Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
- Conditions
- Adult T-Cell Leukemia (ATL)
- Interventions
- Registration Number
- NCT00924170
- Lead Sponsor
- National Cancer Institute (NCI)
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 18
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Fludarabine and Cyclophosphamide/LMB-2 LMB-2 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. Fludarabine and Cyclophosphamide/LMB-2 Fludarabine 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. Fludarabine and Cyclophosphamide/LMB-2 Cyclophosphamide 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With a Minimally Durable Clinical Response Rate 8 weeks 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
Name Time Method Progression Free Survival (PFS) 70 months 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.
Number of Participants With Dose Limiting Toxicity (DLT) 30 days after last dose of LMB2 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.
Percentage of Patients Who Developed Neutralizing Antibodies After One or More Cycles of LMB-2 First 24 hours after the dose given on Cycle 2, day 1 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) 69 months 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.
Volume of Distribution of LMB-2 24 hours 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.
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 7 years and 12 days 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.
Peak Level of LMB-2 in Adult T-Cell Lymphoma First 24 hours after the dose given on Cycle 2, day 1 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.
Overall Survival (OS) 70 months 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 7 years and 12 days 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.
Soluble Cluster of Differentiation 25 (sCD25) Between Responders and Nonresponders First 24 hours after the dose given on Cycle 2, day 1 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 First 24 hours after the dose given on Cycle 2, day 1 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 First 24 hours after the dose given on Cycle 2, day 1 Peripheral blood was obtained and analyzed by flow cytometry.
Plasma Clearance (CL) of LMB-2 First 24 hours after the dose given on Cycle 2, day 1 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.
Half Life (t1/2) of LMB-2 First 24 hours after the dose given on Cycle 2, day 1 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 7 years and 12 days 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).
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States