Study of Oral Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations

Sponsor

QED Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04197986

Collaborator

Helsinn Healthcare SA (Industry)

218

Enrollment

134

Locations

Arms

58.7

Anticipated Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy of infigratinib (an oral targeted FGFR1-3 inhibitor) versus placebo, as adjuvant treatment following surgery in adult subjects with invasive urothelial carcinoma and susceptible FGFR3 genetic alterations (mutations, and gene fusions or rearrangements) who have disease that is considered at high risk for recurrence with surgery alone. The study enrolls subjects with either bladder cancer post radical cystectomy or upper tract urothelial cancer post distal ureterectomy and/or nephrectomy. Study treatment is randomized 1:1 between infigratinib or placebo with treatment up to 1 year or until invasive local, distal, or metastatic disease recurrence confirmed by independent imaging reviewer.

Condition or Disease	Intervention/Treatment	Phase
Upper Tract Urothelial Carcinomas Urothelial Bladder Cancer	Drug: Infigratinib Drug: Placebo	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

218 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomly assigned (1:1) to receive oral infigratinib phosphate or placeboParticipants will be randomly assigned (1:1) to receive oral infigratinib phosphate or placebo

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

As a double-blind study, participants, investigators, study monitor(s) and the clinical study team will be blinded to the treatment administered.

Primary Purpose:

Treatment

Official Title:

Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial of Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations (PROOF 302)

Actual Study Start Date :

Mar 11, 2020

Anticipated Primary Completion Date :

Jan 31, 2024

Anticipated Study Completion Date :

Jan 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Infigratinib 125 mg Participants will be randomly assigned (1:1) to receive oral infigratinib administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks	Drug: Infigratinib Participants randomly assigned to infigratinib will receive hard gelatin capsules for oral administration of infigratinib 125 mg once a day (administered as one 100-mg capsule and one 25-mg capsule) using a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule. Other Names: IP Study drug
Placebo Comparator: Placebo Participants will be randomly assigned (1:1) to receive oral placebo administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks	Drug: Placebo Participants randomly assigned to placebo will receive placebo matching in appearance the investigational product (infigratinib), which will be provided as hard gelatin capsules for oral use and will be administered once daily on a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule.

Arm

Intervention/Treatment

Experimental: Infigratinib 125 mg

Participants will be randomly assigned (1:1) to receive oral infigratinib administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks

Drug: Infigratinib

Participants randomly assigned to infigratinib will receive hard gelatin capsules for oral administration of infigratinib 125 mg once a day (administered as one 100-mg capsule and one 25-mg capsule) using a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule.

Other Names:

Study drug

Placebo Comparator: Placebo

Participants will be randomly assigned (1:1) to receive oral placebo administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks

Drug: Placebo

Participants randomly assigned to placebo will receive placebo matching in appearance the investigational product (infigratinib), which will be provided as hard gelatin capsules for oral use and will be administered once daily on a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule.

Outcome Measures

Primary Outcome Measures

Centrally determine disease-free survival (DFS) [Randomization through up to an approximated 5 years (60 months) after end of treatment]

Secondary Outcome Measures

Compare DFS including intraluminal low-risk recurrence [Randomization through up to an approximated 5 years (60 months) after end of treatment]
Compare metastasis-free survival (MFS) [Randomization through up to an approximated 5 years (60 months) after end of treatment]
Compare overall survival (OS) [Randomization through 15 years after end of treatment]
Compare investigator-reviewed DFS [Randomization through up to an approximated 5 years (60 months) after end of treatment]
Number of participants with adverse events (AEs) and serious adverse events (SAEs) as a measure of safety and tolerability [30-Day Post-Treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria

Are randomized within 120 days following nephroureterectomy, distal ureterectomy or cystectomy.
Have histologically or cytologically confirmed, invasive urothelial carcinoma with susceptible FGFR3 alterations. Variant histology is allowed provided urothelial carcinoma is predominant (>50%). Neuroendocrine (including small and large cell), sarcomatoid, and plasmacytoid variants are excluded (any component).
Regarding samples and documentation of FGFR3

