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 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
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, 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 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 physicians.
It is estimated that 40-50% of patients with CTCL have tumors that express 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 NCI found that the MTD of LMB-2 was 40 microg/Kg 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 PR, 1 SD). In 1999 another
recombinant fusion protein, denileukin diftitox, was approved by the FDA for treatment of
patients with advanced or recurrent CTCL expressing the high affinity 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: ALT and 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), 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
DLT at 30 ug/Kg times 3. 1st stage is 16 patients, to expand to 25 if greater than 1 of 16
- INCLUSION CRITERIA:
Patients must have histopathological evidence of CD25+ CTCL confirmed by the 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
Patients must have a 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 ALT and 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 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 DLCO greater than or equal to 55 percent and
a 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
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
Patients who are HIV positive, hepatitis B antigen positive, hepatitis C 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.