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LMB-2 to Treat Hairy Cell Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00321555
Recruitment Status : Active, not recruiting
First Posted : May 4, 2006
Results First Posted : April 5, 2019
Last Update Posted : April 5, 2019
Sponsor:
Information provided by (Responsible Party):
Robert Kreitman, M.D., National Cancer Institute (NCI)

Brief Summary:

Background:

  • About 80% of patients with hairy cell leukemia (HCL) have tumor cells that have a protein on their surface called cluster of differentiation 25 (CD25).
  • The experimental drug LMB-2 is a recombinant immunotoxin that has been shown to kill leukemia and lymphoma cells with the CD25 protein. (A recombinant immunotoxin is a genetically engineered drug that has two parts - a protein that binds or targets a cancer cell, and a toxin that kills the cancer cell to which it binds.)

Objectives:

  • To evaluate the safety and effectiveness of LMB-2 in patients with HCL whose cancer cells contain the CD25 protein.
  • To evaluate the effects of LMB-2 on the immune system, determine how the drug is metabolized by the body and examine its side effects.

Eligibility:

-Adults with hairy cell leukemia whose tumor cells have CD25 on their surface

Design:

  • Up to 27 patients may be included in the study.
  • Patients receive an infusion of LMB-2 through a vein every other day for three doses (days 1, 3, 5), constituting one treatment cycle.
  • Patients may receive up to six treatment cycles every 4 weeks unless their cancer worsens or they develop unacceptable side effects.
  • Blood is drawn weekly for various tests.
  • Before each cycle and in follow-up visits, disease status is evaluated with a physical examination, blood tests, chest x-ray and electrocardiogram.
  • Before the first cycle, patients may have a computed tomography (CT) scan, echocardiogram (heart ultrasound test) and bone marrow biopsy. With the patient's permission, these tests may be repeated before other cycles also.

Condition or disease Intervention/treatment Phase
Hairy Cell Leukemia Drug: Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin Phase 2

Detailed Description:

Background: About 80% of patients with hairy cell leukemia (HCL) have malignant cells that express cluster of differentiation 25 (CD25) (Tac or Interleukin-2 receptor alpha (IL2Ra)). Normal resting B- and 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 x3). The most common adverse events were transient fever, hypoalbuminemia and transaminase elevations. In that trial, 4 of 4 patients with chemoresistant HCL had major responses, including one complete (CR) and 3 partial remissions. The patient with CR entered the trial transfusion dependent and now still has normal hemoglobin and platelet counts over 7 years later. Because HCL is more frequently cluster of differentiation 22 (CD22+) than CD25+ (100 vs 80%), HCL patients were subsequently treated with the anti-CD22 recombinant immunotoxin BL22 and no further HCL patients were treated with LMB-2. BL22 has induced 25 CRs out of 51 evaluable HCL patients. LMB-2 may be useful in patients incompletely responding to BL22, because it may distribute more evenly through extravascular sites of disease. Moreover, BL22 but not LMB-2 has caused hemolytic uremic syndrome (HUS) in 7 patients, 6 with HCL, and several of these patients could benefit by LMB-2. Thus, LMB-2 may be a useful and potentially lifesaving agent in patients who are unable to receive or who have not responded adequately to BL22.

Objectives: The purpose of this study is to determine the activity of anti-Tac(Fv)-PE38 (LMB-2) in patients with CD25-expressing hairy cell leukemia (HCL). 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: Patients must have CD25+ HCL cells by flow cytometry, cytopenia or high circulating HCL count, prior treatment with or inability to receive BL22, prior treatment with cladribine, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2, at least 18 years old, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) grade 0-2, albumin grade 0-1, bilirubin less than or equal to 2.2, creatinine less than or equal to 1.4 or creatinine clearance greater than or equal to 50, lack of high levels of neutralizing antibodies, lack of anti-CD25 Mab therapy for 12 weeks and other systemic treatment for 4 weeks, no prior treatment with LMB-2, lack of other uncontrolled illness including 2nd malignancy, no human immunodeficiency virus (HIV) or hepatitis C positivity, no coumadin therapy, left ventricular ejection fraction (LVEF) greater than or equal to 45%, diffusing capacity of the lungs for carbon monoxide (DLCO) greater than or equal to 55%, and forced expiratory volume 1 (FEV1) greater than or equal to 60%.

Design: Patients will receive LMB-2 at 40 microg/Kg every other day (QOD) x3 at intervals of at least 25 days for up to 6 cycles. Retreatment is permitted in the absence of neutralizing antibodies or progressive disease. Patients in CR may receive 2 consolidation cycles, or 4 consolidation cycles if CR is with minimal residual disease.

Dose level: LMB-2 40 microg/Kg QOD x3

Expected Accrual: 5-10 patients/year, total of 25 patients


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for CD25 Positive Hairy Cell Leukemia
Actual Study Start Date : May 2, 2006
Actual Primary Completion Date : August 24, 2016
Estimated Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia
Drug Information available for: Daclizumab

Arm Intervention/treatment
Experimental: LMB-2 to Treat Hairy Cell Leukemia
LMB-2 Infusion: 40 micro-g/Kg will be infused in 50 ml of 0.9% Sodium chloride (NaCl) and 0.2% albumin via over 30 minutes every other day for 3 doses. Patients may receive up to six treatment cycles every 4 weeks.
Drug: Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin
LMB-2 Infusion: 40 micro-g/Kg will be infused in 50 ml of 0.9% Sodium Chloride (NaCl) and 0.2% albumin via over 30 minutes every other day for 3 doses. Patients may receive up to six treatment cycles every 4 weeks.




