Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation

Study Overview
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Brief Summary
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This randomized phase III trial studies how well levofloxacin works in preventing infection in young patients with acute leukemia receiving chemotherapy or undergoing stem cell transplant. Giving antibiotics may be effective in preventing or controlling early infection in patients receiving chemotherapy or undergoing stem cell transplant for acute leukemia. It is not yet known whether levofloxacin is effective in preventing infection.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine whether levofloxacin given prophylactically during periods of neutropenia to patients being treated with chemotherapy for acute leukemia (AL) or undergoing hematopoietic stem cell transplantation (HSCT) will decrease the incidence of bacteremia. SECONDARY OBJECTIVES: I. To determine the effect of prophylactic levofloxacin on resistance patterns of bacterial isolates from all sterile site cultures, and the evolution of antimicrobial resistance from peri-rectal swab isolates of Enterobacteriaceae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus mitis. II. To determine the effect of levofloxacin prophylaxis on total number of days of antibiotic administration (prophylactic, empiric, and treatment) in children undergoing therapy for AL or HSCT. III. To determine whether levofloxacin prophylaxis reduces the incidence of fever with neutropenia, severe infection, and death from bacterial infection. IV. To assess the safety of levofloxacin prophylaxis, with specific attention to musculoskeletal disorders including tendinopathy and tendon rupture. V. To assess the impact of prophylactic levofloxacin on the incidence of Clostridium difficile-associated diarrhea (CDAD), and the incidence of microbiologically documented invasive fungal infections (IFI). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive levofloxacin orally (PO) or intravenously (IV) over 60-90 minutes once daily (QD) or twice daily (BID) beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover. ARM II: Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I. After completion of study therapy, patients are followed up for 1 year.

Official Title
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A Randomized Trial of Levofloxacin to Prevent Bacteremia in Children Being Treated for Acute Leukemia (AL) or Undergoing Hematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Acute Leukemias of Ambiguous Lineage, Bacterial Infection, Diarrhea, Fungal Infection, Musculoskeletal Complications, Neutropenia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Intervention / Treatment
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* Drug: levofloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must fit 1 of the following 2 categories: Chemotherapy patients Planned to receive at least 2 consecutive cycles (not required to be the first 2 cycles) of intensive chemotherapy for either: De novo, relapsed or secondary acute myeloid leukemia (AML), or acute leukemia of ambiguous lineage treated with standard AML therapy Relapsed acute lymphoblastic leukemia (ALL) For the purposes of this study, intensive chemotherapy is defined as regimens that are predicted by the local investigator to cause neutropenia for > 7 days; examples include, but are not limited to, treatment with 4-drug induction (anthracycline, vincristine, asparaginase, and steroid), high dose cytarabine, anthracycline/cytarabine, ifosfamide/etoposide, and clofarabine-containing regimens Stem cell transplantation patients Planned to receive at least 1 myeloablative autologous or allogeneic HSCT For the purposes of this study, myeloablative autologous and allogeneic HSCT are those in which the conditioning regimen is predicted by the local Investigator to cause neutropenia for > 7 days Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m^2 OR serum creatinine based on age/gender as follows: 0.5 mg/dL (6 months to < 1 year of age) 0.6 mg/dL (1 to < 2 years of age) 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 mg/dL (male)/1.4 mg/dL (female) (13 to < 16 years of age) 1.7 mg/dL (male)/1.4 mg/dL (female) (>= 16 years of age) Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met Exclusion Criteria: Patients previously enrolled on the trial are not eligible; therefore, patients with AL who were on study during intensive chemotherapy are not eligible to be enrolled during the HSCT Patients with an allergy to quinolones Patients with chronic active arthritis Patients with a known pathologic prolongation of the corrected QT (QTc) Females who are pregnant or breast feeding Patients being treated with antibacterial agents, other than any of the following: Cotrimoxazole or other agents including dapsone, atovaquone, and pentamidine administered for Pneumocystitis jiroveci (PCP) prophylaxis Topical antibiotics Central venous catheter antibiotic lock therapy Note: prophylactic antifungal therapy is NOT an exclusion criterion Patients currently enrolled on the ACCL1034 study are not eligible until they have completed the 90 day observation period of that study

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (levofloxacin)<br>Patients receive levofloxacin PO or IV over 60-90 minutes once or twice daily beginning on day 3 during 2 consecutive courses of chemotherapy or beginning on day -2 during HSCT and continuing until blood counts recover. | Drug: levofloxacin<br>* Given PO or IV<br>* Other names: Quixin;|
| No Intervention: Arm II (standard of care)<br>Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms | A bacteremia incidence is defined as an occurrence of at least 1 episode of true (centrally reviewed) bacteremia among Acute Leukemia (AL) and Hematopoietic stem cell transplantation (HSCT) patients. | Up to 60 days after enrollment or receiving levofloxacin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms | Exposure to antibiotics was considered during the infection observation period(s) was defined a priori as follows: Gram positive agents = vancomycin, linezolid, daptomycin or quinupristin/dalfopristin; Aminoglycosides = amikacin, gentamicin or tobramycin; Third or fourth generation cephalosporins = cefepime, ceftazidime, ceftriaxone or cefotaxime; Empiric antibiotics for fever and neutropenia = imipenem, meropenem, cefepime, ceftazidime or piperacillin/tazobactam | Up to 60 days after enrollment or receiving levofloxacin | 
| Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms | Fever and febrile neutropenia defined as Absolute Neutrophil Count (ANC) < 1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >= 38 degrees C (100.4 degrees F) for more than one hour. | Up to 60 days after enrollment or receiving levofloxacin | 
| Comparison of the Percentage of Patients Having Severe Infection Between Arms | Severe infection defined as any grade 4 or 5 CTCAE catheter-related infection, enterocolitis, lung infection, sepsis, small intestine infection and other infections or infestations | Up to 60 days after enrollment or receiving levofloxacin | 
| Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms |  | Up to 60 days after enrollment or receiving levofloxacin | 
| Comparison of the Percentage of Patients Having Incidence of Musculoskeletal Adverse Events Including Tendinopathy (Tendonitis and Tendon Rupture) Between Arms | Musculoskeletal conditions included at least one occurrence of arthralgia, arthritis, gait abnormality or tendinopathy. | Enrollment, 2 months and 12 months post infection observation period | 
| Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms | Clostridium Difficile Associated Disease (CDAD) is defined as a positive C. difficile toxin assay result and diarrhea, CTCAE version 4, grade 2 and higher. | Up to 60 days after enrollment or receiving levofloxacin |