Safety and Pharmacokinetics of Oral F901318 (Fluconazole and Posaconazole) IN Aml Leukaemia

An Open Label Phase IIa Clinical Study to Evaluate the Safety and Pharmacokinetics of Oral F901318 (Combined With Fluconazole and Posaconazole) in AML

Non-randomized, multi-centre, open label, uncontrolled, multiple dose, phase IIa study.

A total of 18 patients diagnosed with acute myeloid leukaemia (AML) scheduled for chemotherapy and expected to be neutropenic (<500 Absolute neutrophil count (ANC)/µl) for >10 days will be treated. F901318 will be given in conjunction with fluconazole or posaconzaole in order to assess safe treatment regimens for both combinations.

'F901318 has potent in vitro efficacy against Aspergillus spp. including azole-resistant strains and consistent efficacy in in vivo mouse models of infection. F901318 is active by both oral and intravenous routes of administration in preclinical efficacy studies.

Non-clinical studies and phase I clinical trials show that F901318 has a good overall safety profile and limited potential for drug-drug interactions. F901318 exhibits a highly promising profile which can potentially address the critical treatment requirements for invasive Aspergillus infections in a changing clinical environment in which new classes of antifungals are needed.

This phase IIa study aims to confirm PK and safety information of F901318 from phase I and bridge them to a neutropenic AML patient population, which represents the main population for future efficacy trials. Coadministration of fluconazole or posaconazole will allow recognizing potential factors of suboptimal F901318 exposure without the risk of fatal disseminating infection.'

Inclusion Criteria:

• Participating patients need to fulfil all of the following criteria:

  1. Patients diagnosed with AML and entering treatment of chemotherapy.

  2. Patients are expected to be neutropenic (ANC <500/µl) for >10 days.

  3. Provision of written informed consent prior to any study specific procedures.

  4. Ability and willingness to comply with the protocol.

  5. Patients aged over 18 years.

  6. Patients with body weight ≥60 kg

  7. Group F only: patient receives according to local clinical standard either

     • no fungal prophylaxis or
     • only topical fungal prophylaxis (e.g. Ampho moronal®) or
     • fluconazole as routine fungal prophylaxis

  8. Group P only: patient receives posaconazole as fungal prophylaxis according to local clinical standard

Exclusion Criteria:

• Any of the following will exclude a patient from the study:

  1. Documented lung infiltrate at screening.
  2. Evidence for active fungal infection, such as documented serum GMI ≥0.5 at screening (within 5 days before study start)
  3. Current IFD or prior history of IFD or patients who received systemic antifungal therapy for proven or probable IFD in the last 12 months.
  4. Patients who received any systemic antifungal therapy for more than 72 hours immediately prior to first administration of study medication. Echinocandins, posaconazole (group P, see also inclusion criterion 8), and topical polyenes or nystatin are acceptable.
  5. Concomitant exposure to phenobarbital and long acting barbiturates, triazolam, carbamazepine, phenytoin, pimozide, cisaprid, efavirenz, ritonavir, rifabutin, rifampicin, ergot alkaloids (ergotamine, dihydroergotamin), ibrutinib, idelalisib, vinca alkaloids, digoxin, dofetilide, quinidine, St. John´s wort, everolimus, sirolimus, astemizole, terfenadine, methadone, alfentanil, fentanyl and other structurally related opiates, warfarin (see also section 8.8 for details).
  6. Documented prolongation of the QTc interval (>450 ms).
  7. Concomitant medication that prolongs QT interval (except for cytostatic drugs used during chemotherapy, such as mitoxantrone).
  8. Any other 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.
  9. History of convulsion.
  10. Female patients only: Positive result of pregnancy test or breastfeeding.
  11. Female patients of childbearing potential who do not practice sexual abstinence as their common way of life and confirm to stay sexually abstinent also during their participation in the study or who do not use or do not agree to use appropriate contraceptive methods (prior to and during the study, including 14 days after the last dose of study therapy) as defined in ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals (EMA/CPMP/ICH/286/1995). Hormonal contraception alone is not considered appropriate. See section 9.3.2 for additional information.
  12. Known hypersensitivity to any component of the study medication.
  13. A history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalaemia, cardiomyopathy, sinus bradycardia, symptomatic arrhythmias, family history of long QT Syndrome).
  14. Patient has had acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis (any Child-Pugh class), acute hepatic failure, or acute decompensation of chronic hepatic failure
  15. Presence of hepatic disease as indicated by aspartate aminotransferase (AST) or alanine transaminase (ALT) >3 × upper limit of normal (ULN) at Screening. Patients with AST and/or ALT >3 × ULN and <5 × ULN are eligible if these elevations are acute, not accompanied by a total bilirubin ≥2xULN and documented by the investigator as being directly related to an infectious process being treated. During the clinical study, the investigator is responsible for, without delay, determining whether the patient meets potential Hy's law criteria (according to FDA [16]).
  16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to an acute infection or due to known Gilbert's disease.
  17. Calculated creatinine clearance (CrCl) <50 mL/minute.
  18. Medical history of oliguria (<20 mL/h) unresponsive to fluid challenge.
  19. Suspected other or additional cause for neutropenia or immunosuppression (other than AML or myelodysplastic syndrome).
  20. Any other medical condition, which may affect the clinical evaluability of the patient.
  21. Patients previously enrolled in this study.
  22. Patient has participated or intends to participate in any other clinical study that involves the administration of an investigational medication at the time of presentation, during the course of the study, or during the 30 days prior to study start. New combinations of labelled substances for chemotherapy are allowed.
  23. Chronic external ocular disease
  24. Contact lens use intended during study treatment.