Clinical trial NCT00002765: Immunotoxin in Treating Patients With Leukemia or Lymphoma
Official title: PHASE I STUDY OF ANTI-TAC(Fv)-PE38 (LMB-2), A RECOMBINANT SINGLE-CHAIN IMMUNOTOXIN FOR TREATMENT OF TAC-EXPRESSING MALIGNANCIES
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Lymphoma
Keywords: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-05-06
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Laboratory of Molecular Biology
state: Maryland
city: Bethesda
country: United States
facility: Medicine Branch
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Robert Kreitman, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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. doi: 10.1200/JCO.2000.18.8.1622.
citation: 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.