1. FGFR3 mutation is confirmed if: FGFR3 gene is mutated in Exon 7 (R248C, S249C), Exon 10 (G370C, A391E, Y373C), or Exon 15 (K650M/T, K650E/Q)

1. FGFR3 gene fusion or FGFR3 rearrangement is confirmed based on the following genomic criteria if:
Any fusion/rearrangement with a literature-derived known partner gene regardless of strand or frame.
Fusion/rearrangements in the same strand that are in frame with a novel partner gene.
Fusion/rearrangements with one breakpoint in the intron 17 - exon 18 hotspot region and the other breakpoint in an intergenic region or another gene. This rule excludes 3' duplications comprising only exon

1. The amino acid numbers for the FGFR3 mutations refer to the functional FGFR3 isoform 1 (NP_000133.1) that is the NCBI Refseq ID used to report genetic alterations in FGFR3 by the FoundationOne® CDx test (F1CDx, Foundation Medicine, USA).
1. FGFR3 alteration must be confirmed by Foundation Medicine for F1CDx testing:
The tumor sample to be used should be from the definitive surgical resection (cystectomy, nephroureterectomy, or distal ureterectomy), or from an archival biopsy of confirmed invasive urothelial carcinoma (≥pT2).

If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be Stage ≥ ypT2 and/or yN+. Prior neoadjuvant therapy is defined as at least 3 cycles of neoadjuvant cisplatin-based chemotherapy with a planned cisplatin dose of 70 mg/m2/cycle. Subjects who received less than this or non-cisplatin-based neoadjuvant treatment are not excluded.
If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant chemotherapy based on Galsky criteria:
Subjects who refuse cisplatin-based chemotherapy or who are ineligible to receive cisplatin-based chemotherapy based on Galsky criteria must also meet the following criteria:
Must have a centrally reviewed negative postoperative computed tomography (CT) (defined as lymph nodes with short axis <1.0 cm and without growth and no distant metastases according to [RECIST v1.1 criteria or negative biopsy within 28 days before randomization to confirm absence of disease at baseline.
Have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
If a woman of childbearing potential, must have a negative pregnancy test within 7 days of the first dose of study drug. Sexually active males must use a condom during intercourse while taking study drug and for 1 month after the last dose of study drug and should not father a child during this period

Key Exclusion Criteria:

Presence of positive invasive surgical margins following nephroureterectomy, distal ureterectomy, or cystectomy. In subjects not eligible for further surgery, radiotherapy, or other efficacious treatment, microscopic positive noninvasive margins (eg, carcinoma in situ) without gross residual disease are allowed.
Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy for Non-Muscle Invasive Bladder Cancer (NMIBC) within the previous 30 days.
Are currently receiving or are planning to receive during participation in this study, treatment with agents that are known moderate or strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration.

Prior anticancer or other therapies are restricted as follows:

Prior adjuvant treatment for urothelial cancer is not allowed.
Prior neoadjuvant therapy (eg, chemotherapy, immunotherapy, or investigational) is allowed if inclusion criterion #4 is met. Prior neoadjuvant chemotherapy must have been completed within a period of time that is greater than the cycle length used for that treatment before first dose of study drug.
Prior biologic, immunotherapy, or investigational therapy should have been completed within a period that is ≥5 half-lives or 30 days, whichever is shorter, before the first dose of study drug.
Have previously or currently is receiving treatment with a mitogen-activated protein kinase (MEK) or selective FGFR inhibitor.
Have a history of primary malignancy within the past 3 years other than (1) invasive UBC or UTUC (ie, disease under study), (2) noninvasive urothelial carcinoma, (3) any adequately treated in situ carcinoma or non-melanoma carcinoma of the skin, (4) any other curatively treated malignancy that is not expected to require treatment for recurrence during participation in the study, or (5) an untreated cancer on active surveillance that may not affect the subject's survival status for ≥3 years based on clinician assessment/statement and with medical monitor approval.
Have current evidence of corneal keratopathy or retinal disorder confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic conditions assessed by the investigator to pose minimal risk for study participation may be enrolled in the study.
Have a history and/or current evidence of extensive tissue calcification
Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib
Have current evidence of endocrine alterations of calcium/phosphate homeostasis (eg, parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis), unless well controlled.
Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, or Seville oranges or products containing juice of these fruits within 7 days before the first dose of study drug; have taken any Chinese herbal medicine or Chinese patent medicine treatments with anticancer activity within 14 days of the first dose of study drug.
Have insufficient bone marrow function:
Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L).
Platelets <75,000/mm3 (<75 × 109/L).
Hemoglobin <8.5 g/dL; transfusion support is allowed if >1 week before randomization and hemoglobin remains stable.
Have insufficient hepatic and renal function:
Total bilirubin >1.5 × upper limit of normal (ULN) of the testing laboratory (for subjects with documented Gilbert syndrome, direct bilirubin must be ≤1.5 × ULN and enrollment requires approval by the medical monitor).
AST/SGOT and ALT/SGPT >2.5 × ULN of the testing laboratory.
Serum creatinine >1.5 × ULN or a calculated or measured creatinine clearance of <30 mL/min.
Have amylase or lipase >2.0 × ULN.
Have abnormal calcium or phosphorus:
Inorganic phosphorus higher than 1.02 × ULN of the testing laboratory.
Total serum calcium (can be corrected) higher than 1.02 × ULN of the testing laboratory.
Have clinically significant cardiac disease including any of the following:
New York Heart Association (NYHA) Class ≥2B; subjects with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the NYHA classification.
Uncontrolled hypertension
Presence of CTCAE v5.0 Grade ≥2 ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction abnormality.
Unstable angina pectoris or acute myocardial infarction ≤3 months before the first dose of study drug.
Average QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first ECG, a total of 3 ECGs separated by ≥5 minutes should be performed. If the average of these 3 consecutive results for QTcF is ≤470 msec, the subject meets eligibility in this regard.
History of congenital long QT syndrome.
Have had a recent (≤3 months before the first dose of study drug) transient ischemic attack or stroke.
If female, are pregnant or nursing (lactating).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology Associates	Tucson	Arizona	United States	85711
2	City of Hope - Duarte	Duarte	California	United States	91010
3	City of Hope	Duarte	California	United States	91010
4	Loma Linda University Faculty Medical Clinics	Loma Linda	California	United States	92350
5	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
6	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
