Conditions: Lymphoma, B-Cell Lymphoma, Large-Cell, Immunoblastic Lymphoma, Non-Hodgkin
Keywords: Large B-Cell Lymphoma Non-Hodgkin's Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 224
Healthy volunteers: no

Brief summary:
This study is designed as a Phase III, multicenter trial, comparing progression-free survival (PFS) after autologous hematopoietic stem cell transplantation using a standard Rituxan plus BEAM transplant regimen versus a regimen adding Bexxar to BEAM.

Detailed description:
BACKGROUND:

Bexxar (Tositumomab and Iodine I 131 Tositumomab) is a radioimmunoconjugate with demonstrated anti-lymphoma effects. This drug is indicated for the treatment of patients with CD20 positive, relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin's lymphoma. Bexxar has been used in several Phase I and II transplant trials either alone or in combination with high-dose chemotherapy for the treatment of relapsed non-Hodgkin's lymphoma. The Phase I and II trials combining Bexxar with BEAM and autologous hematopoietic stem cell transplantation demonstrated promising early results with 80% event-free survival in relapsed chemosensitive diffuse large B-cell non-Hodgkin's lymphoma patients. The administration of Rituxan to the mobilization and conditioning regimen is now the standard of care at most transplant centers. Therefore, the primary endpoint of this study will be to compare progression-free survival after autologous hematopoietic stem cell transplantation for chemotherapy-sensitive diffuse large B-cell lymphoma using Rituxan/BEAM versus Bexxar/BEAM for pre-transplant conditioning.

DESIGN NARRATIVE:

All patients will receive induction or salvage chemotherapy as indicated by their clinical circumstance to achieve at least a partial response (as defined in the protocol). There must be 20% or less bone marrow involvement after their most recent salvage therapy.

Mobilization therapy may be employed per institutional guidelines, but all patients must receive one dose of rituxan (375 mg/m\^2) at least within 4 weeks of actual stem cell apheresis. Patients must have an adequate autograft (target of at least 2.0 X 10\^6 CD34+ cells/kg; minimum of more than 1.5 X 106 CD34+ cells/kg) to be eligible for the protocol. Eligible patients will be randomized to receive either: 1) Rituxan plus BEAM, with Rituxan 375 mg/m\^2 IV Days -19 and -12, Carmustine (BCNU) 300 mg/m\^2 Day -6, Etoposide 100 mg/m\^2 Days -5 to -2, Cytarabine 100 mg/m\^2 Days -5 to -2, and Melphalan 140 mg/m\^2 Day -1 followed by ASCT; or, 2) Bexxar/BEAM with the dosimetric dose of 5 mCi Bexxar on Day -19 and the therapeutic dose calculated to administer 75 cGy total body dose (TBD) on Day -12. Patients will then receive BCNU 300 mg/m\^2 Day -6, Etoposide 100 mg/m\^2 Days -5 to -2, Cytarabine 100 mg/m\^2 Days -5 to -2, and Melphalan 140 mg/m\^2 Day -1 followed by ASCT.

Patients will be followed for 2 years post-transplant. Survival data, hematopoiesis data, incidence of infection, mucositis assessment data, immune reconstitution data, and toxicity data will be recorded and reported periodically to the BMT CTN Data Coordinating Center (DCC).

Arms:
arm 1: Autologous transplantation using rituxan/BEAM arm 2: Autologous transplantation using Bexxar/BEAM

Interventions: intervention 1: Autologous transplantation using rituxan/BEAM intervention 2: Autologous transplantation using Bexxar/BEAM
Intervention descriptions: intervention 1: Rituxan 375 mg/m2 (Day -19 and Day -12); BCNU 300 mg/m2 (Day -6); Etoposide (VP-16) 100 mg/m2 twice a day (Days -5 to -2); Cytarabine 100 mg/m2 twice a day (Days -5 to -2); Melphalan 140 mg/m2 (Day -1); Followed by autologous transplantation intervention 2: Bexxar dosimetric dose 5 mCi (Day -19); Bexxar therapy dose 75 cGy TBD (Day -12); BCNU 300 mg/m2 (Day -6); Etoposide (VP-16) 100 mg/m2 twice a day (Days -5 to -2); Cytarabine 100 mg/m2 twice a day (Days -5 to -2); Melphalan 140 mg/m2 (Day -1); Followed by autologous transplantation

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
Phase III Rituxan/BEAM vs. Bexxar/BEAM with Autologous 
Hematopoietic Stem Cell Transplantation (ASCT) for Persistent or 
Relapsed Chemotherapy Sensitive Diffuse Large B-cell Non-
Hodgkin’s Lymphoma 
 
 
BMT CTN PROTOCOL 0401 
VERSION 8.0 
 
 
Study Chairperson 
Julie M. Vose, M.D. 1 
 
 
Protocol Team
Linda Burns, M.D.2 
Shelly Carter, Sc.D.3 
Jennierose D’Elia3 
Peter Holman, M.D.4  
Ann Steward LaCasce, M.D.5 
George Nemo, M.D.6 
Oliver W. Press, M.D.7 
Edward Stadtmauer, M.D.8 
Marcie Tomblyn, M.D. 3 
 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
 
 
1 The University of Nebraska Medical Center 
2 University of Minnesota  
3 The EMMES Corporation 
4 University of California, San Diego 
 
5 Dana Farber Cancer Institute 
6 National Heart, Lung, and Blood Institute 
7 Fred Hutchinson Cancer Research Center 
8 University of Pennsylvania 
 


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Protocol Team 
 
Protocol Chair 
Julie M. Vose, M.D. 
987680 Nebraska Medical Center 
Omaha, NE 68198-7680 
Phone: (402) 559-3848 
Fax: (402) 559-6520 
Email: jmvose@unmc.edu 
 
Protocol Officer 
Marcie Tomblyn, MD, MS 
12902 Magnolia Drive, FOB3 
Tampa, FL  33612 
Phone: (813) 745-6284 
Fax: (813) 449-8141 
Email: marcie.tomblyn@moffitt.org 
 
Protocol Coordinator 
Jennierose D’Elia 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Phone: (301) 251-1161 x 2918 
Fax: (301) 251-1355 
Email: jdelia@emmes.com 
 
Linda Burns, MD 
University of Minnesota 
420 Delaware St SE 
Minneapolis, MN 55455 
Phone: (612) 624-8144 
Fax: (612) 625-9988 
Email: Burns019@umn.edu 
 
Shelly Carter, ScD 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Phone: (301) 251-1161 x 2828 
Fax: (301) 251-1355 
Email: scarter@emmes.com 
 
Peter Holman, MD 
9500 Gillman Drive, #0960 
La Jolla, CA 92093 
Phone: (858) 857-6790 
Fax: (858) 657-6837 
Email: pholman@ucsd.edu 
 
Ann S. LaCasce, MD 
Dana-Farber Cancer Institute 
44 Binney Street 
Boston, MA 02115 
Phone: (617) 632-5959 
Fax: (617) 632-3477 
Email: ann_lacasce@dfci.harvard.edu 
 
George Nemo, MD 
6701 Rockledge Drive, MSC 7950 
Bethesda, MD 20892 
Phone: (301) 435-0075 
Fax: (301) 480-0868 
Email: nemog@nhlbi.nih.gov 
 
Oliver W. Press, MD 
1100 Fairview Avenue North, D3-190 
Seattle, WA 98109 
Phone: (206) 667-1872 
Fax: (206) 667-1874 
Email: press@u.washington.edu 
 
Edward Stadtmauer, MD 
3400 Spruce Street, 
16 Penn Tower 
Philadelphia, PA 19104 
Phone: (215) 662-7910 
Fax: (215) 662-4064 
Email: stadtmau@mail.edu.upenn.edu 
 
 
 


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Core Study Participants: 
 Affiliate Study Participants: 
 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
Johns Hopkins University 
Memorial Sloan-Kettering Cancer Center 
UCSD Medical Center 
University Hospitals of Cleveland/Case Western 
University of Florida 
University of Michigan 
University of Minnesota 
University of Nebraska 
University of Pennsylvania 
Washington University/Barnes Jewish Hospital 
  
Baylor University Medical Center 
Cancer Center of the Carolinas 
Emory University 
H. Lee Moffitt Cancer Center 
Hackensack University Medical Center 
Medical College of Wisconsin 
Providence Portland 
Rocky Mountain BMT Program 
Roswell Park Cancer Institute 
Rush University 
Texas Transplant Institute 
Tufts New England Medical Center 
University of Arizona 
University of California, SF 
University of Iowa 
University of Maryland 
University of Miami 
University of North Carolina 
University of Oklahoma 
University of Wisconsin 
Vanderbilt University 
Virginia Commonwealth University 
Wake Forest University 
Weill Cornell Medical College 
Yale University School of Medicine 
 
 
 
SWOG Study Participants: 
 
Baylor College of Medicine/ Stem Cell Transplant Program/ The Methodist Hospital 
Blood & Marrow Transplant Group of Georgia/ Northside Hospital 
Boston University Medical Center 
City of Hope National Medical Center 
City of Hope – Samaritan Bone Marrow Transplantation Program 
Columbia River CCOP/ Legacy Good Samaritan Hospital & Medical Center 
Comprehensive Cancer Institute/ Oncology Specialties, PC 
Dayton CCOP/ Miami Valley Hospital 
Greenville CCOP 
Hawaii CCOP/ St. Francis Medical Center 
Henry Ford Hospital 
Indiana Blood & Marrow 
Intermountain BMT 
John Muir Medical Center 
LDS Hospital of Utah 


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SWOG Study Participants (continued): 
 
Louisiana State University Medical Center 
LSU New Orleans CCOP/ Louisiana State University School of Medicine 
Loyola University 
Medical University of South Carolina/ Hollings Cancer Center 
Memorial Medical Center 
Northwest CCOP / St. Joseph Medical Center 
Oregon Health Sciences University 
St. Joseph’s Hospital 
St. Louis University Medical Center 
St. Luke’s Regional Mt. States Tumor Institute 
Sutter Health Cancer Research Group-Eastern Div. 
Sutter Health Western (Alta Bates Medical Center) 
Swedish Hospital Medical Center/ Tumor Institute 
Southwest Cancer and Research Center 
Thompson Cancer Survival Center 
Tulane University 
University of Arkansas 
University of California, Davis 
University of California, Irvine Medical Center 
University of Colorado Cancer Center 
University of Illinois Medical Center at Chicago 
University of Kansas Medical Center 
University of Kentucky 
University of Louisville Hospital 
University of Mississippi Medical Center 
University of Rochester Medical Center  
University of Southern California (USC) 
University of Texas Health Science Center at San Antonio 
University of Utah Health Sciences Center 
University of Washington Medical Center 
Virginia Mason CCOP 
Wayne State University 
Wichita CCOP 
Wilford Hall U.S.A.F. Medical Center 
 


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PROTOCOL SYNOPSIS - BMT CTN PROTOCOL #0401 
 
Phase III Rituxan/BEAM vs. Bexxar/BEAM with Autologous Hematopoietic Stem Cell 
Transplantation (ASCT) for Persistent or Relapsed Chemotherapy Sensitive Diffuse Large 
B-Cell Non-Hodgkin’s Lymphoma 
 
Study Chairperson: 
Julie M. Vose, M.D.  
Primary Objective: 
The primary objective of this study is to compare progression-free 
survival (PFS) after autologous hematopoietic stem cell transplantation 
(ASCT) for chemotherapy-sensitive diffuse large B-cell lymphoma 
using Rituxan/BEAM versus Bexxar/BEAM for pre-transplant 
conditioning.   
Secondary Objectives: 
Secondary objectives for the comparison are overall survival, time to 
progression, complete response (CR) and partial response (PR) 
proportion at Day 100, time to hematopoietic recovery, hematologic 
function, incidence of infection, maximum mucositis score by Day 21, 
immune reconstitution, treatment-related mortality, and development 
of myelodysplasia, secondary acute myelogenous leukemia, or 
abnormal cytogenetics. 
Study Design: 
This study is designed as a Phase III, multi-center trial, comparing PFS 
after autologous hematopoietic stem cell transplantation using a 
standard Rituxan plus BEAM transplant regimen versus a regimen 
adding Bexxar to BEAM.  
Accrual Objective:  
The trial will accrue 224 patients randomized equally between two 
treatment arms.   
Accrual Period: 
The estimated accrual period is two years. 
Eligibility Criteria: 
Eligible patients are 18-80 years of age with Karnofsky performance 
status ≥ 70% that have persistent or recurrent diffuse large B-cell 
lymphoma.  Patients must have received 1-3 prior treatment regimens, 
including an induction chemotherapy and < 2 salvage regimens. 
Monoclonal antibody therapy and local radiation will not be counted 
as prior therapies.  Patients must have chemosensitive disease as 
demonstrated by at least a partial response (as defined by the criteria in 
Chapter 3) to induction or salvage chemotherapy.  Patients must also 
have ≤ 20% BM involvement after their most recent salvage therapy.  
Patients cannot have transformed follicular lymphoma, evidence of 
MDS/AML, had prior autologous or allogeneic HSCT, or received 
prior radioimmunotherapy.  Patients must also initiate conditioning 
therapy within 3 months of mobilization.  Mobilization therapy may be 
employed per institutional guidelines, but all patients must receive one 
dose of Rituxan (375 mg/m2) within 3 months prior to actual stem cell 
apheresis.  Patients must have an adequate autograft (target ≥ 2.0 X 


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106 CD34+ cells/kg; minimum > 1.5 X 106 CD34+ cells/kg) to be 
eligible for the protocol.   
Treatment Description: 
Eligible patients will be randomized to receive either: 1.) Rituxan plus 
BEAM, with Rituxan 375 mg/m2 IV Days -19 and -12, BCNU 300 
mg/m2 Day -6, Etoposide 100 mg/m2 BID Days -5 to -2, Cytarabine 
100 mg/m2 BID Days -5 to -2, and Melphalan 140 mg/m2 Day -1 
followed by ASCT; or, 2.) Bexxar/BEAM with the dosimetric dose of 
5 mCi Bexxar on Day -19 and the therapeutic dose calculated to 
administer 75 cGy total body dose (TBD) on Day -12.  Patients will 
then receive BCNU 300 mg/m2 Day -6, Etoposide 100 mg/m2 BID 
Days -5 to -2, Cytarabine 100 mg/m2 BID Days -5 to -2, and 
Melphalan 140 mg/m2 Day -1 followed by ASCT.  
Study Duration: 
Patients will be followed for at least two years post-ASCT. 
 


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TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infusion of G-CSF mobilized autologous 
hematopoietic stem cells 
Post-ASCT evaluations, including evaluation 
of immune reconstitution: CD2, CD3, CD4, 
CD8, CD19, CD3+/CD25+, CD45RA/RO, 
CD56+/CD3-, and quantitative 
immunoglobulins (IgM, IgG and IgA) at 
baseline, Day + 100 and yearly for 2 years. 
Rituxan 375 mg/m2 (Day -19 and Day -12)  
BCNU 300 mg/m2 (Day -6) 
VP-16 100 mg/m2 BID (Days -5 to -2) 
Cytarabine 100 mg/m2 BID (Days -5 to -2) 
Melphalan 140 mg/m2 (Day -1) 
 
Infusion of G-CSF mobilized autologous 
hematopoietic stem cells 
Post-ASCT evaluations, including evaluation of 
immune reconstitution: CD2, CD3, CD4, CD8, CD19, 
CD3+/CD25+, CD45RA/RO, CD56+/CD3-, and 
quantitative immunoglobulins (IgM, IgG and IgA) at 
baseline, Day + 100 and yearly for 2 years. 
Bexxar dosimetric dose 5 mCi (Day -19) 
Bexxar therapy dose 75 cGy TBD (Day -12) 
BCNU 300 mg/m2 (Day -6) 
VP-16 100 mg/m2 BID (Days -5 to -2) 
Cytarabine 100 mg/m2 BID (Days -5 to -2) 
Melphalan 140 mg/m2 (Day -1) 
Patient Eligibility Screening 
Randomization to Rituxan/BEAM or 
Bexxar/BEAM  


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TABLE OF CONTENTS 
 
 
1. 
BACKGROUND AND RATIONALE ............................................................................ 1-1 
1.1. 
Background – Autologous Hematopoietic Stem Cell Transplantation for Diffuse 
Large Cell Lymphoma.................................................................................................. 1-1 
1.2. 
Bexxar as Myeloablative Radioimmunotherapy in Transplantation ........................ 1-2 
1.3. 
Phase I/II and Phase II Trials of Bexxar + BEAM and ASCT for Lymphoma ....... 1-2 
1.4. 
In Vivo Purging with Rituximab ..................................................................................... 1-3 
2. 
STUDY DESIGN ................................................................................................................ 2-1 
2.1. 
Study Overview .................................................................................................................. 2-1 
2.1.1. 
Hypothesis ....................................................................................................................... 2-1 
2.1.2. 
Study Objectives ............................................................................................................. 2-1 
2.2. 
Patient Eligibility ................................................................................................................ 2-1 
2.2.1. 
Patient Inclusion Criteria ................................................................................................ 2-1 
2.2.2. 
Patient Exclusion Criteria ............................................................................................... 2-2 
2.3. 
Study Treatments ............................................................................................................... 2-3 
2.3.1. 
Cytoreductive Therapy/Mobilization Regimen ............................................................. 2-3 
2.3.1.1. 
Mobilization regimen and Rituxan administration ....................................................... 2-3 
2.3.1.2. 
Conditioning regimen – Rituxan/BEAM ....................................................................... 2-4 
2.3.1.3. 
Conditioning regimen – Bexxar/BEAM ........................................................................ 2-4 
2.4. 
Supportive Care.................................................................................................................. 2-5 
2.4.1. 
Post-ASCT ....................................................................................................................... 2-5 
2.4.1.1. 
Prophylaxis against infections ........................................................................................ 2-6 
2.4.1.2. 
Blood products ................................................................................................................ 2-6 
2.4.1.3. 
Post-ASCT growth factors .............................................................................................. 2-6 
2.4.1.4. 
Post-ASCT immunization schedule ............................................................................... 2-6 
2.4.1.5. 
Post-ASCT lymphoma therapy ...................................................................................... 2-6 
2.4.1.6. 
Post-ASCT IVIg therapy ................................................................................................ 2-6 
2.5. 
Participant Risks ................................................................................................................ 2-7 
2.6. 
Therapy Toxicities.............................................................................................................. 2-7 
2.6.1. 
Rituxan (Rituximab) ....................................................................................................... 2-7 
2.6.2. 
Bexxar (Tositumomab and Iodine I 131 Tositumomab) .............................................. 2-8 
2.6.3. 
Carmustine (BCNU) ....................................................................................................... 2-8 
2.6.4. 
VP-16 (Etoposide) ........................................................................................................... 2-8 
2.6.5. 
Cytarabine (Ara-C).......................................................................................................... 2-8 
2.6.6. 
Melphalan ........................................................................................................................ 2-9 
2.6.7. 
G-CSF (Filgrastim) ......................................................................................................... 2-9 
2.7. 
Bexxar Administration ...................................................................................................... 2-9 
2.7.1. 
Dosing Schema ................................................................................................................ 2-9 
2.7.2. 
Dosage Preparation ....................................................................................................... 2-10 
2.7.2.1. 
Preparation of Tositumomab infusion ......................................................................... 2-10 
2.7.2.2. 
Preparation of dosimetric Iodine I 131 Tositumomab infusion ................................. 2-11 
2.7.2.3. 
Preparation of therapeutic Iodine I 131 Tositumomab infusion................................. 2-11 
2.7.3. 
Administration of Iodine I 131 Tositumomab ............................................................. 2-12 


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2.7.3.1. 
Thyroid blockade........................................................................................................... 2-12 
2.7.3.2. 
Dosimetric dose administration .................................................................................... 2-12 
2.7.3.3. 
Whole body dosimetry .................................................................................................. 2-13 
2.7.3.4. 
Calculations of therapeutic dose................................................................................... 2-14 
2.7.3.5. 
Therapeutic dose administration .................................................................................. 2-15 
2.7.4. 
Dose Modifications/Discontinuations .......................................................................... 2-16 
2.8. 
Bexxar Ordering Instructions ........................................................................................ 2-20 
3. 
STUDY ENDPOINTS........................................................................................................ 3-1 
3.1. 
Definition of Disease Status .............................................................................................. 3-1 
3.2. 
Primary Endpoint to be Compared Between Rituxan/BEAM and Bexxar/BEAM + 
Autologous HSCT.......................................................................................................... 3-5 
3.3. 
Secondary Endpoints to be Compared Between Rituxan/BEAM and Bexxar/BEAM 
+ Autologous HSCT ...................................................................................................... 3-5 
3.3.1. 
Overall Survival .............................................................................................................. 3-5 
3.3.2. 
Time to Progression ........................................................................................................ 3-5 
3.3.3. 
CR and CR+PR Proportion at Day 100 ......................................................................... 3-5 
3.3.4. 
Time to Hematopoietic Recovery .................................................................................. 3-5 
3.3.5. 
Hematologic Function ..................................................................................................... 3-5 
3.3.6. 
Incidence of Infection ..................................................................................................... 3-6 
3.3.7. 
Maximum Mucositis Score by Day + 21 ....................................................................... 3-6 
3.3.8. 
Treatment-related Mortality ........................................................................................... 3-6 
3.3.9. 
Incidence of MDS/ AML and New, Abnormal Cytogenetics ...................................... 3-6 
3.3.10. 
Immunologic Reconstitution .......................................................................................... 3-6 
4. 
PATIENT ENROLLMENT AND EVALUATION ...................................................... 4-1 
4.1. 
Enrollment Procedures...................................................................................................... 4-1 
4.1.1. 
Screening and Eligibility Procedures ............................................................................. 4-1 
4.1.2. 
SWOG Patient Registration Procedures ........................................................................ 4-1 
4.2. 
Study Monitoring ............................................................................................................... 4-2 
4.2.1. 
Follow-up Schedule ........................................................................................................ 4-2 
4.2.2. 
Adverse Event Reporting ................................................................................................ 4-3 
4.2.3. 
Patient Assessments ........................................................................................................ 4-3 
4.2.3.1. 
Evaluations prior to the ASCT conditioning therapy.................................................... 4-3 
4.2.3.2. 
Evaluations prior to administration of BEAM .............................................................. 4-4 
4.2.3.3. 
Post-ASCT evaluations ................................................................................................... 4-4 
5. 
STATISTICAL CONSIDERATIONS ............................................................................ 5-1 
5.1. 
Study Overview .................................................................................................................. 5-1 
5.1.1. 
Accrual ............................................................................................................................. 5-1 
5.1.2. 
Primary Endpoint ............................................................................................................ 5-1 
5.2. 
Sample Size and Power Calculations .............................................................................. 5-1 
5.3. 
Interim Analysis and Stopping Guidelines..................................................................... 5-1 
5.3.1. 
Interim Analysis for Efficacy ......................................................................................... 5-2 
5.4. 
Statistical Stopping Guidelines ........................................................................................ 5-2 
5.5. 
Analysis Plan ....................................................................................................................... 5-4 
5.5.1. 
Analysis of the Primary Endpoint .................................................................................. 5-4 
5.5.2. 
Analysis of Secondary Endpoints .................................................................................. 5-4 


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LIST OF APPENDICES 
 
APPENDIX A 
 
REFERENCES 
APPENDIX B 
 
CONSENT FORM 
APPENDIX C 
 
LABORATORY PROCEDURES 
APPENDIX D 
 
HUMAN SUBJECTS 
APPENDIX E 
STUDY DRUG (BEXXAR) ORDER FORM 
 


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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. Background – Autologous Hematopoietic Stem Cell Transplantation for Diffuse 
Large Cell Lymphoma 
 
Forty-fifty percent of patients with diffuse aggressive non-Hodgkin’s lymphoma (NHL) are 
cured with standard anthracycline-based combination chemotherapy.  However, among those 
who fail to achieve remission or relapse, standard salvage chemotherapy is effective in producing 
long-term disease-free survival in no more than 10% [1-4].  Based on the Phase III Parma trial 
and other Phase II trials, high-dose chemotherapy and autologous hematopoietic stem cell 
transplantation (ASCT) has become the standard of care for patients with chemotherapy-
sensitive relapsed diffuse aggressive NHL [5-7].  In this setting, standard high-dose therapy and 
ASCT produce disease-free survival rates of 35-50% [8, 9].  Relapse is the major cause of failure 
after ASCT for lymphoma.  It is unknown whether residual disease in the patient or the 
reinfusion of viable tumor cells is the major contributor to relapse – or both [10, 11].  Rituximab, 
a chimeric monoclonal antibody targeting CD20, is effective in treating recurrent follicular and 
diffuse large cell lymphoma [12, 13].  Recently, it has become common to include Rituxan 
during mobilization and as part of the therapeutic regimen in an attempt to decrease post-
transplant relapse risk.   
 
The addition of rituximab to salvage chemotherapy and/or during mobilization has been 
associated with improved progression-free survival [14-16].  In addition, some studies have used 
rituximab in the post-transplant setting [17].  Based on these Phase II studies, the addition of 
rituximab has become standard of care in the pre-transplant setting at many transplant centers. 
 
Radioimmunotherapy is a novel immunotherapy approach recently approved for the therapy of 
recurrent NHL.  This treatment combines monoclonal antibodies directed against the CD20 
antigen with a radioconjugate through a stable conjugate linker.  Consequently, it combines the 
mechanisms of action of the monoclonal antibody, such as complement-dependent cytotoxicity, 
antibody-dependent cytotoxicity, and apoptosis, with radioisotope emissions which are capable 
of killing not only the cell bound by the antibody, but also adjacent cells that may not bind 
antibody.  Iodine 131 (I-131) Tositumomab (Bexxar, Corixa Corp, Seattle, WA, and 
GlaxoSmithKline, Philadelphia, PA) is a radioimmunoconjugate with demonstrated anti-
lymphoma effects.  This molecule is a murine IgG2a antibody radiolabeled with I-131 [18].  
Multiple single agent trials of Bexxar in patients with relapsed NHL demonstrate an overall 
response (OR) rate of 60-80% and a complete response (CR) rate of 20-40% [19-21].  These 
encouraging single agent results led to trials combining radioimmunoconjugates with standard 
chemotherapy.  Press et al [22] studied sequential CHOP chemotherapy followed by 
consolidation with Bexxar therapy.  Bexxar did not appear to add significant toxicity; however, 
the CR rate was increased from 39% to 66% [22].   
 


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1.2. Bexxar as Myeloablative Radioimmunotherapy in Transplantation 
 
Bexxar has also been used in high-dose chemotherapy and ASCT.  One approach is “high dose” 
or myeloablative radioimmunotherapy transplantation, pioneered by Press et al [23].  In this 
method, trace-labeled biodistribution studies first determine the maximum absorbed radiation 
doses to tumor and normal organs such as lung, liver, and kidney.  Subsequent therapeutic 
infusions of Bexxar are given in doses calculated to deliver specific absorbed radiation doses to 
these organs, followed by autologous stem-cell rescue.  Follow-up of 29 patients receiving this 
therapy demonstrated that 14 remained in remission from 27+ to 87+ months following ASCT 
[24].  A Phase I/II trial of Bexxar combined with etoposide, cyclophosphamide, and ASCT was 
subsequently reported [25].  In this trial, 52 patients with relapsed NHL received 1.7 mg/kg 
Tositumomab labeled with an amount of I-131 calculated to deliver target doses of 20-27 Gy to 
critical normal organs, followed by etoposide, cyclophosphamide and ASCT.  The maximum 
tolerated doses of this regimen were the combination of 60 mg/kg etoposide and 100 mg/kg 
cyclophosphamide delivered with 25 Gy to critical normal organs.  The estimated overall and 
progression-free survival (PFS) of all treated patients at two years were 83% and 68%, 
respectively [25]. 
 
1.3. Phase I/II and Phase II Trials of Bexxar + BEAM and ASCT for Lymphoma 
 
An alternative to myeloablative Bexxar regimens is to add standard outpatient doses of Bexxar to 
a high-dose chemotherapy regimen.  Using this type of dosing methodology, the patients 
received a dosimetric dose with 450 mg of unlabeled Tositumomab intravenously followed by a 
trace-labeled 5mCi (35 mg) dose of Iodine I 131 Tositumomab.  Within one hour of the 
dosimetric dose of Iodine I 131 Tositumomab and before urination, a whole-body quantitative 
gamma camera image was obtained for baseline.  Additional scans were performed on Days 2, 3, 
or 4 and 6 or 7 after the dosimetric dose.  The methodology for determining the patient-specific 
millicurie activity was performed in accordance with the Medical Internal Radiation Dose Primer 
for Absorbed Dose Calculations.  One week later, on Day –12 of the transplantation protocol, the 
therapy dose of Iodine I 131 Tositumomab was administered.  The patients received 450 mg of 
unlabeled Tositumomab followed by the patient-specific dose calculated for administration based 
on the whole-body gamma camera images.  Patients treated in the Phase I trial started at a dose 
of 30 cGy total body dose and escalated by 15 cGy every 3 patients to a maximum of 75 cGy 
total body dose of Iodine I 131 Tositumomab.  Additional patients were added at the maximum 
tolerated dose of 75 cGy.  This has been studied in patients with relapsed NHL using Bexxar 
with BEAM chemotherapy (BCNU, etoposide, cytarabine, and melphalan) and ASCT.  A Phase 
I/II study was conducted in 23 patients with chemotherapy resistant relapsed aggressive NHL 
[26].  Their median age was 51 years (range 26 to 65 years).  Patients had autologous stem cells 
collected prior to the initiation of therapy.  They subsequently received a Bexxar dosimetric dose 
on Day -19 and a Bexxar therapeutic dose administered in a range of 30 to 75 cGy total body 
dose on Day -12 of the transplant.  The patients had an average dose rate following the 
therapeutic Bexxar dose of 10 Mr/hr at 1 meter.  The rates ranged from 7-14 Mr/hr.  Patients then 
received a standard BEAM transplant regimen (BCNU 300 mg/m2 Day -6, cytarabine 100 mg/m2 
BID Days -5 to -2, etoposide 100 mg/m2 BID Days -5 to -2, and melphalan 140 mg/m2 Day -1) 
followed by re-infusion of their unmodified autologous stem cells on Day 0.  At 12 days after the 


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Bexxar infusion and prior to the autologous stem cells being infused they had an average dose 
rate of 0.60 Mr/hr (range 0.4 – 0.6 Mr/hr) at 1 meter.  Hematopoietic recovery was similar to 
historical controls treated with BEAM alone with median times to an absolute neutrophil count 
of > 500/mm3 of 10 days, to platelet independence of 12 days, and to red blood cell 
independence of 9 days.  There were no treatment related deaths.  Non-hematologic toxicities 
were similar to historical controls except for a slightly higher mucositis score in the patients 
receiving Bexxar plus BEAM.  Six of the 23 patients received consolidative radiation therapy of 
3600 – 4000 cGy to areas of bulky (> 3 cm) that was present at the time of relapse.  The radiation 
was delivered after recovery of the cytopenias post-transplant and before Day +100.  There were 
no unexpected toxicities from the involved field irradiation.  The CR rate was 59% and the OR 
rate, 68%.  With a median follow-up of 38 months (range, 27 to 60 months), 11 of 23 patients 
progressed.  The 3-year event-free survival was 39% and overall survival, 55%.  Two patients 
developed myelodysplastic syndrome (MDS) at 26 and 29 months post-transplant.  A subsequent 
Phase II clinical trial using the maximum 75 cGy total body dose (TBD) Bexxar + BEAM and 
ASCT is currently finishing accrual and near completion. This Phase II trial is in the indicated 
patient population of chemotherapy sensitive diffuse large B-cell lymphoma.  Thirty out of the 
planned 40 patients have been entered on that trial at the University of Nebraska Medical Center.  
The patients entered in the Phase II study range in age from 25-73 (median 54 years).  Ten of the 
39 patients have received post-transplant involved field irradiation to areas of prior bulky disease 
(> 3 cm) at the time of relapse.  At the time of the last interim analysis, the complete response 
rate for patients on this protocol was 74% and the estimated 1-year event-free survival was 79% 
and overall survival 82%.  The engraftment in this trial so far is also within normal limits as 
expected for the BEAM transplant protocol No increase in unexpected toxicities has been seen in 
this trial, other than the slight increase in mucositis as was seen in the Phase I/II trial.  
 
