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

Diarrhea Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01371656
• Other study ID #: ACCL0934
• Secondary ID: NCI-2011-02636CD
• Status: Completed
• Phase: Phase 3
• Start date: September 2011
• Est. completion date: June 2017

Study information

• Verified date: June 2018
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 624
• Est. completion date: June 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Disease
• Acute Leukemias of Ambiguous Lineage
• Bacterial Infection
• Bacterial Infections
• Communicable Diseases
• Diarrhea
• Fungal Infection
• Infection
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Musculoskeletal Complications
• Mycoses
• Neutropenia
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia
• Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Intervention

Drug:
• levofloxacin
Given PO or IV

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Georgia Regents University	Augusta	Georgia
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Illinois	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	The Children's Medical Center of Dayton	Dayton	Ohio
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Southern California Permanente Medical Group	Downey	California
United States	City of Hope Medical Center	Duarte	California
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Baylor College of Medicine	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Services	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida
United States	Michigan State University - Breslin Cancer Center	Lansing	Michigan
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	University of Kentucky	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's Hospital	Long Beach	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Children's Hospital-Main Campus	New Orleans	Louisiana
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Nemours Children's Hospital	Orlando	Florida
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	University of Rochester	Rochester	New York
United States	Saint John's Mercy Medical Center	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
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	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Madigan Army Medical Center	Tacoma	Washington
United States	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio
United States	Ny Cancer%	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Comparison of the Percentage of Patients That Died Due to Bacterial Infection Between Arms		Up to 60 days after enrollment or receiving levofloxacin
Secondary	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
Secondary	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

External Links

•   Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive