| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Invasive fungal disease in patients with acute myeloid leukemia under chemotherapy |
| Invasive Pilzinfektionen bei Patienten mit akuter myeloischer Leukämie unter Chemotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fungal infections in patients with leukemia |
| Pilzinfektionen bei Leukämiepatienten |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017533 |
| E.1.2 | Term | Fungal infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the safety and tolerability of F901318 tablets in AML patients (all groups).
- To determine the pharmacokinetic profile of F901318 tablets in AML patients (all groups).
- To assess pharmacokinetic variability of F901318 in AML patients during and after concomitant Fluconazole treatment (Groups F1 and F2).
- To assess bioavailability of F901318 in AML patients with concomitant Posaconazole treatment (Group P). |
|
| E.2.2 | Secondary objectives of the trial |
- To provide preliminary information on efficacy of F901318 in prevention of invasive Aspergillus infection for Groups F1 and F2.
- To develop and evaluate pharmacokinetic models (Nonlinear Mixed Effect Model analysis (NONMEM), simulation) and to characterize population PK
- Establish dose adaptation recommendations in the presence of Cytochrome P450 inhibitors
- Describe any potential effect of F901318 on Posaconazole & Fluconazole drug levels |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients diagnosed with AML and entering treatment of chemotherapy.
2. Patients are expected to be neutropenic (< 500 ANC/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
|
|
| E.4 | Principal exclusion criteria |
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 (except for patients in group P receiving posaconazole as fungal prophylaxis; see also inclusion criterion 8). Echinocandins 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.
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 [28]).
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.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Safety and tolerability as assessed by adverse events, physical examination, vital signs, ECGs, and laboratory assessments.
- Concentrations of F901318 in plasma; concentration-time profile of F901318 following intake
- The derived PK parameters Ctrough, Cmin_ss, Cmax_ss, Cav_ss, AUCT,ss, AUC(0-T), AUC0-t, AUC(0-t_last), T1/2, lambda z, Vss, and CL
- Assessment of F901318 plasma concentrations during concomitant Fluconazole treatment and after discontinuation of Fluconazole
- Assessment of F901318 plasma concentrations during concomitant Posaconazole treatment
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-AEs will be assessed on every treatment day and at the follow-up (10 days after end of F901318 treatment) and late follow-up (28 days after end of F901318 treatment) visit.
-F901318 plasma peak concentration after F901318 intake will be assessed on the second day of F901318 treatment and EOT. F901318 trough level assessments will be done on the first 3 days of F901318 treatment, on day 5, 7, 10, 13 and 16 of F901318 treatment, at EOT and FU. From the measured plasma concentrations the PK parameter will be derived. |
|
| E.5.2 | Secondary end point(s) |
- Absence of breakthrough infections. Incidence of invasive fungal disease will be categorized according to EORTC/MSG 2008 criteria into possible/probable/proven IFD by a central end point committee, based on serum galactonannan index and results of bronchoalveolar lavage (BAL, if clinically indicated) and CT (if clinically indicated).
- Estimates of model parameters and their precision, goodness-of-fit, individual and mean predictions.
- Plasma concentrations of F901318 during concomitant Posaconazole or Fluconazole treatment and after discontinuation of Fluconazole.
- Concentration of Fluconazole and Posaconazole in plasma during F901318 treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Efficacy data will be collected at the last day of study drug treatment and at the follow-up (10 days after end of F901318 treatment) and late follow-up visit (28 days after end of F901318 treatment)
-F901318 plasma peak concentration after F901318 intake will be assessed on the second day of F901318 treatment and EOT. F901318 trough level assessments will be done on the first 3 days of F901318 treatment, on day 5, 7, 10, 13 and 16 of F901318 treatment, at EOT and FU. From the measured plasma concentrations the PK parameter will be derived.
- Fluconazole and Posaconazole concentrations will be assessed together with F901318 trough levels on the first 3 days of F901318 treatment, on day 5, 7, 10, 13 and 16 of F901318 treatment, at EOT and FU. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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