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Study on Safety and Pharmacokinetics of Intravenous F901318 for Fungal Prophylaxis in AML Patients (SAFEGUARD)

Primary Purpose

Pulmonary Aspergillosis - Invasive, Acute Myeloid Leukemia

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
F901318
Caspofungin
Sponsored by
F2G Biotech GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Pulmonary Aspergillosis - Invasive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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. Patient has or will receive within 2 days a multi-lumen central venous catheter as standard of care.

Exclusion Criteria:

  1. Documented lung infiltrate at screening.
  2. Documented serum GMI ≥0.5 at screening
  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 and topical polyenes or nystatin are acceptable. Posaconazole and other azoles have to be discontinued at least 3 days before start of F901318.
  5. Concomitant exposure to phenobarbital and long acting barbiturates, triazolam, carbamazepine, phenytoin, pimozide, cisapride, 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.
  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 agree to not have sexual intercourse during 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 ocular disease.
  24. Contact lens use intended during study treatment.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    F901318 + Caspofungin

    Arm Description

    Patients will receive F901318 intravenously, starting 24 - 72 h after last chemotherapy infusion: Day 1: 4.0 mg/kg i.v. b.i.d. Day 2 until resolution of neutropenia (max. until day 14): 2.0 mg/kg i.v. b.i.d. Day after last i.v. application: 2.0 mg/kg oral q.d. Concomitant medication: For Candida prophylaxis, concomitant caspofungin will be administered from the 4th day of chemotherapy until end of neutropenia: Chemo day 4: Caspofungin 70 mg i.v. q.d. Chemo day 5 until resolution of neutropenia or until end of F901318 treatment (day 15): Caspofungin 50 mg i.v. q.d. All patients will undergo chemotherapy for acute leukaemia according to local clinical standard.

    Outcomes

    Primary Outcome Measures

    Collection of adverse events, results of physical examination, vital signs, ECGs, and laboratory assessments during F901318 intravenous infusion and oral formulation.

    Secondary Outcome Measures

    Concentration-time profile of F901318 following i.v. administration
    F901318 trough level assessment for 14 days once per day. On three of these 14 days additional samples for determination of plasma concentration of F901318 will be collected.
    Measured concentration of F901318 at the end of an i.v. dosing interval at steady state (Ctrough)
    Minimum observed plasma or serum, concentration of F901318 during an i.v. dosing interval at steady state (Cmin, ss)
    Maximum observed plasma or serum, concentration of F901318 during an i.v. dosing interval at steady state (Cmax, ss)
    Average plasma or serum concentration of F901318 at steady state after i.v. administration (Cav,ss)
    Area under the concentration-time curve during a F901318 i.v. dosing interval at steady state calculated by trapezoidal rule (AUCT,ss)
    Area under the concentration vs. time curve from point zero up to the end of infusion of F901318 (AUC(0-T))
    T: total time of infusion
    Area under the concentration vs. time curve from time point zero up to the time point t (AUC(0-t)) for F901318 after i.v. administration
    Area under the concentration vs. time curve from time point zero up to the last measured concentration of F901318 above LOQ (AUC(0-t_last)) after i.v. administration
    Apparent terminal half-life (t1/2) of F901318 after i.v. administration
    Terminal rate constant (λz) of F901318 after i.v. administration
    Apparent clearance (Cl) of F901318 after i.v. administration
    Plasma concentration of F901318 after oral application
    Measurement 2h, 4h, 12h and 24h after oral intake of F901318
    Number of patients developing an possible/probable/proven invasive fungal disease (IFD) according to EORTC/MSG criteria
    Patients galactomannan index and body temperature will be assessed regularly. If it is clinically indicated the patients will undergo a CT, which will be checked for infiltrations. If infiltrations are detected the patients will undergo a bronchoalveolar lavage, the result of which will be used to analyse BAL GMI, to grow a microbiological culture, to perform histology and perform an Aspergillus PCR. On the basis of the available data for each patient the scientific advisory committee will assess the number of patients suffering from a possible/probable or proven IFD.

    Full Information

    First Posted
    July 14, 2016
    Last Updated
    February 13, 2018
    Sponsor
    F2G Biotech GmbH
    Collaborators
    University Hospital of Cologne
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02856178
    Brief Title
    Study on Safety and Pharmacokinetics of Intravenous F901318 for Fungal Prophylaxis in AML Patients
    Acronym
    SAFEGUARD
    Official Title
    An Open Label Phase IIa Clinical Study to Evaluate the Safety and Pharmacokinetics of Intravenous and Oral F901318 (Combined With Caspofungin) for Antifungal Prophylaxis in Patients Undergoing Chemotherapy for Acute Myeloid Leukaemia
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2016
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    study no longer required
    Study Start Date
    April 20, 2017 (Actual)
    Primary Completion Date
    April 20, 2017 (Actual)
    Study Completion Date
    April 20, 2017 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    F2G Biotech GmbH
    Collaborators
    University Hospital of Cologne

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    This study assesses the pharmacokinetics and safety of the new antifungal F901318 in AML patients.
    Detailed Description
    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 caspofungin will allow recognizing potential factors of suboptimal F901318 exposure without the risk of fatal disseminating infection.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Pulmonary Aspergillosis - Invasive, Acute Myeloid Leukemia

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    F901318 + Caspofungin
    Arm Type
    Experimental
    Arm Description
    Patients will receive F901318 intravenously, starting 24 - 72 h after last chemotherapy infusion: Day 1: 4.0 mg/kg i.v. b.i.d. Day 2 until resolution of neutropenia (max. until day 14): 2.0 mg/kg i.v. b.i.d. Day after last i.v. application: 2.0 mg/kg oral q.d. Concomitant medication: For Candida prophylaxis, concomitant caspofungin will be administered from the 4th day of chemotherapy until end of neutropenia: Chemo day 4: Caspofungin 70 mg i.v. q.d. Chemo day 5 until resolution of neutropenia or until end of F901318 treatment (day 15): Caspofungin 50 mg i.v. q.d. All patients will undergo chemotherapy for acute leukaemia according to local clinical standard.
    Intervention Type
    Drug
    Intervention Name(s)
    F901318
    Intervention Description
    F901318 treatment starting after completion of chemotherapy. Max. 14 days of intravenous F901318 b.i.d. treatment, followed by one oral dose of F901318. Loading doses 4 mg/kg b.i.d. , maintenance doses 2 mg/kg b.i.d.
    Intervention Type
    Drug
    Intervention Name(s)
    Caspofungin
    Other Intervention Name(s)
    Cancidas®
    Intervention Description
    Intravenous Caspofungin treatment starting during chemotherapy for concomitant prophylaxis of fungal infection. Loading dose 70 mg q.d., maintenance doses 50 mg q.d.
    Primary Outcome Measure Information:
    Title
    Collection of adverse events, results of physical examination, vital signs, ECGs, and laboratory assessments during F901318 intravenous infusion and oral formulation.
    Time Frame
    57 days
    Secondary Outcome Measure Information:
    Title
    Concentration-time profile of F901318 following i.v. administration
    Description
    F901318 trough level assessment for 14 days once per day. On three of these 14 days additional samples for determination of plasma concentration of F901318 will be collected.
    Time Frame
    14 days
    Title
    Measured concentration of F901318 at the end of an i.v. dosing interval at steady state (Ctrough)
    Time Frame
    14 days
    Title
    Minimum observed plasma or serum, concentration of F901318 during an i.v. dosing interval at steady state (Cmin, ss)
    Time Frame
    14 days
    Title
    Maximum observed plasma or serum, concentration of F901318 during an i.v. dosing interval at steady state (Cmax, ss)
    Time Frame
    14 days
    Title
    Average plasma or serum concentration of F901318 at steady state after i.v. administration (Cav,ss)
    Time Frame
    14 days
    Title
    Area under the concentration-time curve during a F901318 i.v. dosing interval at steady state calculated by trapezoidal rule (AUCT,ss)
    Time Frame
    14 days
    Title
    Area under the concentration vs. time curve from point zero up to the end of infusion of F901318 (AUC(0-T))
    Description
    T: total time of infusion
    Time Frame
    14 days
    Title
    Area under the concentration vs. time curve from time point zero up to the time point t (AUC(0-t)) for F901318 after i.v. administration
    Time Frame
    14 days
    Title
    Area under the concentration vs. time curve from time point zero up to the last measured concentration of F901318 above LOQ (AUC(0-t_last)) after i.v. administration
    Time Frame
    14 days
    Title
    Apparent terminal half-life (t1/2) of F901318 after i.v. administration
    Time Frame
    14 days
    Title
    Terminal rate constant (λz) of F901318 after i.v. administration
    Time Frame
    14 days
    Title
    Apparent clearance (Cl) of F901318 after i.v. administration
    Time Frame
    14 days
    Title
    Plasma concentration of F901318 after oral application
    Description
    Measurement 2h, 4h, 12h and 24h after oral intake of F901318
    Time Frame
    1 day
    Title
    Number of patients developing an possible/probable/proven invasive fungal disease (IFD) according to EORTC/MSG criteria
    Description
    Patients galactomannan index and body temperature will be assessed regularly. If it is clinically indicated the patients will undergo a CT, which will be checked for infiltrations. If infiltrations are detected the patients will undergo a bronchoalveolar lavage, the result of which will be used to analyse BAL GMI, to grow a microbiological culture, to perform histology and perform an Aspergillus PCR. On the basis of the available data for each patient the scientific advisory committee will assess the number of patients suffering from a possible/probable or proven IFD.
    Time Frame
    57 days

