Leukemia Clinical Trial
Official title:
A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for Treatment of CD25 Positive Chronic Lymphocytic Leukemia
This study will evaluate the effectiveness of an experimental drug called LMB-2 for treating
chronic lymphocytic leukemia (CLL) 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 cancer cells
with CD25 on their surface, and a toxin produced by bacteria that kills the cancer cells to
which it binds. LMB-2 has killed CD 25-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 CLL who have CD25 receptor proteins on their cancer
cells and whose disease has progressed within 2 years of treatment with fludarabine 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, and a bone marrow biopsy.
Participants receive up to six cycles of LMB-2 therapy. 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. Patients are admitted to
the National Institutes of Health (NIH) Clinical Center for the first treatment cycle. If the
infusion is well tolerated, subsequent cycles may be given on an outpatient basis. 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 physical examination, blood tests, chest x-ray,
and EKG before each treatment cycle and at follow-up visits. With the patient's
permission, CT scans, echocardiogram, and bone marrow biopsies may be repeated before
some treatment cycles if these tests prove useful in evaluating the disease response to
LMB-2.
Patients may receive up to six cycles of LMB-2 as long as their cancer does not worsen and
they do not develop serious side effects. At the end of the treatment cycles, patients will
have blood tests done weekly by their local physician, and the results will be sent to the
NCI study investigators.
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.
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