Empirical Versus Preemptive Antifungal Therapy

Sponsor
European Organisation for Research and Treatment of Cancer - EORTC (Other)
Overall Status
Completed
CT.gov ID
NCT01288378
Collaborator
(none)
556
16
2
85.1
34.8
0.4

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: caspofungin acetate
Phase 3

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
556 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Supportive Care
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 Start Date :
Mar 1, 2012
Actual Primary Completion Date :
Apr 4, 2019
Actual Study Completion Date :
Apr 4, 2019

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Empirical

Empirical approach (fever driven) for starting antifungal therapy

Drug: caspofungin acetate
intravenous route, at a 70 mg loading dose on day 1 of antifungal therapy, followed by 50 mg once a day thereafter.

Experimental: Pre-emptive

Pre-emptive approach (diagnostic driven) for starting antifungal therapy

Drug: caspofungin acetate
intravenous route, at a 70 mg loading dose on day 1 of antifungal therapy, followed by 50 mg once a day thereafter.

Outcome Measures

Primary Outcome Measures

  1. Overall survival at 42 days after randomization [6 weeks after randomization]

Secondary Outcome Measures

  1. Overall survival at 84 days after randomization [12 weeks after randomization]

  2. Development of proven or probable invasive fungal disease (IFD) during the 42 and 84 days following randomization [during 84 days after randomization]

  3. 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 [during 84 days after randomization]

  4. Survival-free of fungal infection during the 42 and 84 days following randomization [during 84 days after randomization]

  5. Safety (adverse event [AE] and serious adverse event [SAE]) as assessed by CTCAE criteria v4.0 [during 84 days after randomization]

  6. 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) [at day 42 and day 84 after randomization]

  7. Costs related to the strategy for initiating and monitoring antifungal treatment during the 42 and 84 days following randomization [during 84 days after randomization]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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)

Contacts and Locations

Locations

Site City State Country Postal Code
1 A.Z. St. Jan Brugge Belgium
2 Cliniques Universitaires Saint-Luc Brussels Belgium
3 Hôpitaux Universitaires Bordet-Erasme - Institut Jules Bordet Brussels Belgium
4 U.Z. Gasthuisberg Leuven Belgium
5 C.H.U. Sart-Tilman Liège Belgium
6 Masaryk University Brno Czechia
7 CHU de Caen - Hopital Cote de Nacre Caen France
8 C.H.U. Henri Mondor AP-HP Créteil France
9 CHRU de Lille - Hopital Hurie Lille France
10 CHU de Limoges - Hopital Dupuytren Limoges France
11 Hopital Universitaire Hautepierre Strasbourg France
12 Institut Gustave Roussy Villejuif France
13 Universitaetsklinikum Freiburg Freiburg Germany
14 Universitaetsklinikum Wuerzburg - Medizinische Klinik und Poliklinik II Wuerzburg Germany
15 Radboud University Nijmegen Medical Centre Nijmegen Netherlands
16 National Cancer Institute Bratislava Slovakia

Sponsors and Collaborators

  • European Organisation for Research and Treatment of Cancer - EORTC

Investigators

  • Study Chair: J. Peter Donnelly, Universitair Medisch Centrum St. Radboud - Nijmegen
  • Study Chair: Johan Maertens, MD, University Hospital, Gasthuisberg
  • Study Chair: Catherine Cordonnier, MD, PhD, Centre Hospitalier Universitaire Henri Mondor
  • Study Chair: Tom Lodewyck, AZ Sint-Jan

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier:
NCT01288378
Other Study ID Numbers:
  • EORTC-65091-06093
  • 2010-020814-27
  • MK-0991-070
First Posted:
Feb 2, 2011
Last Update Posted:
Aug 8, 2019
Last Verified:
Aug 1, 2019

Study Results

No Results Posted as of Aug 8, 2019