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

Urothelial Bladder Cancer Clinical Trial

— PROOF302  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04197986
• Other study ID #: QBGJ398-302
• Secondary ID: 2019-003248-63
• Status: Terminated
• Phase: Phase 3
• Start date: March 11, 2020
• Est. completion date: February 28, 2023

Study information

• Verified date: February 2024
• Source: QED Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 39
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria

1. Are randomized within 120 days following nephroureterectomy, distal ureterectomy or cystectomy.

2. 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).

1. Regarding samples and documentation of FGFR3

• i. 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) OR
• ii. 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 18.
• iii. 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).
• iv. 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).

2. 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.

3. If not status post neoadjuvant chemotherapy, is ineligible to receive

cisplatin-based adjuvant chemotherapy based on Galsky criteria:

4. 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:

5. 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.

3. Have Eastern Cooperative Oncology Group (ECOG) performance status of =2.

4. 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:

1. 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.

2. Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy for Non-Muscle Invasive Bladder Cancer (NMIBC) within the previous 30 days.

3. 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:

1. Prior adjuvant treatment for urothelial cancer is not allowed.

2. 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.

3. 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.

4. Have previously or currently is receiving treatment with a mitogen-activated protein kinase (MEK) or selective FGFR inhibitor.

5. 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.

6. 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.

7. Have a history and/or current evidence of extensive tissue calcification

8. Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib

9. Have current evidence of endocrine alterations of calcium/phosphate homeostasis (eg, parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis), unless well controlled.

10. 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.

11. Have insufficient bone marrow function:

1. Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L).

2. Platelets <75,000/mm3 (<75 × 109/L).

3. Hemoglobin <8.5 g/dL; transfusion support is allowed if >1 week before randomization and hemoglobin remains stable.

12. Have insufficient hepatic and renal function:

1. 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).

2. AST/SGOT and ALT/SGPT >2.5 × ULN of the testing laboratory.

3. Serum creatinine >1.5 × ULN or a calculated or measured creatinine clearance of <30 mL/min.

13. Have amylase or lipase >2.0 × ULN.

14. Have abnormal calcium or phosphorus:

1. Inorganic phosphorus higher than 1.02 × ULN of the testing laboratory.

2. Total serum calcium (can be corrected) higher than 1.02 × ULN of the testing laboratory.

15. Have clinically significant cardiac disease including any of the following:

1. 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.

2. Uncontrolled hypertension

3. Presence of CTCAE v5.0 Grade =2 ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction abnormality.

4. Unstable angina pectoris or acute myocardial infarction =3 months before the first dose of study drug.

5. 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.

6. History of congenital long QT syndrome.

16. Have had a recent (=3 months before the first dose of study drug) transient ischemic attack or stroke.

17. If female, are pregnant or nursing (lactating).

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Upper Tract Urothelial Carcinomas
• Urinary Bladder Neoplasms
• Urothelial Bladder Cancer

Intervention

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.
• 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.

Locations

Country	Name	City	State
Belgium	ZNA Middelheim	Antwerpen
Belgium	Cliniques Universitaires Saint-Luc	Brussel
Belgium	Universitair Ziekenhuis Leuven	Leuven
Belgium	CHU de Liège - Sart Tilman	Liège	Liège/Belgium
Bulgaria	University Multiprofile Hospital For Active Treatment Deva Maria	Burgas
Bulgaria	University Multiprofile Hospital For Active Treatment Dr. Georgi Stranski EAD	Pleven
Bulgaria	Multiprofile Hospital For Active Treatment "Sveta Sofia"	Sofia
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	McGill University Health Centre (MUHC)	Montréal	Quebec
Canada	CHU de Québec Université Laval	Québec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	BC Cancer - Vancouver	Vancouver
Canada	BC Cancer- Vancouver	Vancouver	British Columbia
France	Hôpital Morvan	Brest
France	Centre de Lutte Contre le Cancer - Centre Léon Bérard	Lyon	Rhone-Alpes
France	CHU de Nantes Hopital Hotel Dieu	Nantes
France	CHU de Nantes Hopital Hotel Dieu	Paris	Paris/France
France	Hopital Bichat - Claude - Bernard	Paris
France	Hôpital Européen Georges-Pompidou	Paris	Ile-de-France
France	Hôpital Universitaire Pitié Salpêtrière	Paris	Ile-de-France
France	Centre Eugène Marquis	Rennes
France	Centre Hospitalier Privé Saint-Grégoire	Saint-Grégoire
France	Institut De Cancerologie De L'ouest - Site Saint-Herblain	Saint-Herblain
France	Clinique Mutualiste de l'Estuaire	Saint-Nazaire
France	Institut de Cancerologie Strasbourg Europe	Strasbourg	Strasbourg/France
France	Institut Claudius Regaud	Toulouse	Toulouse/France
France	Gustave Roussy	Villejuif	Villejuif/France
France	Gustave Roussy	Villejuif
Germany	Charité - Universitatsmedizin Berlin	Berlin	Berlin/Germany
Germany	Charite Universitaetsmedizin Berlin	Berlin
Germany	Urologie	Berlin
Germany	Universitätsklinikum Düsseldorf	Duesseldorf	Nordrhein-Westfalen
Germany	University Hospital Duesseldorf	Duesseldorf
Germany	Urologicum Duisburg	Duisburg	Nordrhein-WestFalen
Germany	Universitätsklinikum Essen	Essen	Nordrhein-Westfalen
Germany	Marien Hospital Herne - Universitätsklinikum der Ruhr-Universität Bochum	Herne	Nordrhein-Westfalen
Germany	Universitätsklinikum des Saarlandes Klinik für Urologie & Kinderurologie	Homburg
Germany	Universitatsklinikum des Saarlandes Klinik fur Urologie & Kinderurologie	Homburg/saar
Germany	Universitatsklinikum Magdeburg	Magdeburg
Germany	Caritas-Krankenhaus St. Josef Klinik für Urologie	Regensburg
Germany	Universitätsklinikum Tübingen	Tübingen
Greece	Henry Dunant Hospital Center	Athens	Attica
Greece	Bioclinic Thessalonikis	Thessaloníki	Makedonia
Greece	Anassa General Clinic	Volos
Italy	Centro di Riferimento Oncologico	Aviano
Italy	A.O.U.C. Polclinico di Bari U.O. Oncologia Medica Universitaria	Bari
Italy	Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari	Bari
Italy	ASST Cremona	Casalmaggiore
Italy	Ospedale di Cremona	Cremona	Cremona/Italy
Italy	Ospedale Policlinico San Martino	Genova	Genova/Italy
Italy	Ospedale Policlinico San Martino Irccs	Genova
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	Meldola/Italy
Italy	Fondazione IRCCS INT Milano	Milan
Italy	Istituto Europeo di Oncologia	Milan
Italy	Istituto Europeo di Oncologia	Milano	Milano/Italy
Italy	Int Pascale Napoli	Napoli
Italy	Istituto Nazionale Tumori IRCCS Fondazione G. Pascale	Napoli	Naples
Italy	AOU San Luigi Gonzaga	Orbassano
Italy	Azienda Ospedaliero - Universitaria San Luigi Gonzaga	Orbassano	Torino
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa	Pisa/italy
Italy	Arcispedale Santa Maria Nuova	Reggio Emilia	Reggio Emilia/Italy
Italy	IRCCS di Reggio Emilia	Reggio Emilia
Italy	IRCCS Centro di Riferimento Oncologico di Basilicata	Rionero In Vulture	Potenza
Italy	Policlinico Universitario Campus Biomedico	Roma
Italy	Università Campus Bio-Medico di Roma	Roma	Roma/Italy
Italy	Citta Della Salute e Della Scienz - Torino	Torino
Italy	Ospedale di Trento - Presidio Ospedaliero Santa Chiara	Trento
Italy	Ospedale di Trento - Presidio Ospedaliero Santa Chiara	Trento	Trentino
Italy	IRCCS Centro di Riferimento Oncologico di Basilicata	Volterra
Netherlands	The Netherlands Cancer Institute	Amsterdam
Netherlands	Zuyderland MC locatie Sittard	Geleen
Netherlands	Canisius-Wilhelmina Ziekenhuis	Nijmegen	Gelderland
Spain	Institut Català d'Oncologia Badalona	Badalona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)	Barcelona	Barcelona/Spain
Spain	Sofia	Barcelona	Barcelona/Spain
Spain	VHIO	Barcelona	Barcelona/Spain
Spain	Hospital Universitario Reina Sofía	Córdoba	Córdoba/Spain
Spain	Institut Català d'Oncologia Girona	Girona	Girona/Spain
Spain	Hospital Clinico San Carlos	Madrid	Madrid/Spain
Spain	Hospital Universitario 12 de Octubre	Madrid	Madrid/Spain
Spain	Hospital Universitario HM Sanchinarro	Madrid	Madrid/Spain
Spain	Hospital Universitario La Paz	Madrid	Madrid/Spain
Spain	Hospital Universitario Ramon y Cajal	Madrid	Madrid/Spain
Spain	MD Anderson Cancer Center Madrid	Madrid	Madrid/Spain
Spain	Hospital Universitario Puerta Hierro-Majadahonda	Majadahonda	Madrid
Spain	Althaia Xarxa Assistencial Universitària de Manresa	Manresa
Spain	Hospital Parc Taulí de Sabadell	Sabadell	Barcelona
Spain	Hospital Universitario Virgen del Rocio	Sevilla	Sevilla/Spain
Spain	Hospital Virgen De La Salud	Toledo	Toledo/Spain
Spain	Fundacion Instituto Valenciano de Oncologia	Valencia	València
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Lister Hospital	Stevenage
United States	Albany Medical Center - Division of Urology	Albany	New York
United States	University of Toledo	Arlington	Ohio
United States	Emory University	Atlanta	Georgia
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	UChicago Medicine Duchossois Center for Advanced Medicine (DCAM) - Hyde Park	Chicago	Illinois
United States	Oncology Hematology Care	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	The Ohio State University College of Medicine	Columbus	Ohio
United States	Harold C. Simmons Comprehensive Cancer Center	Dallas	Texas
United States	The Urology Center of Colorado	Denver	Colorado
United States	City of Hope	Duarte	California
United States	City of Hope - Duarte	Duarte	California
United States	Duke University Cancer Center	Durham	North Carolina
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Urological Research Network CORP	Hialeah	Florida
United States	Bayor College of Medicine	Houston	Texas
United States	Houston Methodist Hospital- Department of Urology	Houston	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Lakeland Regional Health Hollis Cancer Center	Lakeland	Florida
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	DuPage Medical Group - Warrenville Road	Lisle	Illinois
United States	Loma Linda University Faculty Medical Clinics	Loma Linda	California
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	West Virginia University	Morgantown	West Virginia
United States	Urology Associates	Nashville	Tennessee
United States	Tulane University/Southeastern Louisiana VA Health Care	New Orleans	Louisiana
United States	Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Accellacare-DuPage Medical Group	Raleigh	North Carolina
United States	UT Southwestern	Richardson	Texas
United States	New Jersey Urology - Saddle Brook	Saddle Brook	New Jersey
United States	Saint Louis University- SLUCare Academic Pavilion	Saint Louis	Missouri
United States	Huntsman Cancer Institute and Hospital	Salt Lake City	Utah
United States	Urology San Antonio	San Antonio	Texas
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Associated Medical Professionals - Syracuse	Syracuse	New York
United States	The University of Toledo Medical Center	Toledo	Ohio
United States	Arizona Oncology Associates	Tucson	Arizona
United States	New Jersey Urology	Voorhees	New Jersey
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
QED Therapeutics, Inc.	Helsinn Healthcare SA

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Canada,  France,  Germany,  Greece,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Centrally Determined Disease-free Survival (DFS)	DFS was defined as the number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause (referred as DFS event), whichever occurs earlier.; Due to early termination of the study by the sponsor, results will focus primarily on the primary and key secondary endpoints of the study. Due to early termination of the study by the sponsor, data were censored for 85.0% to 89.5% of all subjects. Data cutoff 28 Feb 2023.	The number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause.
Secondary	Investigator-assessed DFS	DFS was defined as the number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause (referred as DFS event), whichever occurs earlier. Due to early termination of the study by the sponsor, data were censored for 85.0% to 89.5% of all subjects. Data cutoff 28 Feb 2023.	The number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause.
Secondary	Metastasis-free Survival (MFS)	MFS was defined as the time from randomization to any metastatic recurrence as determined by the investigator, or death due to any cause, whichever occurred earlier. Due to early termination of the study by the sponsor, data were censored for 85.0% to 89.5% of all subjects. Data cutoff 28 Feb 2023.	The time from randomization to any metastatic recurrence as determined by the investigator, or death due to any cause.
Secondary	Overall Survival (OS)	Overall survival time was defined as the number of months from randomization to death. Due to early termination of the study by the sponsor, data were censored for 85.0% to 89.5% of all subjects. Data cutoff 28 Feb 2023.	The number of months from randomization to death.
Secondary	Investigator-reviewed DFS Including Intraluminal Low-Risk Recurrence	Investigator assessment of intraluminal low-risk recurrence as assessed by DFS. Due to early termination of the study by the sponsor, data were censored for 85.0% to 89.5% of all subjects. Data cutoff 28 Feb 2023.	The number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause.
Secondary	Number of Participants With Adverse Events (AEs)	Number of participants with AEs	From first dose to last dose of study treatment +30 days (an average of 4 months for the infigratinib arm and 8 months for the placebo arm).
Secondary	Number of Participants With Serious Adverse Events (SAEs)	Number of Participants with SAEs	From first dose to last dose of study treatment +30 days (an average of 4 months for the infigratinib arm and 8 months for the placebo arm)