Platform Trial for Salvage Consolidation Therapy in Dimorphic Fungi

Dimorphic fungal infections, including coccidioidomycosis, blastomycosis, and histoplasmosis, are commonly treated with azole antifungals such as itraconazole or fluconazole as consolidation therapy. However, some patients experience intolerance, treatment failure, drug interactions, toxicity, or lack of access to standard first-line consolidation therapy. For these patients, treatment options are limited.

This study is an open-label, single-arm Phase II platform trial designed to evaluate investigational antifungal agents as salvage or consolidation therapy in adults with dimorphic fungal infections. The first investigational agent evaluated in this platform is oteseconazole.

Eligible participants will be adults with coccidioidomycosis, blastomycosis, or histoplasmosis who are on active therapy, are expected to require at least 6 additional months of antifungal therapy, and have intolerance, failure, or unavailability of current first-line consolidation therapy. Participants will complete screening and informed consent through REDCap. Study drug will be mailed to participants by the central pharmacy after enrollment.

Participants will complete monthly follow-up surveys assessing symptom status, functional status, quality of life, antifungal therapy changes, and treatment tolerance. Safety monitoring will include adverse event tracking, serious adverse event reporting, and laboratory assessments. Participants will be followed for up to 18 months, including the treatment period and 6 months of post-therapy follow-up.

• Oteseconazole (Drug), also known as VIVJOA: Participants will receive oral oteseconazole 600 mg twice daily for 12 days, followed by 600 mg weekly. Total treatment duration depends on diagnosis: up to 52 weeks for coccidioidomycosis, 26 weeks for blastomycosis, and 26 weeks for histoplasmosis.

Primary outcomes

• Change in Symptom Status [Baseline through 12 months]: Symptom status change over time will be assessed using a 10-point visual analogue scale queried monthly through follow-up surveys.
• Change in Functional Status [Baseline through 12 months]: Functional status change over time will be assessed using a 10-point visual analogue scale queried monthly through follow-up surveys.

Secondary outcomes

• Serious Adverse Event Rate [Through 1 year]: Serious adverse event rate will be assessed through 1 year, including events such as death, all-cause re-hospitalization, permanent neurologic deficit, and other serious adverse events.
• Discontinuation of Study Drug Due to Therapeutic Failure [Through study drug treatment period, up to 12 months]: The number of participants who discontinue study drug due to therapeutic failure with worsening clinical symptoms will be assessed.
• Discontinuation of Study Drug Due to Adverse Events [Through study drug treatment period, up to 12 months]: The number of participants who discontinue study drug due to adverse events will be assessed.
• Study Drug Discontinuation, Dose Reduction, or Interruption Due to Toxicity or Intolerance [Through study drug treatment period, up to 12 months]: The incidence of study drug discontinuation, dose reduction, or interruption due to toxicity or intolerance will be assessed by grade.
• Incidence of Laboratory Adverse Events [Through study drug treatment period, up to 12 months]: Laboratory adverse events will be assessed with focus on alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and direct, indirect, and total bilirubin, using the NIH DAIDS Adverse Event Grading document.
• Change in PROMIS-29 Scores [Baseline through study follow-up, up to 18 months]: PROMIS-29 scores will be assessed over time to evaluate changes in patient-reported health status and quality of life.
• Change in Fatigue Symptom Status [Baseline through 12 months]: Fatigue symptom status change over time will be assessed using a 10-point visual analogue scale queried monthly through follow-up surveys.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Diagnosis of coccidioidomycosis, blastomycosis, or histoplasmosis and on active therapy
* Age 18 years or older
* Anticipated need for at least 6 additional months of antifungal therapy at enrollment
* Intolerance, failure, or unavailability of current first-line consolidation therapy

Exclusion Criteria:

* Currently hospitalized
* Central nervous system involvement of coccidioidomycosis, blastomycosis, or histoplasmosis
* Previous administration of or allergy to study drug
* Any condition for which participation would not be in the best interest of the participant or that could limit protocol-specified assessments
* Females of childbearing potential
* Breast Cancer Resistance Protein substrate medication interaction that cannot be managed by switching medication, discontinuation, 50% dose reduction, or use of the lowest dose
* Children
* Pregnant women/persons
* Fetuses
* Neonates
* Prisoners
* Adults lacking capacity to consent or adults with diminished or fluctuating capacity to consent

• Matthew Pullen, MD, Principal investigator, University of Minnesota