LMB-2 to Treat Hairy Cell Leukemia
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Blood Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 100 |
| Updated: | 4/6/2019 |
| Start Date: | May 2, 2006 |
| End Date: | March 31, 2021 |
A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for CD25 Positive Hairy Cell Leukemia
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.
- 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.
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
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
- 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: (888) NCI-1937
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