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Anti-Infective Agents

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Amphotericin B

Liposomal amphotericin B

Amebicides

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Clotrimazole

Miconazole

Antifungal Agents

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

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

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

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

Placebo

Mike Hawkins, MD

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.

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

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)

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 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.

This endpoint was to evaluate the potential impact of IFI prevention on the efficacy of remission-induction chemotherapy for ALL.

Gilead Sciences

Safety Analysis Set; participants who were randomized and received at least 1 dose of study drug.

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.

Liposomal Amphotericin B

Total

Age, Continuous

≤ 25 years

> 25 to ≤ 60 years

> 60 years

Age, Customized

Sex: Female, Male

Asian

Black

White

Not Permitted

Other

Race/Ethnicity, Customized

Germany

Italy

France

Belgium

Spain

Greece

Portugal

Turkey

Austria

Israel

Switzerland

Brazil

Argentina

Region of Enrollment

Safety Analysis Set: participants who were randomized and received at least 1 dose of study drug.

Clinical Trial Disclosures

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).

Intent-to-Treat (ITT) Analysis Set: participants in the safety analysis set who had no major violations of entrance criteria.

Percentage of Participants With Proven or Probable IFIs During Remission-induction Chemotherapy for Acute Lymphoblastic Leukemia (ALL)

Percentage of Participants With Pulmonary Infiltrates According to the Central Image Reader

Percentage of Participants Diagnosed With Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the Investigator

Time to Diagnosis of Proven or Probable IFIs According to the EORTC/MSG Criteria, as Assessed by the IDRB.

Percentage of Participants Requiring Antifungal Treatment During Remission-Induction Chemotherapy

Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the IDRB.

Percentage of Participants Who Died Due to Fungal Infection; Causality as Assessed by the Investigator.

Time From Beginning of Remission-induction Chemotherapy Until the Beginning of Consolidation Therapy

Participants were not stratified for leukemia risk.

Percentage of Participants With Complete Remission at the End of Remission Induction

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

Overall Study

Syndrome

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Voriconazole

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

3 mg/kg intravenously (IV) three times per week

400 mg oral twice daily day 1 followed by 200 mg twice daily

400 mg by mouth twice daily on day 1, followed by 200 mg by mouth twice daily

3 mg/kg intravenously three times per week over 2 hours +/- 15 minutes

9 mg/kg intravenously once per week over 2 hours +/- 15 minutes

Gloria N Mattiuzzi, MD

The goal of this clinical research study is to compare the effectiveness of liposomal amphotericin B given three times per week , versus liposomal amphotericin B given once per week, versus oral voriconazole in the prevention of fungal infections in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes MDS who are receiving chemotherapy. The safety of these treatments will also be studied and compared.

Ambisome and voriconazole are drugs that have been used to fight fungal infections, which typically occur during chemotherapy as a result of lowered immune system functioning. Ambisome works by binding to the sterol component of the fungal cell membrane. This causes "holes" to appear in the membrane, which leads to death of the fungal cell. Voriconazole inhibits an essential step of the biosynthesis of an important component of the fungal cell wall (ergosterol). This causes the impairment of the fungal cell wall.

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will be asked questions about your medical history. You will have a complete physical exam and a chest x-ray. You will have computed tomography (CT) scans of the chest. You will also have about 1 teaspoon of blood drawn for routine tests. Test results from the pregnancy test that you will have before your leukemia treatment will be looked at for this study. You will not have a pregnancy test performed for this study.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to one of 3 treatment groups (Group 1, Group 2, or Group 3). Participants in Groups 1 and 2 will receive treatment with ambisome. Participants in Group 3 will receive treatment with voriconazole. Participants in all 3 groups will begin treatment 24 hours after the last dose of chemotherapy.

If you are assigned to Group 1, you will receive ambisome by vein as a continuous infusion over 2 hours 1 time per day, 3 times each week.

If you are assigned to Group 2, you will receive ambisome by vein as a continuous infusion over 2 hours 1 time per week.

If you are assigned to Group 3, you will take 2 pills by mouth (1 hour after breakfast) and 2 pills by mouth (1 hour after dinner) for 1 day, which amounts to 4 pills in total on Day 1. You will then take 1 pill by mouth (1 hour after breakfast) and 1 pill by mouth (1 hour after dinner) everyday for the remainder of this study, which amounts to 2 pills in total each day.

You will have about 1 teaspoon of blood drawn for routine tests 2 times each week. You will also receive treatment with standard of care medications. These medications (which will be specified by your doctor) will be used to help decrease the risk of developing bacterial infections and viral infections.

If you develop a fever during treatment on this study, you will have a chest x-ray and a CT scan of the chest within 3 days after the fever started.

You may remain on this study for up to 35 days (if you are receiving chemotherapy for the first time) and up to 42 days (if you have had prior chemotherapy). Your participation may end on this study if your study doctor thinks it is necessary, if other antifungal therapy is required, or if you develop any intolerable side effects.

Liposomal Amphotericin B (Ambisome) Versus Oral Voriconazole for the Prevention of Invasive Fungal Infections

Open, Randomized Comparative Trial of Two Different Schedules of Liposomal Amphotericin B Versus Oral Voriconazole for the Prevention of Invasive Fungal Infections

Endpoint was whether participant had an invasive fungal infection or not, a potentially fatal complication with leukemia patients. Efficacy defined as absence of proven and probable fungal infection. Probable fungal infection is: 1) Positive radiographic findings consistent with fungal infections documented on CT imaging: Lower respiratory tract infection: halo sign, air crescent-sign, or cavity within areas of consolidation; Sinus: erosion of sinus walls or extension of infection to neighboring structures, extensive skull base destruction; and/or 2) Two positive galactomannan index test.

M.D. Anderson Cancer Center

Liposomal Amphotericin B: 3 mg/kg

Liposomal Amphotericin B: 9 mg/kg

Voriconazole: 400 mg

Age Continuous

United States

Jorge Cortes, MD / Professor

Outcome evaluability required at least two doses of study drug.

Number of Participants With Invasive Fungal Infection

C. Orla Morrissey, MB, BCh, FRACP

Anthony P Schwarer, MB, BS, FRACP, MD, FRCPA

Sushrat Patil, MB, BS, FRACP, FRCPA

Anthony P. Schwarer, MB, BS, FRACP, MD, FRCPA

The purpose of this trial is to see which dose of liposomal amphotericin B is the safest when used as a preventer against invasive fungal infection in patients with acute leukaemia who are undergoing chemotherapy.

Invasive Fungal Infections (IFI)are a significant cause of death in patients with acute leukaemia who are undergoing chemotherapy. This is despite improvements in antifungal therapy for the treatment of IFI. The major reason for this is that the current standard diagnostic tests of culture and biopsy lack the ability to make a diagnosis, either early or accurately. Thus other strategies such as the use of prophylaxis are needed. Several antifungal agents have been trialled as prophylaxis but all have disadvantages that limit their effectiveness.

Liposomal amphotericin B(LAB) is a broad spectrum antifungal agent that kills fungal cells. When given in high doses intermittently it supersaturates the liver and the overspill into the bloodstream is absorbed by tissues such as lung, brain and kidneys (i.e. sites where IFI are likely to occur). This effect has been shown in a number of animal and laboratory test-tube studies to reduce fungal burden, improve survival and maintain adequate levels of the drug in between doses. However no intermittent high-dose prophylaxis study has been done in humans. Thus before we proceed to a randomised controlled clinical trial of the efficacy of intermittent high-dose LAB compared with another antifungal agent it is necessary to determine in a phase 2 study which of 2 intermittent dosing LAB regimens (i.e. 3mg/kg three times a week or 10mg/kg once a week) administered during the neutropenic phase of induction-consolidation chemotherapy for treatment of acute leukaemia is safest and best tolerated compared to the standard dosing regimen of 1mg/kg daily of LAB.

Males and females aged \>18 years who are undergoing intensive combination chemotherapy for acute leukaemia will be randomised 1:1:1 to either 1mg/kg daily; 3mg/kg 3 times a week or 10mg/kg once weekly of intravenous liposomal amphotericin B. The 3 arms will be compared for the safety of the 3 dosing regimens.

Intermittent Liposomal Amphotericin B Primary Prophylaxis

A Randomised, Stratified, Open Label, Phase II Pilot Study on the Safety of a Daily, Intermittent, or Weekly Administration of 1, 3 or 10mg/kg of AmBisome® in Antifungal Primary Prophylaxis of High-Risk Patients With Acute Myeloid Leukaemia

Bayside Health

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Prevention of Invasive Fungal Infections (IFIs) in Subjects Receiving Chemotherapy for Acute Lymphoblastic Leukemia	NCT01259713	Invasive Fungal...	Liposomal ampho... Placebo	18 Years -	Gilead Sciences
Prevention of Invasive Fungal Infections (IFIs) in Subjects Receiving Chemotherapy for Acute Lymphoblastic Leukemia	NCT01259713	Invasive Fungal...	Liposomal ampho... Placebo	18 Years -	Gilead Sciences
Liposomal Amphotericin B (Ambisome) Versus Oral Voriconazole for the Prevention of Invasive Fungal Infections	NCT00418951	Acute Myelogeno... Myelodysplastic...	Voriconazole Liposomal ampho... Liposomal ampho...	18 Years -	M.D. Anderson Cancer Center
Intermittent Liposomal Amphotericin B Primary Prophylaxis	NCT00451711	Acute Myeloid L...	Liposomal ampho...	18 Years - 80 Years	Bayside Health

Spots Global Cancer Trial Database for liposomal amphotericin b