A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for Treatment of CD25 Positive Cutaneous T-Cell Lymphomas
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.
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.
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).
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
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.
Robert J Kreitman, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
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