A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for Treatment of CD25 Positive Chronic Lymphocytic Leukemia
It is estimated that 30-50% of patients with CLL have tumors that express cluster of
differentiation 25 (CD25) (Tac or IL2R). Normal resting T-cells are not sensitive to LMB-2
due to insufficient CD25 expression. 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 IV given every other day for 3 doses (every other day (QOD) x3) with
prophylactic IV fluid. The most common adverse events were transient fever, hypoalbuminemia
and transaminase elevations. In that trial, one of eight patients with chronic lymphocytic
leukemia had a partial remission. The other seven CLL patients had stable disease. In
addition, four of four patients with hairy cell leukemia had responses (1 complete response
(CR), 3 partial response (PRs)) and 3 other patients had PRs (1 cutaneous T-cell lymphoma
(CTCL), 1 healthy donor (HD), 1 acute T-cell leukemia/lymphoma (ATL)). Because LMB-2 is
cytotoxic to cells expressing CD25, CD25+ CLL 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 Chronic Lymphocytic Leukemia (CLL). The primary endpoint of
this trial is response rate. We will also evaluate response duration, LMB-2 immunogenicity,
pharmacokinetics, toxicity, and monitor soluble Tac levels in the serum.
CD25 positive CLL or prolymphocytic leukemia (PLL) confirmed by flow cytometry of blood,
with either lymphadenopathy, splenomegaly, hepatomegaly, hemoglobin less than 11 g/dl,
or platelets less than 100,000/ul.
Patients must have progression following purine analog or alkylating agent.
Labs required: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than
or equal to 2.5- time upper limit,
albumin greater than or equal to 3, bilirubin less than equal to 2.2 (unless unconjugated
greater than or equal to 80%)
and creatinine less than or equal to 1.4 (unless creatinine clearance greater than or equal
to 50 ml/min).
Patients receive LMB-2 40 ug/Kg QOD x3 every 4 weeks in absence of neutralizing antibodies
or progressive disease. 1st stage is 16 patients, to expand to 25 if greater than 1 of 16
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Response is measured by the 1996 National Cancer Institute (NCI) Working Group Criteria (NCIWG). Complete response is defined as no hepatomegaly, splenomegaly, or lymphadenopathy by physical examination and appropriate radiographic techniques. Lymph nodes must resolve to <1.0cm of 1-1.5cm at baseline, or <1.5cm if >1.5cm at baseline. Partial response is >=50% decrease in peripheral blood lymphocytes count from the pretreatment baseline value. Progressive disease is >=50% increase in the sum of the products of the greatest perpendicular dimensions of a t least 2 lymph nodes on two consecutive examinations 2 weeks apart (at least 1 node must be >=2cm) or appearance of new palpable lymph nodes. Stable disease is characterized by not meeting the above criteria. For additional details about the NCIWG, see the protocol link module.
Patients were followed for at least 30 days after last treatment. Because the study 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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