Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia

Conditions
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Adult T-Cell Leukemia (ATL)

Intervention / Treatment
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* Drug: LMB-2
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine and Cyclophosphamide/LMB-2<br>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. | Drug: LMB-2<br>* 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.<br>Drug: Fludarabine<br>* 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<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 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<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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. | 70 months | 
| 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. | 70 months | 
| 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. | 7 years and 12 days | 
| 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. | 30 days after last dose of LMB2 | 
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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. | 69 months | 
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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. | 24 hours | 
| 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. | First 24 hours after the dose given on Cycle 2, day 1 | 
| 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). | 7 years and 12 days | 
| 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. | 7 years and 12 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotoxin, CD25, Immunogenicity, Neutralization, Neutralizing Antibodies, Adult T-Cell Leukemia, Leukemia, ATL