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

NCT00077922 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 04012104-C-0121
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukemia; Lymphocytic; Chronic

Keywords

LMB-2; Chronic Lymphocytic Leukemia; CLL; Immunotoxin; Oncology; Lymphocytes; Hematological Disease; Monoclonal Antibody; Neutralizing Antibodies

Outcome Measures

Primary Outcomes (1)

• Response Rate

  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.

  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.

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  54 months

Study Arms (1)

LMB-2 in chronic lymphocytic leukemia

EXPERIMENTAL

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.

Drug: LMB-2

Interventions

LMB-2 DRUG

40 micrograms/kg every other day (QOD) x 3 every 4 weeks

LMB-2 in chronic lymphocytic leukemia

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7. No abstract available.

  PMID: 8652811 BACKGROUND

• Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999 Dec;17(12):3835-49. doi: 10.1200/JCO.1999.17.12.3835.

  PMID: 10577857 BACKGROUND

• Rai KR, Sawitsky A. A review of the prognostic role of cytogenetic, phenotypic, morphologic, and immune function characteristics in chronic lymphocytic leukemia. Blood Cells. 1987;12(2):327-38.

  PMID: 3304471 BACKGROUND

MeSH Terms

Conditions

Leukemia; Bronchiolitis Obliterans Syndrome; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms; Hematologic Diseases

Interventions

B3(Fv)-PE38KDEL recombinant immunotoxin

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Hemic and Lymphatic Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Robert J. Kreitman, M.D.
• Organization: National Cancer Institute, National Institutes of Health

kreitmar@mail.nih.gov

301-496-6947

Study Officials

• Robert J Kreitman, M.D.

  National Cancer Institute, National Institutes of Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr. Robert Kreitman

Study Record Dates

• First Submitted: February 12, 2004
• First Posted: February 13, 2004
• Study Start: February 29, 2004
• Primary Completion: December 31, 2011
• Study Completion: December 31, 2011
• Last Updated: January 23, 2018
• Results First Posted: November 15, 2012

Record last verified: 2017-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)