Invasive Fungal Disease
Conditions
Keywords
Ambisome, ALL, invasive fungal infection, prophylaxis, liposomal amphotericin B, Invasive fungal infection prophylaxis
Brief summary
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.
Interventions
DRUGLiposomal 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
DRUGPlacebo
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
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Proven or Probable IFIs During Remission-induction Chemotherapy for Acute Lymphoblastic Leukemia (ALL) | During remission-induction chemotherapy (average 7 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | During remission-induction chemotherapy (average 7 weeks) | 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. |
| Percentage of Participants Requiring Antifungal Treatment During Remission-Induction Chemotherapy | During remission-induction chemotherapy (average 7 weeks) | — |
| Percentage of Participants With Pulmonary Infiltrates According to the Central Image Reader | 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 | During remission-induction chemotherapy (average 7 weeks) | This endpoint was to evaluate the potential impact of IFI prevention on the efficacy of remission-induction chemotherapy for ALL. |
| Percentage of Participants With Complete Remission at the End of Remission Induction | During remission-induction chemotherapy (average 7 weeks) | This endpoint was to evaluate the potential impact of IFI prevention on the efficacy of remission-induction chemotherapy for ALL. |
| Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the IDRB. | During remission-induction chemotherapy (average 7 weeks) | — |
Countries
United Kingdom
Participant flow
Recruitment details
Participants were enrolled at a total of 86 study sites. The first participant was screened on 13 April 2011. The last study visit occurred on 29 January 2014.
Pre-assignment details
391 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 237 |
| 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 | 118 |
| Total | 355 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 54 | 23 |
| Overall Study | Death Not Related to IFI | 8 | 1 |
| Overall Study | Investigators Discretion | 14 | 6 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Protocol Violation | 5 | 4 |
| Overall Study | Subject Withdrew Consent | 12 | 7 |
Baseline characteristics
| Characteristic | Liposomal Amphotericin B | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.5 years STANDARD_DEVIATION 15.16 | 44.8 years STANDARD_DEVIATION 17.52 | 44.6 years STANDARD_DEVIATION 15.96 |
| Age, Customized > 25 to ≤ 60 years | 160 participants | 64 participants | 224 participants |
| Age, Customized ≤ 25 years | 37 participants | 25 participants | 62 participants |
| Age, Customized > 60 years | 40 participants | 29 participants | 69 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 4 participants | 3 participants | 7 participants |
| Race/Ethnicity, Customized Not Permitted | 17 participants | 15 participants | 32 participants |
| Race/Ethnicity, Customized Other | 4 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized White | 211 participants | 100 participants | 311 participants |
| Region of Enrollment Argentina | 7 participants | 1 participants | 8 participants |
| Region of Enrollment Austria | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Belgium | 20 participants | 11 participants | 31 participants |
| Region of Enrollment Brazil | 8 participants | 7 participants | 15 participants |
| Region of Enrollment France | 33 participants | 19 participants | 52 participants |
| Region of Enrollment Germany | 52 participants | 23 participants | 75 participants |
| Region of Enrollment Greece | 14 participants | 13 participants | 27 participants |
| Region of Enrollment Israel | 9 participants | 0 participants | 9 participants |
| Region of Enrollment Italy | 41 participants | 25 participants | 66 participants |
| Region of Enrollment Portugal | 13 participants | 4 participants | 17 participants |
| Region of Enrollment Spain | 21 participants | 7 participants | 28 participants |
| Region of Enrollment Switzerland | 6 participants | 1 participants | 7 participants |
| Region of Enrollment Turkey | 7 participants | 4 participants | 11 participants |
| Sex: Female, Male Female | 98 Participants | 58 Participants | 156 Participants |
| Sex: Female, Male Male | 139 Participants | 60 Participants | 199 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 233 / 237 | 114 / 118 |
| serious Total, serious adverse events | 79 / 237 | 38 / 118 |
Outcome results
Primary
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.
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: Intent-to-Treat (ITT) Analysis Set: participants in the safety analysis set who had no major violations of entrance criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants With Proven or Probable IFIs During Remission-induction Chemotherapy for Acute Lymphoblastic Leukemia (ALL) | 7.9 percentage of participants |
| Placebo | Percentage of Participants With Proven or Probable IFIs During Remission-induction Chemotherapy for Acute Lymphoblastic Leukemia (ALL) | 11.7 percentage of participants |
Comparison: A two-group Cochran-Mantel-Haenszel (CMH) test with a 0.05 two-sided significance level and 2:1 allocation of 354 randomized subjects (236 AmBisome, 118 placebo) would have 81% power to detect a relative reduction of 75% if the rate of IFI is 10% in the placebo group (based on unpublished data from the German Multicenter Acute Lymphoblastic Leukemia Working Group (GMALL) and consistent with the published rate of 16.4% in patients with hematological malignancies undergoing remission induction).p-value: 0.2495.03% CI: [-0.32, 0.66]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Diagnosed With Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the Investigator
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants Diagnosed With Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the Investigator | 11.0 percentage of participants |
| Placebo | Percentage of Participants Diagnosed With Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the Investigator | 10.8 percentage of participants |
p-value: 0.9795% CI: [-0.94, 0.47]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Requiring Antifungal Treatment During Remission-Induction Chemotherapy
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants Requiring Antifungal Treatment During Remission-Induction Chemotherapy | 16.2 percentage of participants |
| Placebo | Percentage of Participants Requiring Antifungal Treatment During Remission-Induction Chemotherapy | 21.6 percentage of participants |
p-value: 0.2295% CI: [-0.19, 0.53]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the IDRB.
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the IDRB. | 0.9 percentage of participants |
| Placebo | Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the IDRB. | 0 percentage of participants |
p-value: 0.32Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the Investigator.
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the Investigator. | 0.9 percentage of participants |
| Placebo | Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the Investigator. | 0 percentage of participants |
p-value: 0.32Cochran-Mantel-Haenszel
Secondary
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.
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants With Complete Remission at the End of Remission Induction | 72.8 percentage of participants |
| Placebo | Percentage of Participants With Complete Remission at the End of Remission Induction | 79.3 percentage of participants |
Comparison: Participants were not stratified for leukemia risk.p-value: 0.295% CI: [-0.04, 0.19]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Pulmonary Infiltrates According to the Central Image Reader
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liposomal Amphotericin B | Percentage of Participants With Pulmonary Infiltrates According to the Central Image Reader | 20.2 percentage of participants |
| Placebo | Percentage of Participants With Pulmonary Infiltrates According to the Central Image Reader | 27.0 percentage of participants |
p-value: 0.1595% CI: [-0.11, 0.5]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liposomal Amphotericin B | Time From Beginning of Remission-induction Chemotherapy Until the Beginning of Consolidation Therapy | 50 days |
| Placebo | Time From Beginning of Remission-induction Chemotherapy Until the Beginning of Consolidation Therapy | 55 days |
p-value: 0.69Log Rank
Secondary
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.
Time frame: During remission-induction chemotherapy (average 7 weeks)
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liposomal Amphotericin B | Time to Diagnosis of Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the IDRB. | NA days |
| Placebo | Time to Diagnosis of Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the IDRB. | NA days |
p-value: 0.33Log Rank