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

Phase 3

Completed

Conditions: 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

Interventions: Drug: levofloxacin

Registration Number: NCT01371656

Lead Sponsor: Children's Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 624

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (levofloxacin)	levofloxacin	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.

Primary Outcome Measures

Name	Time	Method
Comparison of the Percentage of Patients Having Bacteremia Incidence Between Levofloxacin vs. No Prophylaxis Arms	Up to 60 days after enrollment or receiving levofloxacin	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.

Secondary Outcome Measures

Name	Time	Method
Comparison of the Percentage of Patients Having Antibiotic Exposures Between Arms	Up to 60 days after enrollment or receiving levofloxacin	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
Comparison of the Percentage of Patients Having Incidence of CDAD Between Arms	Up to 60 days after enrollment or receiving levofloxacin	Clostridium Difficile Associated Disease (CDAD) is defined as a positive C. difficile toxin assay result and diarrhea, CTCAE version 4, grade 2 and higher.
Comparison of the Percentage of Patients Having Incidence of Fever and Febrile Neutropenia Between Arms	Up to 60 days after enrollment or receiving levofloxacin	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.
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	Enrollment, 2 months and 12 months post infection observation period	Musculoskeletal conditions included at least one occurrence of arthralgia, arthritis, gait abnormality or tendinopathy.
Comparison of the Percentage of Patients Having Severe Infection Between Arms	Up to 60 days after enrollment or receiving levofloxacin	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

Trial Locations

Locations (84): Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Southern California Permanente Medical Group
🇺🇸
Downey, California, United States
City of Hope Medical Center
🇺🇸
Duarte, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Miller Children's Hospital
🇺🇸
Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
University of California San Francisco Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
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Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States