Open-label Study of APX001 for Treatment of Patients With Invasive Mold Infections Caused by Aspergillus or Rare Molds

Study Overview
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Brief Summary
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This is a Phase 2, multicenter study to evaluate APX001 for the treatment of invasive fungal infections caused by Aspergillus spp. or rare molds (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi).

Official Title
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A Phase 2, Open-Label Study to Evaluate the Safety and Efficacy of APX001 in the Treatment of Patients With Invasive Mold Infections Caused by Aspergillus Species or Rare Molds

Conditions
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Invasive Fungal Infections

Intervention / Treatment
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* Drug: fosmanogepix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, 18 years or older. Patients with proven or probable IMI caused by Aspergillus spp. Patients who present with IMI due to other filamentous fungi (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi such as Mucor spp. or Rhizopus spp.) may also be enrolled. Have limited or no treatment options due to documented or anticipated resistance, contraindication, intolerance, or lack of clinical response to SOC antifungal therapy, as advocated by the relevant regional/country treatment guidelines. Patients where the Investigator considers that there is a potential advantage of using APX001 over current SOC (eg, broad spectrum of activity, emergence of IMI during antifungal prophylaxis, activity against resistant mold pathogens, IV and PO formulations, favorable DDI profile, favorable hepatic and renal safety profile, wide tissue distribution including brain), and/or where the SOC antifungal therapy carries significant risk of toxicity or treatment failure (eg, DDI risk, safety/toxicity risk, site of infection not accessible by SOC). Exclusion Criteria: Refractory hematologic malignancy. Chronic aspergillosis, aspergilloma, or allergic bronchopulmonary aspergillosis. Treatment with systemic (PO, IV, or inhaled) mold active antifungal therapy for 120 hours immediately before initial dosing. Note: patients with invasive fungal infection caused by a mold with documented resistance to or lack of coverage by the prior SOC in question, may have received >120 hours prior treatment and remain eligible for the study. Evidence of significant hepatic dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: fosmanogepix (APX001)<br> | Drug: fosmanogepix<br>* IV and oral fosmanogepix<br>* Other names: E210;|
| Experimental: Cohort B: fosmanogepix (APX001)<br> | Drug: fosmanogepix<br>* IV and oral fosmanogepix<br>* Other names: E210;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died After the First Dose of Study Drug Through Day 42 | Percentage of participants who died after first dose in the study through Day 42 were reported in this outcome measure. This outcome measure included all deaths from Day 1 through Day 42. | After first dose on Day 1 through Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Global Response Based on Data Review Committee (DRC) Assessment at End of Study Drug Treatment (EOST) | Global response was classified as treatment success (complete or partial response [CR or PR]) or treatment failure (stable response [SR], progression of fungal disease [PD], or death) as determined by DRC. CR: survival within prespecified period of observation (PPOB), resolution of all attributable (att) symptoms and signs of disease and radiological (rad) abnormalities, and mycological (myco) evidence of eradication of disease. PR: survival within POB, improvement in att symptoms and signs of disease and rad abnormalities, and evidence of clearance of cultures or reduction of fungal burden. SR: survival within PPOB, minor or no improvement in fungal disease but no evidence of progression based on composite of clinical, rad and myco criteria, PD or death. PD: evidence of progressive fungal disease based on composite of clinical, rad and myco criteria. Death: death during PPOB, regardless of attribution. Data is presented for EOST which could have preceded Day 42 for some participants. | Any day from Day 1 until end of study treatment (any day up to Day 42) | 
| Percentage of Participants With Treatment Success or Treatment Failure for Global Response Based on Data Review Committee (DRC) Assessment at End of Study Drug Treatment (EOST) | Global response was classified as treatment success (CR or PR) or treatment failure (SR, PD or death) as determined by DRC. CR: survival within prespecified POB, resolution of all attributable symptoms and signs of disease and rad abnormalities and myco evidence of eradication of disease. PR: survival within prespecified POB, improvement in attributable symptoms and signs of disease and rad abnormalities and evidence of clearance of cultures or reduction of fungal burden. SR: survival within prespecified POB, minor or no improvement in fungal disease, but no evidence of progression, based on composite of clinical, rad, and myco criteria, PD or death. PD: evidence of PD based on a composite of clinical, rad, and myco criteria. Death: death during prespecified period of evaluation, regardless of attribution. Percentage of participants with treatment success (CR, PR) and treatment failure (SR, PD, death) along with two-sided exact binomial 80% confidence interval is presented. | Any day from Day 1 until end of study treatment (any day up to Day 42) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were events between first dose of study drug and up to 4 weeks post last dose of study treatment that were absent before treatment or that worsened relative to pretreatment state. An SAE was any untoward medical occurrence that occurred, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; was a congenital anomaly/birth defect and other important medical events. AEs included SAEs and all non-SAEs. | Day 1 up to maximum of 31 days of follow up post last dose of study treatment, where maximum treatment duration was 42 days (maximum up to 73 days) | 
| Number of Participants With Clinically Significant Abnormality in Vital Signs | Vital signs included body temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation. Number of participants with clinically significant abnormality in vital signs as judged by investigator were reported in this outcome measure. | Day 1 up to maximum of 31 days of follow up post last dose of study treatment, where maximum treatment duration was 42 days (maximum up to 73 days) | 
| Number of Participants With Clinically Significant Abnormality in Laboratory Test Evaluations | Clinical laboratory assessments included serum chemistry (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, creatine kinase), hematology (including hemoglobin, hematocrit, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils and monocytes), coagulation (including Prothrombin time [PT]/ International normalized ratio [INR]), and urinalysis. Number of participants with clinically significant abnormality in any laboratory parameter as judged by investigator and reported as adverse events were presented. | Day 1 up to maximum of 31 days of follow up post last dose of study treatment, where maximum treatment duration was 42 days (maximum up to 73 days) | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings | ECG parameters included PR interval, QRS interval, QT interval, QT interval corrected using the Fridericia's formula (QTcF), QT interval corrected using the Bazett's formula (QTcB), RR interval and heart rate. Number of participants with clinically significant abnormal ECG findings as judged by investigator were presented. | Day 1 up to maximum of 31 days of follow up post last dose of study treatment, where maximum treatment duration was 42 days (maximum up to 73 days) | 
| Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examinations | Physical examination included an assessment of general appearance, skin, eyes, heart, chest, abdomen, and a neurological examination. Components of the neurological examination included cranial nerve, sensory, and motor examination; reflex and gait testing; and coordination assessment. Clinically significant changes were judged by investigator. | Day 1 up to maximum of 31 days of follow up post last dose of study treatment, where maximum treatment duration was 42 days (maximum up to 73 days) | 
| Plasma Concentrations of Fosmanogepix |  | Days 1, 2, 3, 4, 7: Pre-dose and 3 hours post-dose; Days 6, 13, 14: 3 hours post-dose, Day 15: pre-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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APX001, APX001A, fosmanogepix, manogepix, aspergillus, aspergillosis, covid, covid19, mold, mould, pulmonary aspergillosis, pulmonary aspergillus, galactomannan, Karius, SARS-CoV-2, fusarium, mucorales, mucor, rhizopus, scedosporium, fungal disease, invasive fungal disease, EORTC