7	The Urology Center of Colorado	Denver	Colorado	United States	80211
8	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
9	Urological Research Network CORP	Hialeah	Florida	United States	33016
10	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
11	Lakeland Regional Health Hollis Cancer Center	Lakeland	Florida	United States	33805
12	Emory University	Atlanta	Georgia	United States	30322
13	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
14	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
15	UChicago Medicine Duchossois Center for Advanced Medicine (DCAM) - Hyde Park	Chicago	Illinois	United States	60637
16	DuPage Medical Group - Warrenville Road	Lisle	Illinois	United States	60532
17	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
18	Tulane University/Southeastern Louisiana VA Health Care	New Orleans	Louisiana	United States	70112
19	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
20	Saint Louis University- SLUCare Academic Pavilion	Saint Louis	Missouri	United States	63110
21	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
22	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03766
23	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
24	New Jersey Urology - Saddle Brook	Saddle Brook	New Jersey	United States	07663
25	New Jersey Urology	Voorhees	New Jersey	United States	08043
26	Albany Medical Center - Division of Urology	Albany	New York	United States	12208
27	Associated Medical Professionals - Syracuse	Syracuse	New York	United States	13210
28	Duke University Cancer Center	Durham	North Carolina	United States	27710
29	Accellacare-DuPage Medical Group	Raleigh	North Carolina	United States	27609
30	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
31	University of Toledo	Arlington	Ohio	United States	43606
32	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
33	Cleveland Clinic	Cleveland	Ohio	United States	44195
34	The Ohio State University College of Medicine	Columbus	Ohio	United States	43210
35	The University of Toledo Medical Center	Toledo	Ohio	United States	43614
36	Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
37	Urology Associates	Nashville	Tennessee	United States	37209
38	Harold C. Simmons Comprehensive Cancer Center	Dallas	Texas	United States	75390
39	Bayor College of Medicine	Houston	Texas	United States	77030
40	Houston Methodist Hospital- Department of Urology	Houston	Texas	United States	77030
41	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
42	UT Southwestern	Richardson	Texas	United States	75080
43	Urology San Antonio	San Antonio	Texas	United States	78229
44	Huntsman Cancer Institute and Hospital	Salt Lake City	Utah	United States	84112
45	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
46	West Virginia University	Morgantown	West Virginia	United States	26506
47	CHU de Liège - Sart Tilman	Liège	Liège/Belgium	Belgium	4000
48	ZNA Middelheim	Antwerpen		Belgium
49	Cliniques Universitaires Saint-Luc	Brussel		Belgium	1200
50	Universitair Ziekenhuis Leuven	Leuven		Belgium
51	University Multiprofile Hospital For Active Treatment Dr. Georgi Stranski EAD	Pleven		Bulgaria
52	Multiprofile Hospital For Active Treatment "Sveta Sofia"	Sofia		Bulgaria
53	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
54	BC Cancer- Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
55	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G2M9
56	McGill University Health Centre (MUHC)	Montréal	Quebec	Canada	H4A 3J1
57	CHU de Québec Université Laval	Québec		Canada	G1R 2J6
58	BC Cancer - Vancouver	Vancouver		Canada
59	Hôpital Universitaire Pitié Salpêtrière	Paris	Ile-de-France	France	75013
60	Hôpital Européen Georges-Pompidou	Paris	Ile-de-France	France	75015
61	CHU de Nantes Hopital Hotel Dieu	Paris	Paris/France	France	75018
62	Centre de Lutte Contre le Cancer - Centre Léon Bérard	Lyon	Rhone-Alpes	France	69008
63	Institut de Cancerologie Strasbourg Europe	Strasbourg	Strasbourg/France	France	67200
64	Institut Claudius Regaud	Toulouse	Toulouse/France	France	31059
65	Gustave Roussy	Villejuif	Villejuif/France	France	94805
66	CHU de Nantes Hopital Hotel Dieu	Nantes		France
67	Hopital Bichat - Claude - Bernard	Paris		France
68	Centre Hospitalier Privé Saint-Grégoire	Saint-Grégoire		France	35760
69	Institut De Cancerologie De L'ouest - Site Saint-Herblain	Saint-Herblain		France
70	Gustave Roussy	Villejuif		France
71	Charité - Universitatsmedizin Berlin	Berlin	Berlin/Germany	Germany	10117
72	Universitätsklinikum Düsseldorf	Duesseldorf	Nordrhein-Westfalen	Germany	40225
73	Urologicum Duisburg	Duisburg	Nordrhein-WestFalen	Germany	47179
74	Universitätsklinikum Essen	Essen	Nordrhein-Westfalen	Germany	45147
75	Marien Hospital Herne - Universitätsklinikum der Ruhr-Universität Bochum	Herne	Nordrhein-Westfalen	Germany	44625
76	Charite Universitaetsmedizin Berlin	Berlin		Germany
77	Urologie	Berlin		Germany
78	University Hospital Duesseldorf	Duesseldorf		Germany
79	Universitatsklinikum des Saarlandes Klinik fur Urologie & Kinderurologie	Homburg/saar		Germany
80	Universitätsklinikum des Saarlandes Klinik für Urologie & Kinderurologie	Homburg		Germany
81	Universitatsklinikum Magdeburg	Magdeburg		Germany
82	Caritas-Krankenhaus St. Josef Klinik für Urologie	Regensburg		Germany	93053
83	Universitätsklinikum Tübingen	Tübingen		Germany
84	Ospedale di Cremona	Cremona	Cremona/Italy	Italy	26100
85	Ospedale Policlinico San Martino	Genova	Genova/Italy	Italy	16132
86	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Meldola/Italy	Italy	47014
87	Istituto Europeo di Oncologia	Milano	Milano/Italy	Italy	20141
88	Istituto Nazionale Tumori IRCCS Fondazione G. Pascale	Napoli	Naples	Italy	80131
89	Azienda Ospedaliero-Universitaria Pisana	Pisa	Pisa/italy	Italy	56126
90	IRCCS Centro di Riferimento Oncologico di Basilicata	Rionero In Vulture	Potenza	Italy	85028
91	Arcispedale Santa Maria Nuova	Reggio Emilia	Reggio Emilia/Italy	Italy	42100
92	Università Campus Bio-Medico di Roma	Roma	Roma/Italy	Italy	00128
93	Azienda Ospedaliero - Universitaria San Luigi Gonzaga	Orbassano	Torino	Italy	10043
94	Ospedale di Trento - Presidio Ospedaliero Santa Chiara	Trento	Trentino	Italy	38100
95	Centro di Riferimento Oncologico	Aviano		Italy
96	Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari	Bari		Italy	70124
97	A.O.U.C. Polclinico di Bari U.O. Oncologia Medica Universitaria	Bari		Italy
98	ASST Cremona	Casalmaggiore		Italy
99	Ospedale Policlinico San Martino Irccs	Genova		Italy
100	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola		Italy
101	Fondazione IRCCS INT Milano	Milan		Italy
102	Istituto Europeo di Oncologia	Milan		Italy
103	Int Pascale Napoli	Napoli		Italy
104	AOU San Luigi Gonzaga	Orbassano		Italy
105	Azienda Ospedaliero-Universitaria Pisana	Pisa		Italy
106	IRCCS di Reggio Emilia	Reggio Emilia		Italy
107	Policlinico Universitario Campus Biomedico	Roma		Italy
108	Citta Della Salute e Della Scienz - Torino	Torino		Italy
109	Ospedale di Trento - Presidio Ospedaliero Santa Chiara	Trento		Italy
110	IRCCS Centro di Riferimento Oncologico di Basilicata	Volterra		Italy
111	Canisius-Wilhelmina Ziekenhuis	Nijmegen	Gelderland	Netherlands	6532 SZ
112	The Netherlands Cancer Institute	Amsterdam		Netherlands
113	Zuyderland MC locatie Sittard	Geleen		Netherlands
114	VHIO	Barcelona	Barcelona/Spain	Spain	08003
115	Sofia	Barcelona	Barcelona/Spain	Spain	08041
116	Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)	Barcelona	Barcelona/Spain	Spain	08908
117	Institut Català d'Oncologia Badalona	Badalona	Barcelona	Spain	08916
118	Hospital Parc Taulí de Sabadell	Sabadell	Barcelona	Spain	08208
119	Hospital Universitario Reina Sofía	Córdoba	Córdoba/Spain	Spain	14004
120	Institut Català d'Oncologia Girona	Girona	Girona/Spain	Spain	17007
121	MD Anderson Cancer Center Madrid	Madrid	Madrid/Spain	Spain	28033
122	Hospital Universitario Ramon y Cajal	Madrid	Madrid/Spain	Spain	28034
123	Hospital Clinico San Carlos	Madrid	Madrid/Spain	Spain	28040
124	Hospital Universitario 12 de Octubre	Madrid	Madrid/Spain	Spain	28041
125	Hospital Universitario La Paz	Madrid	Madrid/Spain	Spain	28046
126	Hospital Universitario HM Sanchinarro	Madrid	Madrid/Spain	Spain	28050
127	Hospital Universitario Virgen del Rocio	Sevilla	Sevilla/Spain	Spain	41013
128	Hospital Virgen De La Salud	Toledo	Toledo/Spain	Spain	45005
129	Fundacion Instituto Valenciano de Oncologia	Valencia	València	Spain	46009
130	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain
131	Hospital del Mar	Barcelona		Spain
132	Althaia Xarxa Assistencial Universitària de Manresa	Manresa		Spain
133	Guy's and St Thomas' NHS Foundation Trust	London		United Kingdom
134	Lister Hospital	Stevenage		United Kingdom