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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
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	Drug: levofloxacin	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	740 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Single
Primary Purpose:	Supportive Care
Official Title:	A Randomized Trial of Levofloxacin to Prevent Bacteremia in Children Being Treated for Acute Leukemia (AL) or Undergoing Hematopoietic Stem Cell Transplantation (HSCT)
Actual Study Start Date :	September 2011
Actual Primary Completion Date :	June 2017
Actual Study Completion Date :	June 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm I (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.	Drug: levofloxacin; Given PO or IV; Other Names: Levaquin; Quixin
No Intervention: Arm II (standard of care); Patients receive established standard of care and receive chemotherapy or HSCT as patients in Arm I.

Outcome Measures

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Primary Outcome Measures :

1. Occurrence of at least 1 episode of true bacteremia among AL and HSCT subjects, respectively [ Time Frame: Up to 60 days ]

Secondary Outcome Measures :

1. Susceptibility of E. coli, K. pneumoniae, and P. aeruginosa stool or peri-rectal swab isolates to cefepime, imipenem, and levofloxacin [ Time Frame: Up to 1 year ]
2. Susceptibility of S. mitis peri-rectal swab isolates to cefepime, levofloxacin, and penicillin [ Time Frame: Up to 1 year ]
3. Presence of carbapenem-resistant Enterobacteriaceae [ Time Frame: Up to 1 year ]
4. Resistance patterns for the gastrointestinal isolates colonizing each patient [ Time Frame: Up to 1 year ]
5. Resistance patterns of bacterial isolates from all sterile site cultures [ Time Frame: Up to 1 year ]
6. Duration of parenteral antibiotic administration [ Time Frame: During 2 courses of chemotherapy or 1 transplantation procedure ]
7. Incidence of febrile neutropenia [ Time Frame: Up to 1 year ]
   Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0.
8. Incidence of severe infection [ Time Frame: Up to 1 year ]
   Graded using the NCI CTCAE v. 4.0.
9. Incidence of death from bacterial infection [ Time Frame: Up to 1 year ]
   Graded using the NCI CTCAE v. 4.0.
10. Incidence of musculoskeletal adverse events [ Time Frame: Up to 1 year ]
    Graded using the NCI CTCAE v. 4.0.
11. Incidence of tendinopathy (tendonitis and tendon rupture) [ Time Frame: Up to 1 year ]
12. Incidence of CDAD, defined as a positive C. difficile toxin assay result and diarrhea, CTCAE version 4, grade 2 and higher [ Time Frame: Up to 1 year ]

Eligibility Criteria

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Ages Eligible for Study:	6 Months to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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  Show 84 Study Locations

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Sarah Alexander, MD	Children's Oncology Group

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Children's Oncology Group
ClinicalTrials.gov Identifier:	NCT01371656 History of Changes
Other Study ID Numbers:	ACCL0934; NCI-2011-02636 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000695661 ( Other Identifier: ClinicalTrials.gov ); ACCL0934 ( Other Identifier: Children's Oncology Group ); COG-ACCL0934 ( Other Identifier: DCP ); ACCL0934 ( Other Identifier: CTEP ); U10CA095861 ( U.S. NIH Grant/Contract )
First Posted:	June 13, 2011
Last Update Posted:	February 19, 2018
Last Verified:	February 2018

Additional relevant MeSH terms:

Leukemia; Infection; Communicable Diseases; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Diarrhea; Neutropenia; Acute Disease; Bacterial Infections; Mycoses; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders	Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Diseases; Disease Attributes; Pathologic Processes; Levofloxacin; Ofloxacin; Anti-Infective Agents, Urinary; Anti-Infective Agents