Empirical Versus Preemptive Antifungal Therapy

Condition(s) targeted: Fungal Infection; Leukemia; Myelodysplastic Syndromes

Intervention: caspofungin acetate (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: European Organisation for Research and Treatment of Cancer - EORTC

Official(s) and/or principal investigator(s):
J. Peter Donnelly, Study Chair, Affiliation: Universitair Medisch Centrum St. Radboud - Nijmegen
Johan Maertens, MD, Study Chair, Affiliation: U.Z. Gasthuisberg
Catherine Cordonnier, MD, PhD, Study Chair, Affiliation: Centre Hospitalier Universitaire Henri Mondor
Tom Lodewyck, Study Chair, Affiliation: AZ Sint-Jan

Overall contact:
Kin Jip Cheung, PhD, Phone: +32 2 774 16 07, Email: kin-jip.cheung@eortc.be

RATIONALE: Caspofungin acetate may be effective in treating fungal infections in patients with acute myeloid leukemia or myelodysplastic syndrome who are receiving treatment for their cancer. It is not yet known whether caspofungin acetate is more effective when treatment starts after development of a fever or after the infection is shown in laboratory test, chest x-ray, or CT scan. PURPOSE: This randomized phase III trial is studying the best time to start caspofungin acetate therapy in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly diagnosed or in first relapse.

Official title: Empirical Versus Pre-emptive (Diagnostic-driven) Antifungal Therapy of Patients Treated for Haematological Malignancies or Receiving an Allogeneic Stem Cell Transplant. A Therapeutic Open Label Phase III Strategy Study of the EORTC Infectious Diseases and Leukemia Groups

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Primary outcome: Overall survival at 42 days after randomization

Secondary outcome:

Overall survival at 84 days after randomization

Development of proven or probable invasive fungal disease (IFD) during the 42 and 84 days following randomization

Proper management according to allocated treatment arm (i.e., appropriate administration of caspofungin acetate in compliance to protocol, and compliance to the treatment strategy) during the 42 and 84 days after randomization

Survival-free of fungal infection during the 42 and 84 days following randomization

Safety (adverse event [AE] and serious adverse event [SAE]) as assessed by CTCAE criteria v4.0

Number of days under caspofungin treatment or under another antifungal treatment administered after caspofungin (evaluation will be done at day 42 and day 84 after randomization)

Costs related to the strategy for initiating and monitoring antifungal treatment during the 42 and 84 days following randomization

Detailed description: OBJECTIVES: Primary

- To compare empirical approach (i. e., fever driven) versus preemptive approach (i. e.,

diagnostic driven), for starting antifungal therapy with caspofungin acetate, in patients with acute myeloid leukemia or myelodysplastic syndrome who are starting chemotherapy (for attaining remission induction) or myeloablation (to prepare for an allogeneic hematopoietic stem cell transplantation) for newly diagnosed disease or disease in first relapse. Secondary

- To evaluate clinical validity and utility of a standardized Aspergillus PCR assay.

- To evaluate clinical validity and utility of beta-D-glucan.

- To determine the occurrence of single nucleotide polymorphisms (SNPs) and the

predictive value of SNPs for identifying patients at higher risk of developing invasive fungal infection. OUTLINE: This is a multicenter study. Patients are stratified according to institution, prior allogeneic stem cell transplantation (yes vs no), and type of air flow (laminar air flow vs high-efficiency particulate air). Patients are randomized to 1 of 2 treatment arms.

- Arm A (Empirical approach): Patients start caspofungin acetate treatment when one of

the following criteria are met:

- Presence of unexplained persistent fever refractory to 4 full days of

broad-spectrum antibacterial therapy with any of the following regimens either alone or in combination with an aminoglycoside or a glycopeptide:

- Ceftazidime

- Cefepime

- Piperacillin/tazobactam

- Imipenem-cilastatin

- Meropenem

- New fever occurring > 2 days after resolution of a first fever while continuing

broad-spectrum antibacterial therapy as defined above for which no obvious cause has been documented and fungal infection cannot be excluded Patients receive caspofungin acetate IV once daily. Treatment continues until neutrophil recovers.

