Clinical trial NCT00924170
Conditions: Adult T-Cell Leukemia (ATL)
Keywords: Immunotoxin CD25 Immunogenicity Neutralization Neutralizing Antibodies Adult T-Cell Leukemia Leukemia ATL
Sponsor: National Cancer Institute (NCI)
Start date: 2008-10-31; Completion date: 2021-05-05
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: LMB-2 intervention 2: Fludarabine intervention 3: Cyclophosphamide
Intervention descriptions: intervention 1: Begin with 30 mcg/Kg intravenous (IV) on days 3, 5 and 7. Escalate to 40 mcg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6 have DLT at 40 mcg/Kg. intervention 2: Days 1-3:

Patients 1-7, 10-14, and \>18:25mg/m\^2/day Patients 8 - 9:30 mg/m\^2/day Patients 15- 17:20 mg/m\^2/day intervention 3: 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

Protocol documents:
Prot_SAP_005.pdf: 
Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
1
Abbreviated title:  LMB-2 and FC in ATL 
NIH Protocol Number: 09C0025 
Version Date: 1/31/2023
CTEP Protocol #8226 Closed with CTEP as of 06/19/2017
NCT#:  NCT00924170
Title: PHASE II TRIAL OF LMB-2, FLUDARABINE AND CYCLOPHOSPHAMIDE 
FOR ADULT T-CELL LEUKEMIA
NCI Principal Investigator 
Robert J. Kreitman, M.D. 
Laboratory of Molecular Biology (LMB)
Center for Cancer Research (CCR) 
National Cancer Institute (NCI), NIH 
9000 Rockville Pike, room 37/5124b 
Bethesda, MD  20892
Phone: 301-480-6187 
Email kreitmar@mail.nih.gov
Drug Name:
LMB-2
Fludarabine (Fludara)
Cyclophosphamide 
(Cytoxan)
IND Number:
6662 - Withdrawn 07/25/2017
Sponsor:
CTEP
Manufacturer:
NCI 
Generic
Generic
Supplier
NCI
NIH CC pharmacy
NIH CC pharmacy
Commercial Agents: None 


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
2
PRÉCIS 
Background:  

CD25 (p55, Tac or IL2Rα) is strongly expressed in virtually 100% of patients with adult 
T-cell leukemia/lymphoma (ATL), a highly aggressive 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 > 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 NCI, the MTD of LMB-2 was 40 mcg/Kg·dose IV given every other 
day for 3 doses (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.  
Objective:  

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 CAMPATH.
Eligibility:  

CD25+ ATL, untreated or with prior therapy, leukemic type without malignant masses > 
4 cm.  

ECOG 0-2, 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)
o
Patients 1-7 and 10 -14, and >18:  25 and 250 mg/m2/day
o
Patients 8 – 9:  30 and 300 mg/m2/day
o
Patients 15– 17:  20 and 200 mg/m2/day 

LMB-2 dose:  Begin with 30 mcg/Kg IV on days 3, 5 and 7.  Escalate to 40 mcg/Kg if 
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 evaluable patients, which includes 4 replacements.


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
3
TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................5
1
INTRODUCTION ...................................................................................................................5
1.1
Study Objectives..............................................................................................................5
1.2
Background......................................................................................................................5
1.3
Rationale........................................................................................................................14
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................19
2.1
Eligibility Criteria..........................................................................................................19
2.2
Screening Evaluation.....................................................................................................20
2.3
Participant Registration and Status Update Procedures.................................................21
3
STUDY IMPLEMENTATION .............................................................................................21
3.1
Study Design..................................................................................................................21
3.2
Drug Administration......................................................................................................22
3.3
Treatment Modifications ...............................................................................................24
3.4
Pharmacokinetic Studies (LMB-2 only)........................................................................26
3.5
Protocol Evaluation .......................................................................................................27
3.6
Concurrent Therapies.....................................................................................................28
3.7
Radiation Therapy Guidelines .......................................................................................28
3.8
Cost and Compensation .................................................................................................28
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria ...........................28
3.10
Post Study Evaluation (Follow-up) ...............................................................................29
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................29
4.1
Supportive Care .............................................................................................................29
4.2
Nutritional assessment and psychological support........................................................30
5
DATA COLLECTION AND EVALUATION .....................................................................30
5.1
Data Collection ..............................................................................................................30
5.2
Response Criteria...........................................................................................................31
5.3
Toxicity Criteria.............................................................................................................32
6
STATISTICAL CONSIDERATIONS ..................................................................................32
6.1
Study Design/Endpoints ................................................................................................32
6.2
Dose-escalation phase....................................................................................................32
6.3
Method for efficacy determination ................................................................................33
6.4
Immunogenicity.............................................................................................................33
6.5
Comparing PFS with Alemtuzumab study ....................................................................33
6.6
Complete Remission......................................................................................................34
6.7
Secondary objectives .....................................................................................................34
6.8
Accrual...........................................................................................................................34
7
HUMAN SUBJECTS PROTECTIONS................................................................................34
7.1
Rationale for Subject Selection .....................................................................................34
7.2
Inclusion of Women and Minorities..............................................................................34
7.3
Participation of Children................................................................................................34
7.4
Participation of Subjects Unable to Give Consent ........................................................35
7.5
Evaluation of Benefits and Risks/Discomforts..............................................................35
7.6
Alternative approaches or treatments ............................................................................35


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
4
7.7
Procedures for protecting against or minimizing any potential risks ............................35
7.8
Provisions for monitoring data collection to ensure safety of subjects .........................37
7.9
Consent and Assent Process and Documentation..........................................................37
8
CORRELATIVE STUDIES FOR RESEARCH ...................................................................37
8.1
BIOSPECIMEN COLLECTION...................................................................................37
8.2
Sample Storage, Tracking And Disposition ..................................................................38
9
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....39
9.1
Definitions .....................................................................................................................39
9.2
OHSRP Office of Compliance and Training / IRB Reporting ......................................39
9.3
NCI Clinical Director Reporting ...................................................................................39
9.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN...............................39
10
SPONSOR PROTOCOL/SAFETY REPORTING................................................................40
10.2
Expected Adverse Events ..............................................................................................45
10.3
Record Keeping .............................................................................................................45
11
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................46
11.1
Study Discontinuation and Closure ...............................................................................46
11.2
Quality Assurance and Quality Control.........................................................................46
11.3
Conflict of Interest Policy..............................................................................................46
11.4
Confidentiality and Privacy ...........................................................................................47
12
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION...............47
12.1
Immunotoxin pharmaceutical section............................................................................47
12.2
Chemotherapy pharmaceutical section..........................................................................50
12.3
Premedications (abbreviated pharmaceutical section)...................................................52
13
REFERENCES ......................................................................................................................53
14
APPENDICES .......................................................................................................................62
14.1
Appendix A: Schema & Calendar .................................................................................62
14.2
Appendix B: Performance Status Criteria .....................................................................64


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
5
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 

United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 
21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
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 CAMPATH.
1.1.2
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.
1.2
BACKGROUND 
1.2.1
Introduction to CD25  
The interleukin-2 receptor (IL2R), which binds IL2 with high affinity, is composed of a 
complex of alpha (CD25), beta (CD122) and gamma (CD132) subunits [1].  IL2 binds to 
CD25 with low (Kd ~ 10-8 M), to the complex of CD122 and CD132 with intermediate 
affinity (Kd ~ 10-9 M), and to the complex of CD25, CD122, and CD132 with high affinity 
(Kd ~ 10-11).  However, the anti-CD25 Mab anti-Tac [2-6] binds CD25 alone with high 
affinity (Kd ~10-10 M).  
1.2.2
Introduction to ATL  
ATL is an aggressive CD4+/CD25+ T-cell lymphoproliferative disorder caused by human 
T-cell lymphotropic virus type I (HTLV-I) [7, 8].  Cases are clustered in southwestern 
Japan, the Caribbean basin, northeastern South America, central Africa, and the 


Abbreviated title:  LMB-2 and FC in ATL 
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6
southeastern United States [9]. An individual infected with HTLV-1 appears to have an 
approximately 0.1 percent per year risk of developing frank ATL, a cumulative lifetime 
risk of 2 to 5 percent.  
1.2.3
Mechanism of CD25 positivity in ATL  
The HTLV-I genome contains pX, which encodes nonvirion proteins including 42-kDa 
Tax and 27-kDa rex.  Tax is a trans-activating transcription factor that activates the HTLV-I 
long terminal repeat (LTR), the expression of viral genes, and the transcription of cellular 
genes including those encoding IL-2R (CD25), IL-2, IL-3, IL-15, IL-15R, TNF, GM-
CSF, TGF-1, PTHrP, vimentin, and c-fos [10].  HTLV-I infection of T cells in vivo and in 
vitro leads to constitutive IL-2R gene expression and facilitates IL-2 expression, thereby 
leading to T-lymphocyte immortalization.  It has been proposed that in the early phases of 
ATL the HTLV-I-induced leukemogenesis may be the result of Tax expression through its 
stimulatory effects on genes involved in cellular proliferation.  Specifically, Tax expression 
may begin a process of cellular proliferation via the membrane-localized IL-2/IL-2R 
interaction with subsequent events required for frank malignancy.
1.2.4
Clinical Features of ATL 
Acute ATL usually occurs 20-30 years following perinatal infection from the mother 
infected with HTLV-I.  Clinical features include skin involvement, moderate 
lymphadenopathy with relative sparing of the mediastinum, CNS and lung involvement, 
hepatosplenomegaly, and hypercalcemia [7, 8].  Circulating ATL counts may be high 
without much anemia and with only modest involvement of the bone marrow.  Profound 
immunosuppression results in opportunistic infections including Pneumocystis carinii and 
Cryptococcus meningitis [11].  Nevertheless, ATL patients are still capable of humeral 
immunity, as evidenced by HAMA responses to murine anti-Tac [12-14] and anti-toxin 
response to LMB-2 [15].  Four categories of aggressiveness include: 1) smoldering type 
whose characteristics are 5 percent or more abnormal T lymphocytes in the peripheral 
blood in association with a normal lymphocyte level (<4 x 109/L), lack of hypercalcemia, 
lactic dehydrogenase (LDH) values no greater than 1.5 times the normal upper limit (ULN), 
and no lymphadenopathy or organ involvement other than skin and pulmonary lesions.  
Patients with ATL demonstrable on skin biopsy do not have to manifest 5 percent abnormal 
cells. 2) chronic type, absolute lymphocytosis (4 x 109/L or more) with T-cell 
lymphocytosis more than 3.5 x 109/L, LDH values up to twice the ULN, and no 
hypercalcemia or involvement of the central nervous system, bone or gastrointestinal tract 
or manifestation of associated ascites or pulmonary effusions; 3) lymphoma type, no 
lymphocytosis, 1 percent or less abnormal T cells in the circulation, in conjunction with 
histologically-proven malignant lymphadenopathy; and 4) acute type, that includes the 
remaining ATL patients who usually have leukemic manifestations and tumor lesions.
1.2.4.1
Chemotherapy treatment of ATL  
As reviewed recently [16], there is no effective treatment for ATL which significantly 
improves prognosis.  A common first-line therapy is CHOP, and CHOP alone produced a 
CR rate of 40%, median survival was only 8 months and PFS was not reported [17].  
Intensification of CHOP with VP16, vindesine, ranimustine and mitoxantrone increased 
CR rates but median survival remained low at 8-8.5 months.  A 13 month median survival 
was achieved with a highly intense regimen of VCAP (vincristine, cyclophosphamide, 


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
7
doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), and 
VECP (vindesine, etoposide, carboplatin, and prednisone), but with grade 4 hematologic 
toxicity in most patients.  The purine analog pentostatin (2 deoxycoformycin, DCF) which 
inhibits adenosine deaminase induced 3/18 PRs in a phase I trial, and 2/25 CR + 1/25 PR 
in another trial.  Pentostatin combined with chemotherapy (vincristine, doxorubicin, 
etoposide, and prednisolone) resulted in 52% of 60 patients achieving CR, but the median 
survival was only 7.4 months [18].  The topoisomerase I inhibitor CPT-11 induced 1/13 
CR and 4/13 PR in one study.  Treatment with zidovudine and interferon achieved CR/PR 
rates up to 60% and possibly higher when preceded by CHOP, but median survival 
remained < 1 year.  A zidovudine-interferon trial performed at NIH in 18 previously treated 
ATL patients showed 1 CR and 2 PRs, with median PFS < 1 month [19].  The most 
aggressive large trial of chemotherapy in ATL was a phase III trial comparing alternating 
vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, 
ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin and prednisone 
(VECP) with biweekly CHOP [20].  This trial showed that the CR+CRu rate was higher in 
the VCAP-AMP-VECP group (40%) than the CHOP group (25%, p = 0.02), with 3-year 
overall survival (OS) rates of 24 vs 13% (p = 0.086).  The probability of 1 year PFS was 
28% and 16%, and 65% of the patients were progression free at 4.6 and 4.1 months, 
respectively.  However, all patients were previously untreated and toxicity was very high 
with 98-83% grade 4 neutropenia, 32-17% grade 4 thrombocytopenia, and 32-15% grade 
3-4 infection, respectively, and 3 toxic deaths reported in the VCAP-AMP-VECP arm.  
Finally allotransplant is used for ATL with 3-year DFS of 34%, but the median PFS was 
only 9 months and 65% of the patients had a PFS of only 4.6 months.  
1.2.5
Monoclonal antibody treatment of ATL  
The murine anti-Tac (anti-CD25) Mab resulted in 2 CRs and 4 PRs in 19 patients [12, 13].  
90Y-murine anti-Tac resulted in 2 CR and 7 PRs in 18 patients [14].  In this trial, the median 
PFS was 5.5 months but at 1 month only 65% of had PFS.   Humanized anti-Tac (Zenapax, 
daclizumab) was tested in a phase I trial of 14 ATL patients, with 2 PRs, and in a phase II 
trial 0 of 9 acute/lymphoma and 2 of 7 chronic/smoldering ATL patients responded.  The 
anti-CD52 Mab Alemtuzumab (Campath-1H) has been tested in 24 ATL patients, mostly 
previously treated, on an NIH Phase II study (NCI 03-c-0194).  Of 23 evaluable, 10 (46%) 
responded but only 7 (30%) for > 2 months.  The median PFS in the first 22 patients was 
1.8 months.  Moreover 65% of these patients had a PFS of < 1 month.  NCI 03-c-0194 has 
a maximum accrual of 30 patients.  
1.2.6
Targeting CD25 in disorders other than ATL  
The naked murine Mab anti-Tac and its humanized form (daclizumab, Zenapax) were 
tested in patients with renal transplantation [21-23], and the latter was approved by the 
FDA in 1997 for prevention of renal allograft rejection [24].  90Y-anti-Tac produced 29% 
PRs and 41% CRs out of 17 patients with Hodgkin’s disease (HD) [24].  IL2 fused to either 
the first 485 or 388 amino acids of diphtheria toxin showed clinical activity in patients with 
CD25+ hematologic malignancies [25-30] and the latter agent, DAB389IL2 (Ontak, 
denileukin diftitox) was approved for use in patients with CTCL.  Denileukin diftitox 
produced 10% CRs and 20% PRs in CTCL [29, 30], 17% PRs in CLL [31], and 7% CRs 
and 18% PRs in NHL [32].  Finally, the anti-CD25 Mab RFT5 conjugated to 
deglycosylated ricin A chain (RFT5-dgA) induced 11% PRs in patients with HD [33-36].  


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
8
The dose-limiting toxicity of RFT5-dgA was vascular leak syndrome (VLS).  Denileukin 
diftitox caused less frequent and less severe VLS, with most patients (92%) having 
constitutional and gastrointestinal symptoms consisting of fever, chills, asthenia, nausea, 
vomiting, arthralgia, headache, diarrhea, and anorexia [29].  
1.2.7
Development of Pseudomonas exotoxin (PE) for targeting cells  
The full-length 613 amino acid PE protein contains three functional domains which are 
necessary for cellular intoxication [37, 38].  Domain Ia (amino acids 1-252) is the binding 
domain, domain II (amino acids 253-364) is for translocating the toxin to the cytosol and 
domain III (amino acids 400-613) contains the ADP ribosylating enzyme which inactivates 
elongation factor 2 (EF-2) in the cytosol and results in cell death.  The function of domain 
Ib (amino acids 365-399) is unknown.  A current model of how PE kills cells includes the 
following steps:  1)  The C-terminal residue (lysine-613) is removed by a carboxypeptidase 
in the plasma or culture medium [39].  2)  Domain Ia binds to the a2 macroglobulin 
receptor, present on animal cells [40].  3)  After internalization at low pH, domain II is 
proteolytically cleaved between amino acids 279 and 280 by furin [41-43].  4)  The 
disulfide bond between cysteines 265 and 287 which joins the two fragments is reduced, 
producing an N-terminal fragment of 28 kDa and a C-terminal fragment of 37 kDa.  5)  
Amino acids 609-612 (REDL) bind to an intracellular sorting receptor which transports the 
37 kDa carboxy terminal fragment from the transreticular Golgi apparatus to the 
endoplasmic reticulum [44, 45].  6)  Amino acids 280-313 mediate translocation of the 
toxin to the cytosol [46, 47].  7)  The ADP ribosylating enzyme composed of amino acids 
400-602 inactivates EF-2 [48].  PE40 is a truncated derivative of PE which is missing the 
binding domain and hence will not bind specifically to cells unless attached to an antibody 
or growth factor [37, 49].  PE38 is a truncated version of PE40 which is missing amino 
acids 365-380.  While PE40 and PE38 have similar activities [50, 51], we have preferred 
to use PE38 because it is slightly smaller and is missing a disulfide bond that impairs 
refolding the protein.  
1.2.8
Preclinical development of LMB-2  
To target IL2R+ disorders expressing CD25 regardless of the presence of other subunits of 
the IL2R, the anti-CD25 MAb anti-Tac was used as a ligand instead of IL2.  The rationale 
is based on the higher binding of CD25 alone to anti-Tac (Kd ~ 10-10 M) than to IL2 (Kd 
= 10-8 M) [4].  CD25 greatly outnumbers CD122 and CD132 on most malignant cell types 
[52, 53].  Although early studies indicated CD25 alone would not internalize anti-Tac [54], 
CD25 alone does internalize bound recombinant toxin [51, 55, 56].  A recombinant single-
chain Fv [57, 58] was constructed containing the variable heavy domain (VH) fused to the 
variable light domain (VL) via the peptide linker (G4S)3, and VL was fused to truncated 
PE [59].  The resulting recombinant immunotoxin anti-Tac(Fv)-PE40 and its slightly 
shorter derivative anti-Tac(Fv)-PE38 (called LMB-2) were selectively cytotoxic toward 
CD25+ malignant cell lines and toward leukemic cells freshly obtained from patients [51, 
56, 60-63]. Antitumor studies in mice bearing CD25+ xenografts showed complete 
regressions, and biodistribution studies showed concentration of LMB-2 into such tumors 
in vivo [56, 61].  Primary adult T cell leukemia (ATL) and hairy cell leukemia (HCL) cells 
were much more sensitive than primary CLL cells, probably due to lower CD25 expression 
in the latter.  Administration of LMB-2 to Cynomolgus monkeys at 300 mcg/Kg every 


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other day (QOD) x 3 doses caused transaminase elevations and loss of appetite, but was 
not lethal even at doses of 750 and 1000 mcg/Kg QOD x3 days [62].
1.2.9
Phase I trial of LMB-2 (NIH #96-C-0064): response and immunogenicity 
LMB-2 induced responses in patients with CD25+ chemotherapy-resistant hematologic 
malignancies, including 4 with hairy cell leukemia (1 CR, 3 PR) and one PR each with 
adult T-cell leukemia, Hodgkin's disease, chronic lymphocytic leukemia, and cutaneous T-
cell lymphoma [15].  The published results included 35 patients (age range 24-79), 11 with 
HD, 6 with B-cell lymphoma, 8 with CLL, 4 with HCL, 3 with PTCL, 1 with CTCL, and 
2 with ATL.  Of these 35 patients, 22 received 1 cycle only, 8 received 2 cycles, 2 received 
3 cycles, and 1 each received 4, 5, and 6 cycles.  Four additional patients were treated after 
publication of the phase I trial, including 1 each with ATL, HD, CTCL and NHL.  Of the 
39 patients, after a single cycle, 9 (23%) had low and 6 (15%) had high levels of 
neutralizing antibodies, and after all treatment, 8 (21%) had low and 12 (31%) had high 
levels of neutralizing antibodies.  Low and high levels of neutralizing antibodies were 
defined as > 50% neutralization of 200 ng/ml and > 75% neutralization of 1000 ng/ml of 
the cytotoxicity of LMB-2 toward CD25+ cultured cells.  Thirty-four patients were tested 
by ELISA assay after all treatment for antibodies binding to the toxin, and for antibodies 
binding to murine IgG epitopes (HAMA) [15].  Low and high levels of binding antibodies 
were defined by titers of from 1:10,000 to 1:400,000 and > 1:400,000, respectively.  Out 
of 34 patients, 10 (29%) had low and 10 (29%) had high titers of binding antibodies to 
toxin (PE38), and 4 (12%) had low and 5 (15%) had high titers of HAMA [15].  No patient 
had HAMA without binding antibodies to the toxin or without neutralizing antibodies, but 
4 patients with low titers of binding antibodies to the toxin had no neutralizing antibodies 
or HAMA.  
1.2.10 LMB-2 related toxicity  
All toxicity was reversible.  The maximum tolerated dose (MTD) was 40 mcg/Kg QOD 
x3, where the most common toxicities were transaminase elevations (92%), fever (83%), 
myalgias (58%), hypoalbuminemia (58%), nausea (42%), and weight gain (42%).  
Transaminase elevations were generally asymptomatic and always reversible.  
Hypoalbuminemia and weight gain were evidence of a form of VLS much milder than that 
described for the larger toxin chemical conjugates containing whole Mab [36, 64].  DLT 
was observed in two of three patients at the 63 mcg/Kg·dose QOD x 3 dose level.  The first 
patient (#31, with HD) had asymptomatic grade 4 AST and grade 3 ALT elevations.  The 
second patient (#32, with HCL) developed grade 3 diarrhea, grade 2 fever, nausea, and 
vomiting, and grade 4 cardiomyopathy on day 5.  The patient’s cardiac function returned 
to normal by day 7.  FACS of peripheral blood on day 9 indicated a large number of dead 
tumor cells.  We concluded that the cardiomyopathy was probably cytokine mediated rather 
than direct LMB-2 toxicity on the heart.  The 50 mcg/Kg dose level was dose limiting in 1 
of 6 patients (patient #27 with PTCL) due to an allergic reaction.
1.2.11 Pharmacokinetics of LMB-2  
For pharmacokinetic studies, dilutions of patient plasma were tested in cytotoxicity assays 
against a cell line (SP2/Tac) and compared to a cytotoxicity standard curve created with 
known amounts of LMB-2.  In 12 patients treated at the MTD (40 mcg/kg), peak plasma 
levels after cycle 1 were 340-1040 (median 560) ng/ml, the AUCs were 48-257 (median 


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123) ug-min/ml, the half-lives were 185-322 (median 216) min, and the clearances were 
14-79 (median 25) ml/min).  The median values for the 4 patients with HD were 620 ng/ml, 
AUC 155 ug-min/ml, half-life 193 min, and clearance 19 ml/min.  
1.2.12 Additional patients #36-39 on the phase I trial  
To determine if LMB-2 would be better tolerated if patients received prophylactic i.v. fluid, 
an additional 4 patients were enrolled.   Patient #36 with ATL was treated at 50 mcg/Kg 
QOD x3 and experienced a reversible but dose-limiting syndrome similar to patient #32, 
with 3rd spacing and muscle edema causing grade IV CK elevation and hypoventilation 
leading to supraventricular tachycardia and respiratory failure.  This patient had a muscle 
biopsy which ruled out necrosis or inflammation, indicating that the CK elevation was only 
from passive muscle fiber edema and stretching.  Patients #37-39 with HD, CTCL and 
NHL received 40 mcg/Kg·dose QOD x3 with prophylactic fluid, and tolerated LMB-2 
well.  
1.2.13 Phase II testing of LMB-2 in CLL and CTCL  
LMB-2 has been administered to 13 CLL patients without DLT at 40 mcg/Kg QOD. One 
patient had 6 cycles and a PR. Four additional patients had > 50% reductions in circulating 
CLL cells but did not meet criteria for PR due to limited response duration or due to lymph 
nodes which did not regress by > 50%.  However, 2 additional patients did achieve 
significant reductions in lymph nodes on LMB-2.  On a phase II HCL protocol for patients 
with prior BL22, LMB-2 produced PD in one patient and PR in another.  On a phase II 
CTCL protocol, 1 patient was enrolled at 40 mcg/kg QOD x3 who had transient grade IV 
CPK elevation as his only DLT, so the dose level was lowered for an additional 4 CTCL 
patients to 30 mcg/Kg QOD x3.  None of these patients experienced DLT.  All 5 patients 
experienced a decrease in itching or regression of skin lesions within 1-2 weeks of their 
first dose of LMB-2.  However, 4 of 5 patients developed neutralizing antibodies after the 
first 1-2 cycles of LMB-2, thus preventing cumulative major responses.   The higher rate 
of neutralizing antibodies in CTCL than CLL is attributed to the likely exposure of patients 
to Pseudomonas aeruginosa via skin infections, and the consequent development of low 
levels of neutralizing antibodies prior to treatment with LMB-2.  
1.2.14 Pilot trial of LMB-2 after FC in HD  
To determine if immune suppression with FC would prevent immunogenicity from LMB-
2, a pilot trial in HD was proposed and approved in which patients would receive FC at 30 
and 600 mg/m2 qd x4 at least 27 days prior to LMB-2.  However, after screening > 10 
patients, it was found that the true rate of CD25 positivity on the malignant cells was very 
low (< 20%), and that most CD25+ HD patients had CD25 only on the surrounding T-cells.  
Also since this trial was approved, preclinical data emerged suggesting that high 
concentration of soluble receptor in the interstitial space of the tumor is a major limiting 
step in immunotoxin efficacy [65].  These data suggested that to decrease immunogenicity 
and increase response, chemotherapy should be given with each cycle of LMB-2 rather 
than prior to all cycles.  Because of the difficulty in performing a trial in a single disease 
(HD) which has such a low rate of eligibility, the HD trial was closed prior to accruing any 
patients.  


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1.2.15 Treatment of lymphoma and CLL with FC  
Although trials of FC in ATL have not been reported, the following trials report safety and 
efficacy of FC in other hematologic malignancies:
1.2.15.1 In 1999 several small trials showed response rates of 50-74% with FC in patients with 
indolent and aggressive lymphomas and CLL [66, 67].  
1.2.15.2 In 60 untreated patients with indolent lymphoma and CLL, FC at 20 mg/m2 d1-5 and 600 
mg/m2 d1 resulted in 51% CRs and 41% PRs.  GCSF 5 mcg/Kg/day was started on day 
8 [68].  The mean CD4 count dropped from 799 to 139/ul, IgG from 1110 to 907 mg/dL, 
and IgA from 129 to 99 mg/dl.  
1.2.15.3 A 100% response rate to FC at 20 mg/m2 d1-5 and 600-1000 mg/m2 day 1 was reported 
in indolent lymphoma patients without prior chemotherapy, including 89% CRs and 11% 
PRs [69].   
1.2.15.4 In 30 patients with MCL, half of whom had >1 prior therapy, there were 30% CRs and 
33% PRs, and the CR rate was 100% in the 10 without prior chemotherapy [70].  These 
patients were treated with 3-4 week intervals of fludarabine 20-25 mg/m2 qd x3-5 and 
cyclophosphamide either 275 mg/m2 qd x3 or 500-1000 mg/m2 x1.  Although FC is 
usually administered every 4 weeks, in this trial and in others for MCL where fludarabine 
is combined with idarubicin [71], the interval of 3 was well tolerated.  
1.2.15.5 In 22 patients with recurrent indolent NHL treated with FC at 25 mg/m2 d1-3 and 300 
mg/m2 d1-3, CR and PR rates of 60 and 30% were reported [72].  
1.2.15.6 In 128 patients with CLL treated with FC at 30 and 500-300 mg/m2 on d1-3 q4-6w, the 
ORR was ≥ 80% and 38% in patients who were responsive or refractory to prior 
fludarabine [73].  The cyclophosphamide dose had to be reduced from 500-300 mg/m2 
due to cumulative myelosuppression.  
1.2.15.7 In 27 patients with indolent NHL treated with FC at 30 and 250 mg/m2 on d1-3 q4w, half 
of whom were previously untreated, 41% CRs and 13% PRs were observed, and the ORR 
was 93 vs 85% in patients without or with prior therapy [74]. In this trial, the median CD4 
and CD8 count decreased from 750 and 856 to 155 and 204/ul.  
1.2.15.8 At a slightly lower dose level, 64 patients with CLL and indolent NHL were treated with 
FC at 25 and 250 mg/m2 d1-3 q4w, with CR and PR rates 86 and 29% [75].  
1.2.15.9 To determine the effect of GM-CSF to prevent infections, 34 patients with previously 
treated indolent NHL and CLL received FC at 30 and 300 mg/m2 d1-3 q4w and were 
randomized to receive GM-CSF at 250 mcg/m2/day from day 4 to 2 days before the next 
cycle.  CR and PR rates were 26 and 52% and GM-CSF did not lower the incidence 
neutropenic infections [76].  
1.2.15.10
In 32 elderly CLL patients treated with FC at 25 mg/m2 d1-5 and 250/m2 d1-3 q4w, 
CR and PR rates were 0 and 59%, and a high incidence of infections were observed [77].  
1.2.15.11
In 11 patients with WM treated with FC at 25 mg/m2 and 250 mg/m2 d1-3 q4w x4 
cycles, a PR rate of 55% was observed and FC was found to be well tolerated [78].
1.2.15.12
Treatment of indolent NHL with oral FC.  To determine the benefit of oral FC, 12 
patients received oral FC at 40 and 300 mg/m2 d1-3 q4w x 6 cycles, and CR and PR rates 
were 66 and 0% [79].  In that trial, the CR rate was 83% for 6 with only 1 prior therapy, 
versus 50% for 6 with 2 or more prior therapies. Toxicity was mild, including neutropenia 
in 25% and grade 1-2 thrombocytopenia in only 8%.  Nausea and vomiting were 


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controlled.  In a larger study, 25 elderly patients with untreated indolent NHL were treated 
with oral FC at 25 and 150 mg/m2 d1-4 q4w, resulting in 40% CRs and 44% PRs [80].  
The bioavailability of oral Fludarabine and Cyclophosphamide is approximately 55% 
[81] and 85% [82].
1.2.15.13
Treatment of T-cell malignancies with FC.  Patient with T-cell lymphomas are 
responsive to Fludarabine but there are few trials of FC in such patients.  In a study of 12 
patients with CTCL treated with FC at 18 and 250 mg/m2 d1-3 q4w, 5 of 6 who tolerated 
3 cycles responded, with 1 CR and 4 PRs [83].  In a case report, a patient with PTCL 
resistant to CHOP and ESHAP had a 14-month CR to FC at 20 mg/m2 d1-5 and 600 
mg/m2 d1, given for just 1 cycle [84].
1.2.15.14
Doses of FC used in FCR trials.  More recently, FCR has been used for B-cell 
lymphomas and CLL, and the most common dose of FC was 25 + 250/m2 qd x3.  177 
pretreated patients with CLL were treated with FCR at 25 mg/m2 day 2-4, 250 mg/m2 d2-
4, and 375 mg/m2 d1 of cycle 1 followed every 4 weeks by cycles 2-6 of the same doses 
given d1-3, d1-3 and d1 [85].  224 patients with previously untreated CLL were treated 
with FCR at 25-30 mg/m2 day 2-4, 250-300 mg/m2 d2-4, and 375 mg/m2 d1 of cycle 1 
followed every 4 weeks by cycles 2-6 of the same doses given d1-3, d1-3 and d1 [86].  76 
patients with CLL, FL and other lymphoid malignancies received a median of 4 cycles of 
FCR at 25 mg/m2 day 1-3, 250 mg/m2 day 1-3, and 375 mg/m2 day 1 [87].
1.2.16 Immunogenicity of Mabs and immunotoxins  
1.2.16.1 Human anti-murine antibodies (HAMA).  Although now essentially circumvented by 
humanized and murine-human chimeric antibodies, HAMA was a major issue preventing 
effective use of murine Mabs for cancer detection and treatment.  For example 100% of 
24 patients with colon cancer treated with the radiolabeled murine anti-TAG-72 Mab I-
131-CC49 had HAMA within 4 weeks of treatment [88].  Using the murine Mab T101 
Mab, 100% of 4 CTCL and 0% of 4 CLL patients made HAMA, indicating that the 
hypogammaglobulinemia associated with CLL prevented HAMA [89].  
1.2.16.2 Immunogenicity of immunotoxins.  Conventional immunotoxins composed of whole 
murine Mabs connected to toxins, like anti-B4-Blocked ricin, exhibited humoral 
immunity against the antibody or toxin, or both . [90].  High rates (75%) of antibodies 
were observed with immunotoxins in metastatic colon cancer [91] and lower rates were 
observed in B-cell lymphoma [92].  In the conventional immunotoxin LMB-1, containing 
whole anti-LeY murine Mab connected to truncated Pseudomonas exotoxin, one cycle of 
therapy led to high levels of neutralizing antibodies in 91% of patients [93].  HAMA 
could be reduced or eliminated by using recombinant immunotoxins, which contain only 
the Fv domain of the Mab.  However, the toxin is still immunogenic.  The recombinant 
immunotoxin SS1P, containing the anti-mesothelin Fv fused to truncated Pseudomonas 
exotoxin, induced neutralizing antibodies in 88% of patients after 1 cycle [94].  


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1.2.16.3 Immunogenicity of LMB-2.  As mentioned in section 1.2.9, of the 39 patients treated on 
the phase I trial of LMB-2, after a single cycle, 9 (23%) had low and 6 (15%) had high 
levels of neutralizing antibodies, and after all treatment, 8 (21%) had low and 12 (31%) 
had high levels of neutralizing antibodies.  Low and high levels of neutralizing antibodies 
were defined as > 50% neutralization of 200 ng/ml and > 75% neutralization of 1000 
ng/ml of the cytotoxicity of LMB-2 toward CD25+ cultured cells.  Thirty-four patients 
were tested by ELISA assay after all treatment for antibodies binding to PE38, and for 
antibodies binding to murine IgG epitopes (HAMA) [15].  Low and high levels of binding 
antibodies were defined by titers of from 1:10,000 to 1:400,000 and > 1:400,000, 
respectively.  Out of 34 patients, 10 (29%) had low and 10 (29%) had high titers of 
binding antibodies to PE38, and 4 (12%) had low and 5 (15%) had high titers of HAMA 
[15].  No patient had HAMA without binding antibodies to PE38 or without neutralizing 
antibodies, but 4 patients with low titers of binding antibodies to PE38 had no neutralizing 
antibodies or HAMA.  On the phase II CTCL trial, 4 (80%) of 5 patients made high levels 
of neutralizing antibodies after 1 cycle.  On the phase II CLL trial, only 2 (15%) of 13 
patients made high levels of neutralizing antibodies, each after 6 cycles.  On the phase II 
HCL trial, 1 (50%) of 2 patients have made low levels of neutralizing antibodies after 2 
cycles.  
1.2.17 Reducing humoral immunity with chemotherapy and other agents  
1.2.17.1 Cyclosporine A.  Patients receiving a radiolabeled anti-CEA Mab received cyclosporine 
A to prevent HAMA.  Although HAMA was not eliminated, it was lessened in severity 
so that more Mab could be given [95].  In another study, cyclosporine given to 13 patients 
treated with murine antibody fragments was associated with HAMA in 62%, vs 86% in 
patients not receiving cyclosporine [96].  However, the cyclosporine was complicated by 
hyperbilirubinemia, renal insufficiency, and hypertension.
1.2.17.2 15-deoxyspergualin is an agent which was shown to prevent HAMA in preclinical models, 
and was found in mouse studies to prevent neutralizing antibodies to PE and LMB-1 [97].  
However, later experiments in monkeys showed no prevention of immunogenicity.
1.2.17.3 Cyclophosphamide.  It was recently reported that in patients receiving the anti-
neuroblastoma murine Mab 3F8 after chemotherapy, HAMA incidence was lower if 
patients received high dose cyclophosphamide prior to 3F8 (p < 0.001) [98].  It was found 
that HAMA was least likely if 3F8 followed cyclophosphamide by < 90 days.  In this 
study, high dose cyclophosphamide was given at > 4000 mg/m2 or > 140 mg/Kg per 
cycle.  
1.2.17.4 Fludarabine.  In a trial of the anti-CD20 murine radiolabeled Mab Tositumomab 
following fludarabine for untreated FL, it was found that only 2 (6%) of 35 patients 
developed HAMA [99].  By comparison, 65% of untreated FL patients got HAMA from 
Tositumomab when fludarabine was not used.  The dose of fludarabine used in this study 
was 25 mg/m2 qd x5, and was given only once, 5 weeks before the tositumomab.  
1.2.17.5 Rituximab.  The anti-CD20 human-murine chimeric Mab Rituximab effectively depletes 
normal B-cells [100], raising the possibility that it could be used to blunt humoral 
immunity from immunotoxins.  A prospective trial was done to determine if Rituximab 
could block the immunogenicity of LMB-1, and it was found that it could not [101].  
However, it is possible that Ritixumab could decrease the risk of immunogenicity of 
LMB-2, which is smaller and less immunogenic than LMB-1.  


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1.2.17.6 Treatment with higher-dose FC specifically to decrease immunity.  Breast cancer patients 
have been treated with 1-2 cycles of fludarabine 30 mg/m2 and cyclophosphamide 600 
mg/m2, each qd x4 as part of induction therapy for stem cell transplantation (SCT) [102, 
103].  By day 17 after induction, not only did the median CD4+ lymphocyte count drop 
from 452 to 41/ul, but the CD8+ lymphocyte count dropped from 259 to 47/ul, and B-
cells dropped from 153 to only 1/ul.  CD4 counts of 
< 50/ul were achieved in 13 of 17 breast cancer patients after 1 cycle.   
1.3
RATIONALE
1.3.1
Choice of ATL as a disease model to test LMB2 + chemotherapy  
This protocol tests a 2-pronged approach to improve the activity of LMB-2 toward CD25+ 
malignancies.  First, the FC regimen is known to reduce both T- and B-cell numbers which 
may decrease immunogenicity.  In fact, even patients with prior exposure and a low-level 
of antibodies to PE may not produce a secondary immune response after FC.  Second, 
LMB-2 has difficulty reaching tightly packed tumor cells and may work better when the 
tumor cells are disrupted with chemotherapy, decreasing local tumor concentrations of 
sCD25.  ATL is an excellent model to test this hypothesis, first because of extremely high 
and essentially universal sensitivity of ATL cells to LMB-2 and similar recombinant 
immunotoxins targeting CD25 [51, 63, 104-107].  Second, all of the 3 phase I ATL patients 
responded with rapid > 90% reductions in tumor burden during the first cycle of LMB-2, 
but major response was limited to only 1 PR due to rapid regrowth of tumor.  Third, many 
patients with ATL have solid tumor masses, and high local concentrations of sCD25 could 
be a limiting factor preventing optimum response, and could be prevented by FC prior to 
LMB-2.  This hypothesis is based on published animal data showing soluble mesothelin 
levels in tumor interstitium 10-fold higher than serum soluble mesothelin levels, and 
synergism between chemotherapy and anti-mesothelin recombinant immunotoxins SS1P 
[65].  Moreover, unpublished animal data show soluble CD22 levels 100-fold higher in 
tumors than in serum, as well as synergism between chemotherapy and BL22.  Fourth, 
ATL patients are known to have the highest concentrations of sCD25 in the blood [108], 
which would prevent LMB-2 from reaching tumor cells, and tumor burden with sCD25 
could be at least transiently reduced with FC prior to LMB-2.  Because of its small size (45 
kDa) and short half-life [108], rapid reductions in tumor burden should result in rapid 
clearing of sCD25.  Fifth, 2 out of 3 phase I patients with ATL produced either low or high 
levels of neutralizing antibodies to 1-2 cycles of LMB-2, suggesting that preventing the 
immunogenicity of LMB-2 with FC could improve response.  Finally, we have reported 
that the related anti-CD22 recombinant immunotoxin BL22 can induce CR in a high 
percentage of patients with chemoresistant hairy cell leukemia (HCL) [109, 110], and 
CD25 expression on ATL is similar to CD22 expression on HCL.  LMB-2 could actually 
be more effective for ATL than BL22 is for HCL, if the problems of sCD25, rapid tumor 
progression, and immunogenicity could be eliminated by FC pretreatment.  This is because 
while HCL cells in some patients could originate from CD22 negative clones, the 
clonogenic ATL cells are clearly CD25 positive.  Also, ATL is a disease which lacks 
effective standard therapy with median survivals of only 4 months for acute and 9 months 
for lymphomatous subtypes.  Innovative approaches in this disease are clearly needed.


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1.3.2
Frequency of administration of LMB-2  
An important goal of this trial is to administer multiple cycles of LMB-2, since phase I-II 
data indicate suboptimal response with 1 cycle, and testing prevention of immunogenicity 
requires repeated dosing.  For many tumors which responded at 7 days but progressed by 
28 days, retreatment intervals as short as 3 weeks would be better. This should be well 
tolerated given the rapid reversibility of LMB-2 toxicity.  The LMB-2 phase I protocol was 
amended to deliver LMB-2 at 2 week intervals to patients with ATL, although the trial was 
completed before additional ATL patients were enrolled.  
1.3.3
Rationale of choice of FC regimen  
Based on the clinical efficacy of chemotherapy to prevent immunogenicity (section 1.2.17), 
and the known ability of FC to reduce normal T- and B-cells, we believe the FC 
combination is best to use for prevention of immunogenicity and for decreasing tumor 
burden/sCD25 prior to LMB-2.  There is extensive experience, reviewed above, in using 
FC for B-cell malignancies and the doses chosen, 25 + 250 mg/m2 qd x3, are at the low 
end of those tested.   Although FC is usually given at 4 week intervals, it has been observed 
at NIH that ATL rapidly progresses between cycles if spaced at 4 weeks, even if using 
dose-intense regimens like F-EPOCH.  High dose FC (30 + 600 mg/m2 qd x4) as used at 
NIH [102, 103] is excellent at decreasing T- and B-cells (see section 1.2.17.6), and has 
been well tolerated in breast cancer patients given every 3 weeks for up to 3 cycles.  We 
believe that this regimen would be too toxic in patients with prior chemotherapy for ATL, 
and it could not be administered 6 times.  Even though FC should cause T-cell depression 
lasting much longer than a month [111], the potential antitumor benefit of FC would need 
to be renewed as frequently as possible.  Therefore, we have selected FC at 25 + 250 mg/m2 
for 6 cycles every 3 weeks.  It was found by the NCI MOB transplant group that 
cyclophosphamide dosage was most critical for immune depletion.  The FC combination 
of 30 + 350/m2 qd x3 was used in a trial of 128 patients with CLL pretreated with 
fludarabine (see 1.2.15.6) [73], and although it was more toxic than 30 + 300/m2, FC at 25 
+ 350 mg/m2 may be well tolerated in ATL patients.  
1.3.4
Combined therapy with LMB-2 and chemotherapy 
Combined therapy with LMB-2 and chemotherapy could be synergistic in patients due to 
several mechanisms.  First, high pressures inside the tumor could be liberated by 
chemotherapy.  However, a much more relevant problem may be soluble receptor which 
can reach very high interstitial concentrations within the tumor and present a block to the 
movement of recombinant immunotoxin toward the tumor cell.  This hypothesis is based 
on experiments analyzing soluble mesothelin in the extracellular space of tumors [65].  
Unpublished experiments have already documented the same problem in the targeting of 
BL22 to CD22+ solid tumors in mice.  The experiments indicate that synergism between 
chemotherapy and immunotoxins in vivo could be related to tumor disruption by 
chemotherapy, releasing the high concentration of extracellular antigen, and rendering the 
tumor cells more susceptible to immunotoxins.
1.3.5
Antitumor activity in LMB-2 patients  
As shown in Table 1.A, Table 1.B and Table 1.C, a total of 34 patients had some evidence 
of antitumor activity by LMB-2 including 24 patients who failed to achieve a major 
response.  These 34 patients include 21 (64%) of the 39 on the phase I trial, 7 (54%) of the 


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13 on the phase II CLL trial, all 5 on the CTCL trial, and 1 of 2 on the phase II HCL trial.  
These 3 phase II trials test LMB-2 alone and are still open.  The CLL trial is nearing 
completion with only 4 of 17 slots remaining, the CTCL trial is accruing slowly due to 
competing trials, and the HCL trial is limited mainly to patients who have experienced 
HUS with BL22.  The reasons for treatment failure in patients without major response 
might include problems with tumor penetration due to hydrostatic pressure and high 
interstitial sCD25.  Immunogenicity is a limiting factor in all 3 trials, particularly the CTCL 
trial where it has limited retreatment in nearly all patients.  Two patients, L216 and L219, 
each had PD after having transient tumor reduction, and also had low levels of neutralizing 
antibodies.  Combined treatment with LMB-2 after FC may address both of these problems.  
In addition to these 34 patients who might have benefited by pretreatment with FC, one 
patient on the phase II HCL trial (HC01) had PD despite high sensitivity ex vivo of his 
HCL cells to LMB-2 (IC50 = 3.6 ng/ml).  This patient had a sCD25 level of 235 ng/ml in 
the serum prior to LMB-2, which likely prevented response.  Thus if FC can decrease both 
tumor burden, sCD25, and immunogenicity, it could have beneficially affected the majority 
(58%) of the 59 patients previously treated with LMB-2 on 4 protocols.  Therefore, our 
hypothesis is that FC at 25 and 250 mg/m2 will decrease the immunogenicity of LMB-2 
and prolong its antitumor activity based on in vivo experiments in a related system [65].  If 
so, current trials administering LMB-2 alone could be closed and chemotherapy could be 
made a component of LMB-2 treatment of diseases other than ATL in future trials.  
1.3.6
Eligibility for Acute and Chronic ATL  
As noted above in 1.2.4, ATL has been described with 4 prognostic subtypes, and only the 
smoldering subtype, is somewhat favorable [17, 112, 113].  The chronic subtype, featuring 
malignant lymphocytosis over 3.5 x 109/L or LDH between 1.5 and 2.0-fold elevated but 
not hypercalcemia, still has a median survival of only 24 months for Japanese and 21 
months for Caribbean patients with ATL.  Thus, the chronic subtype of ATL, though less 
severe than the acute subtype, would still clearly be appropriate for testing with FC/LMB2.  
Patients with smoldering ATL with symptomatic skin lesions often progress to acute ATL. 
These patients even before progression are similar to those with cutaneous T-cell 
lymphoma, and are appropriate candidates for trials with monoclonal antibody, 
immunotoxin, and/or chemotherapy.


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
17
Table 1.A:  Antitumor activity in LMB-2 patients who had major response:
Pt#
Dx
Dose
Best
Dura
Tumor
% Neut-
Immuno-
mcg/
resp-
-tion
location 
ralization
genicity
Kgx3 onse
(mo)
200ng/ml
limiting?
L215
HCL
30
PR
2
Blood
100% after C1
Yes
L217
CTCL 30,40 PR
7
Blood, erythroderma
100% after C6 Yes*
L226
CLL
50
PR
10
Blood, nodes
3% after C3
No
L230
HCL
63
CR
89
Spleen, nodes, blood
16% after C2 
No
L232
HCL
63
PR
1
Blood
7% after C1 
No
L233
HD
40
PR
2
Abdominal mass
0% after C1 
No
L234
ATL
40
PR
13
Spleen, blood
100% after C2 Yes*
L235
HCL
40
PR
40
Blood
100% after C2 Yes*
CL03 CLL
40
PR
4
Blood
100% after C6 Yes*
HC02 HCL
40
PR
10
Blood
76% after C3 
Yes
Patients numbers begin with L2 (phase I trial), CL (phase II CLL trial), and HC (phase II HCL 
trial).  Duration indicates duration of major response.
Table 1.B:  Antitumor activity in LMB-2 patients who had minor response:
Pt#
Dx
Dose
Best   
Activity
% Neut-
Immuno-
mcg/
resp-
and/or tumor
ralization
genicity
Kgx3 onse
location
200ng/ml
limiting?
L206
MCL
6
MR
Pulmonary mass
2% after C1 
No
L213
HD
30
MR
Abdominal mass
99% after C2 
Yes*
L218
CLL
40
MR
Lymph nodes, spleen
0% after C1 
No
L229
HD
50
MR
Pulmonary mass
100% after C1 
Yes*
CL04 CLL
40
MR
Neck nodes
6% after C2 
No
CL07 CLL
40
MR
Neck nodes
12% after C2 
No
CL09 CLL
40,30 MR
Blood and nodes
100% after C6 
Yes*
CT02 CTCL 30
MR
Improved skin, pruritis
100% after C2 
Yes*
CT04 CTCL 30
MR
Skin lesions
100% after C2 
Yes*
Patients numbers begin with L2 (phase I trial), CL (phase II CLL trial), and CT (phase II CTCL 
trial).


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
18
Table 1.C:  Antitumor activity in LMB-2 patients with only transient response:
Pt#
Dx
Dose
Best
Activity
% Neut-
Immuno-
mcg/
resp-
and/or tumor
ralization
genicity
Kgx3 onse
location
200ng/ml
limiting?
L207
CLL
10
SD
↓ Spleen, CLL count
2% after C5 
No
L216
ALCL 30
PD
↓ Cutaneous nodules
92% after C1 
Yes
L219
LBCL 40
PD
↓ Cutaneous mass
65% after C1 
Yes
L220
PTCL 40
SD
↓ Skin lesions
74% after C1 
Yes
L224
ATL
50
PD
> 90% ↓ ATL cells
1% after C1 
No
L225
CLL
50
SD
↓ CLL count
0% after C1 
No
L231
HD
63
SD
↓ Neck mass
100% after C1 
Yes*
L236
ATL
50
SD
> 90% ↓ leg mass
68% after C1 
Yes
L238
CTCL 40
SD
↓ Skin lesions
100% after C2 
Yes*
CL06 CLL
40
SD
↓ CLL count
1% after C6 
No
CL11 CLL
40
SD
↓ CLL count
22% after C6 
No
CL12 CLL
40
SD
↓ CLL count
45% after C1 
Yes
CT01 CTCL 40
SD
↓ Itching/pain
3% after C1 
No
CT03 CTCL 30
SD
Improved skin
100% after C1 
Yes*
CT05 CTCL 30
SD
↓ Skin pain
100% after C1 
Yes*
The first 2 characters of the patient number are L2 for the Phase I trial, CL for the phase II trial in CLL, CT for the 
phase II trial in CTCL, and HC for the phase II trial in HCL. Diagnoses (Dx) include mantle cell lymphoma (MCL), 
chronic lymphocytic leukemia (CLL), Hodgkin’s disease (HD), hairy cell leukemia (HCL), anaplastic large cell 
lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), large B-cell lymphoma (LBCL), peripheral T-cell 
lymphoma (PTCL), and adult T-cell leukemia (ATL).  Response abbreviations include complete remission (CR), 
partial response (PR), and marginal response (MR).  Patients are coded for MR based on LMB-2 Phase I trial criteria, 
although later trials did not use MR.  Percentages of neutralizing activity indicate the percent neutralization by serum 
of 200 ng/ml of LMB-2 against SP2/Tac cells, after the indicated cycle number.  Yes* indicates which patients had > 
75% neutralization of 1000 ng/ml of LMB-2, the criteria for ineligibility for retreatment.
1.3.7
Immunogenicity with LMB-2  
As detailed in section 1.2.16.3, immunogenicity is a major limiting factor in LMB-2 
efficacy.  Although only a few ATL patients have been treated, it is clear that 
immunogenicity is a potential problem in the efficacy of LMB-2 in that disease.  This is 
expected given the significant rate of HAMA in ATL patients [12-14].  Thus, the 
enrollment of ATL patients after immunosuppressive treatment to reduce immunogenicity 
is reasonable, particularly since the FC employed for immunosuppression should also 
reduce tumor burden and thereby allow the LMB-2 to distribute to tumor cells more 
efficiently.  If so, FC will also slow the regrowth of disease between cycles of ATL.  
1.3.8
Drug supply and ability to administer 6 cycles of LMB-2  
CTEP currently has enough LMB-2 to treat approximately 200 cycles on this protocol.  
Since the accrual ceiling is 37 patients but 4 of these would not be enrolled unless needed 
to replace patients who could not receive LMB-2, the average numbers of cycles of LMB-2 
per patient is over 6.  Moreover, based on average cycles/patient statistics on the phase II 
trials of CLL, CTCL and HCL, it is extremely likely that a large percentage of LMB-2 
allocated to these trials will be available for ATL patients if needed.  


Abbreviated title:  LMB-2 and FC in ATL 
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19
1.3.9
Ability to achieve the accrual goals of the trial  
The PIs in the Metabolism Branch who treat ATL patients are associate investigators on 
this trial, and ATL patients on this protocol will be treated at NIH in the hematologic 
malignancy section of the Medical Oncology Branch, as they are for ATL protocols 
directed by the Metabolism Branch.  Several ATL trials which are still accruing patients, 
including the EPOCH-Rituximab protocol, and new ATL trials like the Siplizumab-
EPOCH-R protocol, will not compete with this protocol since those trials are only for 
previously untreated ATL.  It is anticipated that most patients on this FC/LMB-2 protocol 
will have had prior therapy, but the eligibility criteria will allow untreated cases in case 
such patients are ineligible for other trials.  Other Metabolism Branch trials open for 
previously treated ATL include the alemtuzumab study, and the Ontak study.  It is 
anticipated that the alemtuzumab study will complete accrual prior to approval of this 
study.  The Ontak study should not compete with this trial since most patients spend only 
a few weeks on protocol and immunogenicity to Ontak would not result in antibodies 
against LMB-2.  Approximately 1 new ATL patient per month is seen by the Metabolism 
Branch and it is estimated that 50-80 of these patients would be eligible either initially or 
eventually for this trial.  Thus, it should be possible to meet the accrual goal of 29 patients 
over 3-4 years without requiring an increase in patient referrals.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Diagnosis of acute or lymphomatous ATL by flow cytometry of blood or 
immunohistochemistry of biopsy tissue, confirmed by NCI Laboratory of Pathology, and 
previously treated unless the patient is ineligible for or refuses other protocols or 
treatments for ATL.  
2.1.1.2
Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of LMB-2. 
2.1.1.3
At least 18 years old.
2.1.1.4
ECOG 0-2 (See Appendix B for definitions).
2.1.1.5
Able to understand and give informed consent.
2.1.1.6
Negative pregnancy test for females of childbearing potential.
2.1.1.7
The transaminases ALT and AST must each be 3-times the upper limits of normal 
(ULN) or <10-times normal if due to ATL.  Albumin must be 3.0 gm/dL.  Total bilirubin 
must be  1.5 mg/dL except in patients with Gilbert’s syndrome (as defined by >80% 
unconjugated bilirubin) it must be <5mg/dl.
2.1.1.8
Creatinine < 2.0 mg/dL.
2.1.1.9
ANC ≥ 1000/uL and Platelets ≥ 50,000/uL.  
2.1.1.10 Current or prior features of acute (corrected Ca++ >2.73 or LDH 2-fold above ULN) or 
chronic (LDH 1.5-2-fold above ULN or absolute lymphocyte count >4 x109/L with T-
cells >3.5 x109/L) ATL. Patients with smoldering ATL (no acute or chronic features) and 
symptomatic ATL skin lesions are also eligible.
2.1.2
Exclusion Criteria
2.1.2.1
Prior therapy with LMB-2.


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
20
2.1.2.2
Central nervous system disease as evidence by clinical symptomatology.
2.1.2.3
Cytotoxic chemotherapy, steroids or 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 the 
patient’s disease burden is not decreasing during that time.
2.1.2.4
Uncontrolled infection.
2.1.2.5
Untreated or uncontrolled 2nd malignancy.
2.1.2.6
Patients who are pregnant or breast-feeding (See section 2.2.6).
2.1.2.7
Patients who have 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.  
2.1.2.8
Patients receiving warfarin (Coumadin®).
2.1.2.9
Patients with a left ventricular ejection fraction of < 45%.
2.1.2.10 Patients with a DLCO <50% of normal or an FEV1 <50% of normal.
2.1.2.11 No concomitant use of alternative complimentary therapies or OTC agents allowed 
without prior approval of the PI.
2.1.2.12 Tumor or lymph node masses > 4 cm.
2.1.3
Recruitment strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites and 
on NIH social media platforms.
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. 
2.2.2
Anytime prior to enrollment: Immunohistochemistry (if flow cytometry negative) to detect 
CD25+ ATL cells in solid masses.
2.2.3
Within 2 months before enrollment: HIV, hepatitis B (Ag and core Ab), and C. CMV/EBV 
PCR (no further follow up required unless clinically indicated). Echocardiogram and 
Pulmonary Function Tests.  
2.2.4
Within 28 days prior to enrollment: Lipid panel, fibrinogen, thrombin time, TSH, Free T3, 
Free T4, T3, T4, 24 hour urine for creatinine clearance, protein, and UPEP, Exercise Stress 
Test (ETT). 
2.2.5
Within 2 weeks prior to enrollment: Physical exam. Flow cytometry to quantify circulating 
ATL cells, CD4+ and CD8+ lymphocytes, and normal B-cells. CT scan of chest, abdomen, 
pelvis, and neck, photography of skin lesions (per PI discretion), dermatology consult (per 
PI discretion), PET CT if needed to better define response (per PI discretion).


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
21
2.2.6
Pregnancy test (urine or blood) within 1 week before enrollment in women of childbearing 
potential.  The effects of LMB-2 combined with FC on the developing human fetus are 
unknown.  For this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation until 1 month after the last cycle of 
LMB-2.  
2.2.7
Within 3 days before enrollment: CBC and diff, Chemistries (albumin, alkaline 
phosphatase, ALT, AST, bilirubin, BUN, calcium, CK, chloride, CO2, creatinine, direct 
bilirubin, glucose, potassium, LDH, magnesium, sodium, phosphorus, total protein, uric 
acid), PT/PTT, urinalysis, IgA, IgG, IgM, GGT, haptoglobin, amylase, lipase and serum 
for tumor markers and neutralizing antibodies.
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, and eligibility criteria.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN  
This is a non-randomized trial of LMB-2 immediately following fludarabine-
cyclophosphamide (FC), preceded by an initial cycle of FC alone.  Patients without high levels 
of neutralizing antibodies (> 75% neutralization of 1000 ng/ml of LMB-2) may be retreated 
with FC/LMB-2 at minimum intervals of 13 days after FC alone and 20 days after FC with 
LMB-2.  The following schema summarizes the timing of doses:
3.1.1
Fludarabine IV days 1-3 (F) 

Patients 1 -7, 10 – 14, and then >18: 25 mg/m2/day

Patients 8 – 9:  30 mg/m2/day

Patients 15-17:  20 mg/m2/day


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
22
3.1.2
Cyclophosphamide IV days 1-3 (C)

Patients 1 -7, 10 – 14, and then >18: 250 mg/m2/day

Patients 8 – 9:  300 mg/m2/day

Patients 15-17:  200 mg/m2/day
3.1.3
LMB-2 QOD x3 doses, days 3, 5, and 7.  Begin with 30 mcg/Kg·dose x3 doses.  Escalate 
to 40 mcg/Kg·dose QOD x3 doses if 0/3 or 1/6 have DLT at 30 mcg/Kg·dose.  Continue 
at 40 mcg/Kg·dose QOD x3 doses if 0-1 of 6 have DLT at 40 mcg/Kg·dose QOD x3 doses.  
3.1.4
Repeat FC-LMB-2 for maximum of 6 cycles.  The minimum interval is 13 days after cycle 
1 and 20 days after cycles 2-6.  Give the 1st cycle of FC without LMB-2 and give LMB-2 
with cycles 2-7 of FC.  
3.1.5
Response on the trial is based on pre-cycle 1 staging but patients will be restaged prior to 
cycle 2 to determine response to LMB-2.  
3.1.6
Patients with CR or PD after FC alone will not receive LMB-2.
3.1.7
Accrual goals:  Minimum 29, maximum 37.
3.1.8
Schema for timing of FC and LMB-2:
Cycle 1:
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day > 14
FC
FC
FC
FC (next cycle)
Cycles 2-7:
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day > 21
FC
FC
FC
FC (next cycle)
LMB-2
LMB-2
LMB-2
3.2
DRUG ADMINISTRATION
3.2.1
FC chemotherapy
3.2.1.1
Fludarabine by 30 minute i.v. infusion days 1 - 3

Patients 1 -7, 10 – 14 and >18: 25 mg/m2/day

Patients 8 – 9:  30 mg/m2/day

Patients 15-17:  20 mg/m2/day
3.2.1.2
 Cyclophosphamide by 60 minute i.v. infusion days 1-3

Patients 1 -7, 10 – 14 and >18: 250 mg/m2/day

Patients 8 – 9:  300 mg/m2/day

Patients 15-17:  200 mg/m2/day
3.2.1.3
Total dose based on weight or BSA from last NIH measurement, measured within 1 week 
from each dose.
3.2.1.4
Prophylactic antiemetics may be given as necessary.  Avoid prophylactic steroids, 
although up to 6 doses of 60 mg of i.v. solumedrol (or equivalent) may be used per cycle 


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
23
to prevent or treat fever associated with LMB-2.  Steroids in excess of this amount may 
be used to manage ATL as needed provided that the patient must be off systemic steroids 
(except to prevent adrenal insufficiency) for at least 6 weeks to be counted as a major 
responder.
3.2.1.5
Recommend at least 2L of water intake per day.
3.2.1.6
Filgrastim:  After the first episode of grade > 2 neutropenia (ANC < 1000/uL), filgrastim 
will be administered at 300 mcg/day subcutaneously from day 5 to 1 day before the next 
cycle, and may be held when the ANC is > 5000/uL.  
3.2.1.7
Example of drug administration days 1 and 2:

Hour 0 - 1 500 ml of D5/0.45% NaCl

Hour 1 - 2 Fludarabine 20-30 mg/m2·day iv over 30 minutes in 100 ml 0.9% NaCl

Hour 2 - 3 Cyclophosphamide 200-300 mg/m2·day IV in 100 ml 0.9% NaCl over 60 
minutes.

Hour 3 - 4 500 ml of D5/0.45% NaCl over one hour
3.2.1.8
Example of drug administration day 3:

Hour 0 - 1 500 ml of D5/0.45% NaCl

Hour 1 - 2 Fludarabine 20-30 mg/m2 iv over 30 minutes in 100 ml 0.9% NaCl

Hour 2 - 3 Cyclophosphamide 200-300 mg/m2 IV in 100 ml 0.9% NaCl over 60 minutes.

Hours 3 - 5 1000 ml of D5/0.45% NaCl over two hours

Hour 4 Hydroxyzine, ranitidine, and acetaminophen 1 hr before LMB-2

Hour 5 - 5.5 LMB-2 iv over 30 min

Hours 5.5 - 7.5 1000 ml of D5/0.45% NaCl over two hours

Hour 10 Acetaminophen

Hour 12 Hydroxyzine and ranitidine

Hour 16 Acetaminophen

Hour 22 Acetaminophen
3.2.1.9
Example of drug administration days 5 and 7:

Hours 0 - 2 1000 ml of D5/0.45% NaCl over two hours

Hour 1 Hydroxyzine, ranitidine, and acetaminophen 1 hr before LMB-2

Hours 2 - 2.5 LMB-2 iv over 30 min

Hours 2.5 - 4.5 1000 ml of D5/0.45% NaCl over two hours

Hour 7 Acetaminophen

Hour 10 Hydroxyzine and ranitidine

Hour 13 Acetaminophen

Hour 19 Acetaminophen
3.2.2
LMB-2
3.2.2.1
30-40 mcg/Kg·dose will be infused through a peripheral I.V. or central line in 50 ml of 
0.9% NaCl and 0.2% albumin via a PAB container over 30 minutes every other day for 3 
doses (QOD x 3).  Additional IV fluid will be given as described below.  FC and LMB-2 
may be administered as an outpatient or inpatient, and the day 3 dose of LMB-2 should 
follow the day 3 doses of FC.
3.2.2.2
Premedication: Patients will be medicated with 25 mg hydroxyzine and 150 mg ranitidine 
orally 1 hour prior to and 8 hours after each dose.  Acetaminophen 650 mg P.O. will be 


Abbreviated title:  LMB-2 and FC in ATL 
Version Date: 1/31/2023
24
given every 6 hours for 4 doses starting 1 hour prior to each LMB-2 dose.  Emergency 
medications such as epinephrine and diphenhydramine should be available in the area 
where the patients will receive the LMB-2 infusion for treatment of an allergic reaction.  
Emergency equipment including oxygen should be available in the patient’s room.

I.V. Fluid:  Patients will receive fluid prophylaxis, consisting of:

500 ml of D5/0.45% NaCl over 1 hours prior to cyclophosphamide.

500 ml of D5/0.45% NaCl over 1 hours after cyclophosphamide.

1000 ml of D5/0.45% NaCl over 2 hours prior to LMB-2

1000 ml of D5/0.45% NaCl over 2 hours after LMB-2

On day 3, cyclophosphamide is given before LMB-2 and the post-hydration fluid for 
cyclophosphamide is replaced by the 1000 ml pre-hydration for LMB-2.

Hydration may be prolonged at the discretion of the PI.
3.2.2.3
Vital signs of inpatients will be obtained at the beginning of infusion, at 15 minutes, & at 
the end of infusion, then every 60 minutes for 2 hours, then as per unit routine.  Daily 
orthostatic blood pressure, weights, I/Os, and physical exam will be done.  Daily 
orthostatic blood pressure will be measured after having the patient in supine and standing 
position for at least 2 minutes.  If standing SBP decreases from supine SBP by > 20 
mmHg, then another standing blood pressure measurement will be done at least 3 minutes 
after the first.
3.2.2.4
Vital signs of outpatients will be obtained at the beginning of infusion, at 15 minutes, & 
at the end of infusion, then every 60 minutes for 2 hours.  Patients will be monitored for 
peripheral edema and orthostatic hypotension at least daily.  Daily weights will also be 
recorded.  
3.3
TREATMENT MODIFICATIONS
3.3.1
Definition of DLT  
Grade III-V LMB-2 or FC-related toxicity, except:
3.3.1.1
Vascular leak syndrome (VLS):  As specified by CTCAE 3.0 to be utilized until 
December 31, 2010, grade II VLS includes symptoms of fluid retention, including grade 
I-II weight gain.  If a patient requires more than an hour's worth of hydration at 20 
ml/Kg/hour for hypotension, then the patient will be considered to have grade III 
hypotension.  Grade III hypotension in temporal association with VLS will also be 
considered grade III VLS.  VLS resulting in respiratory compromise is considered grade 
III according to CTCAE 3.0 to be utilized until December 31, 2010.  Respiratory 
compromise is defined as symptomatic pulmonary edema with at least grade III 
hypoxemia.  Either grade > III VLS or grade > III hypotension is considered DLT.
Definition of Capillary Leak Syndrome (as stipulated by CTEP) to be utilized after 
January 1, 2011:   As specified by CTCAE 4.0, grade II CLS is defined as symptomatic; 
medical intervention is indicated; this protocol further defines that if weight gain is the 
only feature of CLS in a patient, it will be considered a grade II CLS.  If a patient requires 
more than an hour’s worth of hydration of 20 ml/Kg/hour for hypotension, then the patient 
will be considered to have grade III hypotension.  Grade III hypotension in temporal 
association with CLS will be consider also a grade III CLS.  Respiratory compromise in 
the setting of CLS defined as symptomatic pulmonary edema requiring oxygen or > 10% 


Abbreviated title:  LMB-2 and FC in ATL 
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25
decrease in oxygen saturation will be consider a grade III CLS.  Grade III hypotension or 
grade III CLS is dose limiting.
3.3.1.2
Alopecia is not considered DLT.
3.3.1.3
Grade II or III allergic reaction with asymptomatic bronchospasm or urticaria is 
considered DLT.
3.3.1.4
Grade III AST, ALT, GGT, and fever are not considered DLT.  Fever and transaminase 
elevations are common with LMB-2 and have never been associated with poor hepatic 
function (i.e. hyperbilirubinemia, hyperammonemia).  These guidelines are standard from 
immunotoxin trials.
3.3.1.5
Grade IV CPK associated with any other DLT or not resolving to < grade II within 2 
weeks is considered DLT.
3.3.1.6
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.
3.3.1.7 DLT from hepatotoxicity, CPK, and VLS is assumed from LMB-2, and hematologic 
toxicity from FC.  Hemorrhagic cystitis is not expected at the 200-300 mg/m2 dose level 
of cyclophosphamide.
3.3.1.8
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.
3.3.2
Modification based on previous cycle:
3.3.2.1
DLT on previous cycle at least possibly related to LMB-2 requires dose reduction of 
subsequent LMB-2 cycles by 10 mcg/Kg·dose QOD x3.
3.3.2.2
Lymphopenia and leukopenia are expected effects of the FC chemotherapy in order to 
prevent immunogenicity, and neutropenia down to 0.5 (grade 3) is also expected and 
modified by G-CSF, and these would not be considered toxicity requiring delay of 
retreatment or dose reduction.
3.3.2.3
Retreatment may be delayed up to 4 weeks to allow toxicity to resolve to grade 0-1 or to 
baseline.  Prior to resolution of cytopenias, retreatment may resume at 50%, 25% and 0% 
of FC for grades 2, 3 and 4 thrombocytopenia, respectively, and 0% of FC for grade 4 
neutropenia irrespective of the platelet count.  Unless the cytopenias are related to a cause 
other than FC (i.e. sulfa or reversible viral infection), the doses of FC will not increase 
for subsequent cycles.
3.3.2.4
50% and 75% dose reductions (50% and 25% of original FC doses, respectively, are from 
Flinn et al., Blood, 96:71, 2000 [68].
3.3.2.5
For patients 1-7 and 10-14, who began with 25 mg/m2 and 250 mg/m2 dose levels of 
fludarabine and cyclophosphamide, respectively, a milder dose reduction was used for 
DLT [85], in which the 1st dose reduction required 25 mg/m2 of fludarabine and 200 
mg/m2 of cyclophosphamide, and patients could be treated without FC if cytopenias did 
not resolve.
3.3.2.6
For patients 15-17, who began with 20 mg/m2 and 200 mg/m2 dose levels of fludarabine 
and cyclophosphamide, no dose reduction was needed due to lack of hematologic 
toxicity, and efficacy particularly against leukemic ATL was unsatisfactory.


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26
3.3.2.7
Current dose modifications for chemotherapy
Fludarabine
Cyclophosphamide
Indication
Current starting 
doses
25 mg/m2·day days 1-
3
250 mg/m2·day days 
1-3
50% level (50% 
reduced)
12.5 mg/m2·day days 
1-3
125 mg/m2·day days 
1-3
Grade 2 platelets
25% level (75% 
reduced)
6.25 mg/m2·day days 
1-3
62.5 mg/m2·day days 
1-3
Grade 3 platelets
0% level (100% 
reduced)
0
0
Grade 4 platelets or 
ANC
3.3.2.8
Dose modifications for LMB-2 DLT: 
LMB-2
1st dose reduction
10 mcg/Kg·dose x3 doses less than enrollment 
dose
2nd dose reduction
20 mcg/Kg·dose x3 doses less than enrollment 
dose
3rd dose reduction
Off treatment
3.3.3
Modification based on current cycle:
3.3.3.1
Cancel remaining doses of cycle if DLT during the cycle.
3.3.3.2
May delay dosing up to 48 hr if toxicity less than DLT.
3.4
PHARMACOKINETIC STUDIES (LMB-2 ONLY)
3.4.1
Procedures  
Blood samples will be drawn by the nurse at the times outlined below.  Tubes must be 
labeled with the patient’s name, medical record number, date of birth, date, time drawn, 
and time related to LMB-2 end of infusion.  PKs should not be drawn from the line which 
was infusing LMB-2.  Since PKs are not drawn until LMB-2 finishes infusing, it is 
permissible for PKs to be drawn out of a different port of the same catheter that is used to 
infuse the LMB-2.  Samples of 2 ml of blood will be drawn in a 6 ml sodium heparin tube 
(green top) using a syringe or Vacutainer.  Tubes of blood collected at the clinical center 
(including both inpatient and outpatient units) should be stored upright in the “Kreitman” 
container in the refrigerator in the inpatient unit.  These samples will be collected daily 
Monday through Friday and taken to our contract lab at Frederick National Laboratory for 
Cancer Research: David Waters, PhD, Building 560, Lab 11-05, 1050 Boyles St, Frederick, 
MD  21702, Phone: 301-846-5831.
3.4.2
Day 3 (day 1 of LMB-2)  
Pre, and then 2 min, 1, 2, 3, 4, 10 hours after end of infusion, and next morning.  
3.4.3
Day 5 (Day 3 of LMB-2)  
Pre and then 2 min, and next morning. 


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27
3.4.4
Day 7 (Day 5 LMB-2)
Pre and then 2 min, 1, 2, 3, 4, and 10 hours after end of infusion, and next morning.
3.4.5
Acceptable error in PK time points: 
When possible, +/- 2 min for 2 min, +/- 30 min for later samples. The next morning sample 
may be combined with the morning lab draw, and may be combined with the 10 hour time 
point if that time point is within 2 hours of the morning blood draw.  The actual time of 
sample collection should be recorded.
3.5
PROTOCOL EVALUATION 
3.5.1
Prior to each cycle (do precycle tests within 3 days prior to cycle, i.e. day 11 of cycle 2 or 
day 18 of cycles 3-7): 
Labs:  CBC, diff, chemistries (Albumin, alkaline phosphatase, ALT, amylase, AST, bilirubin, 
BUN, calcium, CK, chloride, CO2, creatinine, direct bilirubin, GGT, glucose, potassium, LDH, 
lipase, magnesium, sodium, phosphorus, total protein, uric acid), PT/PTT, urinalysis, IgA, IgG, 
IgM, haptoglobin, beta-2-microglobulin, serum for sCD25 and other tumor markers, and 
neutralizing antibodies, CRP, flow cytometry
3.5.1.1
Chest X-ray (if no Chest CT obtained)
3.5.1.2
EKG
3.5.1.3
CT or other imaging of relevant level based on known disease burden, if needed to 
determine response.
3.5.1.4
Echocardiogram
3.5.2
On days of LMB-2 dosing:
3.5.2.1
Labs:  CBC, diff, Chem-20 (Albumin, alkaline phosphatase, ALT, AST, bilirubin, BUN, 
calcium, CK, chloride, CO2, creatinine, direct bilirubin, glucose, potassium, LDH, 
magnesium, sodium, phosphorus, total protein, uric acid), urinalysis
3.5.2.2
On day 3 (day 1 of LMB-2 dosing): beta-2-microglobulin, serum for sCD25 and other 
markers, CRP
3.5.2.3
On day 5 (day 3 of LMB-2 dosing): EKG 10-30 min after end of infusion (time of 
maximum expected LMB-2 concentration).
3.5.2.4
On day 7 (day 5 of LMB-2 dosing): EKG before dosing.
3.5.3
After LMB-2 dosing (days 8-11 or days 6-9 of LMB-2): 
3.5.3.1
Labs: CBC, diff, Chem-20, urinalysis, PT/PTT, IgA, IgG, IgM, haptoglobin, amylase, 
lipase, beta-2-microglobulin, serum for sCD25 and other tumor markers, and neutralizing 
antibodies, CRP, flow cytometry
3.5.3.2
Chest X-ray
3.5.4
Initial optional studies (at PI discretion):  
3.5.4.1
MRI if needed to better define response
3.5.4.2
PET CT if clinically indicated to better define response.  Cannot be used for response 
assessment but may be used to determine if masses on CT are evaluable.  PET scans if 
clinically indicated are usually performed every 6 weeks during pre-cycle staging
3.5.4.3
Bone marrow biopsy & aspirate if needed to define response


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3.5.4.4
Photography of skin lesions.  
3.5.4.5
Blood for lymphocyte collection for cytotoxicity assays
3.5.4.6
Blood for ELISA assays to correlate with immunogenicity assays
3.5.4.7
Skin biopsy
3.5.4.8
HLA typing to correlate with immunogenicity assays
3.5.4.9
Fine needle aspirates (FNA) of additional sites to determine antigen positivity and assess 
tumor markers or capillary permeability at the tumor site.  FNA of accessible masses by 
pathologists in NCI cytopathology typically requires a 25 gauge needle and up to 3 passes 
for adequate material for cytopathology and flow cytometry.
3.5.5
At follow-up, tests at discretion of PI, at up to 6-month intervals  
Physical exam, & if relevant, dermatology consult, clinical photography, flow cytometry, imaging 
of tumor sites, CBC + diff, chem-20, urinalysis, PT, PTT, IgA, IgG, IgM, GGT, haptoglobin, 
amylase, lipase, sCD25 (& other tumor markers), neutralizing antibodies, CRP, and beta-2-
microglobulin (see Section 14.1).
3.6
CONCURRENT THERAPIES  
3.6.1
Listed in Section 3.1
3.7
RADIATION THERAPY GUIDELINES
Therapeutic radiation may be undertaken to a localized area as long as there is measurable disease 
outside the radiation port and the area rated is not considered a risk for worse immunosuppression.  
Areas treated with radiotherapy will not be used in response assessment.  
3.8
COST AND COMPENSATION
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by an insurance company.  Medicines that are not part of the study treatment will not 
be provided or paid for by the NIH Clinical Center.
3.8.2
Compensation
Participants will not be compensated on this study.
3.8.3
Reimbursement
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 


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29
3.9.1
Off Treatment Criteria: (No treatment but data can be obtained)

Progressive disease unless it occurs during a dosing delay for toxicity as specified by 
protocol Section 3.3.3.2.

