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

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02365597

Collaborator

(none)

236

Enrollment

161

Locations

Arm

86.3

Anticipated Duration (Months)

1.5

Patients Per Site

Patients Per Site Per Month

Study Details

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

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 Design

Study Type:

Interventional

Anticipated Enrollment :

236 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 :

Apr 22, 2015

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Jun 30, 2022

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 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.	Drug: Erdafitinib 8 mg orally once daily for 28 days on a 28 day cycle. Other Names: 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 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.

Drug: Erdafitinib

8 mg orally once daily for 28 days on a 28 day cycle.

Other Names:

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

Percentage of Participants with Best Overall Response [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.

Secondary Outcome Measures

Progression-free survival [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 [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 [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) [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 [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 [Baseline up to end of study (up to 5 years)]
Plasma Clearance of Erdafitinib [Baseline up to end of study (up to 5 years)]
Volume of Distribution of Erdafitinib [Baseline up to end of study (up to 5 years)]
Plasma Concentration of Midazolam and its Metabolite (1-OH-midazolam) [Up to 14 days]
Plasma Concentration of Metformin [Up to 15 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
2	Arizona Oncology Associates, PC - NAHOA	Sedona	Arizona	United States	86336
3	University of Arizona Cancer Center	Tucson	Arizona	United States	85724
4	Marin Cancer Care Inc.	Greenbrae	California	United States	94904
5	Cedars Sinai Medical Center - Pediatric Infectious Disease	Los Angeles	California	United States	90048
6	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
7	University of California Irvine	Orange	California	United States	92868
8	University of California - Davis Medical Center	Sacramento	California	United States	95817
9	Stanford University Medical Center	Stanford	California	United States	94305
10	Rocky Mountain Cancer Center	Aurora	Colorado	United States	80012
11	Georgetown Univ. Medical Center - Lombardi Cancer Center	Washington	District of Columbia	United States	20007
12	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
13	University of Chicago	Chicago	Illinois	United States	60637
14	The University of Iowa - Division of Hematology, Oncology and Blood & Marrow Transplantation	Iowa City	Iowa	United States	52242
15	Norton Cancer Institute	Louisville	Kentucky	United States	40202
16	Univ of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
17	Karmanos Cancer Institute - Wayne State University	Detroit	Michigan	United States	48201
18	Minnesota Oncology	Minneapolis	Minnesota	United States	55404
19	Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
20	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89169
21	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
22	Weill Medical College of Cornell University	New York	New York	United States	10021
23	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
24	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
25	Hematology Oncology Associates, PC	Medford	Oregon	United States	97504
26	Northwest Cancer Specialists PC	Tualatin	Oregon	United States	97062
27	Penn State Milton S. Hershey Medical Ctr.	Hershey	Pennsylvania	United States	17033
28	University of Pittsburgh Medical Center (UPMC)	Pittsburgh	Pennsylvania	United States	15232
29	Carolina Urologic Research Center	Myrtle Beach	South Carolina	United States	29572
30	SCRI - Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
31	Texas Oncology-Dallas Presbyterian Hospital	Dallas	Texas	United States	75231
32	Texas Oncology - Sammons Cancer Center	Dallas	Texas	United States	75246
33	UT Southwestern Medical Center	Dallas	Texas	United States	75390
34	Texas Oncology-Denton South	Denton	Texas	United States	76210
35	Texas Oncology-Memorial City	Houston	Texas	United States	77024
36	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
37	Virginia Oncology Associates	Hampton	Virginia	United States	23666
38	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin	United States	53792
39	LKH-Univ. Klinikum Graz	Graz		Austria	A-8036
40	Krankenhaus der Barmherzigen Schwestern Linz	Linz		Austria	4020
41	Krankenhaus der Barmherzigen Brüder	Vienna		Austria	1020
42	Medical University Vienna	Vienna		Austria	A-1090
43	O.L.V. Ziekenhuis	Aalst		Belgium	9300
44	Cliniques Universitaires Saint Luc	Brussel		Belgium	1200
45	Clinique Notre Dame	Charleroi		Belgium	6000
46	U.Z. Gent	Gent		Belgium	9000
47	GZA Ziekenhuizen- Campus St Augustinus	Wilrijk		Belgium	2610
48	ICO, Site Paul Papin	ANGERS Cedex		France	49055
49	Institut Bergonié	Bordeaux		France
50	Centre Francois Baclesse	Caen Cédex 05		France	14076
51	Centre Georges-François Leclerc	Dijon		France	21000
52	Centre Leon Bérard	Lyon		France	69008
53	APHM Hopital Timone	Marseille		France	13005
54	Centre Antoine Lacassagne	Nice Cedex 2		France	06189
55	Institut de Cancérologie du Gard	Nîmes		France	30029
56	Hospital Saint-Louis	Paris Cedex 10		France	75475
57	Hopital Europeen Georges-Pompidou	Paris Cedex 15		France	75908
58	I.C.O. René Gauducheau	Saint Herblain Cedex		France	44805
59	Hopital Foch	Suresnes		France	92150
60	Institut Universitaire du Cancer Toulouse - Oncopole	Toulouse cedex 09		France	31059
61	Institut Universitaire du Cancer Toulouse Oncopole	Toulouse		France	31000
62	Gustave Roussy	Villejuif Cedex		France	94805
63	Vivantes Klinikum Am Urban, Abt. fur Kardiologie	Berlin		Germany	10967
64	Waldkrankenhaus St. Marien -Urologische Universitätsklinik-	Erlangen		Germany	91054
65	Kliniken Essen-Mitte; Evangelische Huyssens-Stiftung	Essen		Germany	45136
66	Goethe Universität Frankfurt	Frankfurt		Germany	60590
67	Universitatsklinikum Freiburg	Freiburg		Germany	79106
68	Universitätsmedizin Greifswald	Greifswald		Germany	17475
69	Georg-August-Universitaet Goettingen - Innere Medizin - Haematologie, Onkologie	Göttingen		Germany	37075
70	Asklepios Klinik Altona	Hamburg		Germany	22763
71	Medizinische Hochschule Hannover;Klinik f. Urologie u. Urologische Onkologie	Hannover		Germany	30625
72	University Hospital Heidelberg	Heidelberg		Germany	69120
73	Klinikum rechts der Isar der TU Muenchen	Muenchen		Germany	81675
74	University hospital Muenster, Dpt. of Urology	Muenster		Germany	48129
75	Caritas Krankenhaus St. Josef - Innere Medizin II	Regensburg		Germany	93053
76	Klinikum St. Elisabeth	Straubing		Germany	94315
77	Kliniken Nordoberpfalz, Klinik für Urologie	Weiden/Opf		Germany	92637
78	Health Care Global Enterprises pvt Ltd	Bangalore		India	560027
79	Post Graduate Institute of Medical Education & Research (PGIMER)	Chandigarh		India	160012
80	Advanced Centre for Treatment, Research and Education in Cancer (ACTREC)	Kharghar, Navi Mumbai		India	410210
81	Netaji Subhas chandra Bose Cancer Research Institute	Kolkata		India	700094
82	Bhaktivedanta Hospital & Research Institute	Mira Road (East)		India	401107
83	Kokilaben Dhirubhai Ambani Hosp. & Med. Research Inst	Mumbai		India	400053
84	Muljibhai Patel Urological Hospital	Nadiad		India	387001
85	Soroka Medical Center	Be'er Sheva		Israel	84101
86	Asaf Harofe Medical Center	Beer Yaakov		Israel	60930
87	Rambam Medical Center	Haifa		Israel	31096
88	Meir Medical Center	Kfar-Saba		Israel	44281
89	Rabin Medical Center - Bellins	Petah Tikva		Israel	49100
90	Sourasky Medical Center, Tel Aviv Sourasky Med Ctr	Tel-Aviv		Israel	64239
91	Unità Operativa di Oncologia Medica	Arezzo		Italy	52100
92	Oncologia-IRCCS IRST	Meldola		Italy	47014
93	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano		Italy	20100
94	Oncologia Medica A - Ist Naz Tumori G Pascale	Napoli		Italy	80131
95	Ospedale Maggiore della Carità	Novara		Italy	28100
96	Oncologia Medica Azienda Sanitaria Ospedaliera San Luigi Gonzaga	Orbassano		Italy	10043
97	Istituto Oncologico Veneto - IRCCS	Padova		Italy	35128
98	Oncologia Medica - Azienda Ospedaliero Universitaria Di Parma	Parma		Italy	43126
99	Azienda Ospedaliero Universitaria Pisana	Pisa		Italy	56126
100	Azienda Ospedaliera San Camillo - Roma	Roma		Italy	00152
101	UOC di Oncologia Medica Università Cattolica del Sacro Cuore Policlinico Universitario A. Gemelli	Roma		Italy	00168
102	University Hospital Umberto I	Rome		Italy	00161
103	Istituto Clinico Humanitas UO di Emodinamica e Cradiologia Interventistica	Rozzano		Italy	20089
104	Oncologia Medica-Città Della Salute E Della Scienza Di Torino	Torino		Italy	10126
105	Azienda Ospedaliero - Universitaria Ospedali Riuniti	Torrette Di Ancona		Italy	60126
106	Chungnam National University Hospital - Dept. of Internal Medicine	Daejeon		Korea, Republic of	301-721
107	National Cancer Center	Goyangsi		Korea, Republic of	410-769
108	Gachon University Gil Medical Center	Incheon		Korea, Republic of	21565
109	Severance Hospital	Seoul		Korea, Republic of	03722
110	Asan Medical Center (AMC)	Seoul		Korea, Republic of	05505
111	Samsung Medical Center	Seoul		Korea, Republic of	135-710
112	Arensia Exploratory Medicine	Chisinau		Moldova, Republic of	MD 2025
113	Spitalul Clinic de Urologie Prof. Dr. Theodor Burghele	Bucharest		Romania	050659
114	Spitalul Clinic Sf. Maria	Bucharest		Romania	11172
115	Institutul Clinic Fundeni	Bucuresti		Romania	022328
116	Arensia Exploratory Medicine - Romania	Bucuresti		Romania	050159
117	Institutul Oncologic ''Prof Dr. Ion Chiricuta'' Cluj-Napoca	Cluj-Napoca		Romania	400015
118	ONCOLAB	Craiova		Romania	200385
119	Institutul Regional de Oncologie Iasi	Iasi		Romania	700483
120	Spitalul Clinic Municipal De Urgenta Timisoara; Sectia Oncologie	Timisoara		Romania
121	Altai Regional Oncology Dispensary	Barnaul		Russian Federation	656049
122	Cancer Research Center	Moscow N/a		Russian Federation	115478
123	Scientific Research Institute of Urology	Moscow		Russian Federation	105425
124	Hertzen Oncology Research Institute	Moscow		Russian Federation	125284
125	Clinical Oncology Dispensary	Omsk		Russian Federation	644013
126	Pyatigorsk Regional Oncology Dispensary	Pyatigorsk		Russian Federation	357502
127	Leningradski Regional Oncological Dispensary	Saint-Petersburg		Russian Federation	191104
128	Russian Scientific Center of Radiology and Surgical Technologies	Sankt-Peterburg		Russian Federation	197758
129	Bashkiria State Medical University	Ufa		Russian Federation	450000
130	Hospital Universitari Germans Trias i Pujol	Badalona		Spain
131	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
132	Hospital Clinic de Barcelona	Barcelona		Spain	08036
133	Hosp. Univ. de La Princesa	Madrid		Spain	28006
134	Hospital U. Gregorio Marañón	Madrid		Spain	28007
135	Fundacion Jimenez Diaz	Madrid		Spain	28020
136	Hosp. Univ. Ramon Y Cajal	Madrid		Spain	28034
137	Hosp. Univ. 12 de Octubre	Madrid		Spain	28041
138	Hospital Universitario La Paz	Madrid		Spain	28046
139	Centro Integral Oncológico Clara Campal	Madrid		Spain	28050
140	Hosp. Virgen de La Victoria	Málaga		Spain	29010
141	Clinica Universitaria de Navarra	Pamplona		Spain	31008
142	Corporacio Sanitari Parc Tauli	Sabadell		Spain	08208
143	Hosp. Univ. Marques de Valdecilla	Santander		Spain	39008
144	Hosp. Clinico Univ. de Santiago	Santiago de Compostela		Spain	15706
145	Hospital Virgen del Rocío	Sevilla		Spain	41013
146	Hosp. Clinico Univ. de Valencia	Valencia		Spain	46010
147	Taichung Veterans General Hospital	Taichung		Taiwan	40705
148	National Cheng Kung University Hospital	Tainan		Taiwan	70403
149	National Taiwan University Hospital	Taipei		Taiwan	10002
150	Chang Gung Memorial Hospital- Linkou	Taoyuan		Taiwan	333
151	Hacettepe University Medical Faculty	Ankara		Turkey	6100
152	Trakya University Medical Faculty	Edirne		Turkey	22030
153	Istanbul Universitesi Cerrahpasa Tip Fakultesi Ic Hastaliklari Anabilim Dali Medikal Onkoloji Bd	Istanbul		Turkey	34098
154	Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi	Istanbul		Turkey	34722
155	Royal Blackburn Hospital	Blackburn		United Kingdom	BB2 3HH
156	Ninewells Hospital	Dundee		United Kingdom	DD1 9SY
157	Queens Hospital	Essex		United Kingdom	RM7 0AG
158	Charing Cross Hospital	London		United Kingdom	W6 8RF
159	Derriford Hospital	Plymouth		United Kingdom	PL6 8DH
160	Royal Marsden Hospital	Sutton		United Kingdom	SM2 5PT
161	Clatterbridge Centre for Oncology	Wirral		United Kingdom	CH63 4JY