Clinical trial NCT03828773: PTX3-targeted Antifungal Prophylaxis
Official title: PTX3 Genetically Stratified Randomized Double-blinded Allocation Event-driven Clinical Trial for Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Candidiasis
Fungal Infection
Acute Myeloid Leukemia
Genetic Predisposition
Aspergillosis
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
First posted: 2019-02-04
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: prospective genetically-stratified randomized double-blind event-driven multicentre clinical trial
Primary purpose: PREVENTION

Brief summary: This is a prospective genetically-stratified randomized double-blind event-driven multicentre clinical trial to assess the efficacy of posaconazole-based antifungal prophylaxis allocation strategies for patients with acute myeloid leukemia who receive induction chemotherapy. Allocation strategy based on an invasive mold infection genetic risk will be double-blinded.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Cumulative incidence of proven and probable invasive mold infection (IMI)
timeFrame: Day 180
Secondary outcomes:
measure: Cumulative incidence of possible invasive mold infection (IMI)
timeFrame: Day 180
measure: Cumulative incidence of probable and proven Invasive Fungal Infections (IFI)
timeFrame: Day 180
measure: Time to probable and proven invasive mold infection (IMI)
timeFrame: Day 180
measure: Cumulative incidence of mortality
timeFrame: Day 180
measure: Time to use of amphotericin B/echinocandin
timeFrame: Day 180
measure: Number of patient-days of amphotericin B/echinocandin
timeFrame: Day 180
measure: Frequency/distribution of adverse events (AE) of interest
timeFrame: Day 180
measure: Cumulative incidence of probable and proven invasive fungal infections (IFI) in per protocol population
timeFrame: Day 180
Other outcomes:
Locations:
city: Bruges
country: Belgium
facility: AZ Sint-Jan Hospital
city: Ghent
country: Belgium
facility: Ghent University Hospital
city: Leuven
country: Belgium
facility: University Hospital Leuven (UZ Leuven)
city: Créteil
country: France
facility: Henri Mondor Hospital
state: Ile De France
city: Lausanne
country: Switzerland
facility: University Hospital of Lausanne / Centre Hospitalier Universitaire Vaudois (CHUV)
state: Vaud
city: Aarau
country: Switzerland
facility: Cantonal Hospital Aarau
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Fribourg
country: Switzerland
facility: Cantonal Hospital HFR
city: Geneva
country: Switzerland
facility: University Hospital of Geneva (HUG)
Study officials:
affiliation: Centre Hospitalier Universitaire Vaudois
name: Pierre-Yves Bochud, MD
role: PRINCIPAL_INVESTIGATOR
References: