Clinical trial NCT05101187: Olorofim Aspergillus Infection Study
Official title: Phase III, Adjudicator-blinded, Randomised Study to Evaluate Efficacy and Safety of Treatment With Olorofim Versus Treatment With AmBisome® Followed by Standard of Care in Patients With Invasive Fungal Disease Caused by Aspergillus Species
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Invasive Aspergillosis
Keywords: Invasive fungal disease (IFD)
Aspergillus species
Olorofim
Non-azole antifungal
Azole resistance
Lead sponsor: F2G Biotech GmbH
Sponsor class: INDUSTRY
Collaborators: name: Iqvia Pty Ltd
name: Shionogi
First posted: 2021-11-01
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare treatment with olorofim versus treatment with AmBisome® followed by standard of care (SOC) in patients with IFD caused by proven IA or probable lower respiratory tract disease Aspergillus species (invasive aspergillosis, IA).

Detailed description: The mortality rate in immunosuppressed patients with IA is high even with effective modern antifungal drug treatment. Intrinsic and acquired resistance to azoles and amphotericin B, the two most effective classes of treatment, have been identified in Aspergillus species and are linked to this increased mortality.

Currently marketed antifungal drugs have limitations including limited dosage forms, DDIs, and significant adverse reactions.

For patients with IA who do not respond to or cannot tolerate a triazole therapy, treatment options are even more limited.

Olorofim is an antifungal candidate with a novel mechanism of action offering activity against resistant organisms, differences in safety profile, along with oral dosing, predictable and reliable pharmacokinetic (PK) profile and limited potential for DDIs.

The present study is designed to compare the efficacy, safety, and tolerability of olorofim with that of AmBisome® followed by guideline-based hierarchy standard of care (SOC) in patients with IA whose infection is either refractory to or unsuitable for azole therapy.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients ages over 18 years and weighing more than 30 kg
2. Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study and where the duration of specific therapy for this episode of IA has been ≤ 28 days. For purposes of this inclusion, the duration of specific therapy includes any mould-active therapy given for this episode of IA whether subsequently judged potentially effective or not.
3. Patients requiring therapy with an antifungal agent other than a mould-active azole, and who have had ≤ 96 hours of potentially effective prior therapy. Potentially effective prior therapy includes any agent to which the infecting strain of Aspergillus is likely to be susceptible. There are no exclusions or limitations on such agents (eg, AmBisome® is permitted) other than their duration.
4. AmBisome® is an appropriate therapy for the patient.

Exclusion Criteria:

1. Women who are pregnant or breastfeeding.
2. Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug
3. Patients with only chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis.
4. Suspected mucormycosis (zygomycosis).
5. Patients with a known active second fungal infection of any type, other than candidiasis that can be treated with fluconazole.
6. The requirement for ongoing use of echinocandin as Candida prophylaxis.
7. Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features.
8. Human immunodeficiency virus (HIV) infection but not currently receiving antiretroviral therapy.
9. Patients with a baseline prolongation of QT using Fridericia's Correction Formula (QTcF) ≥ 500 msec, or at high risk for QT/QTc prolongation.
10. Evidence of hepatic dysfunction.

Primary outcomes:
measure: All-cause mortality
timeFrame: Treatment Day 42
Secondary outcomes:
measure: Adjudicated Assessment of Overall outcome
timeFrame: Day 42, Day 84, and End of Treatment (anytime during the study between first administration and Day 84)
measure: Investigator-assessed overall response
timeFrame: Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]), and 4-week Follow-up (FU).
measure: To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Galactomannan index.
timeFrame: Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]) and 4-week Follow-up (FU)
measure: To collect additional olorofim and the disproportionate metabolite H26C pharmacokinetic (PK) data for inclusion in a Population PK model
timeFrame: Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 70, Day 84, and at EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
measure: Data Review Committee's Assessment of Patient Mortality
timeFrame: Day 42 and 84 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
measure: Diagnosis of a secondary fungal infection
timeFrame: at any time through End Of Treatment
measure: Quality of life as measured by the 5 Level 5 Dimension (EQ-5D-5L) at Baseline
timeFrame: Days 14 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
measure: Survival status
timeFrame: Day 42, Day 84, and End Of Treatment and at the 4 weeks ± 7 days FU
measure: Safety Assessment
timeFrame: up to the Day 84 and 4-week Follow-up (FU)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Health System
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Medical Center at Parnassus Heights
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Bethesda
country: United States
facility: NIH Clinical Center ,NIAID,NIH
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Las Vegas
country: United States
facility: Clairvoyant Research Group, LLC
state: Nevada
city: New Brunswick
country: United States
facility: Rutgers RWJMS
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Medicine NY Presbyterian Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke Department of Medicine Infectious Diseases Division
state: North Carolina
city: Oklahoma City
country: United States
facility: OU Health OU Medical Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Health System
state: Pennsylvania
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Saint Leonards
country: Australia
facility: Royal NorthShore Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Brugge
country: Belgium
facility: AZ Sint-Jan
city: Bruxelles
country: Belgium
facility: Hôpital Erasme
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Belo Horizonte
country: Brazil
facility: Hospital Felício Rocho
state: Minas Gerais
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte
state: Minas Gerais
city: Passos
country: Brazil
facility: Santa Casa de Misericórdia de Passos
state: Minas Gerais
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer
state: Paraná
city: Porto Alegre
country: Brazil
facility: Irmandade da Santa Casa de Misericórdia de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas da PUCRS
state: Rio Grande Do Sul
city: Santa Maria
country: Brazil
facility: Hospital da Universidade Federal de Santa Maria CEP/UFSM
state: Rio Grande Do Sul
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton Health Sciences - Juravinski Site
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Bengbu
country: China
facility: The First Affiliated Hospital of Bengbu Medical College
state: Anhui
city: Wuhan
country: China
facility: Huazhong University of Science and Technology
state: Hubei
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
state: Jiangxi
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Shanghai
country: China
facility: Huashan Hospital Fudan University
state: Shanghai
city: Heping
country: China
facility: Institute of Hematology and Blood Diseases Hospital
state: Tianjin
city: Wenzhou
country: China
facility: The 1st Affiliated Hosp of Wenzhou Medical University
state: Zhejiang
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Peking University Third Hospital
city: Changchun
country: China
facility: The First Hospital of Jilin University
city: Changsha
country: China
facility: Xiangya Hospital, Central South University
city: Chenzhou
country: China
facility: Chenzhou No.1 People's Hospital
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Sun Yat-sen University
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
city: Hangzhou
country: China
facility: The First Affiliated Hospital of Zhejiang University school of medicine
city: Hefei
country: China
facility: Anhui Provincial Hospital
city: Nanning
country: China
facility: The People's Hospital of Guangxi Zhuang Autonomous Region
city: Shengyang
country: China
facility: Shengjing Hospital of China Medical University
city: Shijiazhuang
country: China
facility: The Second Hospital of Hebei Medical University
city: Xi'an
country: China
facility: Xi'an International Medical Center
city: Zhengzhou
country: China
facility: Henan Provincial People's Hospital
city: Strasbourg
country: France
facility: Institut de Cancérologie de Strasbourg Europe - ICANS
state: Bas Rhin
city: Besançon Cedex
country: France
facility: CHU Besançon - Hôpital Jean Minjoz
state: Doubs
city: Besançon
country: France
facility: CHU de Besancon
state: Doubs
city: Bordeaux
country: France
facility: CHU Bordeaux Hopital Saint André
state: Gironde
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse- IUCT-O
state: Haute Garonne
city: Rennes
country: France
facility: CHU de Rennes - Hôpital Pontchaillou
state: Ille-et-Vilaine
city: Nantes
country: France
facility: CHU de Nantes CIC Hematologie
state: Loire Atlantique
city: Lille
country: France
facility: Hospital Claude Huriez
state: Nord
city: Paris cedex 15
country: France
facility: Hôpital Necker - Enfants Malades
state: Paris
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
state: Saxony
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin
city: Hamburg-Eppendorf
country: Germany
facility: UKE Universitaetsklinikum-Hamburg Eppendorf
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Beer-Sheva
country: Israel
facility: Soroka University Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital - Ein Kerem
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center Pt
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Luigi Vanvitelli
state: Campania
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: Di Monza E Della Brianza
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
city: Genova
country: Italy
facility: IRCCS Ospedale Policlinico San Martino
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Modena
country: Italy
facility: AOU Policlinico di Modena
city: Perugia
country: Italy
facility: Clinica Malattie Infettive Dipartimento di Medicina e Chirurgia dell'Università
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana (Presidio di Cisanello)
city: Roma
country: Italy
facility: Inmi Lazzaro Spallanzani Irccs
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Chiba
country: Japan
facility: Chiba University Hospital
state: Chiba Ken
city: Fukuoka shi
country: Japan
facility: Kyushu University Hospital
state: Fukuoka Ken
city: Sendai-shi
country: Japan
facility: Tohoku University Hospital
state: Miyagi Ken
city: Osaka shi
country: Japan
facility: Osaka International Cancer Institute
state: Osaka Fu
city: Osaka
country: Japan
facility: Osaka Metropolitan University Hospital
state: Osaka Fu
city: Ōsaka-sayama
country: Japan
facility: Kindai University Hospital
state: Osaka Fu
city: Minato-Ku
country: Japan
facility: Toranomon Hospital
state: Tokyo To
city: Minato-Ku
country: Japan
facility: The Jikei University Hospital
state: Tokyo
city: Bunkyō-Ku
country: Japan
facility: Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Saitama
country: Japan
facility: Saitama Medical Center Jichi Medical University
city: Shimotsuke
country: Japan
facility: Jichi Medical University Hospital
city: Bucheon-si
country: Korea, Republic of
facility: The Catholic University of Korea
state: Seoul
city: Irwon-dong
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul
city: Nijmegen
country: Netherlands
facility: Radboud Nijmegen
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Newtown
country: New Zealand
facility: Wellington Regional Hospital
state: Wellington
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital- Parent
city: Retiro
country: Spain
facility: Hospital General Universitario Gregorio Marañón
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: New Taipei City
country: Taiwan
facility: Taipei Medical University - Shuang Ho Hospital, Ministry of Health and Welfare
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Bangkok-noi
country: Thailand
facility: Siriraj Hospital
state: Bangkok
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Ankara City Hospital
city: Diyarbakir
country: Turkey
facility: Dicle University, Medical Faculty
city: Istanbul
country: Turkey
facility: Acibadem Atakent Hospital
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis Univ. Med. Fac.
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
city: London
country: United Kingdom
facility: Kings College Hospital
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: UZ Leuven
name: Johan Maertens, MD
role: PRINCIPAL_INVESTIGATOR
References: