A study to evaluate the efficacy and safety of olorofim versus AmBisome® for treatment of invasive aspergillosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F2G Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

15 Feb 2022 → 26 Feb 2026

Decision date (initial)

2024-07-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F2G Ltd.

External identifiers

EU CT number

2024-513030-38-00

EudraCT number

2021-000386-32

ClinicalTrials.gov

NCT05101187

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To compare ACM at Day 42 following treatment with olorofim versus treatment with AmBisome® followed by SOC in the intent-to-treat (ITT) population of patients with IFD caused by proven IA at any site or probable lower respiratory tract disease (LRTD) Aspergillus species.

Secondary objectives 5

1. Compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on DRC-adjudicated assessment of overall outcome in patients with proven IA or probable LRTD IA at Day 42, Day 84, and End of Treatment (EOT).
2. To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on: o Investigator-assessed overall response (integrating clinical, radiological, and mycological response) at Day 14, Day 28, Day 42, Day 84, EOT, and Follow-up (FU) o Serum galactomannan (GM) at visits from screening to Day 14, Day 28, Day 42, Day 84, EOT, and FU o All-cause mortality rate at Day 84 o Survival time o Data Review Committee attribution of mortality to IA at Day 42 and Day 84 o Diagnosis of a secondary fungal infection at any time through EOT o Quality of life as measured by the 5-Level 5-Dimension EuroQol Group Health-related Quality of Life Questionnaire (EQ-5D-5L) at baseline, Day 14, and EOT.
3. To assess the safety and tolerability of treatment with olorofim relative to treatment with AmBisome® followed by SOC up to the Day 84 and FU visits.
4. To collect olorofim systemic exposure data for olorofim population PK modelling, and to collect H26C metabolite systemic exposure data in certain geographical regions.
5. To collect health variables

Conditions and MedDRA coding

Invasive fungal infections due to Aspergillus spp.

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1.Male and female patients ages ≥ 18 years and weighing ≥ 30 kg, […] or Patients unable to write and/or read but who fully understand the oral information given by the Investigator
2. Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study (see Appendix 2) 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. Patients must meet at least one of these criteria a) Proven or suspected azole resistance in patients who have had ≤ 96 hours of potentially effective prior therapy b) Breakthrough infection on mould-active triazole prophylaxis: patients who have had any duration of prophylaxis prior to the breakthrough but ≤ 96 hours of potentially effective prior therapy. c) Any other medical reason an azole is inappropriate for the patient at screening. In all cases, patients must have had ≤ 96 hours of potentially effective prior therapy. d)Invasive aspergillosis refractory to triazole therapy in patients who have had ≤ 28 days of prior therapy where refractory IA was defined per an international expert meeting report
4. AmBisome® is an appropriate therapy for the patient. a) For avoidance of doubt, prior therapy with an amphotericin B (eg, AmBisome® or other) is not an exclusion provided that such prior therapy does not exceed the rules for maximum duration of potentially effective prior therapy discussed as part of Inclusion Criterion 3.
5. Ability and willingness to comply with the protocol.
6. Female patients must be non-lactating and at no risk of pregnancy
7. Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception

Exclusion criteria 17

1. Women who are pregnant or breastfeeding.
2. Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug (olorofim or AmBisome®).
3. Patients with only chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis.
4. Suspected mucormycosis (zygomycosis). Evidence for the presence of olorofim non-susceptible filamentous fungi such as Mucorales should be urgently followed up. Increased vigilance for the possibility of mucormycosis (zygomycosis) is required for suspected IA with negative baseline GM.
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 (for avoidance of doubt, prior use of an echinocandin is permitted; if ongoing prophylaxis for Candida is needed, then fluconazole must be an acceptable choice [see Section 5.8.4.1, discussion of concomitant antifungal agents]).
7. Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features.
8. Patients with human immunodeficiency virus (HIV) infection who are currently not receiving antiretroviral therapy. Patients with HIV infection receiving antiretroviral therapy can participate in the study. In cases where HIV infection is first diagnosed at the same time as the invasive fungal infection, if antiretroviral therapy is commenced at the time of enrolment, then such patients are eligible for enrolment.
9. Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy (eg, neutropenia not expected to resolve, patients with uncontrolled malignancy who are treatment refractory or receiving only palliative therapy).
10. Patients with a concomitant medical condition that, in the opinion of the Investigator, may be an unacceptable additional risk to the patient should he/she participate in the study
11. Patients previously enrolled in a study with olorofim/F901318.
12. Treatment with any investigational drug in any clinical trial within the 30 days prior to the first administration of study drug except for unblinded protocols (eg, open-label oncological regimen variations or biologic studies). Prior to enrolling patients who are on other open-label studies it is the site’s responsibility to ensure that the study criteria for that study allow for enrolment into this study.
13. Patients receiving treatment limited to supportive care due to predicted short survival time.
14. Patients with a baseline prolongation of Fridericia’s Correction Formula (QTcF) ≥ 500 msec, or at high risk for QT/QTc prolongation
15. Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at screening (for avoidance of doubt, liver transplant recipients may be enrolled if their laboratory parameters do not meet the exclusions): a) Total bilirubin ≥ 2 × upper limit of the normal range (ULN) b) Alanine transaminase or aspartate transaminase (AST) ≥ 3 × ULN c) Patients with known cirrhosis or chronic hepatic failure (regardless of ALT/AST/total bilirubin).
16. Prohibited concomitant medications: concomitant administration of inhibitors of human DHODH (teriflunomide and leflunomide) are prohibited. There are currently no other absolutely prohibited concomitant medications or vaccines, but there are medications with potentially significant DDIs, and the management of potential interactions should be considered before study enrolment
17. Additional exclusion criteria required by local regulatory authorities

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is the ACM rate at Day 42 in the ITT population.

Secondary endpoints 8

1. Investigator-assessed overall response (integrating clinical, radiological, and mycological response) at Day 14, Day 28, Day 42, Day 84, EOT, and FU.
2. Data Review Committee-adjudicated assessment of overall response at Day 42, Day 84, and EOT.
3. Serum GM at Day 14, Day 28, Day 42, Day 84, EOT, and FU.
4. All cause mortality rate at Day 84.
5. Survival time.
6. Data Review Committee attribution of mortality to IA at Day 42 and Day 84
7. Diagnosis of a secondary fungal infection at any time through EOT.
8. Quality of life as measured by the EQ-5D-5L at baseline, Day 14, and EOT.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F2G Limited

Sponsor organisation

F2G Limited

Address

Laboratory B Ground Floor Block 50, Alderley House, Alderley Park Alderley House Alderley Park

City

Macclesfield

Postcode

SK10 4TF

Country

United Kingdom

Scientific contact point

Organisation

F2G Limited

Contact name

Clinical Trial Operations

Public contact point

Organisation

F2G Limited

Contact name

Clinical Trial Operations

Third parties 15

Locations

6 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 106 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications