This study is currently recruiting participants.
Number
000781-I
Sponsoring Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 18 Years Max Age: N/A
Referral Letter Required
Yes
Population Exclusion(s)
Children
Keywords
Aspergillus; Antifungal; Azole Resistance; Invasive Fungal Disease
Recruitment Keyword(s)
None
Condition(s)
Invasive Fungal Disease
Investigational Drug(s)
F901318
Investigational Device(s)
Intervention(s)
Drug: Olorofim (F901318) Drug: Lyophilized Amphotericin B
Supporting Site
National Institute of Allergy and Infectious Diseases
Invasive fungal infections (IFD), caused by molds and yeasts that form lesions in deep tissues, can be severe and life-threatening. Better treatments are needed.
Objective:
To compare the standard treatment for IFD, AmBisome, against an investigational drug called olorofim.
Eligibility:
People aged 18 and older with IFD caused by the Aspergillus species.
Design:
Participants will have up to 18 clinic visits in up to 18 weeks.
Participants will be screened. They will have a physical exam, including blood and urine tests. Their eyes will be checked. They will have a test of heart function. Fluid or a small piece of tissue may be taken from the infected area. They may have X-rays or other imaging scans of the infected area. They will complete a questionnaire about how the infection affects their life.
Participants will be randomly assigned to different groups. Some will take AmBisome. This drug is given through a tube attached to a needle placed in a vein in the arm. This may take 30 to 120 minutes. They will receive the drug once daily for at least 10 days.
Other participants will take olorofim. This drug is in the form of tablets taken by mouth. On the first day, participants will take 5 tablets twice a day. Then they will take 3 tablets every 12 hours for up to 12 weeks.
Participants may receive a Study Diary Card to record when they take the medications. They will also record any side effects.
Previous tests may be repeated during clinic visits.
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INCLUSION CRITERIA: 1) 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 authorized 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. 2) Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study. 3) 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: a) Proven or suspected azole resistance in patients who have had <= 96 hours of potentially effective prior therapy: i) 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. ii) Suspected azole resistance will be based on other information available at the study site (eg, polymerase chain reaction [PCR] for azole-resistance genes). iii) 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. b) 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. c) Azole drug-drug interactions (or potential for drug-drug interactions) in patients who 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: i) After 8 or more days of prior antifungal treatment: (1) On the basis of changes in GM: Either of these, with the proviso that the new GM data meet the study entry rule for GM-based diagnosis of positive GM (2x independent sera tested at >= 0.5; OR 2 results of >= 1.0 on aliquots from one BAL). a) Serum: The serum GM has not fallen by either >= 1 unit or to < 0.5 units based on measurements taken at least 8 days apart b) BAL: 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. Note that there is not a definition for rising GM in BAL as these values are subject to sampling error OR (2) Clinical deterioration with no other identifiable (non-fungal) etiology OR (3) New clearly distinct site of infection is detected clinically or radiologically ii) After 15 or more days on primary antifungal treatment: (1) Meeting any of the above 8 or more days criteria, OR (2) Progression of original lesions on computed tomography (CT) (or other non X-ray imaging) based on > 25 percent growth of initial lesions in the context of no change in immune status (eg, no change in neutropenia). 4) AmBisome(R) is an appropriate therapy for the patient. 5) Ability and willingness to comply with the protocol. 6) Female patients must be non-lactating and at no risk of pregnancy for one of the following reasons: a) Postmenopausal for at least 1 year; b) Post-hysterectomy and/or post-bilateral ovariectomy; c) Of childbearing potential, with a negative urine or serum human chorionic gonadotropin pregnancy test at the screening visit and must be using a highly effective method of birth control throughout the course of the study period and up to and including 30 days after stopping study drug: i) Established use of oral, injected, transdermal, intravaginal, or implanted hormonal methods of contraception associated with inhibition of ovulation ii) Placement of an intrauterine device or intrauterine hormone-releasing system iii) Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate) iv) Bilateral tubal occlusion v) Sexual abstinence (reliable sexual abstinence is acceptable but periodic abstinence [eg, calendar, ovulation, symptom-thermal, or post-ovulation methods] and withdrawal are not acceptable). 7) Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception throughout study participation and agree to continue its use for 30 days after stopping study drug and may not donate semen during this time. 8) Patients must be able to take oral medication. 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 (olorofim or AmBisome(R). 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 a 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 use of an 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. 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 QT using Fridericia s Correction Formula (QTcF) >= 500 msec, or at high risk for QT/QTc prolongation, eg, a) A family history of long QT syndrome b) Other known pro-arrhythmic conditions c) Risk factors for Torsade de Pointes (eg, uncompensated heart failure, abnormal plasma potassium or magnesium levels that cannot be corrected, an unstable cardiac condition during the last 30 days). 15) Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at screening: a) Total bilirubin >= 2 x upper limit of the normal range (ULN) b) Alanine transaminase or aspartate transaminase >= 3 x ULN c) Patients with known cirrhosis or chronic hepatic failure. 16) 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 enrollment. 17) Additional exclusion criteria required by local regulatory authorities.
1) 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 authorized 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.
2) Patients with proven IA at any site or probable LRTD IA per EORTC/MSG 2019 criteria as adapted for this study.
3) 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:
a) Proven or suspected azole resistance in patients who have had <= 96 hours of potentially effective prior therapy:
i) 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.
ii) Suspected azole resistance will be based on other information available at the study site (eg, polymerase chain reaction [PCR] for
azole-resistance genes).
iii) 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.
b) 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.
c) Azole drug-drug interactions (or potential for drug-drug interactions) in patients who 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:
i) After 8 or more days of prior antifungal treatment:
(1) On the basis of changes in GM:
Either of these, with the proviso that the new GM data meet the study entry rule for GM-based diagnosis of positive GM (2x independent sera tested at >= 0.5; OR 2 results of >= 1.0 on aliquots from one BAL).
a) Serum: The serum GM has not fallen by either >= 1 unit or to < 0.5 units based on measurements taken at least 8 days apart
b) BAL: 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. Note that there is not a definition for rising GM in BAL as these values are subject to sampling error
OR
(2) Clinical deterioration with no other identifiable (non-fungal) etiology
(3) New clearly distinct site of infection is detected clinically or radiologically
ii) After 15 or more days on primary antifungal treatment:
(1) Meeting any of the above 8 or more days criteria, OR
(2) Progression of original lesions on computed tomography (CT) (or other non X-ray imaging) based on > 25 percent growth of initial
lesions in the context of no change in immune status (eg, no change in neutropenia).
4) AmBisome(R) is an appropriate therapy for the patient.
5) Ability and willingness to comply with the protocol.
6) Female patients must be non-lactating and at no risk of pregnancy for one of the following reasons:
a) Postmenopausal for at least 1 year;
b) Post-hysterectomy and/or post-bilateral ovariectomy;
c) Of childbearing potential, with a negative urine or serum human chorionic gonadotropin pregnancy test at the screening visit and must be using a highly effective method of birth control throughout the course of the study period and up to and including 30 days after stopping study drug:
i) Established use of oral, injected, transdermal, intravaginal, or implanted hormonal methods of contraception associated with inhibition of ovulation
ii) Placement of an intrauterine device or intrauterine hormone-releasing system
iii) Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate)
iv) Bilateral tubal occlusion
v) Sexual abstinence (reliable sexual abstinence is acceptable but periodic abstinence [eg, calendar, ovulation, symptom-thermal, or
post-ovulation methods] and withdrawal are not acceptable).
7) Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception throughout study participation and agree to continue its use for 30 days after stopping study drug and may not donate semen during this time.
8) Patients must be able to take oral medication.
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 (olorofim or AmBisome(R).
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 a 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 use of an 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. 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 QT using Fridericia s Correction Formula (QTcF) >= 500 msec, or at high risk for QT/QTc prolongation, eg,
a) A family history of long QT syndrome
b) Other known pro-arrhythmic conditions
c) Risk factors for Torsade de Pointes (eg, uncompensated heart failure, abnormal plasma potassium or magnesium levels that cannot be corrected, an unstable cardiac condition during the last 30 days).
15) Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at screening:
a) Total bilirubin >= 2 x upper limit of the normal range (ULN)
b) Alanine transaminase or aspartate transaminase >= 3 x ULN
c) Patients with known cirrhosis or chronic hepatic failure.
16) 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 enrollment.
17) Additional exclusion criteria required by local regulatory authorities.
Principal Investigator
Referral Contact
For more information: