Immunotoxin in Treating Patients With Leukemia or Lymphoma

Study Description

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Brief Summary:

RATIONALE: Immunotoxins can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells.

PURPOSE: Phase I trial to study the effectiveness of LMB-2 immunotoxin in treating patients who have leukemia or lymphoma.

Condition or disease	Intervention/treatment	Phase
Leukemia; Lymphoma	Biological: LMB-2 immunotoxin	Phase 1

Detailed Description:

OBJECTIVES:

• 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.
• Define the pharmacokinetics of LMB-2, including the terminal elimination serum half-life, area under the curve, and volume of distribution.
• Evaluate, in a preliminary manner, the immunogenicity of LMB-2 in these patients.
• Determine the effect of LMB-2 on various components of the circulating cellular immune system.

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.

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Primary Purpose:	Treatment
Official Title:	PHASE I STUDY OF ANTI-TAC(Fv)-PE38 (LMB-2), A RECOMBINANT SINGLE-CHAIN IMMUNOTOXIN FOR TREATMENT OF TAC-EXPRESSING MALIGNANCIES
Study Start Date :	April 1996

Arms and Interventions

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Outcome Measures

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Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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)

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

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

Contacts and Locations

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Locations

United States, Maryland
Laboratory of Molecular Biology
Bethesda, Maryland, United States, 20892
Medicine Branch
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair:	Robert Kreitman, MD	National Cancer Institute (NCI)

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Kreitman RJ, Wilson WH, White JD, Stetler-Stevenson M, Jaffe ES, Giardina S, Waldmann TA, Pastan I. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol. 2000 Apr;18(8):1622-36.

Kreitman RJ, Wilson WH, Robbins D, Margulies I, Stetler-Stevenson M, Waldmann TA, Pastan I. Responses in refractory hairy cell leukemia to a recombinant immunotoxin. Blood. 1999 Nov 15;94(10):3340-8.

Other Publications:

Matsushita K, Margulies I, Onda M, Nagata S, Stetler-Stevenson M, Kreitman RJ. Soluble CD22 as a tumor marker for hairy cell leukemia. Blood. 2008 Sep 15;112(6):2272-7. doi: 10.1182/blood-2008-01-131987. Epub 2008 Jul 2.

Kreitman RJ, Margulies I, Stetler-Stevenson M, Wang QC, FitzGerald DJ, Pastan I. Cytotoxic activity of disulfide-stabilized recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) toward fresh malignant cells from patients with B-cell leukemias. Clin Cancer Res. 2000 Apr;6(4):1476-87.

Robbins DH, Margulies I, Stetler-Stevenson M, Kreitman RJ. 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. 2000 Feb;6(2):693-700.

ClinicalTrials.gov Identifier:	NCT00002765 History of Changes
Obsolete Identifiers:	NCT00001501
Other Study ID Numbers:	CDR0000064729; NCI-96-C-0064F; NCI-T95-0042N
First Posted:	May 6, 2003
Last Update Posted:	April 29, 2015
Last Verified:	March 2003

Keywords provided by National Cancer Institute (NCI):

recurrent adult Hodgkin lymphoma; stage IV cutaneous T-cell non-Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; Waldenström macroglobulinemia; recurrent adult acute myeloid leukemia; recurrent adult acute lymphoblastic leukemia; relapsing chronic myelogenous leukemia; refractory chronic lymphocytic leukemia; refractory hairy cell leukemia; recurrent small lymphocytic lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent grade 3 follicular lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult diffuse mixed cell lymphoma

recurrent adult diffuse large cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent adult Burkitt lymphoma; stage I adult T-cell leukemia/lymphoma; stage II adult T-cell leukemia/lymphoma; stage III adult T-cell leukemia/lymphoma; stage IV adult T-cell leukemia/lymphoma; recurrent adult T-cell leukemia/lymphoma; prolymphocytic leukemia; recurrent mantle cell lymphoma; stage IV mycosis fungoides/Sezary syndrome; recurrent mycosis fungoides/Sezary syndrome; recurrent marginal zone lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue

Additional relevant MeSH terms:

Lymphoma; Leukemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases	Immunoproliferative Disorders; Immune System Diseases; Immunotoxins; Immunologic Factors; Physiological Effects of Drugs