- Guerin (BCG)-unresponsive after adequate BCG therapy or BCG experienced participants
• Refuses or is not eligible for cystectomy (Cohort 1 and Cohort 2 only)
• Eastern Cooperative Oncology Group (ECOG) performance status Grade 0-1
• Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
• A woman of childbearing potential must have a negative pregnancy test (beta-hCG [beta-human chorionic gonadotropin]) (urine or serum) within 7 days before randomization (Cohort 1) or the first dose of study drug (Cohort 2 and Cohort 3)
• Adequate bone marrow, liver, and renal function as specified in the protocol

Exclusion Criteria:

• Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of the bladder
• Histopathology demonstrating any small cell component, pure adenocarcinoma, pure squamous cell carcinoma, or pure squamous CIS of the bladder
• Prior treatment with an FGFR inhibitor
• Active malignancies other than the disease being treated under study. The only allowed exceptions are: (a) skin cancer treated within the last 24 months that is considered completely cured (b) adequately treated lobular carcinoma in situ (LCIS) and ductal CIS (c) history of localized breast cancer and receiving antihormonal agents, or history of localized prostate cancer (N0M0) and receiving androgen deprivation therapy
• Current central serous retinopathy or retinal pigment epithelial detachment of any grade

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Contact; 844-434-4210; Participate-In-This-Study@its.jnj.com

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, China, Czechia, France, Germany, India, Italy, Japan, Korea, Republic of, Poland, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04172675
• Other Study ID Numbers: CR108699; 2019-002449-39 ( EudraCT Number ); 42756493BLC2003 ( Other Identifier: Janssen Research & Development, LLC )
• 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: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Data Access (YODA) Project site at yoda.yale.edu
• URL: https://www.janssen.com/clinical-trials/transparency

• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Janssen Research & Development, LLC
• Verification Date: May 2023