Anti-Tac(Fv)-PE38 (LMB-2) to Treat Chronic Lymphocytic Leukemia

Background:

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.

Objectives:

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.

Eligibility:

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).

Design:

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
patients respond.

- INCLUSION CRITERIA:

Patients must have histopathological evidence of CD25+ CLL or prolymphocytic leukemia (PLL)
confirmed by the NIH pathology department. This requires that at least 50% of the
peripheral malignant lymphocytes be CD25 positive by fluorescence activated cell sorting
(FACS) with anti-CD25 antibody. Positive expression in a FACS assay is defined as more than
2 times the mean fluorescence intensity (MFI) of the control antibody by FACS, or greater
than 400 CD25 sites/cell by FACS or radiolabeled binding assay.

In the three stage modified Rai system, patients must be intermediate or high risk. This
means they must have circulating CLL cells and at least one of the following:
lymphadenopathy, splenomegaly, hepatomegaly, anemia (Hgb less than 11g/dL), or
thrombocytopenia (Plt less than 100,000/ul).

Patients must have had progressive disease after prior standard therapy containing either a
purine analog or an alkylating agent.

Patients must not have received systemic cytotoxic chemotherapy within 4 weeks of
enrollment or systemic steroids (except stable doses of Prednisone less than or equal to 20
mg/day) within 4 weeks of enrollment.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.

At least 18 years old.

Patients must be able to understand and give informed consent.

Female patients of childbearing potential must have a negative pregnancy test and all
patients 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 except
in patients with Gilbert's syndrome (as defined by greater than 80% unconjugated bilirubin)
it must be less than 5 mg/dl.

The creatinine must be less than or equal to 1.4 mg/dL or the creatinine clearance must be
greater than or equal to 50 ml/min as measured from a 24-hour urine collection.

Patients should not have 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.

EXCLUSION CRITERIA:

Patients whose serum neutralizes LMB-2 in tissue culture, due either to anti-toxin or
anti-mouse-lgG antibodies. No patient whose serum neutralizes greater than 75% of the
activity of 1 micro g/mL of LMB-2 will be treated.

Patients who received LMB-2 on another trial.

Monoclonal antibody therapy within 12 weeks of enrollment.

Patients who are pregnant or breast-feeding.

Patients who are human immunodeficiency virus (HIV) positive.

Patients who have hepatitis C or chronic liver disease. Patients would not be excluded for
hepatitis B surface antigen positivity if on Lamivudine.

Patients receiving warfarin for anticoagulation.

Patients with a left ventricular ejection fraction of less than the institutional lower
limit of normal.

Patients with a carbon monoxide diffusing capacity (DLCO) less than 55% of normal or an
forced expiratory volume 1 (FEV1) less than 60% of normal.

Patients who have active cancer requiring treatment.