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JOURNAL ONKOLOGIE – STUDIE
PTX3AML

PTX3-targeted Antifungal Prophylaxis

Rekrutierend

NCT-Nummer:
NCT03828773

Studienbeginn:
Februar 2019

Letztes Update:
14.02.2024

Wirkstoff:
Posaconazole, Fluconazole

Indikation (Clinical Trials):
Candidiasis, Mycoses, Aspergillosis, Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, Genetic Predisposition to Disease

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Bochud Pierre-Yves

Collaborator:
Swiss National Science Foundation

Studienleiter

Pierre-Yves Bochud, MD
Principal Investigator
Centre Hospitalier Universitaire Vaudois

Kontakt

Studienlocations
(3 von 9)

Henri Mondor Hospital
94010 Créteil
FranceRekrutierend» Google-Maps
Ansprechpartner:
Christine Robin, Dr
Phone: +33149812111
E-Mail: christine.robin@aphp.fr

Ludovic Cabanne, Mr
Phone: +33149812058
E-Mail: ludovic.cabanne@aphp.fr» Ansprechpartner anzeigen
University Hospital of Lausanne / Centre Hospitalier Universitaire Vaudois (CHUV)
1011 Lausanne
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Pierre-Yves Bochud, MD
Phone: +41213144379
E-Mail: Pierre-Yves.Bochud@chuv.ch» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

Background:

Invasive mold infections (IMI, grouping infections due to Aspergillus spp [IA] and

non-Aspergillus mold) are a major concern in hematological patients, such as those with acute

myeloid leukemia (AML) or myelodysplastic syndrome in transformation (MDSit), collectively

named AML/MDSit in this protocol, or those undergoing hematopoietic cell transplantation

(HCT), with incidence and mortality rates ranging between 3-15% and 25-45%, respectively.

Primary antifungal prophylaxis has become the standard of care in such patients.

Historically, fluconazole (inactive against IA) was used as prophylaxis and allowed for

significant decrease in invasive candidiasis (IC). More recently, posaconazole (a

broad-spectrum azole active against IA and other non-Aspergillus filamentous molds) was

approved for primary antifungal prophylaxis in high-risk patient categories. However,

universal prophylaxis with posaconazole has been challenged, based on the relatively low

incidence of IMI and the large number of patients needed to treat. Moreover, administration

of broad-spectrum azoles is costly and associated with a large number of complications.

Hence, there is an urgent need to optimize antifungal prophylaxis by identifying those

patients with the highest risk for IMI to receive a broad-spectrum azole. Pentraxin-3 (PTX3),

a pattern recognition receptor, recognizes and binds to Aspergillus conidia, facilitates

opsonization and subsequently leads to complement and phagocyte activation. Two single

nucleotide polymorphisms (SNPs) in the gene encoding PTX3 have been identified as strong

predictors for IA and/or IMI in human studies. What makes PTX3 SNPs different and important

in clinical practice is: (i) the extent and reproducibility of basic science data with

regards to PTX3 and IA, (ii) the validation of PTX3 SNPs associations with IA in many

different patient populations, and (iii) the high frequency of minor allele in the general

population. The investigators hypothesize that PTX3 SNPs could be used to identify patients

at high risk for IMI, who will benefit the most from antifungal prophylaxis with

broad-spectrum azoles.

Overall objective:

The overall aim of this project is to assess the effectiveness of the use of

posaconazole-based antifungal prophylaxis in AML/MDSit patients in high risk group (single or

double single homozygotes PTX-3 SNPs). Exploratory objectives are to assess the effectiveness

of PTX3 SNPs testing to stratify the use of posaconazole-based antifungal prophylaxis in

AML/MDSit patients according to low or high risk genotypes.

Methods:

Eligible patients will be tested by competitive allele-specific Polymerase Chain Reaction

(PCR) from blood-extracted DNA samples for the presence of PTX3 SNPs rs230561 and rs3816527.

