F901318/0041 OASIS

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 IFD caused by proven IA or probable lower respiratory tract disease Aspergillus species (invasive aspergillosis, IA).

• 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 (EOT).
• To compare the effects of treatment with olorofim versus treatment with AmBisome® followed by SOC on:
  • Investigator-assessed overall response (integrating clinical, radiological, and mycological response) at Day 14, Day 28, Day 42, Day 84, EOT, and Follow-up (FU)
  • Serum galactomannan (GM) at visits from screening to Day 14, Day 28, Day 42, Day 84, EOT, and FU
  • All-cause mortality at Day 84
  • Survival time
  • Data Review Committee attribution of mortality to IA at Day 42 and Day 84
  • Diagnosis of a secondary fungal infection at any time through EOT
  • 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, Day 28, Day 42, Day 84, and EOT.
• 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.
• To collect olorofim systemic exposure data for population pharmacokinetic (PK) modelling

• Male and female patients ages ≥ 18 years and weighing more than 40 kg who have been fully informed and who have given voluntary written informed consent, or whose legally authorised representative(s) has been fully informed and has given voluntary written informed consent if applicable, and in compliance with local regulations

OR:

• Patients unable to write and/or read but who fully understand the oral information given by the Investigator (or nominated representative) who have given oral informed consent witnessed in writing by an independent person and in compliance with local regulations. Unconscious patients must not enter the study.
• Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study.
• Patients requiring therapy with an antifungal agent other than a mould-active azole on the basis of IA refractory to mould-active azole therapy, proven resistance to the mould-active azoles, breakthrough infection on mould-active triazole prophylaxis, or azole drug-drug interactions (or potential for drug-drug interactions). Patients must meet at least one of these criteria:
  • Proven or suspected azole resistance in patients who have had ≤ 96 hours of potentially effective prior therapy:
    • Proven azole resistance will be based on in vitro susceptibility testing using local methodology and interpretive guidelines; isolates will be shipped to a central laboratory for confirmatory testing.
    • Suspected azole resistance will be based on other information available at the study site (eg, polymerase chain reaction [PCR] for azole-resistance genes).
    • In either case, enrolment in this category is permitted if the local Investigator feels that available information for the given patient makes initial azole therapy inappropriate.
  • Breakthrough infection on triazole prophylaxis: patients who have had any duration of prophylaxis prior to the breakthrough but ≤ 96 hours of potentially effective prior therapy.
  • Azole drug-drug interactions (or potential for drug-drug interactions) in patients who have had ≤ 96 hours of potentially effective prior therapy.
• Patients must be able to take oral medication
• [...]

• Women who are pregnant or breastfeeding
• Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug (olorofim or AmBisome®).
• Patients with only chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis.
• 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 a negative baseline GM.
• Patients with a known active second fungal infection of any type, other than candidiasis that can be treated with fluconazole.
• The use of an echinocandin as Candida prophylaxis.
• Microbiological findings (eg, bacteriological, virological) or other potential conditions that are temporally related and suggest a different aetiology for the clinical features.
• Human immunodeficiency virus (HIV) infection but not currently receiving antiretroviral therapy. 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.
• 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).
• 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.
• Patients previously enrolled in a study with olorofim/F901318.
• 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.
• Patients receiving treatment limited to supportive care due to predicted short survival time.
• Prohibited concomitant medications: Concomitant administration of inhibitors of human dihydro-orotate dehydrogenase (DHODH) (teriflunomide and leflunomide) are prohibited. There are currently no other absolutely prohibited concomitant medications or vaccines, but there are medications with potentially significant drug-drug interactions (DDIs), and the management of potential interactions should be considered before study enrolment
• [...]

Olorofim will be provided as an oral 30 mg tablet formulation. The dosing regimen for adults who are not being treated with medications that either inhibit or induce CYP enzymes will be a 1-day oral loading dose regimen of 150 mg olorofim bid dosed 12 ± 1 hour apart, followed by a maintenance dose regimen of 90 mg bid dosed 12 ± 1 hour apart from Day 2 onwards.

The active comparator will be initial AmBisome® therapy for at least 10 days given IV. Based on Infectious Diseases Society of America (IDSA) guidance and Cornely et al. (Clin Infect Dis 44:1289-97, 2007), AmBisome® will be given IV at a dose of 3 mg/kg/day. After the initial course of at least 10 days of AmBisome®, subsequent therapy will be SOC therapy as defined in the hierarchy of SOC (Post-AmBisome® Treatment Hierarchy)

A minimum treatment duration of 42 days in both arms is strongly recommended. Patients may receive up to 84 days (± 7 days) of treatment in this study, and the Sponsor recommends that randomised therapy be continued for this duration if possible.