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

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)

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.

Study Overview

• Status: Completed
• Conditions: Invasive Fungal Disease
• Intervention / Treatment: Drug: Liposomal amphotericin B; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 355
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB21 6GT
    • Gilead Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liposomal amphotericin B; 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; 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; Other Names: AmBisome
Placebo Comparator: Placebo; 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; 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Mike Hawkins, MD, Gilead Sciences

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: December 10, 2010
• First Submitted That Met QC Criteria: December 13, 2010
• First Posted (Estimate): December 14, 2010

Study Record Updates

• Last Update Posted (Estimate): May 7, 2015
• Last Update Submitted That Met QC Criteria: April 17, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: ALL; prophylaxis; Ambisome; invasive fungal infection; liposomal amphotericin B; Invasive fungal infection prophylaxis
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bacterial Infections and Mycoses; Leukemia; Infections; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Invasive Fungal Infections; Anti-Infective Agents; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Amphotericin B; Liposomal amphotericin B
• Other Study ID Numbers: GS-EU-131-0247; 2010-019562-91 (EudraCT Number)