Clinical trial NCT01288378: Empirical Versus Preemptive Antifungal Therapy
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Fungal Infection
Leukemia
Myelodysplastic Syndromes
Keywords: fungal infection
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
recurrent adult acute myeloid leukemia
untreated adult acute myeloid leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with del(5q)
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
secondary acute myeloid leukemia
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2011-02-02
Enrollment: 556
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility 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)

Primary outcomes:
measure: Overall survival at 42 days after randomization
timeFrame: 6 weeks after randomization
Secondary outcomes:
measure: Overall survival at 84 days after randomization
timeFrame: 12 weeks after randomization
measure: Development of proven or probable invasive fungal disease (IFD) during the 42 and 84 days following randomization
timeFrame: during 84 days after randomization
measure: 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
timeFrame: during 84 days after randomization
measure: Survival-free of fungal infection during the 42 and 84 days following randomization
timeFrame: during 84 days after randomization
measure: Safety (adverse event [AE] and serious adverse event [SAE]) as assessed by CTCAE criteria v4.0
timeFrame: during 84 days after randomization
measure: 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)
timeFrame: at day 42 and day 84 after randomization
measure: Costs related to the strategy for initiating and monitoring antifungal treatment during the 42 and 84 days following randomization
timeFrame: during 84 days after randomization
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: A.Z. St. Jan
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Brussels
country: Belgium
facility: Hôpitaux Universitaires Bordet-Erasme - Institut Jules Bordet
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Liège
country: Belgium
facility: C.H.U. Sart-Tilman
city: Brno
country: Czechia
facility: Masaryk University
city: Caen
country: France
facility: CHU de Caen - Hopital Cote de Nacre
city: Créteil
country: France
facility: C.H.U. Henri Mondor AP-HP
city: Lille
country: France
facility: CHRU de Lille - Hopital Hurie
city: Limoges
country: France
facility: CHU de Limoges - Hopital Dupuytren
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Wuerzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg - Medizinische Klinik und Poliklinik II
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Bratislava
country: Slovakia
facility: National Cancer Institute
Study officials:
References: