Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Immunotoxin in Treating Patients With Leukemia or Lymphoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 18 and over NCI NCI-96-C-0064F NCI-T95-0042N, T95-0042, NCT00002765

Objectives

1. Assess the therapeutic efficacy and toxicity of the recombinant immunotoxin LMB-2, an anti-Tac murine monoclonal antibody fragment conjugated to a truncated portion of Pseudomonas exotoxin, in patients with Tac-expressing leukemias and lymphomas.
2. Define the pharmacokinetics of LMB-2, including the terminal elimination serum half-life, area under the curve, and volume of distribution.
3. Evaluate, in a preliminary manner, the immunogenicity of LMB-2 in these patients.
4. Determine the effect of LMB-2 on various components of the circulating cellular immune system.

Entry Criteria

Disease Characteristics:

• Histologically confirmed Hodgkin's disease, non-Hodgkin's lymphoma, or leukemia in one of the following categories:
  • Adult T-cell leukemia or lymphoma (ATL)
    • No smoldering ATL
    • No limitation on prior therapy
  • Cutaneous T-cell lymphoma (CTCL)
    • Stages IB-III and failed at least 1 standard therapy
    • Stage IV regardless of prior therapy
  • Stages I-IV peripheral T-cell lymphoma
    • Relapsed after standard chemotherapy
    • Ineligible for or refused salvage chemotherapy or bone marrow transplantation (BMT)
  • B-cell non-Hodgkin's lymphoma (NHL) of any histology
    • Indolent stages II-IV NHL
      • Failed at least 1 standard therapy
      • Disease symptomatic and requiring treatment
    • Aggressive NHL
      • Relapsed after standard chemotherapy
      • Ineligible for or refused salvage chemotherapy or BMT
  • Chronic lymphocytic leukemia (CLL)
    • Rai stages III and IV or Binet stage C
    • Failed standard therapy and at least 1 salvage chemotherapy
  • Primary B-cell prolymphocytic leukemia or prolymphocytic transformation of CLL
    • Failed standard therapy and at least 1 salvage chemotherapy
  • Hairy cell leukemia
    • Failed standard and salvage chemotherapy
    • Ineligible for or refused further salvage chemotherapy or BMT
  • Acute myelogenous leukemia
    • Failed standard chemotherapy
    • Ineligible for or refused salvage chemotherapy or BMT
  • Stages II-IV Hodgkin's disease
    • Failed standard chemotherapy
    • Ineligible for curative salvage radiotherapy or chemotherapy
    • Ineligible for or refused BMT
  • Patients with leukemias or lymphomas not easily classified in above categories who have failed standard therapy and are ineligible for or have refused bone marrow transplant



• Evidence of interleukin-2 receptor-alpha (IL2Ra) expression by one of the following:
  • Greater than 10% of malignant cells reactive with anti-Tac by immunohistochemistry
  • Greater than 10% of malignant cells from a particular site positive by FACS
  • Greater than 400 IL2Ra sites per malignant cell by radiolabeled anti-Tac binding
  • Soluble IL2Ra level greater than 1,000 U/mL (normal geometric mean 235, with 95% confidence levels of 112-502 U)
  • Hodgkin's disease with measurable disease not amenable to biopsy



• No CNS disease requiring treatment
  • Malignant cells in CSF allowed if judged not to represent clinically significant leukemic or lymphomatous meningitis (as in CSF contamination by blood)

Prior/Concurrent Therapy:

Biologic therapy:

• See Disease Characteristics
• At least 3 weeks since prior interferon

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior cytotoxic chemotherapy
• At least 3 weeks since prior retinoids
• No concurrent chemotherapy

Endocrine therapy:

• No concurrent corticosteroids unless begun at least 3 weeks prior to entry and dose not increased during 3 weeks prior to entry

Radiotherapy:

• See Disease Characteristics
• At least 3 weeks since prior whole-body electron beam radiotherapy
• Other radiotherapy allowed within 3 weeks of entry provided less than 10% of marrow irradiated and measurable disease exists outside radiation port

Surgery:

• Not specified

Other:

• See Disease Characteristics
• At least 3 weeks since any prior systemic therapy
• No other concurrent investigational agents

Patient Characteristics:

Age:

• 18 and over

Performance status:

• Karnofsky 50-100%

Life expectancy:

• Greater than 2 months

Hematopoietic:

• Absolute neutrophil count greater than 1,000/mm3*
• Platelet count greater than 50,000/mm3*

 [Note: *nonleukemic patients]

Hepatic:

• AST and ALT less than 5 times normal

Renal:

• Creatinine less than 2.0 mg/dL

  OR

• Creatinine clearance greater than 50 mL/min

Pulmonary:

• FEV1, TLC, and DLCO greater than 50% of predicted if pulmonary or mediastinal involvement with tumor greater than one third of total thoracic diameter

Other:

• HIV negative
• Not pregnant
• Fertile patients must use effective contraception
• Serum must neutralize no more than 75% LMB-2 in tissue culture

Expected Enrollment

A maximum of 40 patients will be accrued for this study.

Outline

This is a dose escalation study.

Patients receive LMB-2 immunotoxin IV over 30 minutes on days 1, 3, and 5. Treatment repeats every 15-21 days for up to 10 courses in the absence of disease progression, neutralizing antibodies, or unacceptable toxicity.

Cohorts of 3-6 patients each receive escalating doses of LMB-2 immunotoxin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 1 patient experiences dose limiting toxicity.

Kreitman RJ, Wilson WH, White JD, et al.: Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol 18 (8): 1622-36, 2000.[PUBMED Abstract]

Kreitman RJ, Wilson WH, Robbins D, et al.: Responses in refractory hairy cell leukemia to a recombinant immunotoxin. Blood 94 (10): 3340-8, 1999.[PUBMED Abstract]

Kreitman RJ, Margulies I, Stetler-Stevenson M, et al.: Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) toward fresh malignant cells from patients with B-cell leukemias. Clin Cancer Res 6 (4): 1476-87, 2000.[PUBMED Abstract]

Robbins DH, Margulies I, Stetler-Stevenson M, et al.: Hairy cell leukemia, a B-cell neoplasm that is particularly sensitive to the cytotoxic effect of anti-Tac(Fv)-PE38 (LMB-2). Clin Cancer Res 6 (2): 693-700, 2000.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Robert Kreitman, MD, Protocol chair		Ph: 301-496-6947 Email: kreitmar@mail.nih.gov

Registry Information
Official Title		PHASE I STUDY OF ANTI-TAC(Fv)-PE38 (LMB-2), A RECOMBINANT SINGLE-CHAIN IMMUNOTOXIN FOR TREATMENT OF TAC-EXPRESSING MALIGNANCIES
Trial Start Date		1996-04-24
Registered in ClinicalTrials.gov		NCT00002765
Date Submitted to PDQ		1996-04-24
Information Last Verified		2003-03-19