Clinical Trials /

LMB-2 to Treat Hairy Cell Leukemia

NCT00321555

Description:

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.

Related Conditions:
  • Hairy Cell Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: LMB-2 to Treat Hairy Cell Leukemia
  • Official Title: A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for CD25 Positive Hairy Cell Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 060150
  • SECONDARY ID: 06-C-0150
  • NCT ID: NCT00321555
  • NCT ALIAS: NCT00337311

Conditions

  • Hairy Cell Leukemia

Interventions

DrugSynonymsArms
Anti-Tac(Fv)-PE38 (LMB-2) ImmunotoxinLMB-2 to Treat Hairy Cell Leukemia

Purpose

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.

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
    

Trial Arms

NameTypeDescriptionInterventions
LMB-2 to Treat Hairy Cell LeukemiaExperimentalLMB-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.
  • Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin

Eligibility 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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Patients Who Obtain Partial Response/Complete Remission
Time Frame:6 months
Safety Issue:
Description: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

Measure:Duration of Response
Time Frame:Participants were assessed at 5.0658, 12.0066, 20.1645, 26.9079, 35.0987, and 45.1316 months
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Biologic Therapy
  • Monoclonal Antibody
  • Immunotherapy
  • Pseudomonas Exotoxin
  • Targeted Therapy
  • Hairy Cell Leukemia
  • HCL

Last Updated