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A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for Treatment of CD25 Positive Cutaneous T-Cell Lymphomas


Phase 2
18 Years
N/A
Not Enrolling
Both
Lymphoma, T-Cell, Cutaneous

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Trial Information

A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for Treatment of CD25 Positive Cutaneous T-Cell Lymphomas


Background:

It is estimated that 40-50% of patients with cutaneous T-cell lymphoma (CTCL) have tumors
that express cluster of differentiation 25 (CD25) (Tac or IL2Ra). Normal resting T-cells do
not express CD25. LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains
of MAb anti-Tac and truncated Pseudomonas exotoxin. A phase I trial at National Cancer
Institute (NCI) found that the maximum tolerated dose (MTD) of LMB-2 was 40 microg/Kg
intravenous (IV) given every other day for 3 doses (QOD times 3) with prophylactic IV fluid.
The most common adverse events were transient fever, hypoalbuminemia and transaminase
elevations. In that trial, two of two patients with cutaneous T-cell lymphoma had clinical
benefit (1 partial response (PR), 1 stable disease (SD)). In 1999 another recombinant fusion
protein, denileukin diftitox, was approved by the Food and Drug Administration (FDA) for
treatment of patients with advanced or recurrent CTCL expressing the high affinity
interleukin-2 (IL-2) receptor. This receptor is composed of three subunits: CD25, CD122 and
CD132. Because LMB-2 is cytotoxic to cells expressing CD25 without the other IL-2 receptor
subunits needed to form the high affinity receptor, CD25+ CTCL patients are good candidates
for further testing with LMB-2.

Objectives:

The purpose of this study is to determine the activity of anti-Tac(Fv)-PE38 (LMB-2) in
patients with Tac-expressing Cutaneous T-cell Lymphoma (CTCL). The primary endpoints of this
trial are the response rate and response duration. We will also evaluate LMB-2
immunogenicity, pharmacokinetics, and toxicity, and monitor soluble Tac levels in the serum.
These will be evaluated using routine hematologic and clinical evaluation, and when
appropriate, by monitoring the phenotype of circulating T-cells or of biopsied tissues using
antibodies to CD25.

Eligibility:

CD25+ CTCL based on immunohistochemistry or flow cytometry of blood. Patients must have
measurable stage 1b-IV disease which progressed after greater than or equal 2 prior systemic
or topical therapies. Labs required: alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) less than or equal to 2.5-time upper limit, albumin greater than or
equal 3, bilirubin less than or equal to 2.2, creatinine less than or equal to 2.0 (unless
creatinine clearance greater than or equal to 50 ml/min), absolute neutrophil count (ANC)
greater than or equal to 1000/ul, and platelets greater than or equal to 50,000/ul (ANC and
platelets greater than or equal 500 and 10,000 if blood/marrow involvement).

Design:

Patients receive LMB-2 30 ug/Kg QOD time 3 every 4 weeks in absence of neutralizing
antibodies or progressive disease. Dose escalation to 40 ug/Kg QOD times 3 if less than 2/6
dose limiting toxicity (DLT) at 30 ug/Kg times 3. 1st stage is 16 patients, to expand to 25
if greater than 1 of 16 patients respond.

Inclusion Criteria


- INCLUSION CRITERIA:

Patients must have histopathological evidence of cluster of differentiation 25 (CD25) +
cutaneous T-cell lymphoma (CTCL) confirmed by the National Institutes of Health (NIH)
pathology department.

One of the following must be present:

Greater than or equal to 20 percent expression of CD25 on the lymphocytes in the skin at a
site of a patch, plaque, or tumor.

Greater than or equal to 20 percent of the peripheral blood Sezary cells must be CD25+.

Measurable stage Ib-IV disease that has progressed after at least 2 prior systemic or
topical therapies.

Patients must have a Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
and be at least 18 years old.

Patients must be able to understand and give informed consent.

Patients must be 4 weeks from any monoclonal antibodies.

Patients must be greater than or equal to 3 weeks from any CTCL-specific therapy and have
evidence of progressive disease.

Patients who are on chronic steroids must be on a stable dose of Prednisone less than or
equal to 20 mg/day (or equivalent dose of another steroid) for at least 3 weeks and have
evidence of progressive disease.

Female patients of childbearing potential must have a negative pregnancy test and must use
effective contraception (a barrier form of contraception).

The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must
each be less than or equal to 2.5-times the upper limits of normal.

Albumin must be greater than or equal to 3.0 gm/dL.

Total bilirubin must be less than or equal to 2.2 mg/dL.

The creatinine must be less than or equal to 2.0 mg/dL or the creatinine clearance must be
greater than or equal to 50 ml/min.

The absolute neutrophil count (ANC) must be greater than or equal to 1000/mm^3 and the
unsupported platelet count must be greater than or equal to 50,000/mm^3 in patients
without blood or bone marrow involvement.

If there is blood or bone marrow involvement, the ANC must be greater than or equal to 500
mm^3 and the platelets must be greater than or equal to 10,000/mm^3.

The cardiac ejection fraction as assessed by echocardiogram or nuclear medicine study must
not be less than the institutional limit of normal.

Pulmonary function studies must demonstrate a carbon monoxide diffusing capacity (DLCO)
greater than or equal to 55 percent and a forced expiratory volume 1 (FEV1) greater than
or equal to 60 percent of normal for inclusion.

EXCLUSION CRITERIA:

Patients whose serum neutralizes LMB-2 in tissue culture, due either to anti-toxin or
anti-mouse-IgG antibodies.

No patient whose serum neutralizes greater than 75 percent of the activity of 1 microg/mL
of LMB-2 will be treated.

Patients who are pregnant or breast-feeding.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection,

symptomatic congestive heart failure,

unstable angina pectoris,

cardiac arrhythmia,

or psychiatric illness/social situations that would limit compliance with study
requirements.

Patients who are human immunodeficiency virus (HIV) positive,

hepatitis B antigen positive,

hepatitis C polymerase chain reaction (PCR) positive,

or who have other chronic liver disease.

Patients with symptomatic cardiac or pulmonary disease.

Patients on warfarin therapy.

Such patients may be eligible if they can be switched to heparin or low-molecular weight
heparin therapy and are off warfarin at least 4 days prior to study enrollment.

Active cancer requiring treatment.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response Rate

Outcome Description:

Response is assessed by the International Workshop's Response Criteria (IWRC) for Non-Hodgkin's Lymphomas which favors the sum of the bidimensional products for tumor measurements. Complete response is no evidence of disease. Complete response unconfirmed (CRu) is a complete response in every category except CRu in lymph nodes. Partial response is a partial response in every measurable category with non-progressive disease elsewhere. Progressive disease is progressive disease in every category. Stable disease is neither partial response nor progressive disease. For additional details about the IWRC see the protocol link module.

Outcome Time Frame:

Patients were followed for at least 30 days after last treatment. Because the protocol allows 6 treatment cycles, this can be up to 7 months.

Safety Issue:

No

Principal Investigator

Robert J Kreitman, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

040142

NCT ID:

NCT00080535

Start Date:

April 2004

Completion Date:

December 2011

Related Keywords:

  • Lymphoma
  • T-Cell
  • Cutaneous
  • LMB-2
  • Cutaneous T Cell Lymphoma
  • CTCL
  • Immunotoxin
  • Oncology
  • Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892