Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	6 months to 21 years	NCI	NCI-04-C-0168 NCI-5903, 5903, NCT00085150

Objectives

Primary

1. Determine the maximum tolerated dose of LMB-2 immunotoxin in pediatric patients with CD-25 positive relapsed or refractory leukemia or lymphoma.
2. Determine the toxic effects of this drug in these patients.
3. 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

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

Entry 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

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

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/mm³
  • Platelet count > 50,000/mm³ (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)

Expected Enrollment

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

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.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Alan Wayne, MD, Principal investigator		Ph: 301-496-4256

Registry Information
Official Title		Pediatric Phase I Trial of LMB-2 for Refractory CD25-Positive Leukemias and Lymphomas
Trial Start Date		2004-04-26
Registered in ClinicalTrials.gov		NCT00085150
Date Submitted to PDQ		2004-04-16
Information Last Verified		2007-02-21