Infections

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Leukemia

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Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Mycoses

Invasive Fungal Infections

Neutropenia

Aspergillosis

Invasive Pulmonary Aspergillosis

Pulmonary Aspergillosis

Lymphoma

Leukemia, Myeloid

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Bacterial Infections

Bacterial Infections and Mycoses

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Lung Diseases, Fungal

Respiratory Tract Diseases

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Anti-Infective Agents

All Drugs and Chemicals

Amphotericin B

Liposomal amphotericin B

Clotrimazole

Miconazole

Antifungal Agents

Amebicides

Antiprotozoal Agents

Antiparasitic Agents

Anti-Bacterial Agents

Drug: AMPHOTERICIN B Dosage form: Abelcet® 5mg/ml administered by inhalation. Dosage: 10 ml (50 mg) for the first week with a frequency twice a week. Dosage: from the second week onwards 5 ml (25 mg) with a frequency of a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.

Duration: 4-5 prophylaxis courses defined as each administration period during a neutropenia period, with a 4-6 weeks length considering the duration of neutropenia.

The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.

AMPHOTERICIN B

Jesus Estella, PhMD

The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive chemotherapy.

In recent years the incidence of invasive fungal infection (IFI) especially when caused by filamentous fungi has increased in patients with haematological malignancies and there exists an international consensus on diagnostic criteria. Despite diagnostic and therapeutic progress, invasive aspergillosis remains a major clinical problem of haematological patients, given the still high mortality rates and the huge economic cost of hospitalization of patients, which is attributable to aspergillosis. In addition to the morbidity and mortality rates, these infections interfere with the chemotherapy treatment plan with the risk of compromising the outcome of the antileukemic treatment.

In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some benefit in haematological patients, however it was not effective in a large multicenter study with neutropenic patients. Based on the outcome of that clinical trial, the use of aerosolised amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a decade. During this time the use of azole agents as drugs of choice for antifungal prophylaxis in high risk patients was consolidated. However, one of the main problems in the use of triazoles with activity against filamentous fungi (itraconazole, voriconazole, posaconazole) is drug-drug interactions due to their CYP3A4 inhibitory activity. One of the most serious interactions is that which occurs with vincristine, used throughout the treatment of acute lymphoblastic leukemia, and which has lead to reports of neurotoxicity due to metabolic inhibition.

ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad spectrum of fungal species, including Aspergillus spp. The active component of ABELCET®, amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action.

Abelcet® is recommended for the intravenous treatment of a broad spectrum of systemic fungal infections in adult patients. Although it has a pediatric indication, there are numerous studies published regarding the safety levels of Abelcet® administered intravenously in children and in haematological adults patients which look very promising. In this context, the working hypothesis proposed in this project is that the administration of aerosolised ABLC for pediatric patients with acute leukemia treated with intensive chemotherapy will be an effective alternative as a prophylaxis of pulmonary fungal infections in these patients.

In the treatment of pediatric patients with haematological malignancies the use of intensive chemotherapy is required, which is immunosuppressive and therefore significantly increases the risk of IFI, especially filamentous fungi. IPA is associated with high mortality (\>50%) in those patients, making it imperative to adopt effective, preventive, prophylactic measures. Drug interactions occur frequently with triazole antifungal drugs; cases of clinically significant interactions with vincristine, an anchor drug in the treatment of the majority of pediatric leukemia, are documented. On the other hand, there are promising data from previous studies regarding the safety and efficacy of the intravenous ABLC formulation (Abelcet®) in the treatment of pediatric patients with fungal infections.

If the working hypothesis is confirmed, the aerosolised ABLC treatment would be an effective, safe and reliable prophylactic option for IPA. It would offer an alternative to the systemic administration of antifungal triazoles without affecting the antileukemic treatment in pediatric patients with AL.

Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia

A Phase II Trial to Evaluate the Safety and Tolerability of Nebulised Amphotericin B Lipid Complex (ABELCET®) in the Prophylaxis of Invasive Pulmonary Aspergillosis During Prolonged Neutropenia in Paediatric Patients With Acute Leukaemia

Anonymized individual data of participants will be shared with Authorities at the end of the Clinical Development Plan by the CTD (Common Technical Document). Results will be published in a scientific publication.

is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each).

The incidence of invasive pulmonary aspergillosis during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with invasive pulmonary aspergillosis and the number of paediatric patients on prophylaxis with Acute Leukaemia (AL) undergoing intensive chemotherapy.

Percentage of deaths related to Invasive Pulmonary Aspergillosis during the prophylactic treatment period with Abelcet® in paediatric patients with Acute Leukaemia undergoing intensive chemotherapy.

Ministry of Health, Spain

Fundació Sant Joan de Déu

Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).

AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.

Amphotericin B (ABELCET®)

Patients fulfilling inclusion criteria and those giving the general informed consent for the study initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).

AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization was 10 ml (50 mg) twice a week for the first week, and then from the second week onwards was reduced to 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count demonstrated to be greater than or equal to 1500 cells/mm3.

>= 3 years to <=18 years

Age, Customized

Sex: Female, Male

caucasian

amerindian

african

gypsies

patients ethnicity percentage : caucasian (84.4%), Amerindian (6.3%), African (3.1%) and gypsies (6.3%).

Race/Ethnicity, Customized

Spain

Region of Enrollment

Rosa Maria morales Palau

Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability

At baseline, none of the 32 pediatric patients with acute leukemia included in the clinical trial had API. During the trial period there were 3 patients who developed API

Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis

Invasive Pulmonary Aspergillosis -Related Mortality During Primary Prophylaxis With Abelcet®.

Overall Study

Hematologic Neoplasms

Voriconazole

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Patients with hematologic malignancies who were given voriconazole to treat invasive (pulmonary) aspergillosis at Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

voriconazole

Multiple factors are associated with a large variability in voriconazole exposure following standard dose administration, such as non-linear saturable pharmacokinetics, drug-drug interactions, liver disease, patient age, and genetic polymorphism of the metabolic enzymes.

Voriconazole is extensively metabolized by the human hepatic enzymes, primarily mediated by CYP2C19. The polymorphisms account for a relatively large portion of inter-individual variance observed in voriconazole plasma concentrations.

However, there are limited data on the relationships between voriconazole blood levels and clinical outcomes or safety in Asian populations.

The purpose of this study is to investigate the relationships of voriconazole blood levels with genetic polymorphism, safety, and clinical outcomes in immunocompromised patients with invasive pulmonary aspergillosis.

The investigators are trying to establish that routine clinical practice for voriconazole therapeutic drug monitoring can improve the efficacy and safety outcomes.

In Korean patients with hematologic malignancy, the investigators also want to propose the optimal dosing guideline of voriconazole with different genetic polymorphisms.

* Venous blood sampling will be carried out at steady state for therapeutic drug monitoring(trough sampling:right before the dose)
* Genotyping will be performed using peripheral blood.

Voriconazole Trough Plasma Levels : Genetic Polymorphism, Efficacy, Safety in Patients With Hematologic Malignancy

The Correlation of Voriconazole Trough Plasma Levels With Genetic Polymorphism, Efficacy, and Safety Outcomes in Hematologic Malignancy Patients With Invasive Pulmonary Aspergillosis

Successful outcome = complete response + partial response Unsuccessful outcome = stable disease + failure of therapy + indeterminate response

IFI (invasive fungal infection)-related mortality at 12 weeks

Successful outcomes at 1 week,2 weeks,4 weeks, and 8 weeks after voriconazole use

Non-IFI (invasive fungal infection)-related mortality at 12 weeks

Adverse drug reactions (liver function test impairment, visual disturbance, hallucination, photosensitive rash, renal impairment)

Asan Medical Center

Assistantant Professor

Caspofungin

Patients will receive caspofungin, starting from the first day of induction chemotherapy for leukemia, as a single daily dose intravenously at the dosage of 70 mg q.d. and followed by 50 mg q.d. thereafter until documentation of complete hematologic remission after the first induction cycle or of leukemia persistence after one cycle of induction and one cycle of salvage chemotherapy.

No stratification is planned.

Giuseppe Rossi, MD

Chiara Cattaneo

* To assess the overall clinical yield - in terms of efficacy and safety endpoints of adding caspofungin as prophylaxis of Invasive Pulmonary Aspergillosis in patients undergoing induction treatment for newly diagnosed acute leukemia
* To investigate the prognostic significance of Ptx3 at diagnosis and during the first chemotherapy cycle with respect to the development of IPA

Invasive aspergillosis (IA), and particularly invasive pulmonary aspergillosis (IPA), is an important cause of morbidity and mortality in patients who are receiving chemotherapy for acute leukemia (AL), being the the most common invasive mycosis which develops in these patients. Proven invasive aspergillosis has been reported in 6,5% of patients with acute leukemia in a retrospective multicenter study (Pagano, Haematologica 2001) but that frequency may be underestimated, since definite diagnosis is difficult to obtain, particularly in leukemic patients.

When the recently developed, internationally recognized IFIGC/MSG/EORTC diagnostic criteria were retrospectively applied to a consecutive series of acute leukemia patients, the overall frequency of IPA was 25,3% (proven/probable 8,5%; possible 16,9%). Criteria for a diagnosis of IPA were fulfilled in 62,8% of pulmonary infiltrates developing in AL patients (proven/probable 17,1%; possible 45,7%). IPA developed both in AML and in ALL patients. Proven/probable IPA developed in 83% of cases during the first induction cycle (Borlenghi, EHA 2003). It may be estimated that such figures would be higher when patients would be followed prospectively and strictly monitored, particularly with GM antigenemia.

The mechanisms by which common colonizing agents like Aspergillus spp. can become invasive pathogens and cause severe tissue damage are only partially known. Recent experimental data in animal models raised the hypothesis that the long pentraxin Ptx3 may play an important role in resistance to selected microbial agents, in particular to Aspergillus fumigatus (Garlanda, Nature 2002).

Caspofungin is an echinocandin with potent antifungal activity against Aspergillus species. Its mechanism of action differs from that of the antifungal agents used so far, like amphotericin and azoles. It has proven effective and well tolerated and its use is therefore currently approved as salvage treatment in patients with invasive aspergillosis refractory to amphotericin, as well as for the empiric treatment of febrile neutropenia. Indeed it has been recently evaluated as empirical treatment in neutropenic patients with persistent fever of unknown origin and proved equally effective and better tolerated than liposomal amphotericin.

There are as yet no data on the use of caspofungin as primary prophylaxis in patients with acute leukaemia, a setting in which the lack of effective preventive treatments together with the generally favourable safety profile and efficacy of caspofungin makes it particularly attractive for investigation.

It can be hypothesized from the above data that the administration of caspofungin as prophylactic treatment of invasive aspergillosis should be safe and well tolerated by patient undergoing chemotherapy for acute leukemia at diagnosis.

It may reduce the high incidence of invasive pulmonary aspergillosis which characteristically develops during the first course of induction treatment, avoiding the direct morbidity and mortality of IPA and its negative impact on the treatment and prognosis of AL as well as the costs for IPA diagnosis and treatment.

The serum levels of the long pentraxin Ptx3 may have interpatient variability and may correlate with the subsequent development of invasive aspergillosis.

These facts led to the present multicenter, phase II, single arm, open study, performed by the Northern Italy Leukemia Group. There will be approximately 12 participating centers, which will enroll a total of 100 patients. Patients will receive caspofungin, starting from the first day of induction chemotherapy for leukemia, as a single daily dose intravenously at the dosage of 70 mg q.d. and followed by 50 mg q.d. thereafter until documentation of complete hematologic remission after the first induction cycle or of leukemia persistence after one cycle of induction and one cycle of salvage chemotherapy.

No stratification is planned. Patients will concurrently receive all the medications needed for the treatment of acute leukemia,according to the ongoing protocols of NILG for acute leukemia at diagnosis. The study period continues

The treatment will be stopped in the presence of any of the following conditions:

* Development of a severe adverse event or of any grade 3-4 toxicity attributable to caspofungin
* Development of proven/probable IPA No caspofungin dose reduction is planned. The dose of caspofungin will be adjusted when patients weight is over 80 kgs and in patients taking rifampin or other liver enzymes-inducing drugs.

Prophylaxis of Fungal Invasive Infections in Leukemia

A Multicenter Phase II Study to Evaluate the Safety, Tolerability and Efficacy of Caspofungin as Prophylactic Treatment of Invasive Fungal Infections in Patients With Acute Leukemia Undergoing Induction Chemotherapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia	NCT01615809	Invasive Pulmon... Lymphoblastic L... Myeloblastic Le... Lymphoblastic L... Myeloblastic Le...	AMPHOTERICIN B	3 Years - 17 Years	Fundació Sant Joan de Déu
Voriconazole Trough Plasma Levels : Genetic Polymorphism, Efficacy, Safety in Patients With Hematologic Malignancy	NCT01148160	Invasive Fungal...	voriconazole	15 Years -	Asan Medical Center
Prophylaxis of Fungal Invasive Infections in Leukemia	NCT00501098	Invasive Pulmon...	Caspofungin	18 Years -	Northern Italy Leukemia Group

Spots Global Cancer Trial Database for invasive pulmonary aspergillosis