1.4. In Vivo Purging with Rituximab 
 
Contamination of the hematopoietic stem cell graft by tumor cells is thought to be one factor 
contributing to the relapse after ASCT.  Treatment aimed at removing lymphoma cells from the 
autologous graft has been used in an attempt to reduce the rate of relapse.  Approaches include 
various in vitro techniques including purging with B-cell monoclonal antibodies, 
chemotherapeutic agents such as mafosfamide or use of CD34+ positive selection [27-30].  While 
all of these methods reduce the level of tumor cell contamination, most grafts remain PCR 
positive for lymphoma cells and there are no randomized trials to date strongly supporting the 
use of in vitro purging in this setting [31].  Additionally, in vitro purging methods are typically 
expensive, labor intensive, require reagents that are not generally available and can be associated 
with substantial cell losses [32].  For example, the negative selection approach used by Freedman 
et al required the use of 3 monoclonal antibodies and rabbit complement to achieve successful 
marrow purging [33].  Consequently, most ASCTs for lymphoma currently use unpurged grafts. 
 
A recent promising strategy for reducing relapse is in vivo purging with rituximab (RTX).  In 
contrast to in vitro purging methods aimed at removing contaminating tumor cells from the 
hematopoietic stem cell harvest, administration of RTX in vivo prior to leukapheresis depletes 
the peripheral blood of all CD20+ cells preventing contamination of the graft by lymphoma cells 
[34].  RTX is a human/mouse monoclonal antibody recognizing CD20+, an antigen expressed on 


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all cells of B cell lineage including B cell NHL [12].  RTX eradicates B cells by complement-
mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity.  It can induce 
apoptosis in CD20+ cells and may be synergistic with chemotherapy.  RTX rapidly and 
efficiently clears B cells in the peripheral blood for more than three months [12].  This strategy 
has been effectively used in patients with previously treated aggressive and indolent lymphomas 
[12, 13]. 
 
RTX has been successfully incorporated into the hematopoietic stem cell mobilization regimen 
by several groups for the purpose of in vivo purging [16, 34-35].  RTX administration does not 
demonstrate any negative effects on hematopoietic stem cell yield or function; hematopoietic 
recovery is comparable following transplantation in purged versus unpurged patients [16].  The 
optimal timing and dosing of RTX administration during mobilization still remains to be clearly 
established but current reports have used from 1 to 4 doses.  Due to these reports, rituximab use 
with transplantation has now become the standard of care at many transplant centers. 
 


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CHAPTER 2 
 
 
2. 
STUDY DESIGN 
 
2.1.  Study Overview 
 
All patients will receive induction or salvage chemotherapy as indicated by their clinical 
circumstance to achieve at least a partial response (as defined by the criteria in Chapter 3) prior 
to conditioning.  There must be < 20% bone marrow involvement after their most recent salvage 
therapy.  All patients will undergo stem cell mobilization per institutional standards, but must 
receive one dose of Rituxan (RTX) 375 mg/m2 within 4 weeks prior to actual stem cell apheresis.  
Patients for whom an adequate graft is collected will be randomized to receive ASCT using 
either a standard RTX plus BEAM regimen versus a regimen adding Bexxar to BEAM. 
 
2.1.1. Hypothesis 
 
The study is designed to test the null hypothesis that adding the radioimmunoconjugate Bexxar 
to the pre-transplant conditioning will not affect toxicity or efficacy of high-dose therapy and 
ASCT for diffuse large B-cell lymphoma. 
 
2.1.2. Study Objectives 
 
The primary objective is to compare PFS between the two transplant arms.  Secondary objectives 
are to compare overall survival, time to progression, CR and PR proportion at Day 100, time to 
hematopoietic recovery, hematologic function, incidence of infection, maximum mucositis score 
by Day +21, immune reconstitution, treatment-related mortality, incidence of myelodysplastic 
syndrome (MDS), secondary acute myelogenous leukemia (AML), or abnormal cytogenetics 
between the two arms.   
 
2.2.  Patient Eligibility 
 
Patients must meet specified eligibility criteria for entry into the study.   
 
2.2.1. Patient Inclusion Criteria 
 
Patients fulfilling the following criteria will be eligible for entry into this study: 
1. Diagnosis of persistent or recurrent REAL classification diffuse large B-cell lymphoma, 
composite lymphoma with > 50% diffuse large B-cell lymphoma, mediastinal B-cell 
lymphoma. 
2. Demonstration of CD20+ on at least one histologic specimen. 
3. 18-80 years old at time of first registration. 


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4. Three or fewer prior regimens of chemotherapy over the entire course of their disease 
treatment (including one induction chemotherapy and no more than 2 salvage 
chemotherapies).  Monoclonal antibody therapy and involved field radiation therapy will 
not be counted as prior therapies.   
5. All patients must have chemosensitive disease as demonstrated by at least a partial 
response (as defined by the criteria in Chapter 3) to induction or salvage therapy. 
6. ≤  20% bone marrow involvement. 
7. Patients with adequate organ function as measured by: 
a) Cardiac:  American Heart Association Class I: Patients with cardiac disease but 
without resulting limitation of physical activity.  Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal pain.  Additionally, 
patients > 60 years of age must have a left ventricular ejection fraction at rest  
≥ 40% demonstrated by MUGA. 
b) Hepatic:  Bilirubin < 2.0 mg/dL (except for isolated hyperbilirubinemia attributed 
to Gilbert syndrome) and ALT and AST < 3x the upper limit of normal. 
c) Renal:  Creatinine < 2.0 mg/dL or creatinine clearance (calculated creatinine 
clearance is permitted) > 40 mL/min; no hydronephrosis on CT scan prior to 
mobilization. 
d) Pulmonary:  DLCO, FEV1, FVC ≥  45% of predicted (corrected for hemoglobin). 
8. Patients must receive one dose of Rituxan (375 mg/m2) within 3 months prior to actual 
stem cell apheresis. 
9. Autologous graft with a minimum of  1.5 x 106 CD 34+ cells/kg (target  2.0 x 106 CD 
34+ cells/kg).  Peripheral blood stem cells (PBSC) are preferred; however, if PBSC 
mobilization fails, cells can be obtained by institutional practices (in cases where bone 
marrow will be used for transplantation, the required CD34+ dose does not apply and 
institutional practice for total nucleated cell dose should be used). 
10. Initiate conditioning therapy within 3 months of mobilization. 
11. Signed informed consent. 
 
2.2.2. Patient Exclusion Criteria 
 
Patients with the following will be ineligible for registration onto this study: 
 
1. Karnofsky performance score < 70%. 
2. Transformed follicular lymphoma.   
3. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with 
progression or no clinical improvement).  
4. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in 
situ.  Cancer treated with curative intent < 5 years previously will not be allowed unless 


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approved by the Medical Monitor or Protocol Chair.  Cancer treated with curative intent  
> 5 years previously will be allowed. 
5. Pregnant (positive β-HCG) or breastfeeding.  This patient population is excluded due to 
the lack of data on the use of Bexxar in patients who are pregnant or breastfeeding. 
6. Seropositivity for HIV.  This patient population is excluded due to the lack of data on the 
use of Bexxar in HIV positive patients and because the treatment regimens are too 
immunosuppressive for this patient population. 
7. Fertile men or women unwilling to use contraceptive techniques from the time of initiation 
of mobilization until six-months post-transplant. 
8. Prior autologous or allogeneic HSCT. 
9. Patients with evidence of MDS/AML or abnormal cytogenetic analysis indicative of MDS 
on the pre-transplant bone marrow examination. 
10. Patients with a prior severe reaction to Rituxan or G-CSF.  Patients with severe reactions 
to G-CSF that receive pre-medication for control of the reaction are not excluded from 
study.  
11. Patients who have received prior radioimmunotherapy. 
12. Known hypersensitivity to murine proteins. 
 
2.3. Study Treatments 
 
The immediate pre-ASCT evaluation will be carried out according to the operating procedures of 
the participating institutions and should be in keeping with the data reporting requirements of 
this study.  Similarly, special orders and procedures will be those defined by the BMT CTN 
Manual of Procedures (MOP).  All patients enrolled on this protocol will be hospitalized in 
accordance with the procedures for recipients of ASCT as defined by the treating institutions.  
 
2.3.1. Cytoreductive Therapy/Mobilization Regimen 
 
2.3.1.1. 
Mobilization regimen and Rituxan administration 
 
Mobilization therapy may be employed per institutional guidelines, but all patients must receive 
one dose of Rituxan (375 mg/m2) within 3 months prior to actual stem cell apheresis 
 
 


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2.3.1.2. 
Conditioning regimen – Rituxan/BEAM  
 
Table 2.3.1.2:  Rituxan/BEAM + ASCT Regimen 
 
Day 
-19 
-12 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Rituxan 
375 
mg/m2 
Rituxan 
375 
mg/m2 
BCNU 
300 
mg/m2 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Melphalan 
140 mg/m2 
ASCT 
1. Rituxan:  375 mg/m2 IV to be administered on Days -19 and -12.   Mix RTX in either 
0.9% NS or D5W, for a final concentration between 1-4 mg/mL.  RTX must be infused 
through an infusion pump and should not be mixed or diluted with any other solutions or 
drugs.  The RTX package insert should be consulted for specific infusion guidelines. 
2. BCNU:  300 mg/m2 on Day –6, to be administered per institutional guidelines. 
3. Cytarabine (Ara-C):  100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to 
be administered per institutional guidelines. 
4. VP-16: 100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to be administered 
per institutional guidelines. 
5. Melphalan: 140 mg/m2 on Day -1, to be administered per institutional guidelines. 
6. Conditioning Regimen Administration Schedule: The conditioning regimen 
administration schedule may be modified ± 1 day according to institutional practice.  Day 
0 will be the day of ASCT. 
 
2.3.1.3. 
Conditioning regimen – Bexxar/BEAM  
 
Table 2.3.1.3:  Bexxar/BEAM + ASCT Regimen 
 
Day 
-19 
-12 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Bexxar 
Dosimetric 
Dose 
Bexxar 
Therapy 
dose  
75 cGy 
TBD 
BCNU 
300 
mg/m2 
Ara-C  
100 
mg/m2 
BID 
 
VP-16 
100 
mg/m2 
BID 
Ara-C 
100 
mg/m2 
BID 
 
VP-16  
100 
mg/m2 
BID 
Ara-C 
100 
mg/m2 
BID 
 
VP-16  
100 
mg/m2 
BID 
Ara-C  
100 
mg/m2 
BID 
 
VP-16  
100 
mg/m2 
BID 
Melphalan 
140 mg/m2 
ASCT 
 


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1. Thyroid Blockade: Patients will be treated with Saturated Solution Potassium Iodide 
(SSKI) 4 drops PO TID, Lugol’s solution 20 drops PO TID, or potassium iodide tablets 
130 mg PO QD starting at least 24 hours prior to the dosimetric dose of the Iodine I 131 
Tositumomab and continuing daily for 14 days following the therapeutic dose of Iodine I 
131 Tositumomab.  In addition, 60–120 minutes before the dosimetric and therapeutic 
dose of Iodine I 131 Tositumomab all patients will be given an additional dose of 
medication for thyroid blockade.  The SSKI or Lugol’s solution may be given with juice 
or cola to mask its taste. 
In no instance should a patient receive the dosimetric dose of Iodine I 131 Tositumomab 
if they have not yet received at least three doses of SSKI, three doses of Lugol’s solution, 
or one 130 mg potassium iodide tablet (at least 24 hours prior to the dosimetric dose).  
Patient compliance will be ascertained and documented prior to administration of the 
dosimetric dose and therapeutic dose. 
2. Bexxar:  Patients will receive a 5 mCi Iodine I 131-Tositumomab dosimetric dose on 
Day -19, followed by 3 whole body gamma scan images over the ensuing week (day of 
administration – prior to urination, Day 2, 3, or 4 following urination, and Day 6 or 7 
following urination).  On Day -12 the patient will receive the amount of Iodine I 131 
Tositumomab calculated to administer 75 cGy Total Body Dose (see Section 2.7).  Prior 
to receiving the Iodine I 131 Tositumomab dosimetric and therapeutic doses, the patient 
will be given 450 mg of Tositumomab infused over 1 hour on Days -19 and -12. 
3. BCNU: 300 mg/m2  on Day –6, to be administered per institutional guidelines. 
4. Cytarabine (Ara-C): 100 mg/m2 BID on Days -5 through -2 for a total of 8 doses, to be 
administered per institutional guidelines. 
5. VP-16: 100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to be administered 
per institutional guidelines. 
6. Melphalan: 140 mg/m2 on Day -1, to be administered per institutional guidelines. 
7. Conditioning Regimen Administration Schedule: The conditioning regimen 
administration schedule may be modified ± 1 day according to institutional practice.  Day 
0 will be the day of ASCT. 
 
2.4. Supportive Care 
 
2.4.1. Post-ASCT 
 
All supportive care will be given in keeping with BMT CTN MOP and local institutional 
guidelines. 
 


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2.4.1.1. 
Prophylaxis against infections 
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the post-
ASCT period according to the BMT CTN MOP.  Additional specifications/requirements for this 
study are summarized below.  Infectious prophylaxis will include prophylaxis for: 
 
1. Bacteria:  In keeping with the BMT CTN MOP and local institutional standards. 
2. Pneumocystis carinii:  Per local institutional guidelines and must be uniformly applied to 
all patients within each respective center. 
3. Fungi:  Anti-fungal prophylaxis will be per local institutional practice and must be 
uniformly applied to all patients within each respective center. 
4. HSV/VZV:  Antiviral prophylaxis will be per local institutional practice and must be 
uniformly applied to all patients within each respective center. 
 
2.4.1.2. 
Blood products 
 
Transfusion thresholds for blood product support will be in keeping with BMT CTN MOP and 
standard institutional guidelines.  All blood products will be irradiated. 
 
2.4.1.3. 
Post-ASCT growth factors 
 
All patients will receive G-CSF 5-10 mcg/kg beginning no later than Day +7 post-transplant 
until an ANC > 500/mm3 is obtained for 3 consecutive days.  If patients fall below this level 
once the G-CSF has been stopped, it can be restarted.  Patients that are known to experience 
severe reactions to G-CSF must be pre-medicated before administration.  
 
2.4.1.4. 
Post-ASCT immunization schedule 
 
Immunizations may be given in keeping with the BMT CTN MOP and local institutional 
practice. 
 
2.4.1.5. 
Post-ASCT lymphoma therapy 
 
Consolidative localized radiation therapy (maximum 3 sites) is allowed to areas of previous bulk 
disease (> 3 cm).  Localized radiation should be completed by Day 100 post-transplant.  No other 
anti-lymphoma therapy is allowed in the post-transplant setting or the patient will be considered 
to have progressed and will be off study.  Specifically NO Rituxan maintenance therapy post-
transplant is allowed. 
 
2.4.1.6. 
Post-ASCT IVIg therapy 
 
Administration of IVIg is not routinely used in autologous transplant patients. 
 


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2.5. Participant Risks 
 
ASCT recipients incur risks from high-dose conditioning and post-ASCT therapy, which must be 
weighed against the risk of the disease for which the ASCT is prescribed.  Major risks following 
transplantation include: 1) Infection which can be bacterial, viral, parasitic, or fungal.  Often, 
these infections are life-threatening, particularly when caused by viral or fungal agents, and are 
associated with high mortality in the transplant population; 2) Damage of all or any of the major 
organs may occur as a result of reactions to drugs (e.g., chemotherapy, antibiotics, anti-fungal 
medications), and as a result of destructive processes (e.g., infection), and may have a fatal 
outcome; brain damage can result in severe loss of cognitive or neurologic function; 3) Relapse 
or progression of lymphoma may occur, especially in patients with advanced disease status at 
time of treatment; 4) Unknown toxicities may occur in any individual patient due to multiple 
events and cumulative effects which may involve any and all organs, including the brain; and 5) 
Death. 
 
