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PHASE I STUDY OF ANTI-TAC(Fv)-PE38 (LMB-2), A RECOMBINANT SINGLE-CHAIN IMMUNOTOXIN FOR TREATMENT OF TAC-EXPRESSING MALIGNANCIES


Phase 1
18 Years
N/A
Not Enrolling
Both
Leukemia, Lymphoma

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Trial Information

PHASE I STUDY OF ANTI-TAC(Fv)-PE38 (LMB-2), A RECOMBINANT SINGLE-CHAIN IMMUNOTOXIN FOR TREATMENT OF TAC-EXPRESSING MALIGNANCIES


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Robert Kreitman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

CDR0000064729

NCT ID:

NCT00002765

Start Date:

April 1996

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • 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
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • Leukemia
  • Lymphoma

Name

Location

Laboratory of Molecular BiologyBethesda, Maryland  20892
Medicine BranchBethesda, Maryland  20892