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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00924170
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 194
• Patients Per Site Per Month: 0.1

Study Details

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....

Condition or Disease	Intervention/Treatment	Phase
Adult T-Cell Leukemia (ATL)	Drug: LMB-2; Drug: Fludarabine; Drug: Cyclophosphamide	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia
• Actual Study Start Date: Oct 31, 2008
• Actual Primary Completion Date: Jan 2, 2016
• Anticipated Study Completion Date: Dec 31, 2024

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Fludarabine and Cyclophosphamide/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.

Drug: LMB-2; 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.; Drug: Fludarabine; 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; Other Names: Fludara ; Drug: Cyclophosphamide; 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; Other Names: Cytoxan

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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).

15. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. 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.

2. Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2.

3. At least 18 years old.

4. Eastern Cooperative Oncology Group (ECOG) 0-2.

5. Able to understand and give informed consent.

6. Negative pregnancy test for females of childbearing potential.

7. 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.

8. Creatinine less than 2.0 mg/dL.

9. Absolute neutrophil count (ANC) greater than or equal to 1000/uL and platelets greater than or equal to 50,000/uL.

10. 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:

1. Prior therapy with LMB-2.

2. Central nervous system disease as evidenced by clinical symptomatology.

3. 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.

4. Uncontrolled infection.

5. Untreated or uncontrolled 2nd malignancy.

6. Patients who are pregnant or breast-feeding.

7. 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.

8. Patients receiving warfarin (Coumadin [R])

9. Patients with a left ventricular ejection fraction of less than 45%.

10. 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.

11. No concomitant use of alternative complimentary therapies or over the counter (OTC) agents allowed without prior approval of the principal investigator (PI).

12. Tumor or lymph node masses > 4 cm.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert J Kreitman, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 31, 2018
• Informed Consent Form: Eligibility Screening - Oct 15, 2018
• Informed Consent Form: Standard - Mar 17, 2021

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• 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.
• 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. Review.
• 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 Sézary 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.

• Responsible Party: Robert Kreitman, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00924170
• Other Study ID Numbers: 090025; 09-C-0025; NCT00794833
• First Posted: Jun 18, 2009
• Last Update Posted: Feb 8, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Robert Kreitman, M.D., Principal Investigator, National Cancer Institute (NCI): Immunotoxin; CD25; Immunogenicity; Neutralization; Neutralizing Antibodies; Adult T-Cell Leukemia; Leukemia; ATL
• Additional relevant MeSH terms: Leukemia; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Cyclophosphamide; Fludarabine

Study Results

Participant Flow

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Period Title: Overall Study
STARTED	10	8
COMPLETED	3	0
NOT COMPLETED	7	8

Baseline Characteristics

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients	Total
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).	Total of all reporting groups
Overall Participants	10	8	18
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 90%	8 100%	17 94.4%
>=65 years	1 10%	0 0%	1 5.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42 (14.25)	39.8 (10.77)	40.9 (12.51)
Sex: Female, Male (Count of Participants)
Female	7 70%	5 62.5%	12 66.7%
Male	3 30%	3 37.5%	6 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%	0 0%	1 5.6%
Not Hispanic or Latino	9 90%	7 87.5%	16 88.9%
Unknown or Not Reported	0 0%	1 12.5%	1 5.6%
Race/Ethnicity, Customized (Count of Participants)
African American	2 20%	2 25%	4 22.2%
Tabago, Black	1 10%	0 0%	1 5.6%
Peruvian, Hispanic	1 10%	0 0%	1 5.6%
American from Jamaica, Black	1 10%	0 0%	1 5.6%
Jamaican, Black	5 50%	2 25%	7 38.9%
Ethiopian, Black	0 0%	1 12.5%	1 5.6%
Jamaican	0 0%	0 0%	0 0%
Barbados, Black	0 0%	2 25%	2 11.1%
American, from Ghana, Black	0 0%	1 12.5%	1 5.6%
Region of Enrollment (Count of Participants)
United States	10 100%	8 100%	18 100%
Prior Treatment (Count of Participants)
CHOP	2 20%	3 37.5%	5 27.8%
EPOCH-C	0 0%	1 12.5%	1 5.6%
C, ESHAP, PTX, Gem	1 10%	0 0%	1 5.6%
Medi507, Ontak, HAT	1 10%	0 0%	1 5.6%
CHOP, C	2 20%	0 0%	2 11.1%
EPOCH-RS	1 10%	1 12.5%	2 11.1%
None	1 10%	0 0%	1 5.6%
Hydroxyurea	1 10%	1 12.5%	2 11.1%
CHOP, Hydroxyurea	1 10%	0 0%	1 5.6%
LSG-15, radiation	0 0%	1 12.5%	1 5.6%
Type of Leukemia (Count of Participants)
Acute	10 100%	3 37.5%	13 72.2%
Lymphoma	0 0%	4 50%	4 22.2%
Extravascular sites (Count of Participants)
Bone, lung, skin	0 0%	1 12.5%	1 5.6%
Thigh (skin)	0 0%	1 12.5%	1 5.6%
Pelvis	1 10%	0 0%	1 5.6%
Muscle	1 10%	0 0%	1 5.6%
Skin	1 10%	0 0%	1 5.6%
Lymph node (LN)	1 10%	2 25%	3 16.7%
Spleen, LN	2 20%	1 12.5%	3 16.7%
Subcutaneous	1 10%	1 12.5%	2 11.1%
None	1 10%	0 0%	1 5.6%
Bone, subcutaneous	0 0%	1 12.5%	1 5.6%
Spleen	2 20%	0 0%	2 11.1%
Participants with High Lactate Hydrogenase (LDH) (Count of Participants)
Yes	10 100%	7 87.5%	17 94.4%
No	0 0%	0 0%	0 0%
Participants with High Calcium++ (Count of Participants)
Yes	5 50%	2 25%	7 38.9%
No	5 50%	5 62.5%	10 55.6%
Adult T-cell Leukemia (ATL) cells/mm^3 in the Peripheral Blood (Count of Participants)
0 cells	0 0%	3 37.5%	3 16.7%
1 cell	0 0%	1 12.5%	1 5.6%
80 cells	1 10%	0 0%	1 5.6%
206 cells	1 10%	0 0%	1 5.6%
246 cells	1 10%	0 0%	1 5.6%
408 cells	1 10%	0 0%	1 5.6%
450 cells	0 0%	1 12.5%	1 5.6%
687 cells	1 10%	0 0%	1 5.6%
5,604 cells	1 10%	0 0%	1 5.6%
7,737 cells	0 0%	1 12.5%	1 5.6%
8,216 cells	1 10%	0 0%	1 5.6%
13,153 cells	1 10%	0 0%	1 5.6%
24,112 cells	1 10%	0 0%	1 5.6%
210,000 cells	1 10%	0 0%	1 5.6%
213,000 cells	0 0%	1 12.5%	1 5.6%
Maximum tumor size (Count of Participants)
<1 cm tumor	4 40%	1 12.5%	5 27.8%
1.9 cm tumor	0 0%	1 12.5%	1 5.6%
2 cm tumor	1 10%	0 0%	1 5.6%
2.2 cm tumor	0 0%	1 12.5%	1 5.6%
5.6 cm tumor	1 10%	0 0%	1 5.6%
5.8 cm tumor	0 0%	1 12.5%	1 5.6%
6 cm tumor	0 0%	1 12.5%	1 5.6%
9 cm tumor	0 0%	1 12.5%	1 5.6%
15, 2.5 cm tumor	0 0%	1 12.5%	1 5.6%
17 cm tumor	1 10%	0 0%	1 5.6%
17.5 cm tumor	1 10%	0 0%	1 5.6%
18.5, 1.7 cm tumor	1 10%	0 0%	1 5.6%
20, 1.8 cm tumor	1 10%	0 0%	1 5.6%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All 10 patients receiving LMB-2 and at least 25+250 mg/m^2 Fludarabine/Cyclophosphamide (FC) were evaluable for response. Of the 8 other patients, only 5 received LMB-2 and were therefore evaluable for response.

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Overall Response	80 800%	0 0%
Complete Response	60 600%	0 0%
Partial Response	20 200%	0 0%
Stable Disease	20 200%	25 312.5%
Progressive Disease	0 0%	37.5 468.8%
Not Evaluable	0 0%	37.5 468.8%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	5
Median (Full Range) [ng/mL]	602	484

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Median (95% Confidence Interval) [Months]	11.6	1.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC, All Other Patients
	Comments	Published response duration of 15 patients with leukemic adult T cell leukemia treated with Alemtuzumab.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Kaplan Meier
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2.

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	7
Median (95% Confidence Interval) [Months]	18.6	3.75

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Count of Participants [Participants]	10 100%	8 100%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The number 8 represents the number of responders in the Arm/Group and the number 2 represents the number of non-responders in the Arm/Group.

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Soluble CD25, lowest post-treatment (nadir) value	1094	34591
Median sCD25 Nadir for responders	1082
Median sCD25 Nadir for non-responders	70713	34591
Median sCD25 PRE-treatment for responders	31893
Median sCD25 PRE-treatment for non-responders	66419	17079

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Three participants were non-evaluable. One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2. One participant had progressive disease before first cycle of LMB2, and one participant had progressive disease after first cycle of LMB2

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	5
Median (Full Range) [µg/-min/mL]	161	144

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

One patient did not have flow cytometry measuring it.

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Normal T-cells	28	23.5
Normal CD4+ cells	99.5	186
Normal CD8+ cells	28	23.5
Normal B-cells	8	0.5

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Three participants were non-evaluable. One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2. One participant had progressive disease before first cycle of LMB2, and one participant had progressive disease after first cycle of LMB2

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	4
Number (95% Confidence Interval) [percentage of participants]	40 400%	0 0%

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	8
Median (95% Confidence Interval) [Weeks]	69.6	0

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Three participants were non-evaluable. One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2. One participant had progressive disease before first cycle of LMB2, and one participant had progressive disease after first cycle of LMB2

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	5
Median (Full Range) [mL/min]	109	101

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Three participants were non-evaluable. One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2. One participant had progressive disease before first cycle of LMB2, and one participant had progressive disease after first cycle of LMB2

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	5
Median (Full Range) [Liters]	49.6	26.6

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Three participants were non-evaluable. One participant withdrew due to inability to receive second cycle, which was the first cycle containing LMB-2. One participant had progressive disease before first cycle of LMB2, and one participant had progressive disease after first cycle of LMB2

Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC	All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.	Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
Measure Participants	10	5
Median (Full Range) [min]	360	251

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data for this outcome measure is reported as in the publication noted in the References module.

Arm/Group Title	Fludarabine and Cyclophosphamide: 20 + 200mg/m^2	Fludarabine and Cyclophosphamide: 25 + 250mg/m^2	Fludarabine and Cyclophosphamide: 30 + 300mg/m^2
Arm/Group Description	Patients CF15, CF16, and CF17. Patient CF15 did not receive LMB-2, others received 40 µg/kg.	All other patients, including CF18 and CF01 who did not receive LMB2. Patients CF02 and CF03 and CF04 received LMB-2 30 µg/kg, others 40 µg/kg.	Patients CF08 and CF09, both received LMB-2 40 µg/kg
Measure Participants	3	12	2
Neutropenia	2 20%	10 125%	2 11.1%
Nausea/vomiting/anorexia	2 20%	10 125%	2 11.1%
Fever/chills	1 10%	10 125%	1 5.6%
Leukopenia/lymphopenia	1 10%	9 112.5%	2 11.1%
Transaminases	3 30%	8 100%	1 5.6%
Hypotension/tachycardia	1 10%	8 100%	2 11.1%
Thrombocytopenia	1 10%	8 100%	2 11.1%
Anemia	0 0%	9 112.5%	1 5.6%
Myalgia/headache	2 20%	7 87.5%	2 11.1%
Hypoalbuminemia	2 20%	6 75%	1 5.6%
Hematuria	1 10%	5 62.5%	1 5.6%
Proteinuria	0 0%	7 87.5%	0 0%
Fatigue/dizziness	1 10%	4 50%	2 11.1%
Edema	0 0%	6 75%	0 0%
Abdominal pain	0 0%	5 62.5%	0 0%
Diarrhea	1 10%	3 37.5%	0 0%
Creatine phosphokinase (CPK)	0 0%	4 50%	0 0%
Mucositis	0 0%	3 37.5%	1 5.6%
Hypomagnesemia	0 0%	3 37.5%	0 0%
Bilirubin	1 10%	2 25%	0 0%
Alkaline phosphatase/gamma-glutamyl transferase	0 0%	3 37.5%	0 0%
Pneumonitis	0 0%	3 37.5%	0 0%
Low cluster of differentiation 4 (CD4) count	1 10%	1 12.5%	1 5.6%
Lipase	0 0%	3 37.5%	0 0%
Bladder infection	0 0%	2 25%	0 0%
Dyspnea	0 0%	2 25%	0 0%
Prothrombin time	1 10%	1 12.5%	0 0%
Pruritis	1 10%	0 0%	1 5.6%

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

*Grade 5 (death) event. Data for this outcome measure is reported as in the publication noted in the References module.

Arm/Group Title	Fludarabine and Cyclophosphamide: 20 + 200mg/m^2	Fludarabine and Cyclophosphamide: 25 + 250mg/m^2	3Fludarabine and Cyclophosphamide: 0 + 300mg/m^2
Arm/Group Description	Patients CF15, CF16, and CF17. Patient CF15 did not receive LMB-2, others received 40 µg/kg	All other patients, including CF18 and CF01 who did not receive LMB2. Patients CF02 and CF03 and CF04 received LMB-2 30 µg/kg, others 40 µg/kg	Patients CF08 and CF09, both received LMB-2 40 µg/kg
Measure Participants	3	12	2
Neutropenia	1 10%	9 112.5%	2 11.1%
Leukopenia/lymphopenia	1 10%	9 112.5%	2 11.1%
Anemia	0 0%	8 100%	0 0%
Transaminases	1 10%	4 50%	0 0%
Thrombocytopenia	0 0%	5 62.5%	1 5.6%
Fever/chills	0 0%	3 37.5%	1 5.6%
Pneumonitis	0 0%	3 37.5%	0 0%
Low cluster of differentiation 4 (CD4) count	1 10%	1 12.5%	1 5.6%
Hypotension/tachycardia	0 0%	2 25%	0 0%
Rectal hemorrhage	0 0%	1 12.5%	0 0%
Bilirubin	0 0%	1 12.5%	0 0%
Dysuria	0 0%	1 12.5%	0 0%
Bladder infection	0 0%	1 12.5%	0 0%
Hypoxia	0 0%	1 12.5%	0 0%
Proteinuria	0 0%	1 12.5%	0 0%
Sepsis*	0 0%	1 12.5%	0 0%

Adverse Events

Time Frame	7 years and 12 days
Arm/Group Title	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC		All Other Patients
Arm/Group Description	Leukemic patients receiving LMB-2 and at least 25+250 mg/m^2 fludarabine and cyclophosphamide; CF03-CF05, CF07-CF10, and CF12-CF14.		Patients CF01-CF02, CF06, CF11, and CF15-CF18. This is a mixture of patients who did not receive LMB-2, who had lymphoma-type adult T-cell leukemia, and who received 20+250 mg/m^2 of fludarabine cyclophosphamide (FC).
All Cause Mortality
	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC		All Other Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		6/8 (75%)
Serious Adverse Events
	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC		All Other Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/10 (70%)		6/8 (75%)
Cardiac disorders
Cardiac arrest	1/10 (10%)	1	0/8 (0%)	0
General disorders
Edema limbs	1/10 (10%)	1	0/8 (0%)	0
Death related to disease	7/10 (70%)	7	6/8 (75%)	6
Infections and infestations
Lung infection	1/10 (10%)	1	0/8 (0%)	0
Sepsis	1/10 (10%)	1	0/8 (0%)	0
Injury, poisoning and procedural complications
Fall	1/10 (10%)	1	0/8 (0%)	0
Metabolism and nutrition disorders
Acidosis	1/10 (10%)	1	0/8 (0%)	0
Dehydration	1/10 (10%)	1	0/8 (0%)	0
Hypercalcemia	1/10 (10%)	1	0/8 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/10 (0%)	0	1/8 (12.5%)	1
Nervous system disorders
Depressed level of consciousness	2/10 (20%)	2	0/8 (0%)	0
Dizziness	1/10 (10%)	1	0/8 (0%)	0
Presyncope	1/10 (10%)	1	0/8 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/10 (10%)	1	0/8 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/10 (20%)	2	0/8 (0%)	0
Hypoxia	1/10 (10%)	1	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC		All Other Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Anemia	8/10 (80%)	108	5/8 (62.5%)	16
Blood and lymphatic system disorders - Other,Prothrombin time prolonged	0/10 (0%)	0	1/8 (12.5%)	1
Febrile neutropenia	3/10 (30%)	6	1/8 (12.5%)	1
Cardiac disorders
Electrocardiogram QT corrected interval prolonged	2/10 (20%)	3	1/8 (12.5%)	1
Sinus tachycardia	4/10 (40%)	6	2/8 (25%)	2
Ear and labyrinth disorders
Ear pain	0/10 (0%)	0	1/8 (12.5%)	1
External ear inflammation	0/10 (0%)	0	1/8 (12.5%)	1
Endocrine disorders
Hypothyroidism	1/10 (10%)	1	0/8 (0%)	0
Eye disorders
Blurred vision	2/10 (20%)	2	0/8 (0%)	0
Conjunctivitis	2/10 (20%)	3	1/8 (12.5%)	1
Dry eye	2/10 (20%)	2	1/8 (12.5%)	1
Eye pain	1/10 (10%)	1	0/8 (0%)	0
Floaters	1/10 (10%)	1	0/8 (0%)	0
Papilledema	1/10 (10%)	1	0/8 (0%)	0
Uveitis	1/10 (10%)	1	0/8 (0%)	0
Gastrointestinal disorders
Abdominal pain	5/10 (50%)	7	3/8 (37.5%)	4
Bloating	0/10 (0%)	0	1/8 (12.5%)	1
Constipation	4/10 (40%)	6	2/8 (25%)	3
Diarrhea	5/10 (50%)	10	1/8 (12.5%)	1
Dyspepsia	2/10 (20%)	2	0/8 (0%)	0
Dysphagia	0/10 (0%)	0	1/8 (12.5%)	1
Mucositis oral	3/10 (30%)	3	0/8 (0%)	0
Nausea	8/10 (80%)	23	6/8 (75%)	10
Oral pain	1/10 (10%)	1	1/8 (12.5%)	1
Rectal hemorrhage	1/10 (10%)	1	0/8 (0%)	0
Vomiting	6/10 (60%)	17	3/8 (37.5%)	6
General disorders
Chills	5/10 (50%)	10	1/8 (12.5%)	1
Edema face	4/10 (40%)	8	0/8 (0%)	0
Edema limbs	7/10 (70%)	12	1/8 (12.5%)	1
Fatigue	5/10 (50%)	7	1/8 (12.5%)	1
Fever	10/10 (100%)	23	7/8 (87.5%)	7
Gait disturbance	1/10 (10%)	1	0/8 (0%)	0
Pain	0/10 (0%)	0	1/8 (12.5%)	3
Immune system disorders
Allergic reaction	1/10 (10%)	1	0/8 (0%)	0
Infections and infestations
Catheter related infection	1/10 (10%)	1	0/8 (0%)	0
Infections and infestations - Other, CMV reaction	2/10 (20%)	2	0/8 (0%)	0
Lung infection	2/10 (20%)	2	0/8 (0%)	0
Mucosal infection	4/10 (40%)	4	0/8 (0%)	0
Rhinitis infective	1/10 (10%)	1	0/8 (0%)	0
Sepsis	1/10 (10%)	1	0/8 (0%)	0
Sinusitis	3/10 (30%)	3	0/8 (0%)	0
Skin infection	1/10 (10%)	2	0/8 (0%)	0
Tooth infection	1/10 (10%)	1	0/8 (0%)	0
Urinary tract infection	3/10 (30%)	7	0/8 (0%)	0
Infections and Infestations - Other, Bladder	0/10 (0%)	0	1/8 (12.5%)	1
Infections and infestations - Other, tooth infection	1/10 (10%)	1	0/8 (0%)	0
Injury, poisoning and procedural complications
Vascular access complication	1/10 (10%)	1	1/8 (12.5%)	1
Wound dehiscence	1/10 (10%)	1	5/8 (62.5%)	22
Investigations
Activated partial thromboplastin time prolonged	1/10 (10%)	2	0/8 (0%)	0
Alanine aminotransferase increased	5/10 (50%)	20	2/8 (25%)	2
Alkaline phosphatase increased	7/10 (70%)	9	3/8 (37.5%)	4
Aspartate aminotransferase increased	7/10 (70%)	44	5/8 (62.5%)	7
Blood bilirubin increased	5/10 (50%)	10	3/8 (37.5%)	3
CD4 lymphocytes decreased	2/10 (20%)	6	1/8 (12.5%)	2
CPK increased	5/10 (50%)	6	3/8 (37.5%)	4
Carbon monoxide diffusing capacity decreased	1/10 (10%)	1	0/8 (0%)	0
Cardiac troponin I increased	1/10 (10%)	1	0/8 (0%)	0
Creatinine increased	0/10 (0%)	0	2/8 (25%)	2
Fibrinogen decreased	2/10 (20%)	3	0/8 (0%)	0
GGT increased	4/10 (40%)	5	1/8 (12.5%)	1
Haptoglobin decreased	2/10 (20%)	2	1/8 (12.5%)	1
Hemoglobin increased	1/10 (10%)	1	0/8 (0%)	0
INR increased	1/10 (10%)	1	0/8 (0%)	0
Investigations - Other, Bicarbonate, low; Bicarbonate, serum-low	1/10 (10%)	3	0/8 (0%)	0
Lipase increased	2/10 (20%)	2	3/8 (37.5%)	3
Lymphocyte count decreased	9/10 (90%)	136	5/8 (62.5%)	22
Neutrophil count decreased	9/10 (90%)	83	5/8 (62.5%)	23
Platelet count decreased	10/10 (100%)	100	4/8 (50%)	6
Serum amylase increased	4/10 (40%)	5	2/8 (25%)	2
Weight gain	2/10 (20%)	2	0/8 (0%)	0
White blood cell decreased	8/10 (80%)	155	0/8 (0%)	0
Metabolism and nutrition disorders
Anorexia	5/10 (50%)	6	2/8 (25%)	2
Dehydration	0/10 (0%)	0	1/8 (12.5%)	1
Hypercalcemia	3/10 (30%)	9	3/8 (37.5%)	4
Hyperglycemia	2/10 (20%)	6	3/8 (37.5%)	4
Hyperkalemia	3/10 (30%)	4	1/8 (12.5%)	1
Hypermagnesemia	3/10 (30%)	5	1/8 (12.5%)	1
Hypernatremia	3/10 (30%)	9	2/8 (25%)	2
Hypertriglyceridemia	3/10 (30%)	4	0/8 (0%)	0
Hyperuricemia	2/10 (20%)	3	0/8 (0%)	0
Hypoalbuminemia	7/10 (70%)	36	5/8 (62.5%)	6
Hypocalcemia	5/10 (50%)	39	0/8 (0%)	0
Hypoglycemia	2/10 (20%)	2	2/8 (25%)	2
Hypokalemia	4/10 (40%)	52	0/8 (0%)	0
Hypomagnesemia	6/10 (60%)	22	1/8 (12.5%)	1
Hyponatremia	8/10 (80%)	33	4/8 (50%)	4
Hypophosphatemia	6/10 (60%)	24	2/8 (25%)	2
Metabolism and nutrition disorders - Other, Bicarbonate, Low	1/10 (10%)	1	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/10 (10%)	1	1/8 (12.5%)	1
Back pain	4/10 (40%)	5	2/8 (25%)	2
Bone pain	3/10 (30%)	3	0/8 (0%)	0
Buttock pain	1/10 (10%)	1	0/8 (0%)	0
Chest wall pain	4/10 (40%)	5	0/8 (0%)	0
Myalgia	8/10 (80%)	16	1/8 (12.5%)	1
Myositis	1/10 (10%)	1	0/8 (0%)	0
Neck pain	1/10 (10%)	1	0/8 (0%)	0
Non-cardiac chest pain	0/10 (0%)	0	1/8 (12.5%)	1
Pain in extremity	4/10 (40%)	12	3/8 (37.5%)	4
Nervous system disorders
Dizziness	5/10 (50%)	7	0/8 (0%)	0
Dysphasia	0/10 (0%)	0	1/8 (12.5%)	1
Encephalopathy	0/10 (0%)	0	1/8 (12.5%)	1
Headache	7/10 (70%)	16	3/8 (37.5%)	5
Memory impairment	0/10 (0%)	0	1/8 (12.5%)	1
Paresthesia	2/10 (20%)	2	0/8 (0%)	0
Presyncope	1/10 (10%)	1	0/8 (0%)	0
Seizure	1/10 (10%)	2	0/8 (0%)	0
Sinus pain	1/10 (10%)	1	0/8 (0%)	0
Somnolence	2/10 (20%)	2	0/8 (0%)	0
Syncope	1/10 (10%)	1	0/8 (0%)	0
Tremor	1/10 (10%)	1	0/8 (0%)	0
Psychiatric disorders
Agitation	1/10 (10%)	1	0/8 (0%)	0
Anxiety	1/10 (10%)	1	0/8 (0%)	0
Confusion	2/10 (20%)	3	1/8 (12.5%)	1
Depression	2/10 (20%)	2	0/8 (0%)	0
Insomnia	1/10 (10%)	1	0/8 (0%)	0
Renal and urinary disorders
Hematuria	5/10 (50%)	10	2/8 (25%)	2
Proteinuria	6/10 (60%)	7	1/8 (12.5%)	1
Urinary incontinence	1/10 (10%)	1	0/8 (0%)	0
Urinary tract pain	3/10 (30%)	3	0/8 (0%)	0
Reproductive system and breast disorders
Vaginal inflammation	1/10 (10%)	1	0/8 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/10 (20%)	2	1/8 (12.5%)	1
Cough	3/10 (30%)	3	1/8 (12.5%)	1
Dyspnea	4/10 (40%)	7	0/8 (0%)	0
Epistaxis	1/10 (10%)	1	0/8 (0%)	0
Hypoxia	2/10 (20%)	3	0/8 (0%)	0
Pharyngolaryngeal pain	3/10 (30%)	3	0/8 (0%)	0
Pleural effusion	1/10 (10%)	1	0/8 (0%)	0
Wheezing	1/10 (10%)	1	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	2/10 (20%)	2	0/8 (0%)	0
Photosensitivity	1/10 (10%)	1	0/8 (0%)	0
Pruritus	6/10 (60%)	8	2/8 (25%)	2
Rash maculo-papular	5/10 (50%)	9	0/8 (0%)	0
Skin and subcutaneous tissue disorders - Other,Dermatology/Skin: Rash	1/10 (10%)	2	0/8 (0%)	0
Skin ulceration	1/10 (10%)	1	0/8 (0%)	0
Vascular disorders
Capillary leak syndrome	1/10 (10%)	1	0/8 (0%)	0
Hot flashes	0/10 (0%)	0	1/8 (12.5%)	1
Hypertension	1/10 (10%)	3	0/8 (0%)	0
Hypotension	9/10 (90%)	15	2/8 (25%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.