Prevention of Invasive Fungal Infections (IFIs) in Subjects Receiving Chemotherapy for Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The study aims to investigate whether prophylaxis with liposomal amphotericin B (AmBisome®) can reduce the incidence of invasive fungal infections (IFIs) in patients with Acute Lymphoblastic Leukemia (ALL) who are undergoing their first remission induction.

Official Title
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A Phase 3, Double-Blind, Multicenter, Randomized, Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability of Prophylactic Liposomal Amphotericin B (AmBisome®) for the Prevention of Invasive Fungal Infections (IFIs) in Subjects Receiving Remission-Induction Chemotherapy for Acute Lymphoblastic Leukemia (ALL)

Conditions
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Invasive Fungal Disease

Intervention / Treatment
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* Drug: Liposomal amphotericin B
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed ALL receiving an ALL chemotherapy regimen that typically induces at least 10 days of neutropenia defined as an absolute neutrophil count < 500 cells/mm^3 or 0.5 × 10^9 cells/L Subjects with lymphoblastic lymphoma or any malignancy other than ALL are NOT eligible for this study. Age ≥ 18 years Able to have all screening tests performed quickly to ensure results can be obtained and evaluated before randomization so that the first dose of randomized study drug for IFI prophylaxis can be administered within 5 days of first remission-induction chemotherapy Preremission induction treatment (ie, pre-phase) with a minimally or nonmyelosuppressive regimen for up to one week is not considered to constitute the beginning of remission induction chemotherapy Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study procedures Exclusion Criteria: Known hypersensitivity to amphotericin B or AmBisome, the metabolites or formulation excipients, in particular known history of anaphylactic reaction to amphotericin B or AmBisome or any of its metabolites or formulation excipients Known hypersensitivity to the excipients of the placebo formulation Current fever (≥ 38°C) unless explained by noninfectious causes Subjects with proven, probable or possible IFI (according to European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria) at screening or in subject history Pulmonary infiltrates Concomitant or previous treatment with an antifungal drug within the previous 30 days unless the plasma level is below the limit of detection or at least 5 half-lives of the antifungal has elapsed since the treatment was given Serum creatinine > 2 × the upper limit of the normal range (ULN) Grade 3 Liver function test results: alanine aminotransferase or aspartate aminotransferase > 5 × ULN; total bilirubin > 2.5 x ULN Any severe co morbidity other than underlying hematological disease (ALL), which in the investigator's judgment may interfere with study evaluations or affect the subject's safety Subjects who have taken any investigational drug in the last 30 days prior to screening, with the exception of ALL chemotherapy investigational products being used as part of the subject's current ALL treatment protocol Pregnant or nursing females Subjects with a prior history of a malignancy that was treated with a myeloablative chemotherapy regimen are NOT eligible for this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liposomal amphotericin B<br>Liposomal amphotericin B 5 mg/kg twice weekly administered by IV route over 2 hours twice weekly (each dose separated alternately by 2 and 3 days each week) during induction chemotherapy | Drug: Liposomal amphotericin B<br>* Ambisome 5 mg/kg twice weekly administered by IV route over 2 hours twice weekly (each dose separated alternately by 2 and 3 days each week during induction chemotherapy<br>* Other names: AmBisome;|
| Placebo Comparator: Placebo<br>Placebo to match liposomal amphotericin B twice weekly administered by IV route over 2 hours twice weekly (each dose separated alternately by 2 and 3 days each week) during induction chemotherapy | Drug: Placebo<br>* Placebo to match liposomal amphotericin B administered by IV route over 2 hours twice weekly (each dose separated alternately by 2 and 3 days each week) during induction chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Proven or Probable IFIs During Remission-induction Chemotherapy for Acute Lymphoblastic Leukemia (ALL) | Diagnoses of proven or probable invasive fungal infections (IFI) were assessed according to European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria by the independent data review board (IDRB) who were blinded to treatment assignment. The duration of remission-induction chemotherapy was defined as the period from the initiation of remission-induction chemotherapy administration to the start of consolidation or salvage therapy. | During remission-induction chemotherapy (average 7 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pulmonary Infiltrates According to the Central Image Reader |  | During remission-induction chemotherapy (average 7 weeks) | 
| Percentage of Participants Diagnosed With Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the Investigator |  | During remission-induction chemotherapy (average 7 weeks) | 
| Time to Diagnosis of Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the IDRB. | Time to diagnosis of proven or probable IFIs is presented as the median (Q1,Q3) days to diagnosis of those participants who experienced a proven or probable IFI. Median was not reached if < 50% of participants had an event; Q1 was not reached if < 25% of participants had an event; Q3 was not reached if < 75% of participants had an event. | During remission-induction chemotherapy (average 7 weeks) | 
| Percentage of Participants Requiring Antifungal Treatment During Remission-Induction Chemotherapy |  | During remission-induction chemotherapy (average 7 weeks) | 
| Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the IDRB. |  | During remission-induction chemotherapy (average 7 weeks) | 
| Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the Investigator. |  | During remission-induction chemotherapy (average 7 weeks) | 
| Time From Beginning of Remission-induction Chemotherapy Until the Beginning of Consolidation Therapy | This endpoint was to evaluate the potential impact of IFI prevention on the efficacy of remission-induction chemotherapy for ALL. | During remission-induction chemotherapy (average 7 weeks) | 
| Percentage of Participants With Complete Remission at the End of Remission Induction | This endpoint was to evaluate the potential impact of IFI prevention on the efficacy of remission-induction chemotherapy for ALL. | During remission-induction chemotherapy (average 7 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ambisome, ALL, invasive fungal infection, prophylaxis, liposomal amphotericin B, Invasive fungal infection prophylaxis