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients diagnosed with AML and entering treatment of chemotherapy. Patients are expected to be neutropenic (< 500 ANC/μl) for > 10 days. Provision of written informed consent prior to any study specific procedures. Ability and willingness to comply with the protocol. Patients aged over 18 years. Patient has or will receive within 2 days a multi-lumen central venous catheter as standard of care. Exclusion Criteria: Documented lung infiltrate at screening. Documented serum GMI ≥0.5 at screening Current IFD or prior history of IFD or patients who received systemic antifungal therapy for proven or probable IFD in the last 12 months. Patients who received any systemic antifungal therapy for more than 72 hours immediately prior to first administration of study medication. Echinocandins and topical polyenes or nystatin are acceptable. Posaconazole and other azoles have to be discontinued at least 3 days before start of F901318. Concomitant exposure to phenobarbital and long acting barbiturates, triazolam, carbamazepine, phenytoin, pimozide, cisapride, 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. Documented prolongation of the QTc interval (>450 ms). Concomitant medication that prolongs QT interval (except for cytostatic drugs used during chemotherapy, such as mitoxantrone). 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. History of convulsion. Female patients only: Positive result of pregnancy test or breastfeeding. Female patients of childbearing potential who do not agree to not have sexual intercourse during 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. Known hypersensitivity to any component of the study medication. 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). 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 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]). Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to an acute infection or due to known Gilbert's disease. Calculated creatinine clearance (CrCl) < 50 mL/minute. Medical history of oliguria (< 20 mL/h) unresponsive to fluid challenge. Suspected other or additional cause for neutropenia or immunosuppression (other than AML or myelodysplastic syndrome). Any other medical condition which may affect the clinical evaluability of the patient. Patients previously enrolled in this study. 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. Chronic ocular disease. Contact lens use intended during study treatment.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Oliver Cornely, PhD, MD
    Organizational Affiliation
    University Hospital Cologne
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided

    Learn more about this trial

    Study on Safety and Pharmacokinetics of Intravenous F901318 for Fungal Prophylaxis in AML Patients

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