2.6. Therapy Toxicities 
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0.  All of the following listed agents are commercially available.  Please 
refer to www.fda.gov for full adverse event information regarding the agents listed below.  All of 
the following agents should be administered per institutional standards, and stored per package 
insert instructions. 
 
2.6.1. Rituxan (Rituximab) 
 
Rituxan (RTX) is a chimeric human/mouse monoclonal antibody directed against CD20+, an 
antigen expressed on all cells of the B cell lineage.  It consists of a murine antigen binding region 
and a human Fc region.  The likely side effects include infusion reactions such as rigors, fevers, 
and itching.  Uncommon side effects include hypotension, dyspnea, rash, and nausea/vomiting.  
Rare non-infusion toxicities include myelosuppression, thrombocytopenia, fatigue and tumor 
pain.  Hepatitis B reactivation with fulminant hepatitis, hepatic failure and death is a risk in 
patients who have ever been infected with the hepatitis B virus and/or are carriers of hepatitis B.  
The risk of hepatitis B reactivation may continue for several months after RTX administration.   
 


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2.6.2. Bexxar (Tositumomab and Iodine I 131 Tositumomab) 
 
The Bexxar therapeutic regimen is an anti-neoplastic radioimmunotherapeutic monoclonal 
antibody regimen composed of the monoclonal antibody, Tositumomab, and the radiolabeled 
monoclonal antibody, Iodine I 131 Tositumomab.  The Bexxar therapeutic regimen consists of 
two discrete steps: the dosimetric and therapeutic steps.  Each step consists of a sequential 
infusion of Tositumomab followed by Iodine I 131 Tositumomab.  The likely side effects include 
myelosuppression and its sequelae (infections, hemorrhage).  Less likely side effects include 
hypersensitivity reactions, and gastrointestinal toxicity including nausea, vomiting, abdominal 
pain and diarrhea.  Uncommonly, a constellation of symptoms, including fever, rigors or chills, 
sweating, hypotension, dyspnea, bronchospasm, and nausea has been reported during or within 
48 hours of infusion.  Also uncommonly, MDS, hypothyroidism, and the development of human 
anti-murine antibodies have been reported.  
 
Bexxar will be supplied by GlaxoSmithKline free of charge.   The administration and ordering 
instructions for Bexxar are outlined in Section 2.7 and Section 2.8, respectively. 
 
2.6.3. Carmustine (BCNU) 
 
Carmustine is an alkylating agent.  Common side effects include myelosuppression, nausea, 
vomiting, headache, and jaw pain.  Less common side effects include transient hypotension, 
dizziness, hyperpigmentation of the skin, hepatoxicity and a delayed inflammatory lung response 
(pneumonitis).   
 
2.6.4. VP-16 (Etoposide) 
 
VP-16 is a semi-synthetic podophyllotoxin derivative.  Side effects that are likely to occur 
include nausea, vomiting and diarrhea, myelosuppression, mucositis, alopecia, and fatigue.  Less 
likely side effects include a skin rash, peripheral neuropathy, and hepatotoxicity.  Hypotension 
may occur if the drug is infused quickly.  A rare but serious side effect is a small risk of 
developing a second cancer.   
 
2.6.5. Cytarabine (Ara-C) 
 
Cytarabine, commonly known as Ara-C, is a synthetic nucleoside.  Likely side effects include 
myelosuppression, nausea, vomiting and diarrhea, oral and anal inflammation or ulceration, 
hepatic dysfunction, fever, rash, and thrombophlebitis.  Less likely side effects include 
conjunctivitis (when Ara-C is given at high doses, and preventable by the prophylactic use of 
corticosteroid eye drops), abdominal pain, alopecia, pruritis, headache, and the occurrence of a 
cytarabine syndrome characterized by fever, myalgias, arthralgias, chest pain, maculopapular 
rash, conjunctivitis and malaise - this syndrome occurs 6-12 hours following drug administration.  
Corticosteroids are beneficial in treating this syndrome.  A rare but serious side effect is 
cerebral/cerebellar dysfunction (more common at very high doses and in older patients).   
 


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2.6.6. Melphalan 
 
Melphalan, an alkylating agent, is a phenylalanine derivative of nitrogen mustard.  At high doses, 
the likely toxicities include myelosuppression, gastrointestinal toxicity and alopecia.  The 
duration of profound myelosuppression decreases with the use of stem cell transplantation and 
colony stimulating factors.  Gastrointestinal toxicity, which includes potentially severe 
stomatitis, esophagitis and diarrhea, may require intravenous narcotics for mucositis related pain, 
intravenous hydration and alimentation, and antibiotics.  Less likely is hepatotoxicity.  Rare but 
serious toxicities reported include pulmonary fibrosis and interstitial pneumonitis, veno-
occlusive disease of the liver, skin hypersensitivity, vasculitis, hemolytic anemia, allergic 
reactions, and a small risk of developing second cancers.   
 
2.6.7. G-CSF (Filgrastim) 
 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF) produced by recombinant 
DNA technology.  G-CSF stimulates the production, maturation and activation of neutrophils 
and activates neutrophils to increase their migration and cytotoxicity.  Toxicities that are likely to 
occur include myalgias and medullary bone pain.  The bone pain can be generally controlled 
with non-narcotic analgesia.  Less likely side effects include fluid retention, pericardial effusion, 
local inflammation at the injection site and transient laboratory abnormalities including mild 
elevations in uric acid, lactic dehydrogenase (LDH), alkaline phosphatase, and leukocytosis.  
Rare but serious side effects include reported cases of spleen swelling resulting in splenic 
rupture, adult respiratory distress syndrome (ARDS) and allergic reactions. 
 
2.7. Bexxar Administration 
 
2.7.1. Dosing Schema 
 
Patients will undergo two dosing phases.  The first phase, termed “dosimetric dose,” involves the 
IV administration of a low radioactive dose (5 mCi) of Iodine I 131 Tositumomab for the 
purpose of determining the rate of whole body clearance of radioactivity (residence time) so that 
the amount of radioactivity to deliver a 75 cGy total body radiation dose can be calculated (see 
Table 2.7.4.2).  The calculated activity of Iodine-131 conjugated with Tositumomab will then be 
administered to deliver a 75 cGy total body radiation dose in the second phase of the study, 
termed “therapeutic dose.”  Patients who are obese will be dosed upon 137% of their lean body 
mass.   
 
Both the dosimetric dose and the therapeutic dose will be immediately preceded by an IV 
infusion of 450 mg Tositumomab.  Patients will be treated with a thyroid blockade medication 
starting at least 24 hours prior to the dosimetric dose of the Iodine I 131 Tositumomab and 
continuing daily for 14 days following the therapeutic dose of Iodine I 131 Tositumomab.   
 
Administration of Iodine I 131 Tositumomab will be performed by personnel that have been 
trained and authorized to deliver such doses of radioisotope to patients.  Special radiation 
precautions will be used during and after the administration of the radioimmunotherapy dose, as 


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required by the national and/or regional regulations for the radiopharmaceutical industry.  
Restrictions on patient contact with others will be set in accordance with these regulatory 
guidelines (NRC and state laws).  The dosimetric and therapeutic doses may be given as either 
an outpatient or in-patient procedure depending on current NRC and state regulations. 
 
Table 2.7.1 
Iodine I 131 Tositumomab (Dosing Schema) 
Time Relative to the  
Dosimetric Dose (Day 0) 
 
Administration 
Day –20 
Initiate daily administration of oral iodine product for 
thyroid blockade at least 24 hours prior to dosimetric dose 
and continuing through 14 days post therapeutic dose 
Day -19  
Dosimetric dosea 
Thyroid blockade 60–120 minutes before Iodine I 131 
Tositumomab infusion 
450 mg of Tositumomab infused over 1 hour  
5 mCi of Iodine I 131 Tositumomab infused over 20 minutes 
followed by a 10 minute saline flush 
Day-12 
Therapeutic dosea  
Thyroid blockade 60–120 minutes before Iodine I 131 
Tositumomab infusion 
450 mg of Tositumomab infused over 1 hour  
Individualized mCi dose of Iodine I 131 Tositumomab 
infused over 20 minutes followed by a 10 minute saline 
flush 
Days -12 to +2 
Oral iodine product discontinued 14 days following the 
therapeutic dose 
a Premedication with acetaminophen and diphenhydramine 30–60 minutes prior to 
Tositumomab dose. 
 
 
2.7.2. Dosage Preparation 
 
Proper aseptic technique and precautions for handling radioactive materials should be employed.  
Appropriate shielding should be used during preparation and during administration to the patient. 
 
2.7.2.1. 
Preparation of Tositumomab infusion 
1) Withdraw 450 mg of Tositumomab by sterile technique. 
2) Dilute with 0.9% sodium chloride, USP, to a total volume of 50 mL. 
3) Gently invert the IV bag to mix the solution.  Avoid foaming.  Tositumomab solution 
may contain particles. 


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2.7.2.2. 
Preparation of dosimetric Iodine I 131 Tositumomab infusion 
1) Allow approximately 60 minutes for thawing (at ambient temperature) the dosimetric 
Iodine I 131 Tositumomab.  Thaw the frozen vial in a room temperature lead pot.   
2) Place a 50-mL vial in a lead pot. 
3) Determine the amount of each component needed according to the directions below (a 
Dose Preparation Worksheet is provided to assist in calculations): 
a. Calculate the volume of Iodine I 131 Tositumomab that is equal to 5.0 mCi, based on 
the activity concentration of the Iodine I 131 Tositumomab vial.  Decay correction 
must be taken into account when determining the necessary volume.  
b. Calculate the volume of Tositumomab needed to bring the 5.0 mCi solution to a total 
protein mass of 35 mg.  
c. Calculate the volume of 0.9% sodium chloride needed to bring the solution to a final 
volume of 30 mL.   
4) Transfer the 5.0 mCi volume of Iodine I 131 Tositumomab (Step 3a) into the shielded 50-
mL vial.   
5) Add the calculated volume of Tositumomab from Step 3b. This additional amount of 
antibody is to be drawn from the 3-mL Tositumomab vial.   
6) Dilute the preparation with 0.9% sodium chloride, USP, to a final volume of 30 mL  
(Step 3c). 
7) Calibrate the prepared solution to confirm the activity dose.  
 
2.7.2.3. 
Preparation of therapeutic Iodine I 131 Tositumomab infusion 
1) Allow approximately 60 minutes for thawing (at ambient temperature) the therapeutic 
Iodine I 131 Tositumomab.  Thaw the frozen vial in a room temperature lead pot.   
2) Place a 50-mL vial in a lead pot. 
3) Determine the amount of each component needed according to the directions below (a 
Dose Preparation Worksheet is provided to assist in calculations): 
a. Calculate the volume of Iodine I 131 Tositumomab that is equal to the specified 
activity determined by dosimetry, based on the activity concentration of the Iodine I 
131 Tositumomab vial.  Decay correction must be taken into account when 
determining the necessary volume.  
b. Calculate the volume of Tositumomab needed to bring the solution to a total protein 
mass of 35 mg.  If the amount of Tositumomab in the dose preparation is already  
 35 mg, no additional Tositumomab will be added. 
c. Calculate the volume of 0.9% sodium chloride needed to bring the solution to a final 
volume of 30 mL.   


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4) Transfer the calculated volume of Iodine I 131 Tositumomab (Step 3a) for a Total Body 
Dose of 75 cGy into the shielded 50-mL vial.   
5) Add the calculated volume of Tositumomab from Step 3b, if needed.  This additional 
amount of antibody is to be drawn from the 3-mL Tositumomab vial.   
6) Dilute the preparation with 0.9% sodium chloride, USP, to a final volume of 30 mL (Step 
3c). 
7) Calibrate the prepared solution to confirm the activity dose.   
 
2.7.3. Administration of Iodine I 131 Tositumomab 
 
2.7.3.1. 
Thyroid blockade 
 
Patients will be treated with Saturated Solution Potassium Iodide (SSKI) 4 drops PO TID, 
Lugol’s solution 20 drops PO TID, or potassium iodide tablets 130 mg PO QD starting at least 
24 hours prior to the dosimetric dose of the Iodine I 131 Tositumomab and continuing daily for 
14 days following the therapeutic dose of Iodine I 131 Tositumomab.  In addition, 60-120 
minutes before the dosimetric and therapeutic dose of Iodine I 131 Tositumomab all patients will 
be given an additional dose of medication for thyroid blockade.  The SSKI or Lugol’s solution 
may be given with juice or cola to mask its taste.  
 
In no instance should a patient receive the dosimetric dose of Iodine I 131 Tositumomab if they 
have not yet received at least three doses of SSKI, three doses of Lugol’s solution, or one 130 mg 
potassium iodide tablet (at least 24 hours prior to the dosimetric dose).  Patient compliance will 
be ascertained and documented prior to administration of the dosimetric dose and therapeutic 
dose. 
 
2.7.3.2. 
Dosimetric dose administration 
 
On Study Day -19 of the Iodine I 131 Tositumomab calendar, patients will receive an IV 
administration of 450 mg Tositumomab followed by an IV administration of the dosimetric dose 
(refer to Section 2.7.2 for dose preparations). 
 
Prior to administration, verify the patient’s compliance with thyroid blockade supplements.  
Sixty to 120 minutes before the Iodine I 131 Tositumomab infusion, patients will be given an 
additional dose of thyroid blockade.  Thirty to 60 minutes before the Tositumomab infusion, 
patients will be premedicated with acetaminophen 650 mg PO and diphenhydramine 50 mg PO 
(unless the patient is hypersensitive to acetaminophen or diphenhydramine). 
 
Vital signs must be taken approximately every 15 minutes during each of the Tositumomab 
infusions. 
 
Tositumomab will be given as an IV infusion, through an in-line filter, over one hour or longer, 
depending on the occurrence of infusion-related AEs.  Following the administration of 


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Tositumomab, infuse the dosimetric dose (35 mg of Tositumomab containing 5mCi of Iodine I 
131 Tositumomab) over 20 minutes.   
 
The patient dose should be measured by a suitable radioactivity calibration system immediately 
prior to administration.  The dose calibrator must be operated in accordance with the 
manufacturer’s specifications and quality control for the measurement of Iodine-131. 
 
At the end of the infusion of the dosimetric dose, the syringe or IV bag must be refilled with 
0.9% Sodium Chloride for Injection, USP, and the contents infused over a period of 10 minutes.   
 
Upon completion of the infusion, all pieces of the administration apparatus (syringe or vial, 
tubing, in-line filters, etc.) must be packaged and placed in a dose calibrator to measure the 
residual activity.  The actual activity administered (net to patient) will be calculated as original 
vial/syringe calibrated activity minus residual activity.  Discard vials, needles, and syringes in 
accordance with local, state, and federal regulations governing radioactive and biohazardous 
waste.  
 
2.7.3.3. 
Whole body dosimetry 
 
Gamma camera images will be used for whole body dosimetry.  Whole body dosimetry for the 
purpose of determining the appropriate activity in mCi for the therapeutic dose will be performed 
for each patient.  Three whole body anterior and posterior gamma camera scans will be obtained.  
The first scan will occur within 1 hour after the completion of the administration of the 
dosimetric dose (before urination).  The remaining two scans will occur on two of the following 
days: Day -17, Day -16, or Day -15, and Day –14, -13 or Day -12.   
 
These scans will be obtained by using a gamma camera with an appropriate high-energy 
collimator at a scan speed of 10-30 cm/min.  The images from these three days will be used to 
perform organ and tumor dosimetry and for a visual assessment of biodistribution.   
 
The counts from Day -19; Day -17, -16, or -15; and Day –12, -13 or -14 will be used to calculate 
the appropriate activity to deliver a total body dose of 75 cGy for the therapeutic dose (when 
calculating whole body dosimetry, the order of preference for the second scan is Day -15, -16,  
-17).  On each of these three days, whole body counts, background counts, and counts of a 
calibrated standard will be obtained and recorded.  Patients who are obese will be dosed upon 
137% of their lean body mass (refer to Table 2.7.4.1 for definition of obese).  The mCi dose will 
be calculated according to instructions provided with this protocol.  Details of the dose 
calculations are provided in Table 2.7.4.2. 
 
The biodistribution of Iodine I 131 Tositumomab should be assessed by determination of total 
body residence time and by visual examination of whole body camera images from the first 
image taken at the time of Count 1 (within an hour of the end of the infusion) and from the 
second image taken at the time of Count 2 (at 2 to 4 days after administration).  To resolve 
ambiguities, an evaluation of the third image at the time of Count 3 (6 to 7 days after 


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administration) may be necessary.  If either of these methods indicates that the biodistribution is 
altered, the Iodine I 131 Tositumomab therapeutic dose should not be administered. 
 
Expected biodistribution: 
 On the first imaging timepoint: Most of the activity is in the blood pool (heart and major 
blood vessels) and the uptake in normal liver and spleen is less than in the heart. 
 On the second and third imaging timepoints: The activity in the blood pool decreases 
significantly and there is decreased accumulation of activity in normal liver and spleen.  
Images may show uptake by thyroid, kidney, and urinary bladder and minimal uptake in 
the lungs.  Tumor uptake in soft tissues and in normal organs is seen as areas of increased 
intensity. 
 
Results indicating altered biodistribution: 
 On the first imaging timepoint: If the blood pool is not visualized or if there is diffuse, 
intense tracer uptake in the liver and/or spleen or uptake suggestive of urinary obstruction 
the biodistribution is altered.  Diffuse lung uptake greater than that of blood pool on the 
first day represents altered biodistribution. 
 On the second and third imaging timepoints: uptake suggestive of urinary obstruction and 
diffuse lung uptake greater than that of the blood pool represent altered biodistribution. 
 
Total body residence times of less than 50 hours and more than 150 hours. 
 
2.7.3.4. 
Calculations of therapeutic dose 
 
Calculation of Iodine-131 Activity 
The following equation is used to calculate the activity of Iodine-131 to administer to the patient 
as Iodine I 131 Tositumomab to achieve the desired total body dose of radiation (75 cGy): 
 
Iodine-131 Activity (mCi)=
(h)
Time
Residence
h)
(mCi
Hours
Activity
  
 
The methods for determining the activity hours (mCi h) and residence time (h) are described 
below. 
 
Activity Hours (mCi h) 
In order to determine the activity hours (mCi h), look up the patient’s maximum effective mass 
based on the patient’s gender and height in Table 2.7.4.1.  Then, using either the patient’s weight 
or maximum effective mass, whichever is less, look up the value for activity hours (mCi h) in 
Table 2.7.4.2. 
 
Residence Time (h) 
The first step in calculating the percent-injected activity is to determine the background-
corrected total body count, as described above, at Day -19; Day -17, -16, or -15, and Day -13 or -
12.  The order of preference for the three scans to be used in dose calculations is Days -19, -15, 
-12; Days -19, -16, -12; and Days -19, -17, -12.  Thus if the Day -15 image was obtained, it 
should be used for dose calculations.  Next, determine the time (in hours) from the start of the 


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Iodine I 131 Tositumomab dosimetric dose infusion to the acquisition of each whole body count.  
The percent injected activity remaining at each time point is then calculated by dividing the 
background-corrected whole body count for that time point by the background-corrected whole 
body count from the first time point (Day -19) and multiplying by 100. 
 
Plot the times from the start of the infusion and the percent injected activity values for the last 2 
time points in the Figure in Section 2.7.4 in order to determine the residence time.  The last 2 
time points would correspond to Day -17, -16, or -15 (the order of preference is Day -15, -16, 
then -17) and Day -12.  Draw a best-fit line from 100% (the pre-plotted Day 0 value) through the 
2 plotted points (if the line does not intersect the two plotted points, one point must lie above the 
best-fit line and one point must lie below the best-fit line).  Determine the x-axis value of the 
graph at the point where the best-fit line intersects the horizontal 37% injected activity line; this 
is the total body residence time (h).  
 
2.7.3.5. 
Therapeutic dose administration 
 
The therapeutic dose will be administered on Day -12 or one week following the dosimetric 
dose.  Those patients who experienced an anaphylactic response following the dosimetric dose 
will not continue into this phase of the study.  
 
The patient’s compliance with thyroid blockade should be verified.  Sixty to 120 minutes before 
the Iodine I 131 Tositumomab infusion, patients will be given a dose of thyroid blockade.  Thirty 
to 60 minutes before the Tositumomab infusion, patients will be pre-medicated with 
acetaminophen 650 mg PO and diphenhydramine 50 mg PO (unless the patient is hypersensitive 
to acetaminophen or diphenhydramine). 
 
Tositumomab will be given as an IV infusion, through an in-line filter, over 1 hour or longer, 
depending on the occurrence of infusion-related AEs.  
 
Vital signs must be taken approximately every 15 minutes during each of the Tositumomab 
infusions. 
 
Following the administration of Tositumomab, infuse the therapeutic dose (35 mg of 
Tositumomab containing the patient-specific amount of tellurium-derived Iodine I 131 
Tositumomab) over 20 minutes. 
 
The patient dose should be measured by a suitable radioactivity calibration system immediately 
prior to administration.  The dose calibrator must be operated in accordance with the 
manufacturer’s specifications and quality control for the measurement of Iodine-131. 
 
At the end of the infusion of the therapeutic dose, the syringe or IV bag must be refilled with 
0.9% Sodium Chloride for Injection, USP, and the contents infused over a period of 10 minutes.   
 
Upon completion of the infusion, all pieces of the administration apparatus (syringe or vial, 
tubing, in-line filters, etc.) must be packaged and placed in a dose calibrator to measure the 


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residual activity.  The actual activity administered (net to patient) will be calculated as original 
vial/syringe calibrated activity minus residual activity.  Discard vials, needles, and syringes in 
accordance with local, state, and federal regulations governing radioactive and biohazardous 
waste. 
 
2.7.4. Dose Modifications/Discontinuations 
 
For excessively obese patients (patients weighing more than 137% of their lean body mass), the 
calculations to determine the Iodine I 131 Tositumomab activity to administer will use 137% of 
the patients' lean body weight rather than their actual body weight (refer to Table 2.7.4.1). 
 
All patients who are discontinued due to an infusion related adverse events should be followed 
until the resolution or stabilization of the event.  Any randomized patient who receives study 
drug then discontinues, regardless of reason, will not be allowed to re-enroll in this study. 
 


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2-17 
Table 2.7.4.1 
Maximum Effective Mass 
 
Men 
 
Women 
Height 
(ft–inches) 
Height 
(cm) 
Maximum 
Effective 
Mass (kg) 
 
Height 
(ft–inches) 
Height 
(cm) 
Maximum 
Effective 
Mass (kg) 
4'–5" 
134.5 
40.5 
 
4'–5" 
134.5 
40.7 
4'–6" 
137.0 
44.2 
 
4'–6" 
137.0 
43.8 
4'–7" 
140.0 
47.9 
 
4'–7" 
140.0 
47.0 
4'–8" 
142.0 
51.6 
 
4'–8" 
142.0 
50.2 
4'–9" 
145.0 
55.3 
 
4'–9" 
145.0 
53.3 
4'–10" 
147.5 
59.0 
 
4'–10" 
147.5 
56.5 
4'–11" 
150.0 
62.7 
 
4'–11" 
150.0 
59.7 
5'–0" 
152.5 
66.3 
 
5'–0" 
152.5 
62.8 
5'–1" 
155.0 
70.0 
 
5'–1" 
155.0 
66.0 
5'–2" 
157.5 
73.7 
 
5'–2" 
157.5 
69.2 
5'–3" 
160.0 
77.4 
 
5'–3" 
160.0 
72.3 
5’–4" 
162.5 
81.1 
 
5’–4" 
162.5 
75.5 
5'–5" 
165.0 
84.8 
 
5'–5" 
165.0 
78.7 
5'–6" 
167.5 
88.5 
 
5'–6" 
167.5 
81.8 
5’–7" 
170.0 
92.2 
 
5’–7" 
170.0 
85.0 
5’–8" 
172.5 
95.8 
 
5’–8" 
172.5 
88.2 
5'–9" 
175.5 
99.5 
 
5'–9" 
175.5 
91.3 
5'–10" 
178.0 
103.2 
 
5'–10" 
178.0 
94.5 
5'–11" 
180.5 
106.9 
 
5'–11" 
180.5 
97.7 
6'–0" 
183.0 
110.6 
 
6'–0" 
183.0 
100.8 
6'–1" 
185.5 
114.3 
 
6'–1" 
185.5 
104.0 
6'–2" 
188.0 
118.0 
 
6'–2" 
188.0 
107.2 
6'–3" 
190.5 
121.7 
 
6'–3" 
190.5 
110.3 
6'–4" 
193.0 
125.4 
 
6'–4" 
193.0 
113.5 
6'–5" 
195.5 
129.0 
 
6'–5" 
195.5 
116.7 
6'–6" 
198.0 
132.7 
 
6'–6" 
198.0 
119.8 
6'–7" 
200.5 
136.4 
 
6'–7" 
200.5 
123.0 
6'–8" 
203.0 
140.0 
 
6'–8" 
203.0 
126.2 
6'–9" 
205.5 
143.8 
 
6'–9" 
205.5 
129.3 
6'–10" 
208.5 
147.5 
 
6'–10" 
208.5 
132.5 
6'–11" 
211.0 
151.2 
 
6'–11" 
211.0 
135.7 
7'–0" 
213.5 
154.9 
 
7'–0" 
213.5 
138.8 
Multiply pounds by 0.454 to obtain kilograms.  Multiply inches by 2.54 to obtain centimeters.  
To calculate the maximum effective mass for patient heights not included in above table, use 
the following formulas: 
 
Males: Maximum Effective Mass (kg)=65.76 + 1.452 (Ht. in cm – 152) 
Females:  Maximum Effective Mass (kg)=62.34 + 1.247 (Ht. in cm – 152) 
 
Adapted from (K. Zasadny, R. Wahl, et al., J Nuc Med 1995; 36(5):214. “Total Body Mass 
Lean”). 


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Table 2.7.4.2 -- Activity Hours 
Mass1 
(kg) 
Activity 
Hours 
(mCi h)  
Mass1 
(kg) 
Activity 
Hours 
(mCi h)  
Mass1 
(kg) 
Activity 
Hours 
(mCi h)  
Mass1 
(kg) 
Activity 
Hours 
(mCi h)  
Mass1 
(kg) 
Activity 
Hours 
(mCi h) 
40.0 
4638 
 
60.0 
6686 
 
80.0 
8670 
 100.0 
10595 
 120.0 
12463 
40.5 
4690 
 
60.5 
6737 
 
80.5 
8718 
 100.5 
10643 
 120.5 
12509 
41.0 
4743 
 
61.0 
6787 
 
81.0 
8767 
 101.0 
10690 
 121.0 
12556 
41.5 
4796 
 
61.5 
6838 
 
81.5 
8816 
 101.5 
10738 
 121.5 
12602 
42.0 
4848 
 
62.0 
6888 
 
82.0 
8864 
 102.0 
10785 
 122.0 
12648 
42.5 
4901 
 
62.5 
6938 
 
82.5 
8913 
 102.5 
10833 
 122.5 
12694 
43.0 
4953 
 
63.0 
6989 
 
83.0 
8961 
 103.0 
10880 
 123.0 
12741 
43.5 
5005 
 
63.5 
7039 
 
83.5 
9010 
 103.5 
10927 
 123.5 
12787 
44.0 
5057 
 
64.0 
7089 
 
84.0 
9058 
 104.0 
10975 
 124.0 
12833 
44.5 
5109 
 
64.5 
7139 
 
84.5 
9106 
 104.5 
11022 
 124.5 
12879 
45.0 
5160 
 
65.0 
7189 
 
85.0 
9154 
 105.0 
11069 
 125.0 
12925 
45.5 
5212 
 
65.5 
7238 
 
85.5 
9202 
 105.5 
11116 
 125.5 
12971 
46.0 
5264 
 
66.0 
7288 
 
86.0 
9251 
 106.0 
11163 
 126.0 
13017 
46.5 
5315 
 
66.5 
7338 
 
86.5 
9299 
 106.5 
11210 
 126.5 
13063 
47.0 
5366 
 
67.0 
7387 
 
87.0 
9347 
 107.0 
11257 
 127.0 
13109 
47.5 
5418 
 
67.5 
7437 
 
87.5 
9394 
 107.5 
11304 
 127.5 
13155 
48.0 
5469 
 
68.0 
7486 
 
88.0 
9442 
 108.0 
11351 
 128.0 
13200 
48.5 
5520 
 
68.5 
7536 
 
88.5 
9490 
 108.5 
11398 
 128.5 
13246 
49.0 
5571 
 
69.0 
7585 
 
89.0 
9538 
 109.0 
11445 
 129.0 
13292 
49.5 
5621 
 
69.5 
7634 
 
89.5 
9585 
 109.5 
11492 
 129.5 
13337 
50.0 
5672 
 
70.0 
7683 
 
90.0 
9633 
 110.0 
11538 
 130.0 
13383 
50.5 
5724 
 
70.5 
7733 
 
90.5 
9682 
 110.5 
11585 
 130.5 
13429 
51.0 
5775 
 
71.0 
7783 
 
91.0 
9730 
 111.0 
11632 
 131.0 
13474 
51.5 
5826 
 
71.5 
7833 
 
91.5 
9779 
 111.5 
11678 
 131.5 
13520 
52.0 
5878 
 
72.0 
7883 
 
92.0 
9827 
 112.0 
11725 
 132.0 
13565 
52.5 
5929 
 
72.5 
7932 
 
92.5 
9875 
 112.5 
11771 
 132.5 
13611 
53.0 
5980 
 
73.0 
7982 
 
93.0 
9924 
 113.0 
11818 
 133.0 
13656 
53.5 
6031 
 
73.5 
8031 
 
93.5 
9972 
 113.5 
11864 
 133.5 
13701 
54.0 
6082 
 
74.0 
8081 
 
94.0 
10020 
 114.0 
11910 
 134.0 
13747 
54.5 
6133 
 
74.5 
8130 
 
94.5 
10068 
 114.5 
11957 
 134.5 
13792 
55.0 
6184 
 
75.0 
8180 
 
95.0 
10117 
 115.0 
12003 
 135.0 
13837 
55.5 
6234 
 
75.5 
8229 
 
95.5 
10165 
 115.5 
12049 
 135.5 
13882 
56.0 
6285 
 
76.0 
8278 
 
96.0 
10213 
 116.0 
12095 
 136.0 
13928 
56.5 
6335 
 
76.5 
8327 
 
96.5 
10261 
 116.5 
12141 
 136.5 
13973 
57.0 
6386 
 
77.0 
8376 
 
97.0 
10309 
 117.0 
12187 
 137.0 
14018 
57.5 
6436 
 
77.5 
8425 
 
97.5 
10357 
 117.5 
12233 
 137.5 
14063 
58.0 
6486 
 
78.0 
8474 
 
98.0 
10404 
 118.0 
12279 
 138.0 
14108 
58.5 
6536 
 
78.5 
8523 
 
98.5 
10452 
 118.5 
12325 
 138.5 
14153 
59.0 
6586 
 
79.0 
8572 
 
99.0 
10500 
 119.0 
12371 
 139.0 
14198 
59.5 
6636 
 
79.5 
8621 
 
99.5 
10548 
 119.5 
12417 
 139.5 
14242 
1 
The minimum of the patient’s actual weight (kg) or maximum effective mass (kg) from Table 2.7.4.1.  For values between 
140 kg and 160 kg, use the following formula:  Activity Hours (mCi h)=14287 + (88.74) (Wt in kg – 140) 


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Figure 2.7.4.3 


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2.8. Bexxar Ordering Instructions 
 
As soon as a patient is randomized to the Bexxar arm, it is recommended that the clinic 
coordinator alert the Nuclear Medicine Department staff so that coordination for patient 
scheduling can begin.   
 
Please note that Bexxar can be ordered as early as 4 weeks, but no less than 1 week, prior to the 
planned date of dosimetric dose administration (Day -19).  Please refer to the “Study Drug Order 
Form” located in Appendix E. 
 
The clinic coordinator should fill out the top portion of the form (i.e. patient ID#, PI, Site 
information, etc.), and submit it to the Nuclear Medicine Department for further completion of 
the form.  The Nuclear Medicine Department will initially be responsible for completing the 
section titled the “Nuclear Medicine/ Radiation Oncology Information,” (i.e. Prescribing 
Physician Name, Main Contact Person name and information).  The Prescribing Physician is also 
responsible for completing the information regarding the expected administration dates and times 
(including possible alternate dates) of the dosimetric and therapeutic doses of Bexxar. 
 
To complete the drug order placement, fax the completed form to the radiopharmacy.  The 
radiopharmacy will then further complete the Study Drug Order Form and fax it to the BEXXAR 
Service Center. 
 


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CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1.  Definition of Disease Status 
 
Patients at each data collection period are classified into one of the following states.  Until 
relapse/progression, all disease classifications are relative to the patient’s pre-ASCT disease 
status.  Once the patient has relapsed/progressed, these states are relative to the patient’s best 
disease state.  Tests used for evaluation of disease status would be physical examination, 
laboratory testing, bone marrow biopsy and aspirate, PET scans, and CT scans of neck, chest, 
abdomen and pelvis as indicated.   
 
Segments of this section are excerpts from the Bruce Cheson, et al, article “Revised Response 
Criteria for Malignant Lymphoma.” [36] 
 
Table 3.1:  Response Definitions 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
 
(a) FDG-avid or PET positive 
prior to therapy; mass of any 
size permitted if PET negative 
(b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT 
 
Not palpable, 
nodules 
disappeared 
 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
Immunohistochemistry 
should be negative 
 
PR 
Regression of 
measurable 
disease and no 
new sites 
 
≥ 50% decrease in SPD of up to 
6 largest dominant masses; no 
increase in size of other nodes 
(a) FDG-avid or PET positive 
prior to therapy; one or more 
PET positive at previously 
involved site 
(b) Variably FDG-avid or PET 
negative; regression on 
CT 
 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen 
 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
 


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Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
SD 
Failure to 
attain CR/PR 
or PD 
 
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no 
new sites on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
 
 
 
Relapsed 
disease or 
PD 
Any new 
lesion or 
increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
 
Appearance of a new lesion(s)  
> 1.5 cm in any axis, ≥ 50% 
increase in SPD of more than 
one node, or ≥ 50% increase in 
longest diameter of a previously 
identified node > 1 cm in short 
axis 
 
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
 
> 50% increase 
from nadir in 
the SPD of any 
previous 
lesions 
 
New or recurrent 
involvement 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed 
tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease. 
 
 
Complete Remission (CR): 
The designation of CR requires the following (Table 3.1): 
 Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
 Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the 
PET scan was positive before therapy, a post-treatment residual mass of any size is 
permitted as long as it is PET negative. 
 Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT to normal size (≤ 1.5 cm in their greatest transverse diameter 
for nodes > 1.5 cm before therapy).  Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment must have 
decreased to ≤ 1.0cmin their short axis after treatment. 
 The spleen and/or liver, if considered to be enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical exam and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable because 
a spleen considered normal in size may still contain lymphoma, whereas an enlarged 


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spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma. 
 If bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core).  If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry.  A sample 
that is negative by immunohistochemistry but that demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in patient outcome. 
Complete Remission Undetermined (CRu):  
 The use of the above definition for CR and that below for PR eliminates the category of 
CRu. 
 
Partial Remission (PR): 
The designation of PR requires all of the following: 
 At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses.  These nodes or masses should be selected 
according to all of the following: they should be clearly measurable in at least 2 
perpendicular dimensions; if possible they should be from disparate regions of the body; 
and they should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved. 
 No increase should be observed in the size of other nodes, liver or spleen. 
 Splenic and hepatic nodules must regress by  50% in their SPD or, for single nodules in 
the greatest transverse diameter. 
 With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
 Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment.  However, if positive, the cell type should be specified (eg, 
large-cell lymphoma or small neoplastic B cells).  Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will be 
considered partial responders.  When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders. 
 No new sites of disease should be observed. 
 Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least 
one previously involved site. 
 Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should be 
used.  In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 


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indicated with one, or at most two, residual masses that have regressed by more than 50% 
on CT; those with more than two residual lesions are unlikely to be PET negative and 
should be considered partial responders. 
 
Stable Disease (SD): 
Stable disease (SD) is defined as the following: 
 A patient is considered to have SD when he or she fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]). 
 Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post-treatment CT or PET. 
 Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no change 
in the size of the previous lesions on the post-treatment CT scan. 
 
Relapsed Disease (RD, after CR)/ Progressive Disease (PD after PR, SD): 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of 
the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0. Lymph nodes ≤ 1.0 x ≤ 1.0cm will not be considered 
as abnormal for relapse or progressive disease. 
 Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
 At least a 50% increase from nadir in the SPD of any previously involved nodes or in a 
single involved node, or the size of other lesions (e.g, splenic or hepatic nodules).  To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by  50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in 
the long axis. 
 At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cmin its short axis 
 Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 1.5 cm in its long axis by CT).  Measurable extranodal disease 
should be assessed in a manner similar to that for nodal disease.  For these 
recommendations, the spleen is considered nodal disease.  Disease that is only assessable 
(e.g. pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found 


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to be histologically negative.  In clinical trials where PET is unavailable to the vast 
majority of participants, or where PET is not deemed necessary or appropriate for use 
(e.g. a trial in patients with MALT lymphoma), response should be assessed as above, but 
only using CT scans.  However, residual masses should not be assigned CRu status, but 
should be considered partial responses. 
 
3.2. Primary Endpoint to be Compared Between Rituxan/BEAM and Bexxar/BEAM + 
Autologous HSCT  
 
The primary endpoint is progression-free survival (PFS).  Patients are considered a failure for 
this endpoint if they die or if they relapse/progress or receive anti-lymphoma therapy, other than 
post-transplant consolidative localized radiation (maximum 3 sites) to sites of prior bulk disease 
pre-transplant (> 3cm).  The time to this event is the time from randomization until death, 
relapse/progression, receipt of anti-lymphoma therapy, or last follow up, whichever comes first.  
 
3.3. Secondary Endpoints to be Compared Between Rituxan/BEAM and Bexxar/BEAM + 
Autologous HSCT  
 
3.3.1. Overall Survival 
 
The event is death from any cause.  The time to this event is the time from randomization to 
death or last follow-up.  Surviving patients are censored at the time of last observation.   
 
3.3.2. Time to Progression 
 
The event is relapse/progression.  The time to this event is measured from randomization.  
Deaths without relapse/progression are considered as a competing risk.  Surviving patients with 
no history of relapse/progression are censored at time of last follow-up. 
 
3.3.3. CR and CR+PR Proportion at Day 100 
 
The event is whether or not the patient has CR (or PR) at Day 100.  The time to event is 
measured from the time of randomization to the time to CR (or PR).   
 
3.3.4. Time to Hematopoietic Recovery  
 
Time to neutrophil recovery will be the first of two consecutive days of > 500 neutrophils/μL 
following the expected nadir.  Time to platelet engraftment will be the date platelet count is  
> 20,000/μL for the first of two consecutive labs with no platelet transfusions 7 days prior. 
 
3.3.5. Hematologic Function  
 
Hematologic function will be defined as ANC > 1,500 neutrophils/μL, hemogloblin > 10 g/dL 
without transfusion support, and platelet count > 100,000/μL without transfusion support and 
will be measured at Day 100 and 1 year. 


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3.3.6. Incidence of Infection 
 
Microbiologically documented infections will be reported by site of disease, date of onset, 
severity, and resolution, if any.  This data will be captured via an event-driven case report form 
and will be collected from Day 0 until two years post-transplant.   
 
3.3.7. Maximum Mucositis Score by Day + 21  
 
Mucositis severity will be recorded twice weekly as per the modified oral mucositis assessment 
scale (OMAS).  Mucositis scores will be recorded for the first three weeks post-transplant.  Both 
peak and mean mucositis scores will be analyzed. 
 
3.3.8. Treatment-related Mortality 
 
Treatment-related mortality (TRM) is defined as death occurring in a patient from causes other 
than relapse or progression and will be measured at 1 year. 
 
3.3.9. Incidence of MDS/ AML and New, Abnormal Cytogenetics  
 
MDS or AML is defined as the existence of a bone marrow biopsy report with the diagnosis of 
MDS or AML. 
 
3.3.10. Immunologic Reconstitution  
 
This will be measured in all patients prior to the initiation of the Day –19 Bexxar or Rituxan 
(baseline), at Day +100, and at 1 year post-transplant.  This will also be measured at 2 years 
post-transplant if the 1 year assessment is abnormal.  Tests to be performed on peripheral blood 
at those time points include CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, CD45 RA/RO, 
CD56+/CD3-, and quantitative immunoglobulins (IgM, IgG and IgA). 


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CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1.  Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCSM).  Southwest Oncology Group (SWOG) centers should follow instructions in 
Section 4.1.2 prior to following the instructions below.  The following procedures should be 
followed: 
1. Within 4 weeks to 1 week prior to initiation of conditioning therapy, an authorized user at 
the transplant center completes initial screening by entering patient demographics and 
Segment A of the Enrollment Form in AdvantageEDC.  The eligibility screening includes 
questions that will verify eligibility, capture the proposed start date of conditioning, date 
of most recent dose of Rituxan, start date of leukapheresis, and a question confirming that 
the patient signed the informed consent form. 
2. If the patient is eligible, a study number is generated. 
3. Immediately after completing Segment A of the Enrollment Form, an authorized user at 
the clinical center completes the enrollment process by entering Segment B of the 
Enrollment Form in AdvantageEDC confirming that the patient is eligible to receive 
conditioning and transplant.  Segment B of the Enrollment Form will capture the total 
number of cells that was collected.  At this time, randomization to a standard RTX plus 
BEAM conditioning regimen or a Bexxar plus BEAM regimen will occur. 
4. Once randomization occurs, the treatment plan is continued and a visit schedule based on 
the treatment start date is displayed for printing and is referred to as ‘Segment B Follow-
up Schedule.’ 
 
4.1.2. SWOG Patient Registration Procedures 
 
Patients from Southwest Oncology Group (SWOG) Member, CCOP and approved Affiliate 
institutions must be registered through the SWOG Data Operations Center in Seattle using the 
SWOG Web Registration System.  The Web Registration System will request the date informed 
consent and HIPAA authorization were obtained, and will obtain the date of IRB approval for 
each entry. 
 


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4.2. Study Monitoring 
 
4.2.1. Follow-up Schedule 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.2.1.  A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide.  The Data 
Management Handbook, including the Forms Submission Schedule, is available on the 
homepage of the Internet data entry system. 
 
Follow-up Visits: Follow-up visits will begin as soon as patients are randomized onto the study.  
The follow-up period for Segment B is 2 years. 
 
Table 4.2.1:  Follow-up Schedule  
 
Study Visit 
Target Day 
(+ 2 Days Prior to Day 100 Post-ASCT) 
(+ 28 Days After Day 100 Post-ASCT) 
1 week 
7 days 
2 week 
14 days 
3 week 
21 days 
4 week 
28 days 
5 week 
35 days 
6 week 
42 days 
8 week 
56 days 
100 day 
100 days 
6 month 
180 days 
12 month 
365 days 
24 month 
730 days 
 
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook and User’s Guide.  Forms that are not entered into 
AdvantageEDC within the specified time will be considered delinquent.  A missing form will 
continue to be requested either until the form is entered into the AdvantageEDC and integrated 
into the Data Coordinating Center’s (DCC) master database, or until an exception is granted and 
entered into the Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Reporting Patient Deaths: Recipient Death Information must be entered into AdvantageEDC 
within 24 hours of knowledge of the patient’s death.  If the cause of death is unknown at that 


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time, it need not be recorded at that time.  However, once the cause of death is determined, the 
form must be updated in AdvantageEDC. 
 
CIBMTR Data Reporting: Centers participating in BMT CTN trials must register pre and post-
transplant outcomes on all consecutive hematopoietic stem cell transplants done at their 
institution during their time of participation to the Center for International Blood and Marrow 
Transplant Research (CIBMTR).  Registration is done using procedures and forms of the Stem 
Cell Transplant Outcomes Database (SCTOD).  (Note: Federal legislation requires submission of 
these forms for all US allotransplant recipients.)  Enrollment of BMT CTN #0403 must be 
indicated on the SCTOD pre-transplant registration form, if applicable.  Additionally, CIBMTR 
pre- and post- transplant Report Forms must also be submitted for all patients enrolled on this 
trial.  CIBMTR forms will be submitted directly to the CIBMTR at the times specified on the 
Form Submission Schedule. 
 
4.2.2. Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of 
knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business days 
of knowledge of the event.  Unexpected, grade 3-5 AEs will be reported using NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  Expected AEs will be reported 
using NCI’s Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 at regular 
intervals as defined on the Form Submission Schedule. 
 
4.2.3. Patient Assessments 
 
Tables 4.2.3.3a and 4.2.3.3b summarize patient clinical assessments over the course of the study. 
 
4.2.3.1. 
Evaluations prior to the ASCT conditioning therapy 
 
The following observations need to be performed within 4 weeks of enrollment. 
1. History, physical examination, height and weight. 
2. Karnofsky performance status. 
3. CBC with differential, platelet count, creatinine, bilirubin, LDH, alkaline phosphatase, 
ALT, AST, sodium, magnesium, potassium, chloride, and CO2. 
4. CMV titer, hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), 
herpes simplex titer, syphilis, HIV and HTLV1 antibody. 
5. EKG. 
6. Thyroid function test. 
7. β-HCG serum pregnancy test for females of childbearing potential. 
8. One vial (10cc) of nucleated cells from patient’s peripheral blood for future testing. 


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9. Signed informed consent form. 
10. Blood samples for evaluation of immune reconstitution by flow cytometry (CD2, CD3, 
CD4, CD8, CD19, CD3+/CD25+, CD45RA/RO, and CD56+/CD3-) and quantitative 
immunoglobulins (IgM, IgG, and IgA). 
 
The following observations need to be performed within 4 months of enrollment: 
1. Creatinine clearance (calculated creatinine clearance is permitted). 
2. Chest X-ray if clinically indicated. 
3. Left ventricular ejection fraction, if the patient is > 60 years of age. 
4. DLCO, FEV1 and FVC. 
5. Toxicity assessment to assess mobilization-related toxicities. 
6. Baseline disease evaluations: 
a. CT scans of neck, chest, abdomen and pelvis.  Neck CT only required if previous site 
of disease. 
b. Bone marrow biopsy and aspirates to pathology and aspirate for cytogenetics.  Flow 
cytometry is not required.  Target bone marrow core should be  2 cm total for a 
unilateral or bilateral sample.  If the bone marrow core is ≤ 2 cm, a second biopsy is 
required only if the results of the first biopsy are suboptimal. 
 
The following observations may be determined any time since diagnosis of DLBCL: 
1. Demonstration of CD20+ on at least one histologic specimen. 
 
4.2.3.2. 
Evaluations prior to administration of BEAM 
 
A toxicity assessment will be performed on Day –7 or – 6, prior to the patient receiving BEAM, 
in order to assess Bexxar and Rituxan-related toxicities. 
 
4.2.3.3. 
Post-ASCT evaluations 
1. CBC at least twice a week from Day 0 until ANC > 500/mm3 for 2 days after nadir 
reached.  Thereafter CBC twice per week until Day 28 (or 4 weeks), then at 8 weeks,  
Day 100, 6 months, one year and two years post-ASCT. 
2. Toxicity assessments at 4 weeks, 8 weeks, Day 100, 6 months, one year and two years 
post-ASCT. 
3. Mucositis assessment twice a week until Day 21 using the modified oral mucositis 
assessment scale (OMAS). 
4. Disease restaging at Day + 100, 6 months, one year and two years post-ASCT. 
a. If patient had known bone marrow involvement with lymphoma prior to conditioning 
therapy, bone marrow biopsy and aspirate to pathology and aspirate for cytogenetics.  


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Flow cytometry is not required.  Target bone marrow core should be ≥ 2 cm total for 
a unilateral or bilateral sample.  If the bone marrow core is ≤ 2 cm, a second biopsy is 
required only if the results of the first biopsy are suboptimal.  If the patient 
demonstrates unexplained cytopenias, regardless of prior marrow involvement, at any 
time point following hematologic recovery, a bone marrow for morphology and 
cytogenetics to rule out MDS/AML should be performed. 
b. CT of neck, chest, abdomen and pelvis.  Neck CT only required if previous site of 
disease. 
5. Thyroid function test at one and two years post-ASCT. 
6. Evaluation of immune reconstitution by flow cytometry (CD2, CD3, CD4, CD8, CD19, 
CD3+/CD25+, CD45 RA/RO, and CD56+/CD3-) and quantitative immunoglobulins 
(IgM, IgG and IgA) at Day 100 and one year post-ASCT.  Evaluation of immune 
reconstitution is also required at two years post-ASCT if results are abnormal at one year 
post-ASCT. 
 
The following observations are recommended, but not required, post-ASCT: 
1. Comprehensive chemistry panel defined as creatinine, LDH, bilirubin, alkaline 
phosphatase, ALT, AST, magnesium, sodium, potassium, chloride, CO2 twice a week 
until Day 28 (or four weeks) and then at 8 weeks, Day 100, 6 months, one year and two 
years post-ASCT. 
2. DLCO, FEV1 and FVC at one and two years post-ASCT. 
 
 


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Table 4.2.3.3a:  Pre-ASCT Evaluations 
 
Required Studies/Testing 
 Prior to 
Conditioning for 
ASCT1  
Prior to 
Administration of 
BEAM 
History, Physical Examination, Height and 
Weight 
X 
 
Karnofsky Performance Score 
X 
 
CBC with differential, Platelet Count, 
Creatinine, Bilirubin, Alkaline 
Phosphatase, AST, ALT, LDH, Sodium, 
Magnesium, Potassium, Chloride and CO2 
X 
 
Creatinine Clearance 
X2, 3 
 
CMV Titer, Hepatitis Panel, Herpes 
Simplex Titer, Syphilis, HIV and HTLV 
antibody 
X4 
 
Chest X-ray, if clinically indicated 
X2, 5 
 
EKG 
X 
 
Left Ventricular Ejection Fraction, if > 60 
years of age  
X2 
 
DLCO, FEV1, FVC 
X2 
 
Thyroid Function Test 
X 
 
β -HCG Serum Pregnancy Test for 
Females of Childbearing Potential 
X 
 
Toxicity Assessment 
X2 
X 
CT Neck, Chest, Abdomen and Pelvis 
X2, 6 
 
Bone Marrow Aspirate and Biopsy 
X2, 7 
 
Immune Reconstitution Assays 
X8 
 
Nucleated Cells 
X9 
 
Informed Consent  
X 
 
 
1 To be performed within 4 weeks of enrollment, unless otherwise indicated. 
2 To be performed within 4 months of enrollment. 
3 Calculated creatinine clearance is permitted. 
4 Hepatitis panel includes HepA Ab, Hep B SAb, Hep B SAg, Hep B Core Ab, and HepC Ab. 
5 To be performed if clinically indicated.  
6 Neck CT only required if previous site of disease. 
7 Bone marrow biopsy and aspirates to pathology and aspirate for cytogenetics.  Flow cytometry not required.  Bone marrow 
core should be ≥  2 cm total for a unilateral or bilateral sample. 
8 Immune reconstitution assays to include CD2, CD3, CD4, CD8, CD19, CD3/CD25, CD45RA/RO, CD56+/CD3-, and 
quantitative immunoglobulin (IgM, IgG and IgA) levels. 
9 One vial (10cc) of nucleated cells from peripheral blood for future testing. 
 
 
 


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Table 4.2.3.3b:  Post-ASCT Evaluations 
 
 
Study Assessments/ 
Testing 
Weeks Post-ASCT 
Months Post-ASCT 
1 
2 
3 
4 
8 
Day 
100 
6 
12 
24 
CBC 
X1 
X 
X 
X 
X 
X 
Chemistry Panel2, 3 
X4 
X 
X 
X 
X 
X 
Toxicity Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
Mucositis Assessment5 
X 
X 
X 
 
 
 
 
 
 
Bone Marrow Aspirate and Biopsy6 
 
 
 
 
 
X 
X 
X 
X 
CT Neck, Chest, Abdomen and Pelvis7 
 
 
 
 
 
X 
X 
X 
X 
DLCO, FEV1, FVC3 
 
 
 
 
 
 
 
X 
X 
Thyroid Function Test 
 
 
 
 
 
 
 
X 
X 
Immune Reconstitution Assays8 
 
 
 
 
 
X 
 
X 
X9 
 
1 To be performed at least twice weekly from Day 0 until ANC > 500/mm3 for 2 days after nadir reached.  Thereafter, twice 
weekly until Day 28 (or 4 weeks). 
2 Chemistry panel to include creatinine, LDH, bilirubin, alkaline phosphatase, ALT, AST, magnesium, sodium, potassium, 
chloride, CO2.  The chemistry panel is recommended, but not required post-ASCT. 
3 The chemistry panel and pulmonary function tests are recommended, but not required post-ASCT. 
4 To be performed twice weekly until Day 28 (or 4 weeks). 
5 To be performed twice weekly until Day 21. 
6 If previously known bone marrow involvement with lymphoma prior to conditioning therapy, bone marrow biopsy and aspirate 
to pathology and aspirate to cytogenetics.  Flow cytometry is not required.  Bone marrow core should be ≥ 2 cm total for a 
unilateral or bilateral sample. 
7 Neck CT only required if previous site of disease. 
8 Immune reconstitution assays include CD2, CD3, CD4, CD8, CD19, CD3/CD25, CD45RA/RO, CD56+/CD3-, and quantitative 
immunoglobulin levels (IgM, IgG and IgA). 
9 Immune reconstitution assays are not required at two years post-ASCT, unless results from the one year post-ASCT assays are 
abnormal. 
 


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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. Study Overview 
 
This study is designed as a Phase III, multi-center trial, comparing progression-free survival 
(PFS) after autologous hematopoietic stem cell transplantation (ASCT) using a standard 
Rituxan/BEAM transplant regimen versus a regimen adding Bexxar to BEAM.  The target 
enrollment is 224 patients.  The study design consists of randomization in a 1:1 ratio of standard 
Rituxan/BEAM transplant regimen versus a regimen adding Bexxar to BEAM.  Randomization 
will be stratified by transplant center. 
 
5.1.1. Accrual 
 
Accrual will remain open until 224 patients are enrolled.  It is estimated that two years of accrual 
will be necessary to enroll the targeted sample size. 
  
5.1.2. Primary Endpoint 
 
The primary endpoint for the study is progression-free survival (PFS).  If any therapy not 
specified in the protocol is given to prevent relapse/progression or to induce a response, the 
patient will be considered an event for this endpoint. Time-to-event is measured from 
randomization to the minimum of the date of death, relapse/progression, or last-follow-up.  If 
any patients are lost to follow-up, they will be censored at the time of the last observation.  The 
study will remain open until the last patient enrolled has been followed for two years. 
 
5.2. Sample Size and Power Calculations 
 
PFS will be compared by treatment arm using a log rank test. Data from the IBMTR/ABMTR 
registry suggest that the hazard for PFS is negligible after two years post-transplant, so power 
calculations are based on two years of follow up.  The sample size of 112 patients per group is 
sufficient to maintain type I error of 5% across all planned interim analyses (see below) while 
providing > 80% statistical power for a two-sided test to detect an increase in the PFS at two 
years from 0.5 in the standard arm to 0.7 in the experimental arm.  It is assumed that there is a 
5% dropout rate. 
 
5.3. Interim Analysis and Stopping Guidelines 
 
Interim analyses for efficacy will be conducted at times coincident with regularly scheduled 
meetings of the NHLBI-appointed Data and Safety Monitoring Board (DSMB) at approximately 
six-month intervals.  Monitoring of primary graft failure as a key safety endpoint will be 
conducted monthly, and if rates significantly exceed pre-set thresholds, the NHLBI will be 
notified in order that the DSMB can be advised.  Policies and composition of the DSMB are 
described in the BMT CTN's Manual of Procedures. 


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5.3.1. Interim Analysis for Efficacy 
 
Analyses will be performed as described below for the primary endpoint.  Toxicity, adverse 
events, and other safety endpoints will be monitored regularly and reported to the DSMB at each 
interim analysis.  Toxicities and adverse events will be captured on case report forms.  A core set 
of toxicities, which include gastrointestinal, renal, hemorrhagic, cardiovascular, neurologic, 
coagulation, vascular, pulmonary, and hepatic toxicities, will be collected in accordance with the 
guidelines outlined the BMT CTN Manual of Operating Procedures.  At each interim analysis 
time point, a log-rank test will be performed to detect a difference in PFS between treatment 
arms.  In order to preserve the over-all type I error rate at 5%, the critical value for the test 
statistic will be inflated above 1.96, the value that would be used if no repeated testing were 
used.  Equivalently, the nominal p-value at which an observed difference is declared significant 
will be reduced below 0.05.  The actual critical values and nominal p-values will be computed 
using statistical methods for group sequential testing with O’Brien Fleming boundaries.   
 
As an example, Table 5.3.1a shows the critical values and nominal p-values for tests conducted 
at 0.5, 1.0, 1.5, 2.0 and 4.0 years after the study opens to enrollment.  The column labeled 
“Number of Events” shows the average number of individuals who have died post-transplant 
assuming uniform accrual over a two-year period.  The fraction of patients who died, as 
compared to a denominator comprised of the total sample of 224, quantifies the “statistical 
information” from which the critical values, nominal p-values and cumulative type I error are 
computed.   
Table 5.3.1a Critical Values and Nominal P-Values 
 
Calendar 
Time 
Number of 
Events 
Statistical 
Information 
Critical 
Value 
Nominal 
P-value 
Cumulative  
Type I Error 
0.5 
3.5 
0.0404 
8.000 
0.00000 
0.00000 
1.0 
13.2 
0.1535 
8.000 
0.00000 
0.00000 
1.5 
28.1 
0.3285 
3.7401 
0.00018 
0.00018 
2.0 
47.6 
0.5555 
2.7939 
0.00509 
0.00527 
4.0 
85.7 
1.0000 
1.9747 
0.04473 
0.05000 
 
In practice, the rate of accrual or timing of DSMB meetings may not be as anticipated.  To 
permit necessary flexibility in scheduling interim analyses, the critical values will be recomputed 
to correspond to the actual available statistical information using the “use-function” approach of 
Lan and DeMets. 
 
5.4.  Statistical Stopping Guidelines 
 
A statistical stopping guideline for primary graft failure will be employed in this study. This 
guideline is designed to assist an independent Data and Safety Monitoring Board (DSMB) in 
overseeing the study.  The DSMB may also request additional interim analyses and develop 
other criteria for determining when to intervene in the enrollment or treatment of patients in the 
study. 
 


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The null hypothesis for sequential monitoring is that the true rate of primary graft failure is less 
than 10%.  Primary graft failure is defined as failure to reach an ANC of 500/dL.  If the observed 
incidence rate is substantially in excess of this target, the null hypothesis will be rejected, and the 
NHLBI will be notified.  These guidelines are provided as an “early warning” system.  
Suspension of enrollment is not automatic, but at the discretion of the NHLBI upon 
recommendation of the DSMB, which will have the opportunity to request and review additional 
analyses. 
 
Primary graft failure at Day 21 will be monitored separately in each treatment arm for all 
transplanted patients.  Patients will be analyzed according to their randomized treatment 
assignment.  Monitoring will be performed monthly until enrollment to that treatment arm is 
closed.  Each month, the null hypothesis that the primary graft failure at Day 21 is less than or 
equal to 10% will be tested against the alternative that it is greater than 10%. 
 
A Sequential Probability Ratio Test (SPRT) based on a binomial test of proportions for primary 
graft failure at Day 21 between each treatment arm will be used.  This sequential testing 
procedure conserves type I error across all of the monthly examinations.  The SPRT can be 
represented graphically.  At each monthly interim analysis, the number of endpoints (e.g., 
subjects with primary graft failure at Day 21), is plotted against the total number of subjects 
observed to Day 21.  The continuation region of the SPRT is defined by two parallel lines.  Only 
the upper boundary will be used for monitoring each treatment arm to protect against excessive 
primary graft failure at Day 21.  If the graph falls above the upper boundary, the SPRT rejects 
the null hypothesis, and concludes that there are more primary graft failures at Day 21 than 
predicted by the number of patients at risk on Day 21.  Otherwise, the SPRT continues until 
enrollment to the treatment arm reaches the target goal. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  The tests to be used in this protocol were developed from the following SPRTs:   
 
 Slope of the parallel lines for monitoring primary graft failure at Day 21 is 0.366 and the 
intercepts are –1.066 and 0.74. 
 An SPRT contrasting 10% versus 20% primary graft failure at Day 21, with nominal type 
I and II errors of 9% and 20%, respectively.   
The actual operating characteristics of the truncated test, shown in Table 5.4.1, were determined 
in a simulation study.  The simulation assumed uniform accrual of 224 patients, 112 assigned to 
each treatment arm, over a two-year time period.   
 


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Table 5.4.1 
Operating Characteristics of Sequential Testing Procedure for  
Primary Graft Failure at Day 21 from a Simulation Study with 100,000 Replications 
 
 
True Rate of Primary Graft 
Failure at Day 21 
10% 
15% 
20% 
Probability Reject Null 
0.06 
0.44 
0.87 
Mean Month Stopped 
23.1 
18.4 
11.6 
Mean # Events in 21 days. 
10.6 
12.7 
10.6 
Mean # Patients Enrolled 
107.9 
86.0 
54.5 
 
Primary graft failure at Day 21 is monitored in all subjects (N = 112) separately in each 
treatment arm.  The SPRT rejects the null hypothesis in favor of the alternative 6% of the time 
when the true 21 day non-engraftment is 10%, and 87% of the time when the true primary graft 
failure at Day 21 is 20%.  This corresponds to a type I error rate of =0.06 and a type II error 
rate of =0.13.  When the true rate of primary graft failure at Day 21 is 20%, on average, the 
DSMB will be consulted 11.6 months after opening, when 10.6 events have been observed in 
54.5 patients. Note that the SPRT procedure is adequately powered to distinguish between a rate 
of primary graft failure at Day 21 of 10% and 20% in each of the arms. 
 
5.5. Analysis Plan 
 
5.5.1. Analysis of the Primary Endpoint 
 
The primary outcome of the trial is lymphoma progression-free survival.  The primary null 
hypothesis of the study is that there is no difference in progression-free survival between the 
treatment arms.  In the primary analysis, the intention-to-treat principle that is based on all 
patients as randomized will be used and progression-free survival will be estimated using the 
Kaplan-Meier product limit estimator, and compared between treatment arms using a log-rank 
test. 
 
5.5.2. Analysis of Secondary Endpoints 
 
Overall Survival 
 
The event is death from any cause.  Patients alive at the time of the last observation are censored 
at the time of the last observation.  In the primary analysis in all enrolled patients, time-to-event 
will be measured from randomization.  In a secondary analysis including only patients who 
received their ASCT, time-to-event will be measured from the date of ASCT.  Overall survival 
will be compared between treatment arms using a log-rank test, and the survival curves will be 
estimated using the Kaplan Meier Estimator. 
 


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Time to Progression 
 
The event is relapse/progression.  Death without relapse/progression is considered a competing 
risk.  Patients alive with no history of relapse/progression are censored at the time of the last 
observation.  In the primary analysis in all enrolled patients, time-to-event will be measured from 
randomization.  In a secondary analysis including only patients who received their ASCT, time-
to-event will be measured from date of ASCT.  Time to progression will be compared between 
treatment arms using a log-rank test, and the cumulative incidence curves will be estimated. 
 
CR and CR+PR Proportion at Day 100 
 
The event is whether or not the patient has CR (CR or PR).  In the primary analysis in all 
randomized patients, time-to-event will be measured from randomization.  In a secondary 
analysis including only patients who received their ASCT, time-to-event will be measured from 
the date of ASCT.  The proportion of CR (CR or PR) will be compared between treatment arms 
using a Fisher’s exact test. 
 
