Olorofim Aspergillus Infection Study

Invasive Aspergillosis Clinical Trial

— OASIS  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05101187
• Other study ID #: F901318/0041
• Status: Recruiting
• Phase: Phase 3
• Start date: March 31, 2022
• Est. completion date: November 1, 2025

Study information

• Verified date: April 2024
• Source: F2G Biotech GmbH
• Contact: Daniela Zinzi, MD
• Phone: +43 06643582281
• Email: DZinzi[@]f2g.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 225
• Est. completion date: November 1, 2025
• Est. primary completion date: September 14, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Aspergillosis
• Invasive Aspergillosis

Intervention

Drug:
• Olorofim
Loading Dose: 5 tablets (150 mg) to be taken twice daily at a 12-hour (± 1 hour) interval on Day 1 Maintenance Dose: 3 tablets (90 mg) to be taken twice daily at 12-hour (± 1 hour) intervals from Day 2 until Day 84 (± 7 days)
• AmBisome®
Initial course of at least 10 days of AmBisome® administered daily at a dose of 3 mg/kg by IV infusion over a 30- to 60-minute period or according to local guidelines Administration of SOC will follow international, national, or local guidelines and product labelling.

Locations

Country	Name	City	State
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal NorthShore Hospital	Saint Leonards	New South Wales
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	UZ Leuven	Leuven
Brazil	Hospital Felício Rocho	Belo Horizonte	Minas Gerais
Brazil	Santa Casa de Misericórdia de Belo Horizonte	Belo Horizonte	Minas Gerais
Brazil	Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer	Curitiba	Paraná
Brazil	Santa Casa de Misericórdia de Passos	Passos	Minas Gerais
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital São Lucas da PUCRS	Porto Alegre	Rio Grande Do Sul
Brazil	Irmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital da Universidade Federal de Santa Maria CEP/UFSM	Santa Maria	Rio Grande Do Sul
Brazil	Universitair Ziekenhuis Gent	Vila Geni	Belgium
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hamilton Health Sciences - Juravinski Site	Hamilton	Ontario
China	The First Affiliated Hospital of Bengbu Medical College	Bengbu	Anhui
China	Institute of Hematology and Blood Diseases Hospital	Heping	Tianjin
China	Qilu Hospital of Shandong University	Jinan	Shandong
China	The First Affiliated Hospital of Nanchang University	Nanchang	Jiangxi
China	Huashan Hospital Fudan University	Shanghai	Shanghai
China	The 1st Affiliated Hosp of Wenzhou Medical University	Wenzhou	Zhejiang
China	Huazhong University of Science and Technology	Wuhan	Hubei
France	CHU de Besancon	Besançon	Doubs
France	CHU Besançon - Hôpital Jean Minjoz	Besançon Cedex	Doubs
France	CHU Bordeaux Hopital Saint André	Bordeaux	Gironde
France	Hospital Claude Huriez	Lille	Nord
France	CHU de Nantes CIC Hematologie	Nantes	Loire Atlantique
France	Hôpital Necker - Enfants Malades	Paris cedex 15	Paris
France	Laboratoire Parasitologie	Rennes	Ille-et-Vilaine
France	Institut de Cancérologie de Strasbourg Europe - ICANS	Strasbourg	Bas Rhin
Germany	Charite Universitatsmedizin Berlin	Berlin
Germany	Universitaetsklinikum Koeln	Koeln
Germany	Universitatsklinikum Leipzig	Leipzig	Saxony
Israel	Soroka University Medical Center	Beer-Sheva
Israel	Hadassah University Hospital - Ein Kerem	Jerusalem
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center Pt	Tel Aviv
Italy	IRCCS Ospedale Policlinico San Martino	Genova
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Ospedale San Raffaele	Milano
Italy	AOU Policlinico di Modena	Modena
Italy	Azienda Ospedaliera Universitaria Luigi Vanvitelli	Napoli	Campania
Italy	Clinica Malattie Infettive Dipartimento di Medicina e Chirurgia dell'Università	Perugia
Italy	Edificio 13 Malattie infettive AOUP Cisanello Piano Terrax	Pisa
Italy	Inmi Lazzaro Spallanzani Irccs	Roma
Japan	Chiba University Hospital	Chiba	Chiba Ken
Japan	Kyushu University Hospital	Fukuoka shi	Fukuoka Ken
Japan	The Jikei University Hospital	Minato-Ku	Tokyo
Japan	Toranomon Hospital	Minato-Ku	Tokyo To
Japan	Nagasaki University Hospital	Nagasaki
Japan	Okayama University Hospital	Okayama
Japan	Osaka Metropolitan University Hospital	Osaka	Osaka Fu
Japan	Osaka International Cancer Institute	Osaka shi	Osaka Fu
Japan	Kindai University Hospital	Osaka-sayama	Osaka Fu
Japan	Tohoku University Hospital	Sendai-shi	Miyagi Ken
Korea, Republic of	The Catholic University of Korea	Bucheon-si	Seoul
Korea, Republic of	Samsung Medical Center	Irwon-dong	Seoul
Netherlands	Radboud Nijmegen	Nijmegen
Netherlands	UMC Utrecht	Utrecht
New Zealand	Auckland City Hospital	Auckland
New Zealand	Wellington Regional Hospital	Newtown	Wellington
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital- Parent	Singapore
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital General Universitario Gregorio Marañón	Retiro	Madrid
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Taipei Medical University - Shuang Ho Hospital, Ministry of Health and Welfare	New Taipei City
Taiwan	National Taiwan University Hospital	Taipei
Thailand	Siriraj Hospital	Bangkok-noi	Bangkok
Thailand	Srinagarind Hospital	Khon Kaen
Thailand	King Chulalongkorn Memorial Hospital	Pathum Wan	Bangkok
Turkey	Ankara City Hospital	Ankara
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Dicle University, Medical Faculty	Diyarbakir
Turkey	Acibadem Atakent Hospital	Istanbul
Turkey	Ege University Medical Faculty	Izmir
Turkey	Ondokuz Mayis Univ. Med. Fac.	Samsun
United Kingdom	Haematology Trials Unit	Cardiff	Wales
United States	University of Michigan	Ann Arbor	Michigan
United States	The Johns Hopkins Hospital	Baltimore	Maryland
United States	NIH Clinical Center ,NIAID,NIH	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	City of Hope National Medical Center	Duarte	California
United States	Duke Department of Medicine Infectious Diseases Division	Durham	North Carolina
United States	Houston Methodist	Houston	Texas
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Clairvoyant Research Group, LLC	Las Vegas	Nevada
United States	University of Minnesota	Minneapolis	Minnesota
United States	Weill Cornell Medicine NY Presbyterian Hospital	New York	New York
United States	OU Health OU Medical Center	Oklahoma City	Oklahoma
United States	University of Pittsburgh Medical Center Health System	Pittsburgh	Pennsylvania
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of California Davis Health System	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	UCSF Helen Diller Medical Center at Parnassus Heights	San Francisco	California
United States	Fred Hutchinson Cancer Center	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
F2G Biotech GmbH	Iqvia Pty Ltd, Shionogi

