SUBA-Itraconazole Therapy for Coccidioidomycosis Refractory or Intolerant to Fluconazole

SUBA-Itraconazole Therapy for Coccidioidomycosis Refractory or Intolerant to Fluconazole

The purpose of this study is to determine how safe, effective, and well tolerated a new investigational antifungal drug, SUBA-itraconazole, is for patients who have been previously treated with fluconazole and have had either an insufficient response to treatment with fluconazole or a negative reaction to fluconazole preventing their further treatment with it.

This is a prospective, multi-center, open-label study involving subjects with proven or probable coccidioidomycosis refractory to fluconazole therapy following >40 days of treatment or subjects with proven or probable coccidioidomycosis who are intolerant to fluconazole.

The availability "Super Bioavailability" (SUBA) itraconazole 65 mg capsules with twice-daily dosing options with improved pharmacokinetics and lack of food or acidity requirements offers a substantial opportunity to improve the treatment of subjects with coccidioidomycosis.

Inclusion Criteria:

1. All subjects ≥ 18 years who have given written informed consent to participate

2. Subjects with a proven or probable coccidioidomycosis according to current European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, including subjects who:

   • Are immunosuppressed, including as a result of HIV/AIDS
   • Have had a heart, lung or bone marrow transplant
   • Have had chemotherapy for cancer
   • Are otherwise not immunocompromised

   Note: central nervous system (CNS) infection is an exclusionary criteria

3. Refractory for ≥ 40 days, or intolerant to fluconazole treatment for coccidioidomycosis in the opinion of the investigator

   • Refractory disease defined as failure to obtain an adequate therapeutic response after ≥40 days of therapy:
   • Lack of improvement in signs, symptoms or imaging findings OR
   • Continued isolate of Coccidioides or histopathologic findings of • Coccidioides despite antifungal therapy
   • Rising Complement Fixation Titers
   • Progression of disease (requires worsening of attributable signs, symptoms or imaging, or a new site of infection
   • Intolerance defined as adverse events attributable to fluconazole therapy defined as organ toxicity of grade 3 or higher, nephrotoxicity (Creatinine twice the upper limit of normal), or idiosyncratic reactions therapy that in the opinion of the investigator may be relieved by a therapeutic change OR refusal of the patient to take further fluconazole

4. Subjects of childbearing potential should be non-pregnant and not breastfeeding (and not planning to become pregnant)

   • Postmenopausal for ≥1 year
   • Post-hysterectomy or bilateral oophorectomy
   • If of child-bearing potential have a negative pregnancy test at screening and using an acceptable effective method of birth control throughout course of study or remain abstinent for duration of study. Subjects with a partner of childbearing potential should agree to use appropriate contraception.

Exclusion Criteria:

1. Significant liver dysfunction as evidenced by total bilirubin > 1.5 × the upper limit of normal (ULN) range unless considered due to Gilbert syndrome, in which case > 3 × the ULN, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 1.5 x the ULN.

2. Evidence of CNS infection.

3. Unable to take PO medications.

4. Documented intolerance, allergy or hypersensitivity to itraconazole.

5. Inability to comply with study treatment, study visits, and study procedures.

6. Known history or presence of congestive cardiac failure, fungal endocarditis, or other causes of ventricular dysfunction that may outweigh the benefit of itraconazole.

7. Subjects with active tuberculosis.

8. Concurrent use of drugs that effect SUBA™-itraconazole concentrations

   • Subjects who washout from prohibited medications can be included

9. Any known or suspected condition of the subject that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy.

10. Treatment with any investigational agent in the 30 days prior to study entry.

11. Subjects unlikely to survive 30 days based on the opinion of the investigator.

12. Subjects with body weight < 40 kg.