> 75% neutralization of 1000 ng/ml of LMB-2.  

Grade III Allergic Reaction and grade II urticaria despite premedication.

More than 2 dose reductions of LMB -2.

Grade IV DLT other than ALT, AST, GGT, CPK.

Intercurrent illness or medical circumstances.

General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator.
3.9.2
Off-Study Criteria

Screen failure

Patient decides to withdraw from the study

Completed study follow-up period

Death
3.10 POST STUDY EVALUATION (FOLLOW-UP)  
May repeat baseline testing at up to 6-month intervals as deemed necessary by the PI to follow 
response status and toxicity. 
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
SUPPORTIVE CARE 
4.1.1
Allergic reaction
Treated acutely with antihistamines (including diphenhydramine, hydroxyzine, & ranitidine), 
fluids, bronchodilators, and/or epinephrine.
4.1.2
Nausea and Vomiting
 Patients who develop nausea will be treated with a serotonin 5-HT3 receptor inhibitor for at 
least 24 hours after their last episode of nausea.  Other antiemetics such as prochlorperazine, 
metoclopramide, or lorazepam may be used in addition if necessary. 
4.1.3
Myalgias 
Patients who develop myalgias may be given acetaminophen 650 to 1000 mg every 6 hours 
until 24 hours after completing the last dose of LMB-2.  It may then be given as needed. 
Patients may receive opioid analgesics if acetaminophen is inadequate. 
4.1.4
Vascular/Capillary leak syndrome 
Supportive care may include fluid and electrolyte management, diuresis, albumin, and 
cardiovascular support. 
4.1.5
Hypotension 
Patient will be encouraged to increase oral fluid intake.  In addition, for an orthostatic SBP 
change of >20 mm Hg and an absolute SBP of <100 mm Hg, an IVF bolus may be given as 
deemed clinically appropriate.  Refractory hypotension may require treatment in the intensive 
care unit with pressors.


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30
4.1.6
Fever 
Patients who develop temperatures >38.0° C may receive scheduled acetaminophen 650 to 
1000 mg every 6 hours until 24 hours after completing the last dose of LMB-2. It may then be 
given as needed.
4.1.7
Thrombocytopenia 
Should be treated conservatively. In the absence of bleeding or a planned invasive procedure, 
platelet transfusions should only be given for a platelet count below 10,000/uL. If invasive 
procedures are planned or the patient develops bleeding, platelet transfusions should be 
administered in accordance with standard of practice, usually maintaining a platelet count > 
50,000/uL. 
4.1.8
Symptomatic anemia 
Should be treated with appropriate red blood cell support. Transfusion is recommended if the 
hemoglobin falls below 8g/dL.  Recombinant erythropoietin may be also used. 
4.1.9
Febrile Neutropenia 
Life-threatening complication requiring hospitalization and urgent broad-spectrum antibiotics. 
Hematopoietic growth factors may be used if clinically indicated.  Such cases will be evaluated 
individually to determine the toxicity grade.  Neutropenia due to LMB-2 is not expected.
4.1.10  Central venous access devices 
Such as a temporary internal jugular or subclavian lines, PICC lines, semi-permanent 
HICKMAN, Groshong catheters, or medi-port implanted devices can all be used in this study.  
All devices will have nursing supervision and include patient self-care instruction. 
4.2
NUTRITIONAL ASSESSMENT AND PSYCHOLOGICAL SUPPORT 
Refractory neoplasms are commonly complicated by malnutrition. Patients with weight loss or 
evidence of wasting syndrome should have a nutritional consult.  When necessary, social work 
will be proactively involved with these patients’ psychosocial well-being.
5
DATA COLLECTION AND EVALUATION
5.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a 
contracted data manager will assist with the data management efforts. Primary and final 
analyzed data will have identifiers so that research data can be attributed to an individual 
human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event. 
Document AEs from the first study intervention, Study Day 1, through 30 days after removal 
from study treatment or until off-study, whichever comes first.


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31
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.

A pre-existing (baseline) laboratory abnormality will be considered the last one obtained 
prior to the first dose of drug, unless the PI considers an abnormality of higher grade 
occurring within 100 days prior to the first dose to be a truer baseline.

Each AE will be reported with an onset date when it begins above baseline, a resolution 
date as the last time during a cycle that it resolves to or below baseline, and the maximum 
grade achieved. Thus, the same AE might recur after each cycle, but would not be reported 
multiple times per cycle unless it is judged by the PI to be significantly different in its 
attribution.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
5.2
RESPONSE CRITERIA 
5.2.1
Response criteria are based on the International Workshop to Standardize Response 
Criteria for non-Hodgkin’s Lymphoma.
5.2.2
Duration.   A response must last for at least four weeks to be considered a major response, 
but > 8 weeks to meet the primary endpoint of the study.  
5.2.3
Complete Remission (CR).  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 (for example 
LDH) definitely assignable to the lymphoma.  All lymph nodes must have regressed to 
normal size (less than or equal to 1.5 cm in greatest diameter if > 1.5 cm before therapy).  
Previously involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased 
to less than or equal to 1 cm or by more than 75 percent in the sum of the products of the 
greatest diameters.  The spleen, if considered to be enlarged before therapy, must have 
regressed in size and not be palpable on physical examination.  The bone marrow must 
show no evidence of disease by histology, and need not be repeated if otherwise in CR.  
Peripheral blood must show a normal pattern by flow cytometry to qualify for a complete 
remission.  Molecular studies will be used to determine response.  Because of the limitation 
in performing serial PET scans and difficulty in verifying that PET abnormalities indicate 
malignant disease, they will not be used to determine response.  
5.2.4
Complete response unconfirmed (CRu).  As per complete remission criterion except that 
if a residual node is greater than 1.5 cm, it must have decreased by greater than 75 percent 
in the sum of the products of the perpendicular diameters.  Lymphocyte aggregates within 


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32
the bone marrow must be negative for T-cell markers characteristic of adult T-cell leukemia 
lymphoma.
5.2.5
Partial response (PR).  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.  Flow cytometry will not prevent consideration of PR 
or determine relapse from PR if the ATL count by flow cytometry remains below 100 
cells/mm3 and the patient qualifies for PR by other parameters.
5.2.6
Stable disease (SD).  Neither a response nor progressive disease.
5.2.7
Progressive disease (PD).  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.
5.2.8
PET scanning.  Because PET scanning may not be obtained on every cycle and may not 
be routinely obtainable at baseline, it may not be used for response assessment.
5.3
TOXICITY CRITERIA  
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized until December 
31, 2010 for AE reporting.  CTCAE version 4.0 will be utilized beginning January 1, 2011. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
6
STATISTICAL CONSIDERATIONS
6.1
STUDY DESIGN/ENDPOINTS  
The primary objective of this study is to determine, in a nonrandomized pilot fashion, if after 
verifying its safety, the use of fludarabine and cyclophosphamide (FC) prior to LMB2 in patients 
with ATL is able to result in a minimally durable clinical response rate and an immunogenicity 
rate which may be an improvement over that demonstrated previously from CAMPATH.
6.2
DOSE-ESCALATION PHASE  
In order to establish the safety of the proposed regimen, initially a small number of patients will 
be treated at 30 mcg/Kg·dose x3 doses prior to evaluating the intended dose of 40 mcg/Kg·dose 
x3 doses as follows.  Initially, three patients will be enrolled and treated with LMB-2 at 30 
mcg/Kg·dose x3 doses after receiving FC days 1-3. If 0/3 experience DLT at this level, then 3 
patients will be enrolled at 40 mcg/Kg·dose x3 doses.  On the other hand, if 1/3 have DLT at 30 
mcg/Kg·dose x3 doses, then 3 more patients will be added at 30 mcg/Kg·dose x3 doses level and 
if 1/6 total have DLT, then accrual will proceed to 40 mcg/Kg·dose x3 doses. If2 of 3-6 patients 
are noted to have a DLT at 30 mcg/Kg·dose x3 doses, then accrual to the trial will end.  If 0/3 
experience DLT at 40 mcg/Kg·dose x3 doses, then 3 more patients will be enrolled at 40 
mcg/Kg·dose x3 doses, and if 0/6 or 1/6 have DLT, then 40 mcg/Kg·dose x3 doses will be the full 
treating dose for the phase II portion of the trial. On the other hand, if 1/3 have DLT at 40 
mcg/Kg·dose x3 doses then 3 more patients will be added at this level, and if 1/6 total have DLT, 
then 40 mcg/Kg·dose x3 doses will be the full treating dose for the phase II portion. However, if 
2 patients have DLT at 40 mcg/Kg·dose x3 doses, then 30 mcg/Kg·dose x3 doses will become the 


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full treating dose after demonstrating that 6 patients have been treated at 30 mcg/Kg·dose x3 doses 
and no more than 1/6 have a DLT.
6.3
METHOD FOR EFFICACY DETERMINATION  
In the previous trial with CAMPATH alone, there were a total of 10 clinical responses in 23 
evaluable patients, and 7 of the 23 responses lasted for at least 8 weeks (30.4% minimally durable 
responses). It would be of interest to determine if in the present trial, the combination of agents 
would be able to result in a proportion of patients with responses lasting longer than 8 weeks which 
is more than previously identified. Since the 30% rate has its own confidence interval associated 
with it, the objective of the present trial will be to conduct a phase II study using a two-stage Simon 
optimal design which will rule out a 35% rate of patients having responses lasting > 8 weeks, and 
which will target a 60% rate of this outcome. To do so, using alpha=0.10 and beta=0.10, the trial 
will initially enroll 16 evaluable patients (which include patients from the phase I portion of the 
trial who were treated at the phase II dose level) and if 0 to 6 have PR or CR lasting over 8 weeks, 
then no further patients will be accrued.  A pause in the accrual may be necessary to determine if 
this is the case prior to beginning to enroll to the second stage. If 7 or more patients in the 16 
evaluable patients have responses lasting over 8 weeks, then accrual will continue until a total of 
27 evaluable patients have been enrolled. If 7 to 12 of 27 have responses lasting over 8 weeks, this 
will be considered to be unsatisfactory, while if there are at least 13 patients of 27 with responses 
lasting over 8 weeks, this will be considered sufficiently promising for further development. Under 
the null hypothesis (35% proportion with responses lasting > 8 weeks), the probability of early 
termination is 69%.
6.4
IMMUNOGENICITY
As well, the rate of immunogenicity (defined as > 25% neutralization of 1000 ng/ml of LMB-2) is 
an important endpoint for the trial.  The previous fraction of all non-CLL patients treated with 
LMB2 experiencing this degree of immunogenicity is 29/48 (60.4%). It would be desirable to be 
able to demonstrate if the treatment in the current trial is associated with a lower rate of 
immunogenicity than suggested by this group of historical controls. As one type of evaluation, if 
we enroll 27 evaluable patients on this trial, and if the proportion with immunogenicity were 30% 
(a 30% reduction), there would be 85% power to identify this difference as being lower than 
controls, with a one-tailed 0.10 Fisher’s exact test. This would provide at least modest evidence 
that a reasonable level of improvement was associated with this treatment. As an alternative 
interpretation, if there are 12 or fewer of 27 evaluable patients with immunogenicity, then the 
probability of observing this number is 96.4% if the true rate of immunogenicity were 30%. It 
would be 7.4% if the true rate was 60%. Finally, the one sided 95% upper confidence interval 
bound on 12 of 27 is 62% and the one sided 90% upper confidence interval bound on 12 of 27 is 
58%. Thus, observing 9 patients of 27 with immunogenicity would allow us to state that there is a 
trend toward a difference compared to 29 of 48, and observing 12 or fewer of 27 with 
immunogenicity would suggest that the rate was lower than 60% if this were to be interpreted as a 
fixed parameter. Since observing > 12 patients with immunogenicity any time during accrual 
would indicate consistency with the previously noted 60% immunogenicity rate, or higher, we 
would plan to stop accrual to the trial if a 13th patient with immunogenicity were noted any time 
during the phase II portion of the trial. Patients at all dose levels of LMB-2 and FC are evaluable 
for early stop with respect to immunogenicity.


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6.5
COMPARING PFS WITH ALEMTUZUMAB STUDY  
As a secondary evaluation, a comparison of Kaplan-Meier curves from the prior CAMPATH-only 
trial and the present one will be done using a log-rank test, with the recognition that the comparison 
will be done using the limited number of patients available and the associated imprecision 
associated with it.
6.6
COMPLETE REMISSION  
It should be noted that if patients experience a complete response to FC with no evaluable disease 
remaining, then they will not be offered LMB-2 and these patients will be replaced in the phase II 
evaluation with other patients. It is expected that no more than 4 such patients will need to be 
replaced. These patients will not be included in the PFS curve or evaluation but will be described 
when the study is published.
6.7
SECONDARY OBJECTIVES  
Other secondary objectives will be evaluated using standard statistical techniques such as 
correlation coefficients, trend tests, and multi-group comparisons, either with parametric methods 
or non-parametric depending on the distributions of values obtained. These evaluations include 
describing how blood levels of LMB-2 (AUC, Cmax) are related to toxicity and response; 
describing how the development of neutralizing antibodies affects blood levels of LMB-2 and 
toxicity; and describing how soluble Tac-peptide (sIL2Ra) levels are associated with response to 
treatment with LMB-2. Since these evaluations will all be considered secondary, the results will 
be presented using unadjusted p-values and will be accompanied by an explanation that the 
evaluations were secondary and hypothesis generating.
6.8
ACCRUAL  
It is expected that 1-2 patients per month can be recruited for enrollment onto this trial.  Allowing 
for up to 6 patients on a lower dose than used for the phase II evaluation, 27 patients in the phase 
II evaluation, and then up to 4 patients who may be replaced if they are not offered LMB-2 or non-
evaluable for some other reason, a total of 37 patients may be required to be accrued onto the trial. 
It is expected that 2-3 years is a reasonable time frame in which to accrue all needed subjects. The 
accrual ceiling will be 48 to account for inevaluable participants.
7
HUMAN SUBJECTS PROTECTIONS
7.1
RATIONALE FOR SUBJECT SELECTION 
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria. To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in any one patient group.  Efforts will be made 
to extend accrual to a representative population, but in this preliminary study, a balance must be 
struck between patient safety considerations and limitations on the number of patients exposed to 
a potentially toxic treatment on the one hand and the need to explore gender and ethnic aspects of 
clinical research on the other.  If differences in the outcome which correlate with gender or ethnic 
identity are noted, accrual may be expanded, or a follow-up study may be written to investigate 
these differences.
7.2
INCLUSION OF WOMEN AND MINORITIES.  
Both men and women and members of all races and ethnic groups are eligible for this trial.


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7.3
PARTICIPATION OF CHILDREN  
Only patients 18 years of age or older will be enrolled on this study, since the safety of this agent 
has not been previously defined in a pediatric population.
7.4
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 7.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. 
Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed.
Please see Section 7.9.1 for consent procedure.
7.5
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS  
Patients will receive evaluation and treatment of their tumor at the National Cancer Institute’s 
Clinical Center.  This protocol may or may not benefit an individual, but the results may help the 
investigators learn more about the disease and develop new treatments for patients with this 
disease.   Benefit cannot be promised, nor can the chance of benefit be accurately predicted.  This 
research treatment is unlikely to be curative but may offer temporary control of the disease.  The 
disease eligible for this protocol is considered incurable.  Patients will generally have a poor 
prognosis and have no standard options known to significantly improve survival. 
The risks and benefits of participation for adults who become unable to consent, are no different 
than those described for patients who are less vulnerable. 
7.6
ALTERNATIVE APPROACHES OR TREATMENTS  
Patients will be consented verbally and in writing regarding the risks and benefits of this trial, the 
treatment requirements, and alternative approaches to entering on this trial.
7.7
PROCEDURES FOR PROTECTING AGAINST OR MINIMIZING ANY POTENTIAL RISKS  
All care will be taken to minimize side effects, but they can be unpredictable in nature and severity.  
This study may involve risks to patients which are currently unforeseeable.  Patients will be 
examined and evaluated prior to enrollment and prior to each cycle.  The Clinical Center staff will 
observe all patients during the drug administration.  All evaluations to monitor the treatment of 
patients will be recorded in the patient chart.  Patients are required to have a local physician to 
provide long-term care and to monitor for complications.  They will have blood draws at home to 
monitor side effects.  If patients suffer any physical injury as a result of the participation in this 
study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, 
Bethesda, Maryland.  Although no compensation is available, any injury will be evaluated and 
treated in keeping with the benefits or care to which patients are entitled under applicable 
regulations.


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7.7.1
Identified Risks to Study Procedures 
7.7.1.1
Blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up 
to 45 mL of research blood may be collected at any follow-up visit.
7.7.1.2
Urine Collection
No physical risks are associated with urine collection.
7.7.1.3
Clinical Photography
No physical risks are associated with clinical photography.
7.7.1.4
Ultrasound
No physical risks are associated with ultrasound procedures.
7.7.1.5
Imaging/scans
In addition to the radiation risks discussed below, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling.
7.7.1.6
MR Imaging
The risks of MR imaging are relatively small.
The US Food and Drug Administration has issued warnings that administration of gadolinium 
(updated September 9, 2010), the MRI contrast imaging agent used in this protocol, has been 
associated with development of a disease called nephrogenic systemic fibrosis (NSF). The 
syndrome is rare (approximately 600 cases reported worldwide as of September 2010, out of 
several million administrations of gadolinium), but disabling and in some cases, fatal. All cases to 
date have occurred in patients with severe renal disease, including patients on dialysis. NSF has 
been nearly eradicated secondary to careful screening of renal function and avoiding use of 
gadolinium in patients with eGFR <30 ml/min/1.73 BSA. Even in patients with end stage renal 
disease, there have been only rare occurrences of NSF because of precautions taken to use more 
stable contrast agents at lower doses. This protocol excludes patients with severe renal 
insufficiency (eGFR <30 ml/min/1.73 BSA). The FDA has issued warnings in 2017 and 2018 that 
some gadolinium may be retained in the brain, bone and skin although health risks of accumulation 
have not been reported to date. In accordance with the FDA Drug Safety Communication of 
05/16/2018, the Medication Guide for gadobutrol (or other macrocyclic gadolinium contrast agent 
if applicable) will be made available to all subjects with scans that will involve gadolinium-based 
contrast agent administration.
7.7.1.7
Risks from Radiation Exposure


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On this study, during follow-up, participants may receive up to 2 CT and 2 PET/CT scans per year. 
The total radiation dose for research purposes will be approximately 5 rem. The risk of getting 
cancer from the radiation exposure in this study is 0.5% and of getting a fatal cancer is 0.3%.
7.8
PROVISIONS FOR MONITORING DATA COLLECTION TO ENSURE SAFETY OF SUBJECTS  
As information is gathered from this trial, clinical results will be shared with patients while 
maintaining patient confidentiality. Laboratory and clinical data will be frequently gathered, and 
any new significant findings found during the course of the research, which may affect a patient’s 
willingness to participate further, will be explained.  Moreover, in all publications and 
presentations resulting from this trial, patients’ anonymity will be protected to the maximum extent 
possible.  Authorized personnel from the National Cancer Institute (NCI) and Food and Drug 
Administration (FDA) may have access to research files in order to verify that patients’ rights have 
been safeguarded.  In addition, patient names will be given to the Central Registration Office to 
register and verify patients’ eligibility.
7.9
CONSENT PROCESS AND DOCUMENTATION  
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or, 

iMedConsent platform (which is 21 CFR Part 11 compliant)


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During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
7.9.1
Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 7.4, an LAR will be identified consistent with Policy 403 and 
informed consent obtained from the LAR, as described in Section 7.9.
8
CORRELATIVE STUDIES FOR RESEARCH
8.1
BIOSPECIMEN COLLECTION
8.1.1
Blood, bone marrow, lymph node, skin, and other tumor samples.
Research being conducted:  Malignant cells may be stored to determine sensitivity to LMB-
2 or to related agents.  T-cell receptors may be cloned to serve as sensitive indicators of 
minimal residual disease, and serum markers for disease may also be determined.   
Samples to be collected: 
Soluble CD25, and other tumor markers:  To estimate the amount of cancer cells in the 
body by measuring proteins which fall off cancer cells and go into the blood. Requires 
about 1 teaspoon.  Soluble CD25 can also be measured on tumor tissue, including lymph 
node or skin biopsies which can be done non-invasively or are performed for diagnosis.
Skin biopsy:  To determine whether skin lesions have ATL cells, and if so, to determine 
the extent to which ATL cells are cleared with FC or FC/LMB2.
HLA typing to better understand the immune system in patients getting LMB-2. 
Requires about 1 teaspoon.
PAX-gene tube: To obtain RNA to study tumor markers, and an assay called micro-
arrays, to study why some patients do not respond as well as others to LMB-2. Candidate 
genes to study would be those mediating apoptosis and cytokine release.  Requires about 
1/2 teaspoon.
DNA samples to look for abnormalities which might make a patient more susceptible to 
toxicity. Candidate genes to study would be those mediating apoptosis and cytokine 
release.  Requires about 1/2 teaspoon.
Samples to determine levels of LMB-2 in the blood, urine, and other tissues by activity 
or immuno (ELISA) assays.
Flow cytometry assays to quantify tumor markers on the malignant cells.  Requires about 
1/2 tablespoon.


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Cytotoxicity assays.  Leukemia or lymphoma cells from the blood, bone marrow, or 
other tissues may be tested with LMB-2 and related drugs to determine if the malignant 
cells can be killed outside the body.  Requires 1-3 tablespoons. For follow-up studies in 
patients off-treatment, which will not affect eligibility for enrollment or retreatment, a non-
radioactive neutralization assay may be used, under non-CLIA conditions.  For additional 
correlation between the 2 assays, serum samples are saved to enable the new assay to be 
run with historical samples previously tested using the radioactive CLIA assay.
Assays which would have significant risk to the patient, including studies of genetic cancer 
susceptibility, will not be done.
Note: tubes and media for research tests may be substituted based on availability with the 
permission of the PI or laboratory investigator
8.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.
8.2.1
Timeframe and location of storage:  
Samples will be stored and cataloged longer than a year, in alarmed freezers at our Leidos 
Biomedical Research, Inc. contract lab in Frederick, MD where neutralizing antibodies and PK 
samples are tested.  The contact information is:  David Waters, PhD, Building 560, Lab 11-05, 
1050 Boyles St, Frederick, MD  21702, Phone: 301-846-5831.  Portions of samples which are 
stored at Frederick National Laboratory for Cancer Research may also be stored and tested in the 
LMB lab (Building 37) for longer than a year providing there is sample remaining after studies are 
done.  All samples will be stored with unique patient numbers and without personal identifiers. 
After closure of the protocol, the samples will either be destroyed, or their storage and use will be 
governed by a subsequent protocol.   Samples at Frederick National Laboratory for Cancer 
Research will be tracked in a secure electronic database and the PI will report destroyed samples 
per the requirements of Section 9.2 if samples become unsalvageable because of environmental 
factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient withdraws 
consent. 
9
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
9.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
9.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
9.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-


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800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety Reports 
that meet the definition of an unanticipated problem will need to be reported per these policies.
9.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
9.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
9.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
9.4.1
Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (every 1-2 weeks) when patients are being 
actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in Section 
9.2.1 will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 

All serious adverse events must be reported immediately by telephone to the Principal 
Investigator, Dr. Robert Kreitman (301-480-6187).  Call 301-496-1211 after hours.

A summary of the completed study will be submitted to IDB/CTEP within 2 months of 
study completion.  A status report will be submitted and presented at upcoming NCI 
meetings as requested.  


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10 SPONSOR PROTOCOL/SAFETY REPORTING
10.1.1 Phase 2 and 3 Adverse Event Reporting Table
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  Reporting Requirements for Adverse 
Events That Occur Within 30 Days1 of the Last Dose of the Investigational Agent
Grade 1
Grade 2 Grade 2 Grade 3
Grade 3
Grades
4 & 5
Grades
4 & 5
Unexpecte
d 
and 
Expected
Unex-
pected
Expecte
d
Unexpected
Expected
Unex-
pected 
Expecte
d
with 
Hospitali
-zation
without 
Hospitali
- zation
with 
Hospitali
-
zation
without 
Hospitali
-
zation
Unrelate
d
Unlikely
Not
Required
Not
Require
d
Not
Require
d
10 
Calendar
Days
Not
Required
10 
Calendar
Days
Not
Required
10
Calenda
r
Days
10
Calenda
r
Days
Possible
Probable
Definite
Not
Required
10 
Calenda
r
Days
Not
Require
d
10 
Calendar
Days
10 
Calendar
Days
10 
Calendar
Days
Not
Required
24-
Hour;
5 
Calenda
r
Days
10
Calenda
r
Days
1
Adverse events with attribution of possible, probable, or definite that occur greater than 
30 days after the last dose of treatment with an agent under a CTEP IND require reporting as 
follows:
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for:
·
Grade 4 and Grade 5 unexpected events 
CTEP-AERS 10 calendar day report:
·
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
·
Grade 5 expected events
2
Although a CTEP-AERS 24-hour notification is not required for death clearly related to 
progressive disease, a full report is required as outlined in the table.
December 15, 2004
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided.
10.1.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) for LMB-2 (anti-Tac 
(114)-PE-38, NSC 676422)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the Specific 


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Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification. The CAEPR does not provide frequency data; refer to the Investigator's 
Brochure for this information. Below is the CAEPR for LMB-2 (Anti-Tac (114)-PE-38).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required.


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Version 1.3, July 26, 20131
Adverse Events with Possible
Relationship to LMB-2 (Anti-Tac[114]-PE-38)
(CTCAE 4.0 Term)
Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
(formerly known as ASAEL) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
CARDIAC DISORDERS
Left ventricular systolic dysfunction
Left ventricular systolic dysfunction 
(Gr 2)
Pericardial effusion
Pericardial effusion (Gr 2)
Sinus tachycardia
GASTROINTESTINAL DISORDERS
Abdominal distension
Diarrhea
Nausea
Nausea (Gr 2)
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS
Edema face
Edema face (Gr 2)
Edema limbs
Edema limbs (Gr 2)
Fatigue
Fatigue (Gr 2)
Fever
Fever (Gr 2)
IMMUNE SYSTEM DISORDERS
Allergic reaction
Allergic reaction (Gr 2)
INVESTIGATIONS
Alanine aminotransferase increased
Alanine aminotransferase increased 
(Gr 2)
Alkaline phosphatase increased
Aspartate aminotransferase increased
Aspartate aminotransferase increased 
(Gr 2)
CPK increased
Creatinine increased
Creatinine increased (Gr 2)
GGT increased
Platelet count decreased
Platelet count decreased (Gr 2)
Weight gain
Weight gain (Gr 2)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Hypoalbuminemia
Hypoalbuminemia (Gr 2)


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MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS
Back pain
Chest wall pain
Myalgia
Myalgia (Gr 2)
NERVOUS SYSTEM DISORDERS
Dizziness
Headache
Headache (Gr 2)
RENAL AND URINARY DISORDERS
Hematuria
Hematuria (Gr 2)
Proteinuria
Proteinuria (Gr 2)
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS
Dyspnea
Pleural effusion
VASCULAR DISORDERS
Capillary leak syndrome
Capillary leak syndrome (Gr 2)
Hypotension
Hypotension (Gr 2)
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol 
and the agent should be included in the e-mail.
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3Muscle weakness includes Generalized muscle weakness, Muscle weakness left-sided, Muscle 
weakness lower limb, Muscle weakness right-sided, Muscle weakness trunk, and Muscle weakness 
upper limb under the MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS SOC.
Also reported on LMB-2 (Anti-Tac[114]-PE-38) trials but with the relationship to LMB-2 
(Anti-Tac[114]-PE-38) still undetermined:
CARDIAC DISORDERS - Acute coronary syndrome; Myocardial infarction; Paroxysmal atrial 
tachycardia; Restrictive cardiomyopathy; Supraventricular tachycardia
EYE DISORDERS - Blurred vision; Eye pain
GASTROINTESTINAL DISORDERS - Dyspepsia
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Non-
cardiac chest pain
IMMUNE SYSTEM DISORDERS - Anaphylaxis
INFECTIONS AND INFESTATIONS – Infection2
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall
INVESTIGATIONS - Blood bilirubin increased; Cardiac troponin I increased; Fibrinogen 
decreased; Weight loss


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METABOLISM AND NUTRITION DISORDERS - Hypokalemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle 
weakness3; Musculoskeletal and connective tissue disorder -  Other (acute rhabdomyolysis); Neck 
pain; Pain in extremity
NERVOUS SYSTEM DISORDERS - Dysgeusia; Presyncope; Syncope; Vasovagal reaction
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Pneumonitis
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Rash maculo-papular
VASCULAR DISORDERS - Hypertension
Animal Data: The following toxicities have been observed in animal studies with LMB-2 
(Anti-Tac[114]-PE-38):
leukocytosis
Note: LMB-2 (Anti-Tac[114]-PE-38) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent.

Expedited AE reporting timelines defined:
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS report 
within 5 calendar days of the initial 24-hour report.
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 
10 calendar days of the investigator learning of the event. 

Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of designation as 
expected or unexpected and attribution with the exception of events listed in Section 3.3.1 
(Definition of DLT).

Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND.

Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports.

An expedited AE report for all protocols utilizing agents under a CTEP IND must be 
submitted electronically to CTEP via CTEP-AERS.

Adverse events that fulfill the 24-hour reporting requirement must be reported 
electronically via CTEP-AERS at http://ctep.cancer.gov.  In the rare event when Internet 
connectivity is disrupted, a 24-hour notification is to be made to CTEP by telephone at 
301-897-7497.  Once Internet connectivity is restored, a 24-hour notification phoned in 
must be entered electronically into CTEP-AERS by the original submitter at the site.

Templates must be FAXED to CTEP at 301-230-0159

When internet connectivity is restored, a report submitted on a paper template must be 
entered into electronic CTEP-AERS by the original submitter of the report at the site. All 
expedited AE reports must also be sent to the local IRB according to local IRB policy and 
procedure.


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
All AEs reported via CTEP-AERS must also be reported via the routine AEs reporting 
defined by the protocol.
10.2 EXPECTED ADVERSE EVENTS
10.2.1 Grade 4: none
10.2.2 Grade 3: AST, SGOT, ALT, SGPT, GGT, Albumin, serum-low (hypoalbuminemia), 
platelets.
10.2.3 Grade 2:  
10.2.3.1 Blood Bone Marrow: platelets, hemoglobin, Neutrophils/granulocytes (ANC/AGC), 
Leukocytes (total WBC), lymphopenia.
10.2.3.2 Cardiovascular: Acute Vascular/Capillary Leak syndrome (CTEP defined section 
3.3.1.1), edema, hypotension, pericardial effusion/pericarditis, PTT, INR (International 
Normalized Ratio of prothrombin time).
10.2.3.3 Constitutional: fatigue, fever, weight gain.
10.2.3.4 GI: nausea, vomiting, diarrhea.
10.2.3.5 Hepatic: AST, SGOT, ALT, SGPT, GGT, Albumin, serum-low (hypoalbuminemia), 
alkaline phosphatase.
10.2.3.6 Metabolic/Laboratory: bicarbonate, CPK, Calcium, serum-low (hypocalcemia), 
Potassium, serum-low (hypokalemia), Magnesium, serum-low (hypomagnesemia), 
Sodium, serum-low (hyponatremia), Phosphate, serum-low (hypophosphatemia).
10.2.3.7 Musculoskeletal: muscle weakness.
10.2.3.8 Pain: myalgia.
10.2.3.9 Renal: creatinine, proteinuria.
10.3 RECORD KEEPING
10.3.1 Complete records must be maintained on each patient; these will consist of the hospital 
chart with any supplementary information obtained from outside laboratories, a copy of the 
signed consent, radiology reports, or physician’s records.  These records will serve as the 
primary source material that forms the basis for the research record.  The primary source 
documentation will assure the following:  1. on-study information, including patient 
eligibility data and patient history, 2. flow sheets, 3. specialty forms for pathology, 
radiation, or surgery, and 4. off-study summary sheets, including a final assessment by the 
treating physician.
10.3.2 An electronic research record including the following items will be kept on the study 
database: 1. On/off study dates, 2. response and progression dates, 3. drug administration 
with dose and cycle, 4. toxicity with grade and attribution, 5. concomitant medications.
10.3.3 All patients must have given an informed consent and an on-study confirmation of 
eligibility form will be filled out before entering on the study.  
10.3.4 The data will be submitted electronically from the study database to CTEP.
11 REGULATORY AND OPERATIONAL CONSIDERATIONS
11.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 


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termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
11.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
11.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 


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a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
11.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site and by NCI CCR research staff will be secured and password protected. At the end of 
the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.


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12 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION
12.1 IMMUNOTOXIN PHARMACEUTICAL SECTION
LMB-2 (NSC 676422)
Other Names: Anti-TAC (Fv) PE 38.
Classification: Recombinant immunotoxin.
Description: LMB-2, a 63-kD single-chain recombinant immunotoxin, is comprised of variable 
regions of the light and heavy chains (Fv) of a murine monoclonal antibody (anti-TAC) against 
the 55-kD subunit of the low affinity interleukin-2 receptor (IL-2R) fused to a truncated derivative 
of Pseudomonas exotoxin, (PE 38).
Mode of Action: The human IL-2R (also known as TAC antigen and CD25) plays an important 
role in lymphocyte differentiation and immune response regulation. It is overexpressed on various 
types of malignant cells and lymphocytes mediating autoimmune disease, making IL-2R a 
potential cancer therapy target. Anti-TAC is a murine monoclonal antibody that binds to the IL-
2R alpha with high affinity blocking the interaction of IL-2 with IL-2R. Pseudomonas exotoxin 
(PE) 38 is a truncated portion of a protein secreted by P. aeruginosa that lacks the native cell-
binding site and kills mammalian cells by catalyzing irreversible ADP-ribosylation and 
inactivating elongation factor 2, halting protein synthesis. LMB-2 selectively binds to cells bearing 
IL-2R and is internalized to release PE 38, causing cell destruction.
How Supplied: LMB-2 is available as a sterile frozen solution in phosphate buffered saline and 
may be vialed and labeled at different concentrations (i.e. 420 mcg/mL, 436 mcg/mL, 484 
mcg/mL, 534 mcg/mL, etc.). The pH is approximately 7.4.
Please note: The concentration of LMB-2 may vary from lot to lot. Please check the label for 
the correct concentration prior to the preparation of each dose.  
Preparation: Thawing instructions: Warm vials in the hand for 10 to 20 seconds before placing 
them in a water bath to thaw. Place vials in a cup of room temperature (15-30ºC) sterile water for 
injection, USP such that when the vial is upright, the water level will be at the neck of the vial. 
Visually inspect the vials after thawing. Do not use if solution appears turbid. Do not shake; 
proteins can foam and may denature.
LMB-2 should only be diluted in 0.2% human serum albumin (HSA) in 0.9% sodium chloride. 
Please note: Particulate matter was found in vials from lots 103037 and 103038 during the 60-
month stability testing. The lots met all other release specifications, including composition and 
potency. Tests were conducted with a Millex GV 25 mm (0.2 micron) filter to remove the 
particulates. Post filtration studies demonstrated minimal loss of potency. LMB-2 undiluted 
solution must be filtered with a 0.2 micron low protein binding Millex GV filter prior to 
adding to the 0.2% HSA in 0.9% sodium chloride.
IV infusion: The required amount of LMB-2 (436 mcg/mL, the undiluted vial) will be diluted 
with 0.2% HSA in 0.9% sodium chloride to a total volume of 50 mL in an empty Partial Additive 
Container (PAB®). Filter LMB-2 with a 0.2 micron low protein binding Millex GV filter prior to 
adding to the 0.2% HSA in 0.9% sodium chloride. Agitate gently to disperse.
A PAB® container is a standard, commonly-used parenteral product container that is composed of 


