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

• ClinicalTrials.gov Identifier: NCT02365597
• Recruitment Status: Active, not recruiting
• First Posted: February 19, 2015
• Results First Posted: October 10, 2023
• Last Update Posted: May 7, 2024
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: January 29, 2015
• First Posted Date: February 19, 2015
• Results First Submitted Date: September 14, 2023
• Results First Posted Date: October 10, 2023
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: April 22, 2015
• Actual Primary Completion Date: September 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 14, 2023)

• Main Study: Percentage of Participants With Best (Overall) Objective Response [ Time Frame: From Cycle 1 Day 1 up to 6 years 2 months ]
  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.
• Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone or in Combination With Erdafitinib [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose ]
  Cmax is the maximum observed plasma concentration of midazolam alone or in combination with erdafitinib.
• Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  Cmax is the maximum observed plasma concentration of 1-OH-Midazolam (midazolam metabolite) alone or in combination with erdafitinib.
• Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Metformin Alone or in Combination With Erdafitinib [ Time Frame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) ]
  Cmax is the maximum observed plasma concentration of metformin alone or in combination with erdafitinib
• Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Midazolam Alone or in Combination With Erdafitinib [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  Tmax is the time to reach the maximum observed plasma concentration of midazolam alone or in combination with erdafitinib.
• 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 [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  Tmax is the time to reach the maximum observed plasma concentration of 1-OH-Midazolam alone or in combination with erdafitinib.
• Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Metformin Alone or in Combination With Erdafitinib [ Time Frame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) ]
  Tmax is the time to reach maximum observed plasma concentration of metformin alone or in combination with erdafitinib
• 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 [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  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.
• 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 [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  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.
• 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 [ Time Frame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) ]
  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.
• 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 [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  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.
• 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 [ Time Frame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days) ]
  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.
• 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 [ Time Frame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days) ]
  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

Original Primary Outcome Measures (submitted: February 18, 2015)

Percentage of Participants with Best Overall Response [ Time Frame: 1 year ]

The objective response rate is defined as the percentage of participants with measurable lesions achieving a Complete Response (CR) or Partial Response (PR) based on Response Evaluation Criteria In Solid Tumors Version 1.1(RECIST v1.1) criteria. Per RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to (>=) 30 percent (%) decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Current Secondary Outcome Measures (submitted: September 14, 2023)

• Main Study: Progression-free Survival (PFS) [ Time Frame: From screening up to 6 years 2 months ]
  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.
• Main Study: Duration of Response (DoR) [ Time Frame: From screening up to 6 years 2 months ]
  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.
• Main Study: Overall Survival [ Time Frame: From screening up to 6 years 2 months ]
  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.
• Main Study: Percentage of Participants With Treatment-emergent Adverse Event (TEAEs) [ Time Frame: From Day 1 up to 6 years 2 months ]
  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.
• Main Study: Plasma Concentration of Erdafitinib at 2 Hours (C2h) [ Time Frame: Cycle 1 Days 1 and 21: Pre-dose up to 2 hours post-dose (each cycle length=28 days) ]
  C2h is the plasma concentration of erdafitinib at 2 hours.
• Main Study: Plasma Concentration of Erdafitinib at 4 Hours (C4h) [ Time Frame: Cycle 1 Days 1 and 21: Pre-dose up to 4 hours post-dose (each cycle length=28 days) ]
  C4h is the plasma concentration of erdafitinib at 4 hours.

Original Secondary Outcome Measures (submitted: February 18, 2015)

• Progression-free survival [ Time Frame: From the date of the first dose of study drug until disease progression or death as assessed up to the last efficacy assessment for disease progression (approximately 3 years 9 months) ]
  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 a complete response during the study) or death, whichever comes first.
• Duration of Response [ Time Frame: From the date of the first dose of study drug until disease progression or death as assessed up to the last efficacy assessment for disease progression (approximately 3 years 9 months) ]
  The duration of response (CR or PR) is defined as the earliest date a participant achieved a complete response (CR) or a partial response (PR), calculated from the date of initial documentation of a response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death.
• Overall survival [ Time Frame: From the date of the first dose of study drug until death (up to 3 years 9 months) ]
  Overall survival is defined as the time interval in days between the date of the first dose of study drug and the participant's death from any cause. If the participant is alive or the vital status is unknown, the participant's data will be censored at the date the participant was last known to be alive.
• Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Screening up to end of study (approximately 3 years 9 months) ]
  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. An SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above.
• Percentage of Participants With Biomarker Assessment [ Time Frame: Baseline up to end of study (approximately 3 years 9 months) ]
  Presence of circulating biomarkers (DNA, RNA, or proteins) associated with FGFR aberrations will be observed.
• Plasma Concentration of JNJ 42756493 [ Time Frame: Baseline up to end of study (approximately 3 years 9 months) ]
• Plasma Clearance of JNJ 42756493 [ Time Frame: Baseline up to end of study (approximately 3 years 9 months) ]
• Volume of Distribution of JNJ 42756493 [ Time Frame: Baseline up to end of study (approximately 3 years 9 months) ]

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

Descriptive Information

• Brief Title: An Efficacy and Safety Study of Erdafitinib (JNJ-42756493) in Participants With Urothelial Cancer
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Urothelial Cancer

Intervention

• Drug: Erdafitinib
  8 mg orally once daily for 28 days on a 28 day cycle.
  Other Name: JNJ-42756493
• Drug: Midazolam
  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.
• Drug: Metformin
  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.

Study Arms

Experimental: Erdafitinib (8 milligram)

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.

Interventions:

• Drug: Erdafitinib
• Drug: Midazolam
• Drug: Metformin

Publications *

• Siefker-Radtke AO, Necchi A, Park SH, Garcia-Donas J, Huddart RA, Burgess EF, Fleming MT, Rezazadeh Kalebasty A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Akapame S, Santiago-Walker AE, Monga M, O'Hagan A, Loriot Y; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248-258. doi: 10.1016/S1470-2045(21)00660-4. Epub 2022 Jan 11.
• Dosne AG, Valade E, Goeyvaerts N, De Porre P, Avadhani A, O'Hagan A, Li LY, Ouellet D, Perez Ruixo JJ. Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma. Cancer Chemother Pharmacol. 2022 Feb;89(2):151-164. doi: 10.1007/s00280-021-04381-4. Epub 2022 Jan 3.
• Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. doi: 10.1056/NEJMoa1817323.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 14, 2023): 239
• Original Estimated Enrollment (submitted: February 18, 2015): 165
• Estimated Study Completion Date: December 31, 2024
• Actual Primary Completion Date: September 15, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

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: Austria, Belgium, France, Germany, India, Israel, Korea, Republic of, Moldova, Republic of, Romania, Russian Federation, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Italy

Administrative Information

• NCT Number: NCT02365597
• Other Study ID Numbers: CR105065; 42756493BLC2001 ( Other Identifier: Janssen Research & Development, LLC ); 2014-002408-26 ( EudraCT Number ); 2023-510273-34-00 ( Registry Identifier: EUCT number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• 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 2024