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

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ClinicalTrials.gov Identifier: NCT02365597

Recruitment Status : Active, not recruiting

First Posted : February 19, 2015

Results First Posted : October 10, 2023

Last Update Posted : October 10, 2023

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Sponsor:

Information provided by (Responsible Party):

Janssen Research & Development, LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Urothelial Cancer	Drug: Erdafitinib Drug: Midazolam Drug: Metformin	Phase 2

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public. More info ...

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	239 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	April 22, 2015
Actual Primary Completion Date :	September 15, 2022
Estimated Study Completion Date :	December 29, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Metformin Midazolam Erdafitinib

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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.	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.

Arm

Intervention/treatment

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.

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02365597

Locations

Show 108 study locations

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United States, Arizona

Sedona, Arizona, United States
United States, California

Los Angeles, California, United States

Orange, California, United States

Sacramento, California, United States

Stanford, California, United States
United States, Colorado

Aurora, Colorado, United States
United States, District of Columbia

Washington, District of Columbia, United States
United States, Illinois

Chicago, Illinois, United States
United States, Iowa

Iowa City, Iowa, United States
United States, Kentucky

Louisville, Kentucky, United States
United States, Minnesota

Minneapolis, Minnesota, United States
United States, Nebraska

Omaha, Nebraska, United States
United States, Nevada

Las Vegas, Nevada, United States
United States, New York

New York, New York, United States
United States, North Carolina

Charlotte, North Carolina, United States
United States, Oregon

Medford, Oregon, United States

Tualatin, Oregon, United States
United States, Pennsylvania

Hershey, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States
United States, South Carolina

Myrtle Beach, South Carolina, United States
United States, Tennessee

Nashville, Tennessee, United States
United States, Texas

Dallas, Texas, United States

Denton, Texas, United States

Houston, Texas, United States
United States, Virginia

Hampton, Virginia, United States
Austria

Graz, Austria

Linz, Austria

Vienna, Austria
Belgium

Aalst, Belgium

Brussel, Belgium

Charleroi, Belgium

Gent, Belgium

Wilrijk, Belgium
France

ANGERS Cedex, France

Bordeaux, France

Caen Cédex 05, France

Dijon, France

Lyon, France

Nice Cedex 2, France

Nîmes, France

Paris Cedex 10, France

Paris Cedex 15, France

Saint Herblain Cedex, France

Suresnes, France

Villejuif Cedex, France
Germany

Berlin, Germany

Erlangen, Germany

Essen, Germany

Freiburg, Germany

Greifswald, Germany

Göttingen, Germany

Hamburg, Germany

Hannover, Germany

Heidelberg, Germany

Muenchen, Germany

Muenster, Germany

Regensburg, Germany

Straubing, Germany

Weiden/Opf, Germany
India

Bangalore, India

Kolkata, India

Mira Road (East), India

Nadiad, India
Israel

Be'er Sheva, Israel

Beer Yaakov, Israel

Haifa, Israel

Kfar-Saba, Israel

Petah Tikva, Israel

Tel-Aviv, Israel
Korea, Republic of

Daejeon, Korea, Republic of

Goyangsi, Korea, Republic of

Incheon, Korea, Republic of

Seoul, Korea, Republic of
Moldova, Republic of

Chisinau, Moldova, Republic of
Romania

Bucharest, Romania

Cluj-Napoca, Romania

Craiova, Romania

Iasi, Romania
Russian Federation

Barnaul, Russian Federation

Moscow N/a, Russian Federation

Moscow, Russian Federation

Omsk, Russian Federation

Pyatigorsk, Russian Federation

Saint-Petersburg, Russian Federation

Sankt-Peterburg, Russian Federation

Ufa, Russian Federation
Spain

Badalona, Spain

Barcelona, Spain

Madrid, Spain

Málaga, Spain

Pamplona, Spain

Sabadell, Spain

Santander, Spain

Santiago de Compostela, Spain

Sevilla, Spain

Valencia, Spain
Taiwan

Taichung, Taiwan

Tainan, Taiwan

Taipei, Taiwan

Taoyuan, Taiwan
Turkey

Istanbul, Turkey
United Kingdom

Blackburn, United Kingdom

Dundee, United Kingdom

Essex, United Kingdom

London, United Kingdom

Plymouth, United Kingdom

Sutton, United Kingdom

Wirral, United Kingdom

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

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

Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol [PDF] October 4, 2022

Statistical Analysis Plan [PDF] September 29, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT02365597
Other Study ID Numbers:	CR105065 42756493BLC2001 ( Other Identifier: Janssen Research & Development, LLC ) 2014-002408-26 ( EudraCT Number )
First Posted:	February 19, 2015 Key Record Dates
Results First Posted:	October 10, 2023
Last Update Posted:	October 10, 2023
Last Verified:	September 2023

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

Keywords provided by Janssen Research & Development, LLC:


Urothelial Cancer JNJ-42756493 Erdafitinib Tyrosine Kinase Inhibitor

Additional relevant MeSH terms:

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Metformin Midazolam Hypoglycemic Agents Physiological Effects of Drugs Adjuvants, Anesthesia Hypnotics and Sedatives Central Nervous System Depressants Anti-Anxiety Agents Tranquilizing Agents	Psychotropic Drugs Anesthetics, Intravenous Anesthetics, General Anesthetics GABA Modulators GABA Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action

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