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  China,  France,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  New Zealand,  Singapore,  Spain,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause mortality	To compare all-cause mortality (ACM) at Day 42 following treatment with olorofim versus treatment with AmBisome® followed by standard of care (SOC) in the intent-to-treat (ITT) population of patients with Invasive Fungal Disease (IFD) caused by proven Invasive Aspergillosis (IA) at any site or probable lower respiratory tract disease (LRTD) Aspergillus species (invasive aspergillosis, IA).	Treatment Day 42
Secondary	Adjudicated Assessment of Overall outcome	To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Data Review Committee (DRC)-adjudicated assessment of overall outcome in patients with proven IA or probable LRTD IA at Day 42, Day 84, and End of Treatment.	Day 42, Day 84, and End of Treatment (anytime during the study between first administration and Day 84)
Secondary	Investigator-assessed overall response	Investigator-assessed overall response (integrating clinical, radiological, and mycological response).	Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]), and 4-week Follow-up (FU).
Secondary	To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on Galactomannan index.	The Sponsor's expert advisors suggested that an appropriate rule would be a failure of the GM to decline from baseline. The experts also state that they have seen very significant variation on retesting of both BAL and serum GM samples and believe it is more appropriate to state a fixed reduction of = 1.0 units than any percentage reduction.; These rules are used for changes in GM that document failure of therapy: Serum: After 8 or more days of treatment, serum GM has neither (1) fallen by = 1 unit nor (2) to < 0.5 based on measurements taken at least 8 days apart.; BAL: After 8 or more days of treatment, positive GM from BAL in a patient with a previous BAL test that did not meet the definition of positive (too low or entirely negative) without regard for the interval of time between samples.	Day 14, Day 28, Day 42, Day 84, EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days]) and 4-week Follow-up (FU)
Secondary	To collect additional olorofim and the disproportionate metabolite H26C pharmacokinetic (PK) data for inclusion in a Population PK model	To collect plasma concentration of olorofim and H26C metabolic for for PK analysis (pre-dose and intensive PK). No non-compartmental PK analysis will be performed on the data relating to pre-dose samples and intensive PK samples, apart from data collected from selected regions, which will be reported separately. All relevant olorofim data will be provided to support population PK modelling, which will be reported separately.	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])
Secondary	Data Review Committee's Assessment of Patient Mortality	Study data will be independently assessed by a blinded DRC consisting of independent experts in the diagnosis and management of IA, providing an independent adjudication of each patient's mortality based on the survival status collect at time frame.	Day 42 and 84 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
Secondary	Diagnosis of a secondary fungal infection	To compare incidence of a secondary fungal infection when patients treated with olorofim versus treatment with AmBisome followed by SOC.	at any time through End Of Treatment
Secondary	Quality of life as measured by the 5 Level 5 Dimension (EQ-5D-5L) at Baseline	To assess patient's quality of life measured by the 5-Level 5-Dimension EuroQol Group Health-related Quality of Life Questionnaire (EQ-5D-5L) in both treatment groups	Days 14 and EOT (End of Treatment - Maximum Treatment 84 days [± 7 Days])
Secondary	Survival status	All-cause mortality will be assessed using survival status at time frame.	Day 42, Day 84, and End Of Treatment and at the 4 weeks ± 7 days FU
Secondary	Safety Assessment	To monitor incidence of Adverse Events and Serious Adverse Events in both treatment arms (Olorofim or AmBisome followed by Standard of Care).	up to the Day 84 and 4-week Follow-up (FU)