This study will evaluate the effectiveness of an experimental drug called LMB-2 for treating
cutaneous T-cell lymphoma in patients who have a protein called cluster of differentiation 25
(CD25) on their cancer cells. LMB-2 is a recombinant immunotoxin. It is made up of two parts:
a genetically engineered monoclonal antibody that binds to CD25, and a toxin produced by
bacteria that kills the cancer cells to which it binds. LMB-2 has killed CD25-containing
cells in laboratory experiments and has caused tumors in mice to shrink. Preliminary studies
in humans have shown some effectiveness in shrinking tumors in patients with various types of
lymph and blood cancers.
Patients 18 years of age and older with stage 1b to IV cutaneous T-cell lymphoma that has
progressed within 2 years of systemic or topical therapy and who have CD25 receptor proteins
on their cancer cells may be eligible for this study. Candidates are screened with a medical
history and physical examination, blood and urine tests, electrocardiogram (EKG),
echocardiogram, chest x-ray, computed tomography (CT) scans of the chest, abdomen and pelvis,
skin punch biopsy to evaluate tumor infiltration in the skin, and a bone marrow biopsy on
patients with stage IIa disease and higher. In addition, the patient's blood, bone marrow,
tumor, or other tissue is tested to determine the presence of CD25 on cancer cells.
Participants receive up to nine cycles of LMB-2 therapy as long as their cancer does not
worsen and they do not develop serious side effects. Each 28-day cycle consists of 30-minute
infusions of LMB-2 on cycle days 1, 3, and 5. The drug is infused through an intravenous (IV)
catheter (plastic tube placed in a vein) or a central venous line - an IV tube placed in a
large vein in the neck or chest that leads to the heart. In addition to drug therapy,
patients undergo the following procedures:
Blood draws: Blood is drawn before, during, and after each LMB-2 infusion to measure blood
levels of the drug, evaluate its effects on the cancer cells, and monitor side effects. Blood
tests are also done before and during each cycle to determine how the immune system is
interacting with the drug.
Disease evaluations: Patients undergo a careful skin examination, blood tests, chest x-ray,
and EKG before each treatment cycle and at follow-up visits. A CT scan and echocardiogram
(heart ultrasound) are done before the first cycle. Before the first and second cycles,
patients have a biopsy of the lymphoma on the skin. If the biopsy is helpful in evaluating
the disease response to LMB-2, additional biopsies may be requested prior to other cycles as
well. A nuclear medicine scan may be done, and a bone marrow biopsy may be done in patients
with stage II to IV disease. If these tests are helpful in understanding the response of the
lymphoma to treatment, they may also be repeated prior to other cycles, with the patient's
Patients are admitted to the National Institutes of Health (NIH) Clinical Center for the
first treatment cycle. Subsequent cycles are given as outpatients. If the infusions are well
tolerated, patients may return home after about one week (or possibly longer if complications
occur). After returning home, patients have blood tests done weekly by their local
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.
- 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)
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
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.
Patients whose serum neutralizes LMB-2 in tissue culture, due either to anti-toxin or
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
symptomatic congestive heart failure,
unstable angina pectoris,
or psychiatric illness/social situations that would limit compliance with study
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.