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

Phase 2

Completed

Conditions: Lymphocytic
Leukemia
Chronic

Interventions: Drug: LMB-2

Registration Number: NCT00077922

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LMB-2 in chronic lymphocytic leukemia	LMB-2	40 micrograms/kg every other day (QOD) x 3 every 4 weeks in patients with chronic lymphocytic leukemia, the most prevalent form of adult leukemia.

Primary Outcome Measures

Name	Time	Method
Response Rate	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.	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	54 months	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.