Back to resultsPhase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
Primary Purpose
Adult T-Cell Leukemia (ATL)
Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
LMB-2
Fludarabine
Cyclophosphamide
Sponsored by
About this trial
This is an interventional treatment trial for Adult T-Cell Leukemia (ATL) focused on measuring Immunotoxin, CD25, Immunogenicity, Neutralization, Neutralizing Antibodies, Adult T-Cell Leukemia, Leukemia, ATL
Eligibility Criteria
INCLUSION CRITERIA:
- Diagnosis of acute or lymphomatous adult T-cell leukemia (ATL) by flow cytometry of blood or immunohistochemistry of biopsy tissue, confirmed by National Cancer Institute (NCI) Laboratory of Pathology, and previously treated unless the patient is ineligible for or refuses other protocols or treatments for ATL.
- Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2.
- At least 18 years old.
- Eastern Cooperative Oncology Group (ECOG) 0-2.
- Able to understand and give informed consent.
- Negative pregnancy test for females of childbearing potential.
- The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must each be less than or equal to 3-times the upper limits of normal (UNL) or less than or equal to 10-times normal if due to ATL. Albumin must be greater than or equal to 3.0 gm/dL. Total bilirubin must be less than or equal to 1.5 mg/dL except in patients with Gilberts syndrome (as defined by greater than 80 percent unconjugated bilirubin) it must be less than 5mg/dl.
- Creatinine less than 2.0 mg/dL.
- Absolute neutrophil count (ANC) greater than or equal to 1000/uL and platelets greater than or equal to 50,000/uL.
- Current or prior features of acute ( corrected calcium (Ca)++ > 2.73 or lactate dehydrogenase (LDH) 2- fold above ULN) or chronic (LDH 1.5-2-fold above ULN or absolute lymphocyte count >4 x10^9/L with T-cells >3.5 x10^9/L) ATL. Patients with smoldering ATL (no acute or chronic features) and symptomatic ATL skin lesions are also eligible.
EXCLUSION CRITERIA:
- Prior therapy with LMB-2.
- Central nervous system disease as evidenced by clinical symptomatology.
- Cytotoxic chemotherapy, steroids or monoclonal antibody (Mab) within 3 weeks of enrollment, except anti Tac Mab (i.e. daclizumab), which cannot be used within 12 weeks of enrollment. Hydroxyurea is considered different from cytotoxic chemotherapy and may be used up to the day before enrollment providing it is not increased during the week prior to enrollment and that patients disease burden is not decreasing during that time.
- Uncontrolled infection.
- Untreated or uncontrolled 2nd malignancy.
- Patients who are pregnant or breast-feeding.
- Patients who have human immunodeficiency virus (HIV) or hepatitis C, since in these patients reductions in normal T- or B-cells would increase the risk of exacerbation of their underlying disease. Patients would not be excluded for hepatitis B surface antigen positivity if on Lamivudine or Entecavir.
- Patients receiving warfarin (Coumadin [R])
- 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 50% of normal or an forced expiratory volume 1 (FEV1) less than 50% of normal.
- No concomitant use of alternative complimentary therapies or over the counter (OTC) agents allowed without prior approval of the principal investigator (PI).
- Tumor or lymph node masses > 4 cm.
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Fludarabine and Cyclophosphamide/LMB-2
Arm Description
Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
Outcomes
Primary Outcome Measures
Percentage of Participants With a Minimally Durable Clinical Response Rate
Response is based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma and must last >8 weeks to meet the primary endpoint of the study. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion. Stable disease is neither a response nor progressive disease. Progressive disease is appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
Secondary Outcome Measures
Peak Level of LMB-2 in Adult T-Cell Lymphoma
The maximum analyte concentration in serum was reported using a cytotoxicity assay measuring the level of LMB-2 in the plasma and using purified LMB-2 as a standard curve.
Progression Free Survival (PFS)
PFS was determined by the Kaplan Meier method beginning at the on study date and continuing until progression or last follow-up without progression. Progressive disease is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma, and is the appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
Overall Survival (OS)
OS is the time between the first day of treatment to the day of disease progression. Progressive disease is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma, and is the appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
Number of Participants With Serious and Non-serious Adverse Events
Here is the number 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.
Number of Participants With Dose Limiting Toxicity (DLT)
DLT is a grade II-IV LMB-2 or fludarabine and cyclophosphamide (FC)-related toxicity, except vascular leak syndrome, alopecia, grade II-III allergic reaction with asymptomatic bronchospasm or urticarial is considered DLT. Grade III aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, and fever are not considered DLT. Grade IV creatine phosphokinase associated with any other DLT or not resolving to <grade II within 2 weeks is considered DLT. Hematologic toxicity is not considered DLT unless it fails to resolve to <grade 2 or baseline by day 18 after cycle 1 or after day 25 after cycles 2-7. DLT from hepatotoxicity, creatine phosphokinase, and vascular leak syndrome is assumed from LMB-2, and hematologic toxicity from fludarabine and cyclophosphamide. Grade III proteinuria lasting <2 weeks after the last dose of LMB-2 is not considered DLT, and needs to resolve to grade 0-2 prior to retreatment.
Soluble Cluster of Differentiation 25 (sCD25) Between Responders and Nonresponders
Tumor tissue, including lymph node or skin biopsies was examined and analysis performed by flow cytometry to determine the amount of cancer cells in the body by measuring proteins which fall off cancer cells and go into the blood.
Area Under the Plasma Concentration (AUC) - LMB2
AUC is a measure of the plasma concentration of drug over time. It is used to characterize drug absorption. Plasma levels were analyzed by cytotoxicity assay.
Post Treatment Effects of LMB-2 + Fludarabine and Cyclophosphamide (FC) on Normal B and T Cell Subsets by Flow Cytometry
Peripheral blood was obtained and analyzed by flow cytometry.
Percentage of Patients Who Developed Neutralizing Antibodies After One or More Cycles of LMB-2
Blood was drawn prior to each cycle of LMB-2 to determine if the level, >75% neutralization of 1000ng/ml of LMB-2 of neutralizing antibodies is too high to give additional LMB-2. Analysis was performed by cytotoxicity assay.
Duration of Response (Complete Response + Partial Response)
Duration of response is defined as a response lasting for at least 4 weeks but >8 weeks and is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion.
Plasma Clearance (CL) of LMB-2
Dilutions of patient plasma was tested by cytotoxicity assays to determine plasma clearance of LMB-2.The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Volume of Distribution of LMB-2
Dilutions of patient plasma were tested by cytotoxicity assays to determine volume of distribution of LMB-2. Volume distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. This was measured during the first 24 hours after administration of the dose on cycle 2 day 1.
Half Life (t1/2) of LMB-2
Dilutions of patient plasma was tested by cytotoxicity assays to determine half life. Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Count of Participants With Grades 3-5 Adverse Events of > 1 Adult T-Cell Leukemia (ATL) Patients Treated With 20+200, 25+250, and 30+300 mg/m^2 LMB-2/Fludarabine and Cyclophosphamide
Adverse events is 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. Grade 3 (mild), Grade 4 (life threatening) and Grade 5 (death).
Count of Participants With Adverse Events Attributed At Least Possibly to Patients Treated With Fludarabine and Cyclophosphamide Dose Levels 20+200, 25+250, and 30+300 mg/m^2
Adverse events is 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.
Full Information
NCT ID
NCT00924170
First Posted
June 17, 2009
Last Updated
January 18, 2023
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00924170
Brief Title
Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
Official Title
Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 31, 2008 (Actual)
Primary Completion Date
January 2, 2016 (Actual)
Study Completion Date
December 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
BACKGROUND:
Cluster of differentiation 25 (CD25) (p55, Tac or interleukin 2 receptor (IL2R) alpha) is strongly expressed in virtually 100% of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
In ATL, the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14% responses, and the anti-CD52 Mab Alemtuzumab (Campath-1H) produced response lasting greater than 2 months in 30% of 23 patients.
LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 microg/Kg intravenous (IV) given every other day for 3 doses (every other day (QOD) times 3). LMB-2 induced greater than 90% tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due to reduction of soluble receptor in tumor interstitium.
OBJECTIVES:
-To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting greater than 2 months, which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).
Secondary objectives:
To determine the effect of 1 cycle of FC alone in ATL.
To examine progression-free and overall survival in ATL after FC/LMB-2.
Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
To study the effects of LMB-2 plus FC on normal B- and T-cell subsets by fluorescence-activated cell sorting (FACS).
ELIGIBILITY:
CD25 plus ATL, untreated or with prior therapy
Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0.
DESIGN:
Fludarabine 25 mg/m(2) IV days 1-3
Cyclophosphamide 250 mg/m(2) IV days 1-3
LMB-2 30-40 micro g/Kg IV days 3, 5 and 7.
LMB-2 dose: Begin with 30 microg/Kg times 3. Escalate to 40 microg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 microg/Kg. Continue at 40 microg/Kg if 0-1 of 6 have DLT at 40 microg/Kg.
Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
Accrual goals: 29-37 patients, which includes 4 replacements....
Detailed Description
BACKGROUND:
Cluster of differentiation 25 (CD25) (p55, Tac or interleukin receptor 2 (IL2Ra) is strongly expressed in virtually 100 % of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
In adult T-cell leukemia (ATL), the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14 % responses, and the anti-CD52 Mab Alemtuzumab (Campath- 1H) produced response lasting > 8 weeks in of 30 % of 23 patients.
LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 mcg/Kg dose intravenous (IV) given every other day for 3 doses (every other day (QOD) x3). LMB-2 induced > 90 % tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due reduction of soluble receptor in tumor interstitium.
OBJECTIVES:
To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting > 8 weeks which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).
Secondary objectives
To determine the effect of 1 cycle of FC alone in ATL.
To examine progression-free and overall survival in ATL after FC/LMB-2.
Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
To study the effects of LMB-2 +FC on normal B- and T-cell subsets by FACS.
ELIGIBILITY:
CD25+ ATL, untreated or with prior therapy, leukemic type without malignant masses > 4 cm.
Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0 respectively.
DESIGN:
IV fludarabine and cyclophosphamide (FC) days 1-3 (doses listed respectively)
Patients 1-7 and 10-14, and >18: 25 and 250 mg/m^2/day
Patients 8-9: 30 and 300 mg/m^2/day
Patients 15-17: 20 and 200 mg/m^2/day
LMB-2 dose: Begin with 30 mcg/Kg IV on days 3,5 and 7. Escalate to 40 mcg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6 have DLT at 40 mcg/Kg.
Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20 day intervals.
Accrual goals: 29-37 patients, which includes 4 replacements.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult T-Cell Leukemia (ATL)
Keywords
Immunotoxin, CD25, Immunogenicity, Neutralization, Neutralizing Antibodies, Adult T-Cell Leukemia, Leukemia, ATL
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Fludarabine and Cyclophosphamide/LMB-2
Arm Type
Experimental
Arm Description
Administer cycle 1 with Fludarabine and Cyclophosphamide (FC) alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
Intervention Type
Drug
Intervention Name(s)
LMB-2
Intervention Description
Begin with 30 mcg/Kg intravenous (IV) on days 3, 5 and 7. Escalate to 40 mcg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6 have DLT at 40 mcg/Kg.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Days 1-3:
Patients 1-7, 10-14, and >18:25mg/m^2/day Patients 8 - 9:30 mg/m^2/day Patients 15- 17:20 mg/m^2/day
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Days 1-3:
Patients 1-7, 10 -14, and >18:250 mg/m^2/day Patients 8 - 9:300 mg/m^2/day Patients 15-17:200 mg/m^2/day
Primary Outcome Measure Information:
Title
Percentage of Participants With a Minimally Durable Clinical Response Rate
Description
Response is based on the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma and must last >8 weeks to meet the primary endpoint of the study. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion. Stable disease is neither a response nor progressive disease. Progressive disease is appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Peak Level of LMB-2 in Adult T-Cell Lymphoma
Description
The maximum analyte concentration in serum was reported using a cytotoxicity assay measuring the level of LMB-2 in the plasma and using purified LMB-2 as a standard curve.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Progression Free Survival (PFS)
Description
PFS was determined by the Kaplan Meier method beginning at the on study date and continuing until progression or last follow-up without progression. Progressive disease is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma, and is the appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
Time Frame
70 months
Title
Overall Survival (OS)
Description
OS is the time between the first day of treatment to the day of disease progression. Progressive disease is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma, and is the appearance of new lesions, or an increase of 50% or greater in the sum of the product of the perpendicular diameters of the measurable lesions or persistent (at least two determinations) doubling of the peripheral blood leukemic cell count.
Time Frame
70 months
Title
Number of Participants With Serious and Non-serious Adverse Events
Description
Here is the number 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.
Time Frame
7 years and 12 days
Title
Number of Participants With Dose Limiting Toxicity (DLT)
Description
DLT is a grade II-IV LMB-2 or fludarabine and cyclophosphamide (FC)-related toxicity, except vascular leak syndrome, alopecia, grade II-III allergic reaction with asymptomatic bronchospasm or urticarial is considered DLT. Grade III aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, and fever are not considered DLT. Grade IV creatine phosphokinase associated with any other DLT or not resolving to <grade II within 2 weeks is considered DLT. Hematologic toxicity is not considered DLT unless it fails to resolve to <grade 2 or baseline by day 18 after cycle 1 or after day 25 after cycles 2-7. DLT from hepatotoxicity, creatine phosphokinase, and vascular leak syndrome is assumed from LMB-2, and hematologic toxicity from fludarabine and cyclophosphamide. Grade III proteinuria lasting <2 weeks after the last dose of LMB-2 is not considered DLT, and needs to resolve to grade 0-2 prior to retreatment.
Time Frame
30 days after last dose of LMB2
Title
Soluble Cluster of Differentiation 25 (sCD25) Between Responders and Nonresponders
Description
Tumor tissue, including lymph node or skin biopsies was examined and analysis performed by flow cytometry to determine the amount of cancer cells in the body by measuring proteins which fall off cancer cells and go into the blood.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Area Under the Plasma Concentration (AUC) - LMB2
Description
AUC is a measure of the plasma concentration of drug over time. It is used to characterize drug absorption. Plasma levels were analyzed by cytotoxicity assay.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Post Treatment Effects of LMB-2 + Fludarabine and Cyclophosphamide (FC) on Normal B and T Cell Subsets by Flow Cytometry
Description
Peripheral blood was obtained and analyzed by flow cytometry.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Percentage of Patients Who Developed Neutralizing Antibodies After One or More Cycles of LMB-2
Description
Blood was drawn prior to each cycle of LMB-2 to determine if the level, >75% neutralization of 1000ng/ml of LMB-2 of neutralizing antibodies is too high to give additional LMB-2. Analysis was performed by cytotoxicity assay.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Duration of Response (Complete Response + Partial Response)
Description
Duration of response is defined as a response lasting for at least 4 weeks but >8 weeks and is assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. Complete remission (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities definitely assignable to the lymphoma. Partial response is reduction by ≥50% of leukemia cell count or ≥50% reduction in the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion.
Time Frame
69 months
Title
Plasma Clearance (CL) of LMB-2
Description
Dilutions of patient plasma was tested by cytotoxicity assays to determine plasma clearance of LMB-2.The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Volume of Distribution of LMB-2
Description
Dilutions of patient plasma were tested by cytotoxicity assays to determine volume of distribution of LMB-2. Volume distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. This was measured during the first 24 hours after administration of the dose on cycle 2 day 1.
Time Frame
24 hours
Title
Half Life (t1/2) of LMB-2
Description
Dilutions of patient plasma was tested by cytotoxicity assays to determine half life. Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Time Frame
First 24 hours after the dose given on Cycle 2, day 1
Title
Count of Participants With Grades 3-5 Adverse Events of > 1 Adult T-Cell Leukemia (ATL) Patients Treated With 20+200, 25+250, and 30+300 mg/m^2 LMB-2/Fludarabine and Cyclophosphamide
Description
Adverse events is 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. Grade 3 (mild), Grade 4 (life threatening) and Grade 5 (death).
Time Frame
7 years and 12 days
Title
Count of Participants With Adverse Events Attributed At Least Possibly to Patients Treated With Fludarabine and Cyclophosphamide Dose Levels 20+200, 25+250, and 30+300 mg/m^2
Description
Adverse events is 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.
Time Frame
7 years and 12 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
Diagnosis of acute or lymphomatous adult T-cell leukemia (ATL) by flow cytometry of blood or immunohistochemistry of biopsy tissue, confirmed by National Cancer Institute (NCI) Laboratory of Pathology, and previously treated unless the patient is ineligible for or refuses other protocols or treatments for ATL.
Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2.
At least 18 years old.
Eastern Cooperative Oncology Group (ECOG) 0-2.
Able to understand and give informed consent.
Negative pregnancy test for females of childbearing potential.
The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must each be less than or equal to 3-times the upper limits of normal (UNL) or less than or equal to 10-times normal if due to ATL. Albumin must be greater than or equal to 3.0 gm/dL. Total bilirubin must be less than or equal to 1.5 mg/dL except in patients with Gilberts syndrome (as defined by greater than 80 percent unconjugated bilirubin) it must be less than 5mg/dl.
Creatinine less than 2.0 mg/dL.
Absolute neutrophil count (ANC) greater than or equal to 1000/uL and platelets greater than or equal to 50,000/uL.
Current or prior features of acute ( corrected calcium (Ca)++ > 2.73 or lactate dehydrogenase (LDH) 2- fold above ULN) or chronic (LDH 1.5-2-fold above ULN or absolute lymphocyte count >4 x10^9/L with T-cells >3.5 x10^9/L) ATL. Patients with smoldering ATL (no acute or chronic features) and symptomatic ATL skin lesions are also eligible.
EXCLUSION CRITERIA:
Prior therapy with LMB-2.
Central nervous system disease as evidenced by clinical symptomatology.
Cytotoxic chemotherapy, steroids or monoclonal antibody (Mab) within 3 weeks of enrollment, except anti Tac Mab (i.e. daclizumab), which cannot be used within 12 weeks of enrollment. Hydroxyurea is considered different from cytotoxic chemotherapy and may be used up to the day before enrollment providing it is not increased during the week prior to enrollment and that patients disease burden is not decreasing during that time.
Uncontrolled infection.
Untreated or uncontrolled 2nd malignancy.
Patients who are pregnant or breast-feeding.
Patients who have human immunodeficiency virus (HIV) or hepatitis C, since in these patients reductions in normal T- or B-cells would increase the risk of exacerbation of their underlying disease. Patients would not be excluded for hepatitis B surface antigen positivity if on Lamivudine or Entecavir.
Patients receiving warfarin (Coumadin [R])
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 50% of normal or an forced expiratory volume 1 (FEV1) less than 50% of normal.
No concomitant use of alternative complimentary therapies or over the counter (OTC) agents allowed without prior approval of the principal investigator (PI).
Tumor or lymph node masses > 4 cm.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert J Kreitman, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
IPD Sharing Time Frame
Clinical data available during the study and indefinitely.
IPD Sharing Access Criteria
Clinical data will be made available via subscription to Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).
Citations:
PubMed Identifier
6327770
Citation
Waldmann TA, Greene WC, Sarin PS, Saxinger C, Blayney DW, Blattner WA, Goldman CK, Bongiovanni K, Sharrow S, Depper JM, et al. Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sezary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. J Clin Invest. 1984 Jun;73(6):1711-8. doi: 10.1172/JCI111379.
Results Reference
background
PubMed Identifier
6815536
Citation
Leonard WJ, Depper JM, Uchiyama T, Smith KA, Waldmann TA, Greene WC. A monoclonal antibody that appears to recognize the receptor for human T-cell growth factor; partial characterization of the receptor. Nature. 1982 Nov 18;300(5889):267-9. doi: 10.1038/300267a0. No abstract available.
Results Reference
background
PubMed Identifier
16155612
Citation
Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL. Global epidemiology of HTLV-I infection and associated diseases. Oncogene. 2005 Sep 5;24(39):6058-68. doi: 10.1038/sj.onc.1208968.
Results Reference
background
PubMed Identifier
26350263
Citation
Kreitman RJ, Stetler-Stevenson M, Jaffe ES, Conlon KC, Steinberg SM, Wilson W, Waldmann TA, Pastan I. Complete Remissions of Adult T-cell Leukemia with Anti-CD25 Recombinant Immunotoxin LMB-2 and Chemotherapy to Block Immunogenicity. Clin Cancer Res. 2016 Jan 15;22(2):310-8. doi: 10.1158/1078-0432.CCR-15-1412. Epub 2015 Sep 8.
Results Reference
background
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2009-C-0025.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
We'll reach out to this number within 24 hrs