LMB-2 Immunotoxin in Treating Young Patients With Relapsed or Refractory Leukemia or Lymphoma

National Cancer Institute (NCI)

Status and phase: Completed; Phase 1

Conditions: Lymphoma; Leukemia

Treatments: Biological: LMB-2 immunotoxin

Study type: Interventional

Funder types: NIH

Identifiers

NCT00085150

NCI-04-C-0168

CDR0000367333

NCI-5903

Details and patient eligibility

About

RATIONALE: LMB-2 immunotoxin can locate cancer cells and kill them without harming normal cells.

PURPOSE: This phase I trial is studying the side effects and best dose of LMB-2 immunotoxin in treating young patients with relapsed or refractory leukemia or lymphoma.

Full description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of LMB-2 immunotoxin in pediatric patients with CD-25 positive relapsed or refractory leukemia or lymphoma.
• Determine the toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug, including the terminal elimination serum half-life, area under the curve, volume of distribution, and relationship to disease burden, in these patients.

Secondary

• Evaluate the immonogenicity of this drug in these patients.
• Determine response in patients treated with this drug.
• Determine changes in lymphocyte subsets, immunoglobulin levels, serum cytokines, and soluble cytokine receptor levels in patients treated with this drug.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive LMB-2 immunotoxin IV over 30 minutes on days 1, 3, and 5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression, neutralizing antibodies (i.e., > 75% of the activity of 1 µg/mL of LMB-2 immunotoxin), or unacceptable toxicity. Patients achieving complete remission (CR) receive 2 additional courses beyond CR. Patients with acute lymphoblastic leukemia also receive cytarabine and hydrocortisone intrathecally once monthly concurrent with restaging lumbar punctures.

Cohorts of 3-6 patients receive escalating doses of LMB-2 immunotoxin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, a total of 12 patients are treated at that dose level.

Patients are followed weekly for 1 month and then monthly thereafter.

PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study within 2-4 years.

Enrollment: 40 estimated patients

Sex: All

Ages: Under 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

  • Non-Hodgkin's lymphoma, including the following subtypes:

    • Lymphoblastic lymphoma
    • Burkitt's lymphoma
    • Large cell lymphoma
    • Adult T-cell leukemia/lymphoma
    • Cutaneous T-cell lymphoma
    • Peripheral T-cell lymphoma

  • Hodgkin's disease

  • Acute myeloid leukemia

  • Chronic myelogenous leukemia

  • Acute lymphoblastic leukemia (ALL)

    • More than 5% blasts in the bone marrow (i.e., M2 marrow classification)

  • Acute hybrid leukemia, including the following subtypes:

    • Mixed lineage leukemia
    • Biphenotypic leukemia
    • Undifferentiated leukemia

• CD25-positive (CD25+) disease, meeting 1 of the following criteria:

  • More than 15% of malignant cells are CD25+ by immunohistochemistry with anti-CD25 antibody
  • More than 30% of malignant cells from a site are CD25+ by fluorescence-activated cell sorting analysis

• Measurable or evaluable disease

• Relapsed or refractory disease after at least 1 standard chemotherapy regimen AND 1 salvage regimen

• No available alternative curative therapies

• Ineligible for or refused hematopoietic stem cell transplantation OR disease activity that prohibits the required time to identify a suitable stem cell donor

• No CNS leukemia or lymphoma, as evidenced by any of the following criteria:

  • Cerebrospinal fluid (CSF) WBC > 5/µl AND confirmation of CSF blasts

  • Cranial neuropathies secondary to underlying malignancy

  • CNS lymphoma detected by radiological imaging

    • Prior CNS involvement with no current evidence of CNS malignancy allowed

• No isolated testicular ALL

PATIENT CHARACTERISTICS:

Age

• 6 months to 21 years

Performance status

• ECOG 0-3 (≥ 12 years of age)
• Lansky 40-100% (< 12 years of age)

Life expectancy

• Not specified

Hematopoietic

• Pancytopenia due to disease allowed

• For patients without bone marrow involvement:

  • Absolute neutrophil count > 1,000/mm^3
  • Platelet count > 50,000/mm^3 (transfusion independent)

Hepatic

• Bilirubin ≤ 2.0 mg/dL
• AST and ALT ≤ 5 times upper limit of normal
• Hepatitis B surface antigen negative
• Hepatitis C antibody negative

Renal

• Creatinine clearance ≥ 60 mL/min OR

• Creatinine, meeting the following age-related criteria:

  • ≤ 0.8 mg/dL (≤ 5 years of age)
  • ≤ 1.0 mg/dL (6 to 10 years of age)
  • ≤ 1.2 mg/dL (11 to 15 years of age)
  • ≤ 1.5 mg/dL (> 15 years of age)

• Calcium 2.0-2.9 mmol/L

Cardiovascular

• Ejection fraction ≥ 45% by MUGA OR
• Shortening fraction ≥ 28% by echocardiogram

Pulmonary

• Oxygen saturation ≥ 90%

Other

• Sodium 130-150 mmol/L
• Potassium 3.0-5.5 mmol/L
• Magnesium 0.5-1.23 mmol/L
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No clinically significant unrelated systemic illness that would preclude study participation
• No conditions that would preclude study compliance
• No serum that neutralizes > 75% of the activity of 1 μg/mL of LMB-2 immunotoxin in tissue culture (due to either anti-toxin or anti-mouse immunoglobulin G antibodies)
• No active graft-vs-host disease (i.e., off immunosuppression)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior autologous bone marrow transplantation (BMT) allowed
• At least 100 days since prior allogeneic BMT
• At least 1 week since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)

Chemotherapy

• At least 2 weeks since prior chemotherapy (4 weeks for nitrosoureas) except intrathecal chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• Concurrent corticosteroids allowed provided the dose has been stable for the past week and does not increase during study treatment

  • Tapering or discontinuation of steroids allowed

Radiotherapy

• At least 3 weeks since prior radiotherapy unless < 10% of marrow is irradiated and measurable disease exists outside the radiation port

Surgery

• Not specified

Other

• Recovered from all prior therapy
• At least 30 days since prior investigational agents
• Concurrent oral supplementation to maintain normal electrolyte levels allowed
• No concurrent anticoagulation therapy for disease-related conditions
• No other concurrent investigational agents