Recombinant Human Mannose-Binding Lectin (MBL) in Treating Young Patients With MBL Deficiency and Fever and Neutropenia

A Multi-Center Study of the Safety, Tolerability, Pharmacokinetics and Dose Escalation of Intravenous Recombinant Human Mannose-Binding-Lectin (rhMBL) in MBL Deficient Pediatric Hematology/Oncology Patients With Fever and Neutropenia

RATIONALE: Recombinant human mannose-binding lectin (MBL) may be effective in preventing infection in young patients with fever and neutropenia receiving chemotherapy for blood disease or cancer.

PURPOSE: This phase I trial is studying the side effects and best dose of recombinant human mannose-binding lectin in treating young patients with MBL deficiency and fever and neutropenia.

OBJECTIVES:

Primary

• Determine the safety and tolerability of recombinant human mannose-binding lectin (MBL) in pediatric patients with MBL deficiency and fever and neutropenia who are undergoing cytotoxic chemotherapy for hematological/oncological disease.
• Determine the pharmacokinetics of this drug in these patients.

Secondary

• Determine the pharmacodynamic effect of this drug in these patients.
• Determine nonspecific activation of complement by in vivo determination of C3d complement activation in patients treated with this drug.
• Determine the ex-vivo activity of recombinant MBL in opsonization capacity of patients' sera to yeast and bacteria.
• Determine immunogenicity of this drug in these patients.
• Determine the incidence and duration of fever and breakthrough infections in patients treated with this drug.

OUTLINE: This is a non-randomized, multicenter, open-label, prospective, cohort study. Patients are assigned to 1 of 2 treatment groups.

• Group I: Patients receive low-dose recombinant human mannose-binding lectin (MBL) IV over 1 hour within 72 hours of onset of fever and neutropenia.
• Group II: Patients receive high-dose recombinant human MBL IV over 1 hour within 72 hours of onset of fever and neutropenia.

Patients undergo blood collection periodically during study for pharmacokinetic, pharmacodynamic, MBL immunogenicity, and opsonization/phagocytosis studies.

After completion of study treatment, patients are followed for 30 days.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Undergoing cytologic chemotherapy for hematological/oncological disease

• Must meet all of the following criteria:

  • Documented mannose-binding lectin (MBL) levels < 300 ng/mm³ within the past week
  • Fever (oral temperature > 100.4° F)
  • Neutropenia, defined as absolute neutrophil count ≤ 1,000/mm³ with the anticipation that the counts will fall below 500/mm^3
  • Receiving broad spectrum antibiotic therapy for fever and neutropenia

PATIENT CHARACTERISTICS:

• No serious illness, in the opinion of the principal investigator, that would preclude study compliance

• No known allergic reactions to mannose-binding lectin or other human plasma products

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier method contraception during and for ≥ 30 days after completion of study treatment

• AST and ALT ≤ 5 times upper limit of normal (ULN)

• Bilirubin ≤ 2.5 times ULN

• Creatinine clearance > 60 mL/min OR creatinine based on age as follows:

  • No more than 0.8 mg/dL (for patients 5 years of age and under)
  • No more than 1.0 mg/dL (for patients 6-9 years of age)
  • No more than 1.2 mg/dL (for patients 10-12 years of age)
  • No more than 1.4 mg/dL (for patients over 13 years of age [female])
  • No more than 1.5 mg/dL (for patients 13-15 years of age [male])
  • No more than 1.7 mg/dL (for patients of 16 years of age [male])

• No poor venous access that would preclude IV drug delivery or multiple blood draws

• Patients on hemodialysis must be able to tolerate IV fluid on non-dialysis days

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• More than 30 days since prior investigational agents

  • Investigational use of an FDA-approved drug allowed

• No concurrent preparative regimen for a bone marrow or hematopoietic stem cell transplantation

• No concurrent participation in another clinical trial with an investigational agent