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an ethylene and propylene co-polymer without plasticizer. It is an empty sterile bag to which 
pharmacy personnel add the various components specified by the protocol to a specific prescribed 
volume. It is preferred over other plastic containers because it is manufactured without 
polyvinylchloride (PVC) and plasticizers such as di-(2-ethylhexyl) phthalate (DEHP) with which 
some chemotherapy agents interact. 
Storage: Intact vials should be stored in the freezer at -70ºC or below. The intravenous admixture 
should be stored in the refrigerator (2-8ºC). Thawed vials should not be refrozen.
Stability: Intact vials of LMB-2 are stable for at least 5 years when stored at -70ºC. Once thawed, 
intact vials are stable for 24 hours when stored in the refrigerator (2-8ºC) and for 4 hours when 
stored at room temperature (15-30ºC). LMB-2 is stable for 25 hours at 2-8ºC once further diluted 
in 0.2% HSA in 0.9% sodium chloride. Vials cannot be refrozen.
Route(s) of Administration: Intravenous (IV).
Method of Administration: Treatment doses should be infused intravenously over 30 minutes.
Patient Care Implications: If necessary, supportive care for vascular/capillary leak syndrome 
should be instituted and may include fluid and electrolyte management, diuresis, albumin, 
glucocorticoids, and cardiovascular support. Other toxicities should be managed clinically.
Anti-emetics or hematologic growth factors are not expected to be required but are permitted if 
indicated. Patients who develop nausea may be treated with a serotonin 5-HT3 receptor antagonist 
for at least 24 hours after their last episode of nausea. Other antiemetics, such as prochlorperazine, 
metoclopramide, or lorazepam may be used in addition if necessary.
Patients who develop myalgias may be given acetaminophen 650 mg to 1000 mg every 6 hours 
until 24 hours after completing the last dose of LMB-2. 
It may then be given as needed. Patients may receive NSAIDs or narcotics if acetaminophen is 
inadequate. Patients who develop temperatures >38.0ºC may receive scheduled acetaminophen 
650 mg to 1000 mg every 6 hours until 24 hours after completing the last dose of LMB-2. It may 
then be given as needed.
Emergency medications should be available in the treatment unit in the event of an anaphylactic 
reaction. Allergic reactions should be treated acutely with antihistamines, and if needed, with 
glucocorticoids, fluids, and/or epinephrine.
12.1.1 Toxicity of LMB-2
12.1.1.1 Preclinical studies.  In a GLP toxicology study, 4 Cynomolgus monkeys received 20 
mcg/Kg·dose days 1, 3 and 5 with no significant toxicity.  Another four monkeys were 
then given 300 mcg/Kg·dose days 1, 3 and 5 and experienced dose-limiting toxicity with 
anorexia and 2 to 4-fold transaminase elevations.  The LD10 and LD50 in mice were 200 
and 257 mcg/Kg·dose every other day for 3 doses.  The cause of death was liver damage.
12.1.1.2 Phase I grade III-IV toxicities.  Adverse events were reported in relationship to treatment 
cycle.  Grade III-IV toxicities included reversible transaminase elevation, fever, CK 
elevation, cardiomyopathy, thrombocytopenia, allergic reaction, and diarrhea.
12.1.1.3 The most common grade I-II toxicities were transaminase elevation, fever, 
hypoalbuminemia, and fatigue.  Other grade I-II toxicities included vascular leak 


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syndrome, weight gain, hypotension, nausea, pericardial effusion, allergy, proteinuria, 
and increased creatinine.
12.1.2 Agent Ordering and Agent Accountability
12.1.2.1 NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.) The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution.
12.1.2.2 LMB-2, NSC 676422  may be requested by completing a Clinical Drug Request (NIH-
986) and mailing it to the Drug Management and Authorization Section, PMB, DCTD, 
NCI, 9000 Rockville Pike, EPN Room 7149, Bethesda, MD 20892-7422 or faxing it to 
(301) 480-4612.  For questions call (301) 496-5725.
12.1.2.3 Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record (DAR) Form.  (See the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.)
12.2 CHEMOTHERAPY PHARMACEUTICAL SECTION
12.2.1 Cyclophosphamide (CTX, Cytoxan, NSC-26271)
12.2.1.1 Availability – Cyclophosphamide will be obtained commercially and is supplied as a 2 
gram lyophilized powder.
12.2.1.2 Storage and Stability - The vials are stored at room temperature and Reconstituted vials 
and diluted solutions are stable under refrigeration for 14 days.
12.2.1.3 Preparation - will be reconstituted with sterile water for injection to yield a final 
concentration of 20 mg/ml as described in the package insert.
12.2.1.4 Route of Administration - The cyclophosphamide used in this regimen will be mixed in 
100 ml 0.9% sodium chloride injection and given as an IVPB over 60 minutes. Patients 
will receive hydration prior to and after administration.
12.2.1.5 Toxicity:
12.2.1.5.1 Nausea and vomiting - variable; symptomatically improved with standard anti-emetics 
and/or benzodiazepines (e.g., lorazepam).
12.2.1.5.2 Water retention – cyclophosphamide metabolite may cause renal tubular injury which 
may mimic the clinical picture of inappropriate antidiuretic hormone secretion, usually 
manifested 4-8 hrs after I.V. administration, necessitating frequent accurate (q 1-2 hrs) 
assessment of intake, urine output and urine specific gravity.  Effect can be counteracted 
by furosemide.  Fluid restriction is not feasible during administration of high dose 
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12.2.1.5.3 Cardiomyopathy - cyclophosphamide may cause severe, sometimes lethal, hemorrhagic 
myocardial necrosis or congestive cardiomyopathy.  Patients may present with 
congestive cardiomyopathy as late as 2 weeks after the last dose of cyclophosphamide.  
The clinical syndrome has been observed in patients receiving a higher dose of 
cyclophosphamide (1200 mg/m2) used in transplant protocols.
12.2.1.5.4 Hemorrhagic cystitis - this is a serious, potentially life-threatening complication related 
to the interaction of cyclophosphamide metabolites and the bladder epithelium. 
Although subclinical hematuria is not uncommon at this dose level, clinically significant 
hematuria or serious hemorrhage can usually be avoided by maintaining a high urine 
volume and frequent voidings. The patient will receive 1 liter 0.9% sodium chloride 
prior to each dose of cyclophosphamide.
12.2.1.5.5 Careful monitoring of serum and urine electrolytes is mandated.  Furosemide may be 
required to insure this diuresis.  Bladder irrigation (Murphy’s drip) may be used for 
control of significant hematuria, where saline is infused into the bladder to prevent clot 
formation.
12.2.1.5.6 Sterility
12.2.1.5.7 Myelosuppression
12.2.1.5.8 Less common but serious complications include pulmonary fibrosis and secondary 
malignancies. Less common but reversible toxicities include alopecia and skin rash.
12.2.2 Fludarabine (Fludara, Berlex Laboratories)
12.2.2.1 Availability - Fludarabine monophosphate is commercially available as Fludarabine, and 
is supplied as a white, lyophilized powder.  Each vial contains 50 mg of fludarabine 
phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH.  Fludara is stored at 
room temperature.
12.2.2.2 Storage and Stability - Reconstituted Fludarabine is chemically and physically stable for 
24 hours at room temperature, or for 48 hours if refrigerated.  Because reconstituted 
Fludarabine contains no antimicrobial preservative, care must be taken to assure the 
sterility of the prepared solution; for this reason, reconstituted FLUDARA IV should be 
used or discarded within 8 hours.
12.2.2.3 Preparation - Fludarabine should be prepared for parenteral use by aseptically adding 
Sterile Water for Injection, USP.  When reconstituted with 2 ml of Sterile Water for 
Injection, each ml of the resulting solution will contain 25 mg of Fludarabine Phosphate, 
25 mg of mannitol, and sodium hydroxide to adjust the pH to 7-8.5.  Fludarabine will be 
mixed in 100 ml of 0.9% NaCl.
12.2.2.4 Administration - Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration.  Fludarabine will be infused I.V. over 30 
minutes.
12.2.2.5 Toxicity - Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, 
nausea, vomiting, stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin 
rashes, myalgia, headache, agitation, hearing loss, transient episodes of somnolence and 
fatigue, autoimmune hemolytic anemia, autoimmune thrombocytopenia, paresthesias, 
peripheral neuropathy, renal, and pulmonary toxicity (interstitial pneumonitis).  Severe 
fatal CNS toxicity presenting with loss of vision and progressive deterioration of mental 
status were encountered almost exclusively after very high doses of fludarabine 


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monophosphate.  Such toxicity has only rarely been demonstrated at the 25-30 
mg/m2/day dosage of fludarabine.  Very rarely described complications include 
transfusion-associated graft-versus-host disease, thrombotic thrombocytopenic purpura, 
and liver failure. Tumor lysis syndrome following fludarabine administration has been 
observed, especially in patients with advanced bulky disease.  Opportunistic infections 
(protozoan, viral, fungal, and bacterial) have been observed post-fludarabine, especially 
in heavily pre-treated individuals, and in individuals receiving fludarabine combined with 
other agents.
12.2.3 Filgrastim (granulocyte colony-stimulating factor, G-CSF, filgrastim, Neupogen)
12.2.3.1 Availability – Filgrastim will be obtained commercially and is supplied in 300 g/1 ml 
vials.
12.2.3.2 Storage and Stability – filgrastim should be refrigerated and not allowed to freeze. The 
product bears the expiration date. It is generally stable for at least 10 months when 
refrigerated.
12.2.3.3 Preparation – The appropriate dose is drawn up into a syringe.
12.2.3.4 Administration – filgrastim will be given as a daily subcutaneous injection. Prescribers 
will be permitted to round down to doses within 10% of the patient’s calculated dose to 
use the drug cost-effectively.
12.2.3.5 Toxicities - The side effects of filgrastim are skin rash, myalgia and bone pain, an increase 
of preexisting inflammatory conditions, enlarged spleen with occasional associated low 
platelet counts, alopecia (with prolonged use) and elevated blood chemistry levels.
12.2.3.6 Relevance to protocol – Rather than wait until patients have fever and neutropenia, since 
ATL patients are quite immunosupressed even without neutropenia, filgrastim will be 
given prophylactically after grade III or higher neutropenia is observed.  Filgrastim will 
be administered at 300 mcg qd from d5 to 1 day prior to the next cycle of FC or until the 
ANC > 5000.
12.3 PREMEDICATIONS (ABBREVIATED PHARMACEUTICAL SECTION) 
These agents will be provided by the Clinical Center Pharmacy and will be given orally.  Please 
refer to the package inserts for complete pharmaceutical information on these products.
12.3.1 Acetaminophen (Tylenol):  Side effects are unlikely. Regular use of acetaminophen can 
cause liver damage especially at high doses (>4000 mg/day or >12 regular strength tablets 
per day).  To minimize this possibility patients should not take over-the-counter products 
containing acetaminophen during the time periods they are taking scheduled 
acetaminophen doses on this study.
12.3.2 Ranitidine (Zantac):  Side effects include tiredness, dizziness, headache, and diarrhea.
12.3.3 Hydroxyzine (Atarax):  Side effects include sleepiness, dizziness, restlessness, and 
irritability.


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14 APPENDICES
14.1 APPENDIX A: SCHEMA & CALENDAR
Pre13
Pre-
Cycle 6
d1
d2
d3
d5
d7
d8-11
F/U14
FC administered cycles 1-7
X
X
X
LMB-2 administered cycles 2-7
X
X
X
Immunohistochemistry
X1
Hepatitis B & C9, HIV, PFTs, 
CMV/EBV PCR
X2
Lipid panel, fibrinogen, 
thrombin time, TSH, Free T3, 
Free T4, T3, T4, 24 hour urine 
for creatinine clearance, protein, 
and UPEP, Exercise Stress Test 
(ETT)
X10
Pregnancy test
X3
Physical exam, & if relevant, 
dermatology consult, clinical 
photography
X4
X
X
Flow cytometry
X4
X7
X
X
Imaging with CT chest, 
abdomen, pelvis, neck, MRI, 
U/S, or PET/CT (PI discretion)
X4
X
X
CBC + diff, Chemistries11, 
urinalysis
X5
X7
X
X
X
X
X
X
PT, PTT, IgA, IgG, IgM, GGT, 
haptoglobin, amylase, lipase
X5
X
X
X
sCD25 (& other tumor 
markers), 
X5
X7
X
X
X
Neutralizing antibodies
X5
X7
X
X
Pharmacokinetic Studies (per 
section 3.4)
X
X
X
CRP, beta-2-microglobulin
X5
X
X
X
X
Echocardiogram
X2
X
Chest X-ray
X12
X
Electrocardiogram (EKG)
X1
X7
X8
X


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1Any time before enrollment
2Within 2 months before enrollment
3Within 1 week before enrollment
4Within 2 weeks before enrollment 
5Within 3 days before enrollment
6 Begin cycle 2 on day 14-43 and cycles 3-7 on day 21-50 of the previous cycle.  Do precycle 
tests 0-3 days before the cycle begins.  Day 1 is considered precycle.
7 Also draw at study exit or completion
8 EKG to be performed 10-30 min after end of infusion day 5 and before dosing day 7
9HBsAg and core Ab
10Within 28 days before enrollment
11 Chemistries (Chem-20): Albumin, alkaline phosphatase, ALT, AST, bilirubin, BUN, 
calcium, CK, chloride, CO2, creatinine, direct bilirubin, glucose, potassium, LDH, 
magnesium, sodium, phosphorus, total protein, uric acid
12Chest X-ray pre-cycle if no chest CT has been obtained
13 EKG, CRP and beta 2 microglobulin, PT/PTT, IgA, haptoglobin and urinalysis are baseline 
tests, all others are used to determine research eligibility
14 Follow-up tests performed at up to 6-month intervals, at discretion of PI


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14.2 APPENDIX B: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Descriptions
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

ICF_002.pdf: 













ICF_006.pdf: 
IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Robert Kreitman, M.D.
STUDY TITLE:
Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide 
for Adult T-Cell Leukemia
STUDY SITE:
NIH Clinical Center
Cohort: 
Standard 
Consent Version:  
1/31/2023
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:Robert Kreitman, M.D. 
Phone: 301-480-6187 
Email: kreitmar@mail.nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research.  
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
Description of Research Study
This is a clinical trial for the treatment of adult T-Cell leukemia with an experimental drug called 
LMB-2 after the combination of the chemotherapy drugs fludarabine and cyclophosphamide (FC).  
The 2 drugs in addition to LMB-2 are abbreviated FC.  You will be treated with FC on days 1, 2, 


IRB NUMBER: 09C0025
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and day 3 for each of 7 cycles.  The beginning of the 2nd cycle is about 2 weeks after first, and after 
that the cycles are about 3 weeks apart.  Starting with the 2nd cycle, on the last day of FC (day 3), 
you will be treated with LMB-2 every other day for 3 doses.  After this 2nd cycle, you can be 
retreated with FC/LMB-2 a maximum of 5 more times provided certain requirements are met.  
LMB-2 is a recombinant immunotoxin that has been shown to kill leukemia and lymphoma cancer 
cells that have a protein on their surface called “CD25”.  To be eligible for treatment on this study, 
your malignant cells must have CD25 on their surface.  However, the presence of CD25 on your 
malignant cells does not guarantee that you will be enrolled on the protocol.  We plan to include 
at most 48 patients on this trial.
LMB-2 is an experimental drug called a recombinant immunotoxin. Each LMB-2 molecule is 
made up of two parts: a protein part that binds or targets a cancer cell and a toxin (a type of poison) 
part that goes inside and kills the cancer cell.  The binding part is part of an antibody that binds to 
human CD25, a protein on your leukemia or lymphoma cells.  The toxin portion of LMB-2 is 
naturally produced by bacteria.  In laboratory experiments using leukemia or lymphoma cells 
outside the body, LMB-2 kills cells which have CD25 on their surface.  LMB-2 also causes a 
significant decrease in the size of tumors in mice that were given doses similar to those used in the 
first human trial of LMB-2.
A preliminary study of LMB-2 has been performed at the National Cancer Institute (NCI) in which 
39 patients with various leukemias and lymphomas were treated.  In that trial, patients with hairy 
cell leukemia (4 patients), cutaneous T cell lymphoma (1), adult T-cell leukemia/lymphoma (1), 
Hodgkin’s disease (1) and chronic lymphocytic leukemia (1) had reduction in their tumors.  
LMB-2 Treatment
LMB-2 will only be given to patients at the NIH Clinical Center.  Each cycle of LMB-2 is given 
by an intravenous (into a vein) infusion every other day for 3 doses.  You will receive up to 6 
cycles of LMB-2 every 3 weeks unless you develop worsening of disease, serious side effects, or 
voluntarily withdraw.    
A small amount of blood (up to 10 teaspoons) will be drawn before, during, and after treatment.  
These blood tests allow us to measure how much LMB-2 is in your blood, the effects of LMB-2 
on your cancer cells in your blood and monitor for side effects.  We will also do blood tests prior 
to each cycle and during each cycle to know how your immune system is interacting with LMB-
2.
Before each cycle and in follow-up visits you will undergo repeat disease evaluation.  This will 
include a careful physical examination, blood and urine tests, and tumor-measuring scans like 
computed tomography (CT) scan.  If these studies help us understand how your leukemia or 
lymphoma is reacting to FC chemotherapy and LMB-2, we may ask for your permission to repeat 
these tests again prior to other cycles.
The infusion of LMB-2 takes 30 minutes.  You will also receive a liter (about 8 cups) of fluid 
through an IV or central venous catheter before and after each dose of LMB-2.   A central venous 
catheter (CVC) is a plastic IV tube that is placed in a large vein that leads to the heart.  You may 
already have a CVC in place.  If not, depending on the size of your arm veins, one may need to be 
placed prior to treatment.  A CVC makes treatment on this study easier and less painful by 


IRB NUMBER: 09C0025
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decreasing the need for IVs and needle sticks to draw blood.  If a CVC is required or requested, 
you will be asked to review another consent form and give consent prior to its placement.
You will receive LMB-2 as an inpatient (admitted to the hospital) or as an outpatient (not admitted 
to the hospital).  If the infusions are well tolerated, you may return home after about 1 week 
(possibly longer if complications occur).  After returning home, you will have blood tests done 
weekly and the results will be faxed to us by your local physician.  During the course of this study, 
you may also require other treatments such as transfusions and antibiotics.  Hospitalization may 
be needed if complications develop.  If there is evidence that therapy with LMB-2 is no longer 
effective, it will be discontinued.
Fludarabine and cyclophosphamide chemotherapy 
One goal of the fludarabine and cyclophosphamide (FC) chemotherapy (FC) is to prevent 
neutralizing antibodies (antibodies your body makes which inactivate LMB-2) from forming once 
you receive LMB-2.  Since LMB-2 contains a bacterial toxin, your body may make antibodies to 
it which will eliminate the ability of LMB-2 to bind to malignant cells and kill them.  Experience 
in patients suggests but does not prove that FC may decrease the risk that you would make 
neutralizing antibodies to LMB-2.  Another goal for the FC is to help the LMB-2 work better by 
first making the tumor smaller.  Because the FC and LMB-2 are given so close together, it may be 
impossible to determine whether the LMB-2 is helping as well.  However, during the trial we will 
be determining whether you respond well and make antibodies to LMB-2, and also other measures 
of your immunity.  FC chemotherapy will be administered intravenously, daily for 3 days (days 1-
3).  It is possible that FC may harm your immune system without preventing neutralizing 
antibodies to LMB-2.  The FC chemotherapy could cause problems because of a decreased number 
of neutrophils, which are a type of infection-fighting white blood cell.  If you have fever and low 
neutrophils, you may need to take filgrastim (G-CSF) then and on future cycles where FC is given.  
G-CSF is given by an injection under the skin starting on day 5 and continuing until the absolute 
neutrophil count has exceeded 5000, or 1 day prior to the next cycle.  The LMB-2 will begin on 
the 3rd day of the FC chemotherapy and will be repeated every other day for a total of 3 doses.  
Blood will be drawn prior to each cycle of LMB-2 to determine if the level of neutralizing 
antibodies is too high to give additional LMB-2.  If it is too high, further LMB-2 will not be given.  
Because the result may not be known before the next cycle, you may receive one cycle of LMB-2 
in the presence of antibodies.  If you don’t make antibodies and your disease is stable or decreasing 
with FC and LMB-2, you may continue to receive FC and LMB-2 for up to a total of 6 cycles each 
beginning 3 weeks apart.  
What Happens After This Treatment is Completed?
This depends on how you have responded to the experimental therapy.  If you do not have evidence 
that the disease is worsening, we will schedule visits to the Clinical Center approximately every 6 
months for follow-up examination and tests (blood draws and imaging tests, if needed).  If the 
disease worsens then you may need other therapy.  At that time, you will be given the opportunity 
of participating in additional research protocols that may be appropriate for you. If no such 
protocols are available, you will be returned to the care of your local physician.  It is important to 
stress that participation in this protocol does not constitute a promise of long-term medical care 
here at the Clinical Center.  If there is no research study that is suitable for you and your stage of 
disease, you will be returned to the care of your private doctor or to a clinic in your local 


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IRB APPROVAL DATE: 2/27/2023
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community.  It is conceivable that participation in this study may make you ineligible to participate 
in certain other research protocols because the requirements for entry onto these protocols may 
disallow patients who have already been treated with certain drugs or who have had certain side 
effects from previous treatment.  You may decide now not to receive treatment on this protocol, 
or you may choose at any point in time to stop the treatment and withdraw from the protocol; in 
either case you will be returned to the care of your referring physician.
Risks or Discomforts of Participation
Administration of FC and LMB-2 will be through a central venous catheter (CVC) or a peripheral 
I.V.  The CVC is inserted by experienced staff using local anesthesia.  The risks associated with 
the procedure include pain, bleeding, infection, and development of air in the chest.  However, 
these complications are rare.  Air in the chest outside the lung may require temporary placement 
of a chest tube by a surgeon.  The risks of chest tube placement include pain, bleeding, and 
infection.  Other risks of the catheter include infection and clotting of your veins, which could 
require removal of the catheter for treatment.  These risks will be explained to you in more detail 
at the time of insertion.  When a peripheral line is used, there is a small risk of infection, clot or 
bleeding at the site of the IV line.  There is also a risk of some of the drug leaking out, also called 
extravasating.  If that occurs there may be some destruction of skin tissue in a limited area.  Patients 
are urged to alert the study physicians at the first sign of any skin changes, for example redness or 
tenderness, around the infusion site but also with any discomfort in the involved extremity as well.  
If there is any evidence of toxicity from leaking, the infusion will be held until a central line can 
be placed for the infusion of drug.  In addition, any toxic effects to the skin will be treated to the 
fullest extent possible.
LMB-2:
There is limited experience with LMB-2 in humans.  In the Phase I trial, a total of 39 patients 
received 65 cycles of LMB-2.  On that trial, all side effects of LMB-2 went away when LMB-2 
was stopped.  In some cases, this required additional medical treatments.  Possible side effects of 
LMB-2 are summarized below:
Possible:

Bloating, diarrhea

Anemia which may require blood transfusions

Pain

Dizziness, headache

Swelling of the body

Fluid in the body which may cause low blood pressure, shortness of breath, swelling of 
ankles

Abnormal heartbeat

Decrease in heart's ability to pump blood during the "active" phase of the heartbeat (systole)

Diarrhea

Nausea or the urge to vomit

Vomiting

Swelling of the extremities (arms and/or legs)

Fatigue or tiredness


IRB NUMBER: 09C0025
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
Fever

Abnormal reaction of the body to substances, called allergens, that are contacted through 
the skin, inhaled into the lungs, swallowed, or injected (allergic reaction)

Bruising, bleeding

Increased blood level of a liver enzyme (ALT/SGPT)

Increased blood level of a liver or bone enzyme (alkaline phosphatase)

Increased blood level of a liver enzyme (AST/SGOT)

Increased blood level of enzyme (creatine phosphokinase) from muscle

Increased blood level of creatinine (a substance normally eliminated by the kidneys into 
the urine)

Decreased number of a type of blood cell that help to clot blood (platelet)

Weight gain, loss of appetite

Decreased levels of a blood protein called albumin

Muscle pain

Blood in the urine

More protein in the urine than usual, often a sign of kidney disease

Shortness of breath

Increase in the number and size of the pores in the capillaries (small blood vessels) which 
causes leakage of fluid from the blood to the tissue spaces, resulting in dangerously low 
blood pressure, swelling and multiple organ failure

Heart failure which may cause shortness of breath, swelling of ankles, and tiredness

Low blood pressure which may cause feeling faint
A common side effect of immunotoxin drugs similar to LMB-2 is vascular leak syndrome, where 
fluid leaks out of blood vessels into the skin, lungs, and other organs.  The symptoms may include 
swelling, weight gain, loss of blood pressure, shortness of breath.  This can be severe, and although 
vascular leak syndrome usually gets better, it may require intubation and can be fatal.  Patients 
may have protein leak into the urine.  Other side effects associated with immunotoxins include 
edema (swelling), aches and pains of the muscles, joints, and/or bones, headache, fatigue, 
dizziness, blurred vision, lowering of normal blood cells including the red cells (with risk of 
anemia), white cells (with risk of infection), and platelets (with risk of bleeding), abnormal blood 
clotting tests and risk of bleeding, muscle damage, diarrhea, constipation, stomach or intestinal 
ulcers, stomach pain, indigestion, dehydration, kidney damage, abnormal blood salt levels, fluid 
leak in the lungs with shortness of breath, inflammation of the pancreas gland (the organ involved 
in diabetes), chills, decreased function of the thyroid gland, and neurologic problems including 
sleepiness, decreased level of alertness, weakness, painful tingling (“pins and needles”), numbness 
(decreased feeling), and coma.  It is not known whether LMB-2 poses a risk to the developing 
fetus and breast-fed infants.  All patients with childbearing potential, both male and female, must 
agree to use effective measures of contraception while on study.  Patients that are pregnant or 
breast-feeding will be excluded from this trial because the effect of LMB-2 on a developing fetus 
or a nursing infant is unknown and potentially harmful.  Whether you are a male or female, you 
should practice contraception for at least one month after receiving the last dose of LMB-2 or 
chemotherapy on this trial.


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A condition known as hemolytic uremic syndrome (HUS) has been seen with related immunotoxin 
drugs although not with LMB-2.  HUS is a potentially fatal problem that can cause fever, anemia 
(low red blood cell count), thrombocytopenia (low platelet count), bleeding, stroke, and kidney 
failure.  Treatment of severe HUS includes a procedure known as plasma exchange or 
plasmapheresis, where the liquid portion of the blood (plasma) is removed from the body and 
replaced with plasma from blood donors using a special machine.  Even with treatment, HUS may 
lead to death or permanent kidney and/or brain damage.  Adverse reactions associated with 
plasmapheresis are rare and are generally mild.  They include pain and bruising at the insertion 
site of the intravenous line, and a temporary decrease in the platelet count and/or red blood cell 
count.  Fainting episodes related to needle insertion can occur, and skin tingling caused by low 
calcium levels can rarely occur.  Interrupting the plasmapheresis procedure can reverse this latter 
reaction.  During plasmapheresis, at least two nurses will be present, and a blood bank physician 
will be available in the clinic area where the procedure is performed.
LMB-2 and other similar drugs can cause allergic reactions that may range from mild to severe.  
Symptoms of allergic reactions may include hives (red rash with bumps, wheals, or welts), and 
other skin rashes, swelling, itching, fever, chills, low blood pressure, fast heart rate, wheezing, 
shortness of breath, and rarely, death.  In an attempt to decrease the risk of such reactions, you will 
be given a number of additional medications (“Premedications”) before and after each dose of 
LMB-2.
Cyclophosphamide toxicity
a.
Nausea and vomiting - variable; can be improved with standard medications (e.g., lorazepam).
b. Water retention – cyclophosphamide inside the body may turn into a drug which can hurt the 
kidney.  This side effect can be counteracted by a diuretic called furosemide.
c.
Cardiomyopathy - cyclophosphamide may cause severe, sometimes fatal, heart damage.  
Patients may present with heart failure as late as 2 weeks after the last dose of 
cyclophosphamide.  The clinical syndrome has been observed mainly in patients receiving a 
higher dose of cyclophosphamide (1200 mg/m2) used in transplant protocols.
d. Hemorrhagic cystitis - this is a serious, potentially life-threatening complication to the bladder. 
Although unnoticeable blood in the urine is not uncommon at this dose level, clinically 
significant blood in the urine can usually be avoided by maintaining a high urine volume and 
frequently urinating. The patient is encouraged to drink plenty of fluids, at least 2 liters per 
day, while taking FC.
e.
Sterility
f.
Less common but serious complications include lung damage and new cancers. Less common 
but temporary toxicities include balding and skin rash.
Fludarabine toxicity
Fludarabine toxicities include bone marrow damage with low blood counts, fever, nausea, 
vomiting, sores in the mouth, diarrhea, stomach bleeding, low appetite, swelling, skin rashes, 
muscle aches, headache, nervousness, hearing loss, temporary episodes of fatigue, destruction of 
red cells and platelets by the body’s immune system, abnormal sensations, kidney damage, and 


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lung damage.  Severe fatal brain toxicity with loss of vision and progressive deterioration of mental 
status were seen almost exclusively after very high doses of fludarabine.  This toxicity has only 
rarely been seen at the dosage of fludarabine used for this trial.  Very rarely described 
complications include severe autoimmune disease and liver failure. Tumor lysis syndrome 
following fludarabine administration has been observed, especially in patients with advanced 
bulky tumors.  The symptoms of tumor lysis syndrome include rapid reduction in tumor size, fever, 
low blood pressure, abnormal blood chemistry results, and decreased kidney function.  Unusual 
infections seen in immunosuppressed people (protozoan, viral, fungal, and bacterial) have been 
observed after-fludarabine, especially in heavily pre-treated patients, and in patients receiving 
fludarabine combined with other agents.
Patients with lymphoma and leukemia often have low blood counts and require red blood cell 
and/or platelet transfusions, with associated risks including transfusion reactions and infections 
(such as HIV and hepatitis).  Prior treatment may have weakened your immune system.  It is 
possible that LMB-2 may also weaken your immune system.  Infections that develop in individuals 
with cancer can be very serious.  You should seek immediate medical attention for fever greater 
than or equal to 100 degrees or any signs of infection.
Toxicity of filgrastim (G-CSF)
Filgrastim can cause skin rash, muscle and/or bone pain, an increase in any inflammatory 
conditions which you had before, like arthritis, enlarged spleen possibly causing a lowering of the 
platelet count, and abnormal blood chemistry levels.  Loss of hair can occur with prolonged use.
Summary of severe toxicity of FC chemotherapy and antibody therapy:

Likely (50-75% of patients):  Low neutrophils

Less Likely (25-50% of patients):  Low platelets

Unlikely (10-25% of patients):  Infections including pneumonia
Risks Associated with Routine Procedures
Blood Drawing 
To monitor the effects of therapy frequent blood tests will be necessary.  Up to a one unit (about 
50 teaspoons) of blood, may be drawn every 4 weeks while you are participating in the study and 
up 3 tablespoons of blood may be collected every 6 months during each follow-up visit for research 
purposes.  Every effort will be made to keep blood tests to a minimum.  You will be monitored for 
anemia and given blood transfusions if needed.  Side effects of blood draws include pain and 
bruising in the area where the needle was placed, lightheadedness, and rarely, fainting.
Urine Collection
There is no risk related to urine collection.
Medical photography
There are no risks associated with medical photography.
Bone Marrow TestsIf a bone marrow aspiration is done, your hipbone will be numbed with 
anesthesia, a small needle will be inserted into the hipbone, and about two tablespoons of bone 


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marrow will be removed through the needle.  This procedure usually causes only brief discomfort. 
Very rarely, infection or bleeding may occur at the needle site.
Ultrasound
The ultrasound procedure will take about 15-30 minutes. Ultrasound has extremely minimal risk 
with no use of ionizing radiation or adverse heating or pressure effects in tissue in the way that it 
is being utilized.
Imaging/scans
You may receive a contrast agent injected into your arm as part of your scan. Contrast agents can 
cause allergic reactions and kidney damage. Allergic reactions can include mild itching associated 
with hives but can also result in a serious life-threatening emergency from difficulty breathing. If 
this occurs, it is treatable. You may feel discomfort when the contrast material is injected. You 
may feel warm, flushed, get a metallic taste in your mouth or, rarely, may make you vomit or feel 
sick to your stomach.  Please ask the study doctor if you have questions about the risks of these 
scans.
MRI 
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of the body.  We will obtain pictures of your chest, abdomen and pelvis for this study. The MRI 
scanner is a metal cylinder surrounded by a strong magnetic field.  People are at risk for injury 
from the MRI magnet if they have some kinds of metal in their body.  It may be unsafe for you to 
have an MRI scan if you have pacemakers or other implanted electrical devices, brain stimulators, 
some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metal 
prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent 
eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. Welders and metal workers 
may have small metal fragments in the eye. You will be screened for these conditions before 
having any MRI scan.  If you have a question about metal in your body, you should inform the 
staff. You will be asked to complete an MRI screening form before each MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Gadolinium 
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (IV) 
catheter (small tube). It will be done for both research and medical purposes. 
It is not known if MRI with contrast is completely safe for a developing fetus. Therefore, all 
women of childbearing potential will have a pregnancy test performed no more than 24 hours 
before each MRI scan with contrast. The scan will not be done if the pregnancy test is positive.


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The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of deaths.  
A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney 
function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to years.  
The effects of the retained gadolinium are not clear. At this time, retained gadolinium has not been 
linked to health risks in people whose kidneys work well.  Some types of gadolinium contrast 
drugs are less likely to remain in the body than others. In this study, we will use the gadolinium 
contrast drugs that are less likely to remain in the body.
What are the risks of radiation from research?
During your participation in this research study, you may be exposed to radiation from up to 2 CT 
scans and up to 2 PET/CT scans each year. The amount of radiation exposure from these 
procedures is equal to approximately 5 rem. A rem is a unit of absorbed radiation.  
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and PET/CT scans that you get in this study will expose you to the roughly the same 
amount of radiation as 16.7 years’ worth of background radiation.  Most of the time, this amount 
of extra radiation is not harmful to you.  However, scientists believe that being exposed to too 
much radiation can cause harmful side effects.  This could include getting a new cancer.  We 
estimate that this could happen in about 1 out of every 1000 people who get a very large amount 
of extra radiation.
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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Premedications: 
Acetaminophen (Tylenol): side effects are extremely unlikely. Regular use of acetaminophen can 
cause liver damage especially at high doses (more than 4000mg/day or 12 regular strength tablets 
per day).  To minimize this possibility you should not take over-the-counter products containing 
acetaminophen during the time periods you are taking scheduled acetaminophen doses on this 
study.
Ranitidine (Zantac): possible side effects include tiredness, dizziness, headache, and diarrhea.
Hydroxyzine (Atarax): Possible side effects include sleepiness, dizziness, restlessness, and 
irritability.
Patients infected with HIV will be excluded from this trial because the effect of LMB-2 on HIV 
replication and/or the immune system is unknown and potentially harmful.  Patients with hepatitis 
C surface antigen positivity are excluded from this trial because the effect of LMB-2 on hepatitis 
C and/or the immune system is unknown and potentially harmful.  
We will carefully monitor you to detect any of these side effects; in addition, you will be taught 
about side effects, which you may experience and must report immediately.  Although side effects 
of this treatment usually last for a short period of time and completely resolve, you may experience 
side effects that are permanent.  Although not expected, death could occur from this experimental 
treatment.  It is very important that you notify us as soon as possible if you experience any type of 
side effect so that you can be carefully examined.   All precautions will be taken to prevent these 
side effects and you will be treated promptly (if treatment is required and possible) if they occur.  
Treatment on this study will require a significant amount of your time and may be stressful.  
Participating in this study may prevent you from being in other research studies in the future.
Potential Benefits of Participation
While we hope that LMB-2 treatment will be beneficial to you, you may not benefit from this 
treatment.  LMB-2 treatment may cause improvement in your leukemia such as reduction in 
cancer-related symptoms.  Your participation in this study may help us advance the understanding 
of the use of biologic agents in the treatment of leukemia and lymphoma.
Alternative Approaches or Treatments
You may decide now not to receive treatment in this protocol or you may choose at any point in 
time to stop the drug and withdraw from the protocol.  In either case you would be returned to the 
care of your referring physician.
Because of the type and extent of your tumor, chemotherapy is felt to be more beneficial than 
surgery or radiation alone.  Alternative approaches that could be used may include:
1.
Other forms of treatment:
a.
Additional chemotherapy drugs and chemotherapy drug combinations which might 
be of benefit for your disease.  
b.
Radiation treatment, which sometimes can control tumor growth in local areas such 
as lymph nodes, spleen and bones.  However, this approach will not effectively 
treat disease that has spread beyond the areas that are irradiated.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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c.
Surgery, which can be used to remove tumor that is pressing on important body 
parts due to fast growth.  
2. 
Other experimental agents that have not been conclusively demonstrated to be effective.
3. 
Getting no treatment.
4.
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible.
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to NCI or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.
Conflict of Interest
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study have developed a drug, being 
used in this study. This means it is possible that the results of this study could lead to payments to 
NIH scientists and to the NIH. By law, government scientists are required to receive such payments 
for their inventions. You will not receive any money from the development of LMB-2.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Use of Specimens and Data for Future Research
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Optional Studies (not required) 
Soluble CD22, CD25, CD30, and other tumor markers:  To estimate the amount of cancer 
cells in the body by measuring proteins which fall off cancer cells and go into the blood. 
Requires about 1 teaspoon.  Soluble CD25 may also be measured in your tumors if they 
need to be removed as part of your medical care, or if tumors can be easily and safely 
removed like with a skin biopsy.
Skin biopsy:  To determine whether skin lesions have ATL cells, and if so, to determine the 
extent to which ATL cells are cleared with FC or FC/LMB2.
HLA typing to better understand the immune system in patients getting LMB-2. HLA is the 
human leukocyte antigens, a complex of proteins on your white blood cells which allow 
your body to determine whether the cell is yours or not.  Requires about 1 teaspoon.
PAX-gene tube: To obtain RNA to study tumor markers, and an assay called micro-arrays, 
to study why some patients do not respond as well as others to LMB-2. PAX-gene tubes 
contain a special liquid that keeps RNA in the blood stable, and it mixes with your blood 
only after it is drawn.  Requires about 1/2 teaspoon.
DNA samples to look for abnormalities which might make a patient more susceptible to 
toxicity. The genes to look at would include those that trigger cells to die, and those that 
help make hormones which cause inflammation.  Requires about 1/2 teaspoon.
Assays to identify genes in your DNA which would have significant risk to you, including 
how likely you or your children might be to get cancer, will not be done.
Samples to determine levels of LMB-2 in the blood, urine, and other tissues by activity or 
immuno (ELISA) assays.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Flow cytometry assays to quantify tumor markers on the malignant cells.  In flow cytometry, 
your blood after being drawn goes into a tiny tube where lasers determine whether the tumor 
markers are present if so how much.  Requires about 1/2 tablespoon.
Cytotoxicity assays.  Leukemia or lymphoma cells from the blood, bone marrow, or other tissues 
may be tested with LMB-2 and related drugs to determine if the malignant cells can be killed 
outside the body.  Requires 1-3 tablespoons.
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals.  Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy.  You will be given a summary of the policy which provides 
more information.
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, 
NIH if the study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs if they are not 
covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be provided 
by the Clinical Center, NIH.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.    
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Robert 
Kreitman, M.D, kreitmar@mail.nih.gov, at 301-480-6187. You may also call the NIH Clinical 
Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-
3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.


IRB NUMBER: 09C0025
IRB APPROVAL DATE: 2/27/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 1/31/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either: 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness
Print Name of Witness
Date
NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.