- Arm B (Preemptive approach): Patients start caspofungin acetate treatment when at least

one of the following criteria* are met:

- Single plasma or serum galactomannan ELISA with index > 0. 5

- New pulmonary infiltrate on chest x-ray and IFD cannot be readily excluded

- New dense well-circumscribed lesions with or without a halo sign, on a CT scan,

consistent with IFD

- Aspergillus sp. recovered by culture from sputum Patients receive caspofungin

acetate IV once daily. Treatment continues until neutrophil recovers. NOTE: *These criteria are not sufficient to warrant preemptive caspofungin acetate therapy: skin lesions evocative of IFD, sinusitis or orbititis, hepatosplenic abscesses (hypodensities on CT scan), or unexplained persistent fever for more than 7 days or recurrent fever whatever its duration. All patients undergo blood sample collection periodically for the detection of galactomannan and beta-D-glucan and for the detection of single nucleotide polymorphisms. Some patients undergo blood sample collection for the detection of Aspergillus via PCR. An economic evaluation is performed for cost-effectiveness analysis. After completion of study treatment, patients are followed periodically.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

- Newly diagnosed disease or disease in first relapse after hematological

remission lasting for a minimum of 6 months AND meets one of the following criteria:

- Starting remission-induction chemotherapy within 3 days prior to study

randomization

- Starting myeloablative conditioning regimen to prepare for a first

allogeneic hematopoietic stem cell transplantation within 3 days prior to study randomization

- Planning a hospital admission for the duration of the neutropenic phase (ANC < 0. 5 x

10^9 /L)

- Planning to receive oral or intravenous fluconazole for Candida prophylaxis at a dose

of 400 mg/day

- Fluconazole is discontinued during caspofungin acetate administration

- No previous or current history of proven or probable invasive fungal disease (IFD)

PATIENT CHARACTERISTICS:

- See Disease Characteristics

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients muse use effective contraception during and for at least 3 months

after completion of study therapy

- No current clinical diagnosis of pneumonia

- No serious, uncontrolled, concomitant disease or comorbidity that, in the opinion of

the investigator, may compromise adherence to the study protocol

- No history of allergy or any adverse reaction to echinocandin drugs (i. e.,

caspofungin acetate, micafungin, or anidulafungin)

- No hypersensitivity to caspofungin active substance or to any of the excipients

- No inadequately treated infection

- No documented HIV infection

- No psychological, familial, sociological, or geographical condition potentially

hampering compliance with the study protocol and follow-up schedule

- No history of liver cirrhosis or severe hepatic insufficiency (i. e., Child Pugh Class

C, D, or E) PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No concurrent participation on another clinical trial using an investigational drug

for infectious diseases

- No other concurrent systemic antifungal therapy (oral or intravenous)

Kin Jip Cheung, PhD, Phone: +32 2 774 16 07, Email: kin-jip.cheung@eortc.be

A.Z. St. Jan, Brugge, Belgium; Recruiting

Cliniques Universitaires Saint-Luc, Brussels, Belgium; Recruiting

Hôpitaux Universitaires Bordet-Erasme - Institut Jules Bordet, Brussels, Belgium; Recruiting

U.Z. Gasthuisberg, Leuven, Belgium; Recruiting

C.H.U. Sart-Tilman, Liège, Belgium; Recruiting

Masaryk University, Brno, Czech Republic; Recruiting

CHU de Caen - Hopital Cote de Nacre, Caen, France; Recruiting

C.H.U. Henri Mondor AP-HP, Créteil, France; Recruiting

CHRU de Lille - Hopital Hurie, Lille, France; Recruiting

CHU de Limoges - Hopital Dupuytren, Limoges, France; Recruiting

Hopital Universitaire Hautepierre, Strasbourg, France; Recruiting

Institut Gustave Roussy, Villejuif, France; Recruiting

Universitaetsklinikum Freiburg, Freiburg, Germany; Recruiting

Universitaetsklinikum Wuerzburg - Medizinische Klinik und Poliklinik II, Wuerzburg, Germany; Recruiting

Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; Recruiting

National Cancer Institute, Bratislava, Slovakia; Recruiting

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2012
Last updated: April 13, 2015