Primary Outcome Measures :
  1. Number of Patients Who Obtain Partial Response/Complete Remission [ Time Frame: 6 months ]
    Partial response requires all of the following for a period of at least 4 weeks: ≥50% decrease in hairy cell count from pretreatment baseline value by flow cytometry. ≥50% reduction in abnormal hepatosplenomegaly by computed tomography or physical exam. No growth in lymphadenopathy. Neutrophils ≥1,500/µL or 50% improvement over baseline without growth factors for at least 4 weeks. Platelets ≥100,000/µL or 50% improvement over baseline. Complete remission requires all of the following: no evidence of leukemic cells by routine hematoxylin and eosin stains of the peripheral blood and bone marrow. No hepatomegaly, splenomegaly, or lymphadenopathy (not >2 cm in short axis) by physical examination and appropriate radiographic techniques. Normal complete blood count as exhibited by Neutrophils ≥1,500/µL, Platelets ≥100,000/µL, and Hemoglobin ≥11.0g/dL without transfusions or growth factors for at least 4 weeks.


Secondary Outcome Measures :
  1. Duration of Response [ Time Frame: Participants were assessed at 5.0658, 12.0066, 20.1645, 26.9079, 35.0987, and 45.1316 months ]
    Duration of response is the duration that the patients qualifies for at least a Partial Response (PR). Partial response requires all of the following for a period of at least 4 weeks: ≥50% decrease in hairy cell count from pretreatment baseline value by flow cytometry. ≥50% reduction in abnormal hepatosplenomegaly by computed tomography or physical exam. No growth in lymphadenopathy. Neutrophils ≥1,500/µL or 50% improvement over baseline without growth factors for at least 4 weeks. Platelets ≥100,000/µL or 50% improvement over baseline. Hemoglobin ≥11.0 g/dL or 50% improvement over baseline without transfusions or growth factors for at least 4 weeks.

  2. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) [ Time Frame: Date treatment consent signed to date off study, approximately 83 months and 15 days. ]
    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Histopathological evidence of cluster of differentiation 25 (CD25)+ Hairy Cell Leukemia (HCL) confirmed by the National Institutes of Health (NIH) pathology department. This will require a monoclonal population of peripheral malignant lymphocytes that are 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. HCLv (HCL variant) is usually CD25 negative, and eligibility would require CD25+ HCLv.
    2. At least one of the following indications for treatment: neutropenia (absolute neutrophil count (ANC) less than 1000 cells/ microL), anemia (hemoglobin (Hgb) less than 10g/dL), thrombocytopenia (platelet (Plt) less than 100,000/ microL), an absolute lymphocyte count of greater than 20,000 cells/microL or symptomatic splenomegaly.
    3. Previous treatment with or inability to receive BL22 or HA22 recombinant immunotoxin. Patients must have had at least 2 prior systemic therapies, including 2 courses of a purine nucleoside analog (PNA), or 1 course of either rituximab or BRAF inhibitor following a single prior course of PNA.
    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.
    5. At least 18 years old.
    6. Understand and give informed consent.
    7. A negative pregnancy test in female patients of childbearing potential. Women must not be breast-feeding.
    8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 5-times the upper limits of normal. Albumin greater than or equal to 3.0 gm/dL. Total bilirubin less than or equal to 2.2 mg/dL.
    9. Creatinine less than or equal to 1.4 mg/dL or creatinine clearance greater than or equal to 50 ml/min.
    10. Serum that neutralizes less than or equal to 75% of the activity of 1 microg/mL of LMB-2 using a bioassay.
    11. No systemic cytotoxic chemotherapy within 4 weeks of enrollment or systemic steroids (except stable doses of Prednisone less than or equal to 20 mg/day, or up to 4 doses of steroid given for non-therapy reasons) within 4 weeks of enrollment.
    12. No anti-cluster of differentiation 25 (CD25) monoclonal antibody therapy within 12 weeks of enrollment.
    13. No prior treatment with LMB-2.
    14. Patients may not be receiving any other investigational agents.
    15. Patients should not have uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

EXCLUSION CRITERIA:

  • Patients who have human immunodeficiency virus (HIV) or hepatitis C. Patients would not be excluded for hepatitis B surface antigen positivity if on Lamivudine.
  • Patients receiving coumadin.
  • Patients with a left ventricular ejection fraction of less than 45%.
  • Patients with a diffusing capacity of the lungs for carbon monoxide (DLCO) less than 55% of normal or an forced expiratory volume 1 (FEV1) less than 60% of normal based on either National Institutes of Health (NIH) or United States of America (USA) normal ranges.
  • Patients who have an active 2nd malignancy requiring systemic treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00321555


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Robert J Kreitman, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Robert Kreitman, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] July 14, 2018


Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Robert Kreitman, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00321555     History of Changes
Obsolete Identifiers: NCT00337311
Other Study ID Numbers: 060150
06-C-0150
First Posted: May 4, 2006    Key Record Dates
Results First Posted: April 5, 2019
Last Update Posted: April 5, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Robert Kreitman, M.D., National Cancer Institute (NCI):
Biologic Therapy
Monoclonal Antibody
Immunotherapy
Pseudomonas Exotoxin
Targeted Therapy
Hairy Cell Leukemia
HCL
Additional relevant MeSH terms:
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Leukemia
Leukemia, Hairy Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Immunotoxins
Daclizumab
Antibodies, Monoclonal
Antibodies
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents