Clinical trial NCT02365597: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Urothelial Cancer
Keywords: Urothelial Cancer
JNJ-42756493
Erdafitinib
Tyrosine Kinase Inhibitor
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-02-19
Enrollment: 239
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Main Study: Percentage of Participants With Best (Overall) Objective Response
timeFrame: From Cycle 1 Day 1 up to 6 years 2 months
measure: Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone or in Combination With Erdafitinib
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose
measure: Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of 1-OH-Midazolam (Midazolam Metabolite) Alone or in Combination With Erdafitinib
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: Drug-Drug Interaction (DDI) Substudy: Maximum Observed Plasma Concentration (Cmax) of Metformin Alone or in Combination With Erdafitinib
timeFrame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
measure: Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Midazolam Alone or in Combination With Erdafitinib
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: Drug-Drug Interaction (DDI) Substudy: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of Metformin Alone or in Combination With Erdafitinib
timeFrame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -2 (predose) up to Day 13 post dose (each cycle length=28 days)
measure: 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
timeFrame: Cycle 1 Day -1 (predose) up to Day 14 post dose (each cycle length=28 days)
Secondary outcomes:
measure: Main Study: Progression-free Survival (PFS)
timeFrame: From screening up to 6 years 2 months
measure: Main Study: Duration of Response (DoR)
timeFrame: From screening up to 6 years 2 months
measure: Main Study: Overall Survival
timeFrame: From screening up to 6 years 2 months
measure: Main Study: Percentage of Participants With Treatment-emergent Adverse Event (TEAEs)
timeFrame: From Day 1 up to 6 years 2 months
measure: Main Study: Plasma Concentration of Erdafitinib at 2 Hours (C2h)
timeFrame: Cycle 1 Days 1 and 21: Pre-dose up to 2 hours post-dose (each cycle length=28 days)
measure: Main Study: Plasma Concentration of Erdafitinib at 4 Hours (C4h)
timeFrame: Cycle 1 Days 1 and 21: Pre-dose up to 4 hours post-dose (each cycle length=28 days)
Other outcomes:
Locations:
city: Sedona
country: United States
state: Arizona
city: Los Angeles
country: United States
state: California
city: Orange
country: United States
state: California
city: Sacramento
country: United States
state: California
city: Stanford
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Washington
country: United States
state: District of Columbia
city: Chicago
country: United States
state: Illinois
city: Iowa City
country: United States
state: Iowa
city: Louisville
country: United States
state: Kentucky
city: Minneapolis
country: United States
state: Minnesota
city: Omaha
country: United States
state: Nebraska
city: Las Vegas
country: United States
state: Nevada
city: New York
country: United States
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Medford
country: United States
state: Oregon
city: Tualatin
country: United States
state: Oregon
city: Hershey
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Myrtle Beach
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Denton
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Hampton
country: United States
state: Virginia
city: Graz
country: Austria
city: Linz
country: Austria
city: Vienna
country: Austria
city: Aalst
country: Belgium
city: Brussel
country: Belgium
city: Charleroi
country: Belgium
city: Gent
country: Belgium
city: Wilrijk
country: Belgium
city: ANGERS Cedex
country: France
city: Bordeaux
country: France
city: Caen Cédex 05
country: France
city: Dijon
country: France
city: Lyon
country: France
city: Nice Cedex 2
country: France
city: Nîmes
country: France
city: Paris Cedex 10
country: France
city: Paris Cedex 15
country: France
city: Saint Herblain Cedex
country: France
city: Suresnes
country: France
city: Villejuif Cedex
country: France
city: Berlin
country: Germany
city: Erlangen
country: Germany
city: Essen
country: Germany
city: Freiburg
country: Germany
city: Greifswald
country: Germany
city: Göttingen
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Heidelberg
country: Germany
city: Muenchen
country: Germany
city: Muenster
country: Germany
city: Regensburg
country: Germany
city: Straubing
country: Germany
city: Weiden/Opf
country: Germany
city: Bangalore
country: India
city: Kolkata
country: India
city: Mira Road (East)
country: India
city: Nadiad
country: India
city: Be'er Sheva
country: Israel
city: Beer Yaakov
country: Israel
city: Haifa
country: Israel
city: Kfar-Saba
country: Israel
city: Petah Tikva
country: Israel
city: Tel-Aviv
country: Israel
city: Daejeon
country: Korea, Republic of
city: Goyangsi
country: Korea, Republic of
city: Incheon
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Chisinau
country: Moldova, Republic of
city: Bucharest
country: Romania
city: Cluj-Napoca
country: Romania
city: Craiova
country: Romania
city: Iasi
country: Romania
city: Barnaul
country: Russian Federation
city: Moscow N/a
country: Russian Federation
city: Moscow
country: Russian Federation
city: Omsk
country: Russian Federation
city: Pyatigorsk
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Sankt-Peterburg
country: Russian Federation
city: Ufa
country: Russian Federation
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Málaga
country: Spain
city: Pamplona
country: Spain
city: Sabadell
country: Spain
city: Santander
country: Spain
city: Santiago de Compostela
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Taoyuan
country: Taiwan
city: Istanbul
country: Turkey
city: Blackburn
country: United Kingdom
city: Dundee
country: United Kingdom
city: Essex
country: United Kingdom
city: London
country: United Kingdom
city: Plymouth
country: United Kingdom
city: Sutton
country: United Kingdom
city: Wirral
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.