Randomisation based on genetic testing will be performed at the latest 24h after the first

neutropenia day (D0). Patients will be stratified based on genotyping results in two

unbalanced strata: stratum A (high-risk PTX3 SNPs) to be randomized 1:1 posaconazole

prophylaxis vs fluconazole and stratum-B (low-risk PTX3 SNPs) to be randomized 1:3 in favour

of Fluconazole. Patients will be assessed for a diagnosis of possible, probable or proven

Invasive Fungal Infections (IFI) based on consensus definition guidelines by the European

Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) groups

during 180 days after prophylaxis initiation.

Impact:

The results of this study may contribute to the optimization of primary antifungal

prophylaxis, by preventing IMI while limiting the use of broad-spectrum azoles, thus

decreasing complications and costs. This study is one of the first interventional clinical

trials to use genetic factors for risk stratification in the field of hematology and

infectious diseases, a concept frequently emphasized, however barely transcribed in practice,

as precision medicine. Furthermore, the scope of the proposed study expands beyond the

specific patient population. The results of this study could be used in the design and

initiation of similar efforts in other high-risk patient categories, including allogeneic HCT

and solid organ transplant (SOT) recipients.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Signed Informed Consent according to national/local regulations.

2. Age ≥18 years.

3. Diagnosis of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome in

transformation (MDSit) treated with an intensive chemotherapy regimen, including

induction / consolidation / salvage remission chemotherapy.

4. Planned hospital admission for the duration of the neutropenic phase (absolute

neutrophils count <500 cells/mm3).

Exclusion Criteria:

1. Patients with neutropenia (absolute neutrophils count<500 cells/mm3) upon presentation

and prior to chemotherapy initiation.

2. Patients with a diagnosis of acute promyelocytic leukemia (APL) or AML-M3.

3. Patients with known history of allergy, hypersensitivity or serious reaction to azole

antifungals

4. Women who are pregnant (positive blood/urine pregnancy test within 10 days before

randomization) or breast-feeding.

5. Diagnosis and treatment for an Invasive Fungal Infection (IFI) within 3 months prior

to study enrolment and an Invasive Mold Infection (IMI) at any point prior to or at

the time of enrolment.

6. Severe liver dysfunction, defined as at least one of the following markers: Aspartate

Aminotransferase (AST), Alanine Aminotransferase (ALT) or alkaline phosphatase above

>5x upper limit of normality: and/or total bilirubin above >3x upper limit of

normality.

7. Patients with an ECG with a prolonged QTc interval: QTc greater than 450 msec for men

and greater than 470 msec for women.

8. Patients who are receiving and cannot discontinue the following drugs at least 24

hours prior to randomization: terfenadine, astemizole, cisapride, pimozide,

halofantrine or quinidine (because of the possibility of QT prolongation), sirolimus,

rifampin, rifabutin, carbamazepine, long-acting barbiturates (e.g., phenobarbital,

mephobarbital), ritonavir, efavirenz, or ergot alkaloids (e.g., ergotamine,

dihydroergotamine).

9. Serious uncontrolled concomitant disease or comorbidity that, in the opinion of the

investigator, may compromise adherence to the study protocol.

10. Receipt of a prior allogeneic Hematopoietic Cell Transplantation (HCT).

11. Previous exposure to mold-active prophylaxis (>48 hours within 7 days of inclusion).

Studien-Rationale

Primary outcome:

1. Cumulative incidence of proven and probable invasive mold infection (IMI) (Time Frame - Day 180):
The cumulative incidence of proven and probable invasive mold infection (IMI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) in the intention-to-treat (ITT) population by day 180.



Secondary outcome:

1. Cumulative incidence of possible invasive mold infection (IMI) (Time Frame - Day 180):
The cumulative incidence of possible invasive mold infection (IMI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) by day 180 in the ITT population.

2. Cumulative incidence of probable and proven Invasive Fungal Infections (IFI) (Time Frame - Day 180):
The cumulative incidence of probable and proven Invasive Fungal Infections (IFI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms), namely: (a) all IFI, (b) Invasive Aspergillosis (IA) only and (c) Invasive Candidiasis (IC) only in the ITT patient population by day 180.

3. Time to probable and proven invasive mold infection (IMI) (Time Frame - Day 180):
The time to probable and proven invasive mold infection (IMI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) during 180 days in the ITT population

4. Cumulative incidence of mortality (Time Frame - Day 180):
The cumulative incidence of mortality in the ITT population by day 180.

5. Time to use of amphotericin B/echinocandin (Time Frame - Day 180):
The time to use of amphotericin B/echinocandin in the ITT population during 180 days.

6. Number of patient-days of amphotericin B/echinocandin (Time Frame - Day 180):
The number of patient-days of amphotericin B/echinocandin in the ITT population during 180 days.

7. Frequency/distribution of adverse events (AE) of interest (Time Frame - Day 180):
The frequency/distribution of AE of interest in posaconazole and fluconazole treated participants in the ITT population during 180 days, namely: Hepatotoxicity, defined by elevation of at least one of the following markers above >5x upper limit of normal: transaminases, alkaline phosphatase and/or above >3x upper limit of normal total bilirubin New QTc prolongation, defined as QTc >450 msec for men and >470 msec for women

8. Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population (Time Frame - Day 180):
The cumulative incidence of probable and proven invasive fungal infections (IFI) (based on published consensus guidelines by the EORTC/MSG groups and after validation by an independent adjudication committee of infectious disease experts blinded to treatment arms) , namely: all Invasive Fungal Infections (IFI), all Invasive Mold Infections (IMI), Invasive Aspergillosis (IA) only and Invasive Candidiasis (IC) only in the per protocol (PP) population by day 180.

Studien-Arme

  • Other: high-risk PTX3 SNPs
    risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): homozygous for rs230561 and/or rs381652
  • Other: low-risk PTX3 SNPs
    risk predicted by genotyping two PTX3 single nucleotide polymorphisms (SNPs): other than homozygous for rs230561 and/or rs381652

Geprüfte Regime

  • Posaconazole (Noxafil):
    Posaconazole is a triazole with broad-spectrum activity, to include Candida species, Aspergillus species, and other fungal pathogens, including the Zygomycetes. Posaconazole is available as slow release tablets (300mg/day) and as intravenous (IV) formulation (300mg/day) and is licensed and approved in Switzerland for the prevention of IFI, including mold and yeast infections, in patients >18 years who are at high risk of developing these types of infection (patients with long-term neutropenia or HCT recipients). Furthermore, international guidelines recommend posaconazole for primary antifungal prophylaxis in high-risk patients, such as AML patients with prolonged neutropenia. Posaconazole is available in Switzerland under the name of Noxafil® in capsules of 100mg, suspension of 40mg/mL and intravenous formulation of 300mg/16.7 mL.
  • Fluconazole (Diflucan):
    Fluconazole is an antifungal with activity against most Candida species. Fluconazole is licensed and approved in Switzerland for prophylaxis of IC in patients with neutropenia induced by chemotherapy or radiotherapy at a daily dose of 200 to 400 mg once daily. Fluconazole (200 mg or 400 mg once daily) is still currently used as primary antifungal prophylaxis (standard of care) in all 7 centers participating in this trial. Fluconazole is available in Switzerland under the name of Diflucan® in capsules of 50 mg, 150 mg and 200 mg and in powder for preparation of suspension (50 mg/5 ml and 200 mg/5 ml (forte)) or perfusion (2 mg/1 ml). Several generics of Diflucan® are authorized in Switzerland. Prescribing Diflucan® or any of its generics will remain at the discretion of and based on the standard operating procedures (SOP) at each institution.

Quelle: ClinicalTrials.gov


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