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

• ClinicalTrials.gov Identifier: NCT02365597
• Recruitment Status: Recruiting
• First Posted: February 19, 2015
• Last Update Posted: April 27, 2022
• 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
• Last Update Posted Date: April 27, 2022
• Actual Study Start Date: April 22, 2015
• Estimated Primary Completion Date: June 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2020)

Percentage of Participants with Best Overall Response [ Time Frame: From the start of the study treatment until the end of treatment (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.

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 18, 2020)

• 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 (up to 5 years) ]
  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 (up to 5 years) ]
  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 5 years) ]
  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 (up to 5 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. 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 (up to 5 years) ]
  Presence of circulating biomarkers (DNA, RNA, or proteins) associated with FGFR aberrations will be observed.
• Plasma Concentration of Erdafitinib [ Time Frame: Baseline up to end of study (up to 5 years) ]
• Plasma Clearance of Erdafitinib [ Time Frame: Baseline up to end of study (up to 5 years) ]
• Volume of Distribution of Erdafitinib [ Time Frame: Baseline up to end of study (up to 5 years) ]
• Plasma Concentration of Midazolam and its Metabolite (1-OH-midazolam) [ Time Frame: Up to 14 days ]
• Plasma Concentration of Metformin [ Time Frame: Up to 15 days ]

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, 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) or until the last participant enrolled under the drug-drug interaction (DDI) substudy completes the end of treatment visit,(whichever happens last). 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 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.

Interventions:

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

Publications *

• Siefker-Radtke AO, Necchi A, Park SH, García-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: Recruiting
• Estimated Enrollment (submitted: September 18, 2020): 236
• Original Estimated Enrollment (submitted: February 18, 2015): 165
• Estimated Study Completion Date: June 30, 2022
• Estimated Primary Completion Date: June 30, 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 who 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: Study Contact; Participate-In-This-Study@its.jnj.com

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

Administrative Information

• NCT Number: NCT02365597
• Other Study ID Numbers: CR105065; 42756493BLC2001 ( Other Identifier: Janssen Research & Development, LLC ); 2014-002408-26 ( EudraCT 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
• Responsible Party: Janssen Research & Development, LLC
• Study Sponsor: Janssen Research & Development, LLC
• 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 2022