Time to Hematopoietic Recovery   
 
Time to neutrophil recovery will be the first of two consecutive days of > 500 neutrophils/µL 
following the expected nadir.  Time to platelet engraftment will be the first day of one week 
without a platelet transfusion when the platelet count is > 20,000/μL. Time to neutrophil 
recovery and platelet engraftment will be compared between treatment arms using a log-rank 
test, and the cumulative incidence curves will be estimated. 
 
Hematologic Function at Day 100 
 
Hematologic function will be ANC > 1,500 neutrophils/μL, hemogloblin > 10 g/dL without 
transfusion support, and platelet count > 100,000/μL without transfusion support.  Hematologic 
function at Day 100 and 1 year will be compared between treatment arms. 
 
Incidence of Infections 
 
Microbiologically documented infections will be reported by site of disease, date of onset, 
severity, and resolution, if any.  This data will be captured via an event-driven case report form 
and will be collected from Day 0 until two years post-transplant.  The incidence of definite and 
probably viral, fungal and bacterial infections will be tabulated for each patient according to the 
BMT CTN Manual of Procedures.  The proportion of patients developing infections will be 
compared between treatment arms.   
 
Maximum Mucositis Score by Day +21  
 
Mucositis score will be computed using the modified oral mucositis assessment scale (OMAS), a 
continuous measurement between certain ranges.  This score can then be used to compare the 
treatment arms and analyzed with the t-test or multiple regressions, adjusting for other important 
variables.  


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Transplant-related Mortality  
 
Transplant related mortality (TRM) is defined as death occurring in a patient from causes other 
than relapse or progression.  Time to TRM will be compared between treatment arms using a 
log-rank test, and the cumulative incidence curves will be estimated. 
 
Incidence of MDS/ AML and New, Abnormal Cytogenetics  
 
The rate of MDS/AML and new, abnormal cytogenetics will be compared between the treatment 
arms using test of proportions or logistic regression, adjusting for other variables. 
 
Immunologic Reconstitution  
 
Immune reconstitution assays, which will include CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, 
CD45RA/RO, CD56+/CD3-, and quantitative immunoglobulins (IgM, IgG and IgA), will be 
performed at baseline, Day +100, and 1 year post-transplant and will be compared between the 
treatment arms.  This will also be assessed at 2 years post-transplant, if the 1 year assessment is 
abnormal. 
 


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APPENDIX A 
 
REFERENCES 
 


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APPENDIX A 
 
REFERENCES 
 
 
1.  Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with 
three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma.  N Engl J 
Med 328: 1002-1006, 1993. 
 
2.  Armitage JO: Treatment of non-Hodgkin’s lymphoma. N Engl J Med 328: 1023-1030, 1993. 
 
3.  Velasquez WS, McLaughlin P, Tucker S, et al: ESHAP- An effective chemotherapy regimen 
in refractory and relapsing lymphoma: A 4-year follow-up study. J Clin Oncol 12: 1169-
1176, 1994. 
 
4.  Wilson WH, Bryant G, Bates S, et al: EPOCH chemotherapy: Toxicity and efficacy in 
relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol 11: 1573-1582, 1993. 
 
5.  Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as 
compared to salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s 
lymphoma. N Engl J Med 333: 1540-1545, 1995. 
 
6.  Horning SJ, Negrin RS, Chao NC, et al: Fractionated total-body irradiation, etoposide, and 
cyclophosphamide plus autografting in Hodgkin’s disease and non-Hodgkin’s lymphoma. J 
Clin Oncol 12: 2552-2558, 1994. 
 
7.  Petersen FB, Appelbaum FR, Hill R, et al: Autologous marrow transplantation for malignant 
lymphoma: a report of 102 cases from Seattle. J Clin Oncol 8: 638-647, 1990. 
 
8.  Weaver CH, Petersen FB, Appelbaum FR, et al: High-dose fractionated total body irradiation, 
etoposide, and cyclophosphamide followed by autologous stem cell support in patients with 
malignant lymphoma. J Clin Oncol 12: 2559-2566, 1994. 
 
9.  Hahn T, Wolff SN, Czuczman M, et al: The role of cytotoxic therapy with hematopoietic 
stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin’s lymphoma: 
an evidence based review. Biol Blood Marrow Transplant 7: 308-331, 2001. 
 
10. Freedman AS, Takvorian T, Anderson KC, et al: Autologous bone marrow transplantation in 
B-cell non-Hodgkin’s lymphoma: very low treatment-related mortality in 100 patients in 
sensitive relapse.  J Clin Oncol 8: 748-791, 1990. 
 
11. Vose JM, Anderson JR, Bierman PJ, et al: High-dose chemotherapy and autologous 
hematopoietic stem cell transplantation for aggressive non-Hodgkin’s lymphoma. J Clin 
Oncology 11:1846-1851, 1993. 
 


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12.  Maloney DG, Liles TM, Czerwinski DK, et al: Phase I clinical trial using escalating single-
dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with 
recurrent B cell lymphoma. Blood 84: 2457-2466, 1994. 
 
13.  Coiffier B, Hauioun C, Ketterer N, et al: Rituximab (Anti-CD20 monoclonal antibody) for 
the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter 
phase II study.  Blood 92: 1927-1932, 1998. 
 
14. Kewalramani T, Zelenetz, aD, Nimer SD, et al: Rituximab and ICE as second-line therapy 
before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-
cell lymphoma.  Blood 103: 3684-3688, 2004. 
 
15. Flinn IW, O’Donnell PV, Goodrich A, et al: Immunotherapy with rituximab during 
peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma.  Biol Blood Marrow 
Transplant. 6: 628-632, 2000. 
 
16. Benekli M, Hahn T, Shafi F, et al: Effect of Rituximab on peripheral blood stem cell 
mobilization and engraftment kinetics in non-Hodgkin’s lymphoma patients. Bone Marrow 
Transplant  32: 139-143, 2003. 
 
17. Horwitz SM, Negrin RS, Blume KG, et al: Rituximab as adjuvant to high-dose therapy and 
autologous hematopoietic cell transplantation for aggressive non-Hodgkin’s lymphoma. 103: 
777-783, 2004. 
 
18. Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma 
with 131-Iodine anti-B1 (anti-CD20) antibody. N Engl J Med 329: 459-465, 1993. 
 
19. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of Iodine I 131 Tositumomab for 
chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s 
lymphomas. J Clin Oncol 19: 3918-3928, 2001. 
 
20. Vose JM, Wahl RL, Saleh M, et al: Multicenter Phase II study of Iodine I 131 tositumomab 
for chemotherapy-relapsed/refractory low-grade B-cell non-Hodgkin’s lymphoma. J Clin 
Oncol 18: 1316-1323, 2000. 
 
21. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with Iodine I 131 
tositumomab for relapsed or refractory B-cell non-Hodgkin’s lymphoma: Updated results and 
long-term follow-up of the University of Michigan experience. Blood 96: 1259-1266, 2000. 
 
22. Press OW, Unger JM, Braziel RM, et al: CHOP followed by Tositumomab/Iodine 131 
Tositumomab (BEXXAR) for treatment of newly diagnosed follicular non-Hodgkin’s 
lymphomas: A phase II trial of the Southwest Oncology Group. Blood 102: 90a, 2003. 
 
23.  Press OW, Eary J, Appelbaum FR, et al: Radiolabeled antibody therapy of B cell 
lymphomas with autologous bone marrow support. N Engl J Med 324: 1219-1224, 1993. 
 


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24. Liu SY, Eary JF, Petersdorf SH, et al: Follow-up of relapsed B-cell lymphoma patients 
treated with Iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin 
Oncol 16: 3270-3278, 1998. 
 
25. Press OW, Eary JF, Gooley T, et al: A phase I/II trial of iodine-131-tositumomab (anti-
CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed 
B-cell lymphoma.  Blood 96: 2934-2942, 2000. 
 
26. Vose JM, Bierman PJ, Lynch JC, et al: Long term results of radioimmunotherapy with 
Bexxar/BEAM and autologous stem cell transplantation (ASCT) for chemotherapy resistant 
aggressive non-Hodgkin’s lymphomas.  Blood 102: 872a, 2003. 
 
27. Paulus U, Dreger P, Viehmann K, et al: Purging peripheral blood progenitor cell grafts from 
lymphoma cells: quantitative comparison of immunomagnetic CD34+ selection systems. 
Stem Cells 15: 297-304, 1997. 
 
28. Martin-Henao GA, Picon M, Limon A, et al: Immunomagnetic bone marrow and peripheral 
blood progenitor cell urging in follicular lymphoma. Bone Marrow Transplant 23: 579-587, 
1999. 
 
29. Williams CD, Goldstone AH, Pearce RM, et al: Purging of bone marrow in autologous bone 
marrow transplantation for non-Hodgkin’s lymphoma: a case-matched comparison with 
unpurged cases by the European Blood and Marrow Transplant Lymphoma Registry. J Clin 
Oncol 14: 2454-2464, 1996. 
 
30. Yearly-Motta V, Racadot E, Fest T, et al Comparative preclinical study of three bone marrow 
purging methods using PCR evaluation of residual t(14;18) lymphoma cells. Leuk 
Lymphoma 23: 313-321, 1999. 
 
31. Gribben JG, Freedman AS, Neuberg D, et al: Immunologic purging of marrow assessed by 
PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 
325: 1525-1533, 1991. 
 
32. Bensinger WI. Should we purge? Bone Marrow Transplant 21: 113-115, 1998. 
 
33. Freedman AS, Neuberg D, Mauch P, et al: Long-term follow-up of autologous bone marrow 
transplantation in patients with relapsed follicular lymphoma. Blood 94: 3325-3333, 1999. 
 
34. Hess G, Flohr T, Derigs, HG: Rituximab as in vivo purging agent in autologous stem cell 
transplantation for relapsed B-NHL. Ann Hem 81(supl2): 54-55, 2002. 
 
35. Flohr T, Hess G, Kolbe K, et al: Rituximab in vivo purging is safe and effective in 
combination with CD34-positive selected autologous stem cell transplantation for salvage 
therapy in B-NHL. Bone Marrow Transpl 29: 769-775, 2002. 
 


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36. Cheson B, Pfistner B, Juweid M, et al: Revised Response Criteria for Malignant Lymphoma. 
J Clin Oncol 25: 579-586, 1997 
 


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APPENDIX B 
 
CONSENT FORM 


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B-1 
 
Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Contact Information 
(Insert contact information for PI at your site) 
 
 
Study Sponsor: The National Institutes of Health (NIH) is sponsoring this study by providing 
financial support through the Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN).  Additional support is provided by GlaxoSmithKline Corporation, which makes one of the 
drugs (Bexxar) used in this study.  GlaxoSmithKline will provide this drug free of charge.  
However, this company did not plan or design this clinical trial and will not have a part in 
analyzing the results of this study. 
 
 
Introduction 
This is a clinical trial, which is a research study to answer specific medical questions.  The 
information from this study will help future patients.  The Study doctor (the person in charge of 
the research) will explain the clinical trial to you.  Clinical trials include only people who choose 
to join the study.  
 
Please take your time to decide if you want to join this study.  Some people find it helpful to talk 
about the study with their family and friends before they make a decision.  It may also be useful 
to talk with your doctor and other people on your health care team about the study.  If you have 
questions or want to know more about the study, you can ask them for more information. 
 
You are being asked to take part in this study because you have Non-Hodgkin’s Lymphoma 
(NHL) which has either not fully responded to treatment or has returned after an initial response.  
In this situation, many patients with NHL are treated with autologous peripheral blood stem cell 
transplantation.  An autologous peripheral blood stem cell transplant is when your own stem 
cells are collected from your blood, frozen, and then given back to you after you receive 
chemotherapy, also referred to as conditioning therapy.  There are a number of ways that an 
autologous stem cell transplant can be done.   
 
 


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Why is this study being done?  
An important part of the transplant procedure is the high dose chemotherapy (called the 
conditioning regimen) given to try to get rid of all lymphoma cells.  Although many people are 
cured of their NHL with this therapy, the lymphoma comes back in a large minority.  This study 
compares two different conditioning regimens, one using the drugs Rituxan and BEAM (a 
mixture of the chemotherapy drugs BCNU, Etoposide, Ara-C, and Melphalan) and the other 
using the drugs Bexxar and BEAM, to find out which is better at curing lymphoma or if they are 
the same.  In this study, you will get either the Rituxan/BEAM conditioning regimen or the 
Bexxar/BEAM conditioning regimen.  You will not get both.  Results of this trial will help 
doctors make better treatment decisions for future patients. 
 
 
How many people will take part in the study? 
Two hundred twenty-four patients will take part in this study.  Half of the patients (112 patients) 
will receive the Rituxan/ BEAM pre-transplant conditioning and half (112 patients) will receive 
the Bexxar/ BEAM pre-transplant conditioning.   
 
 
What will happen if I take part in this research study? 
Before you begin the study -- You will need to have the following exams, tests or procedures to 
find out if you can be in the study.  These exams, tests or procedures are part of regular cancer care 
and may be done even if you do not join the study.  If you have had some of them recently, they 
may not need to be repeated.  This will be up to your study doctor.  The tests include: 
 Medical history 
 Physical examination, including height and weight 
 Blood and urine tests 
 EKG 
 Heart function tests 
 Pulmonary (lung) function tests  
 Thyroid function test 
 Tests to evaluate your lymphoma including scans and a bone marrow biopsy 
 A blood pregnancy test if you are a woman able to have children; if you are pregnant, you 
will not be able to take part in this study. 
 
During the study (you can refer to the Study Chart later in this consent as you read this) – 
 
Randomization 
 
All the exams, tests, and procedures described to this point are part of regular cancer care and 
may be done even if you do not join the study.  However, if you were receiving regular cancer 
care, your doctor would choose the next treatment for you.  As part of this study, we want to 
compare regular cancer care to an experimental treatment.  To do this, you will be randomized 


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into one of the two conditioning regimen study groups described below.  Randomization means 
that you are put into a group by chance.  A computer program will place you in one of the study 
groups.  You have a 50/50 chance of receiving each therapy.  Neither you nor your doctor can 
choose the group you will be in. 
 
Conditioning Regimen 
 
The conditioning regimen is used to kill the lymphoma cells in your body. 
 If you are in Group 1, you will receive the Rituxan/BEAM pre-transplant conditioning 
regimen.  You will receive Rituxan on the 19th and 12th days before your transplant by 
intravenous infusion (through your vein).  You will receive BEAM chemotherapy starting 
6 days before your transplant.  You will then receive the autologous cells that were 
collected and frozen during mobilization (this day that you receive your cells is referred 
to as Day 0).  BEAM is a very common combination of chemotherapy drugs that has 
been widely used in transplants for NHL.  Rituxan is an antibody against lymphoma cells 
that is commonly used both to treat lymphoma without a transplant and as part of 
transplant care. 
 If you are in Group 2, you will receive the Bexxar/BEAM pre-transplant conditioning 
regimen.  You will receive Bexxar on the 19th and 12th days before your transplant by 
intravenous infusion.  You will receive BEAM chemotherapy starting 6 days before your 
transplant.  On Day 0, you will receive the autologous cells that were collected and 
frozen after during mobilization.  Bexxar is a new drug that was FDA approved for 
treatment of certain types of lymphoma but has not been used extensively in treatment of 
diffuse large B cell lymphoma or in transplants for NHL.  The use of Bexxar is the 
investigational part of this study. 
 
Reinfusion of Stem Cells (Transplantation) 
 
After the conditioning regimen, the stem cells that were previously collected and frozen will be 
thawed and reinfused into you through your catheter.  The cells will travel to your bone marrow 
where they’ll begin making healthy, new blood cells.  This step is necessary because the high 
dosages of chemotherapy given to you during the conditioning regimen will not only destroy 
lymphoma cells, but healthy cells in your bone marrow as well.  Until the new stem cells begin 
producing healthy blood cells, you will be at an increased risk of excessive bleeding or 
developing an infection. 
 
 
Description of Study Drugs 
 
Rituxan (Rituximab) - Rituxan is a drug that can recognize lymphoma cells and either kill them 
and/or cause other immune cells in the body to kill them.   
 
Bexxar - Bexxar is also a drug that recognizes lymphoma cells but, in addition, has a radioactive 
compound attached to it.  When Bexxar attaches to lymphoma cells, the cells are killed by the 
radiation released by the radioactive compound.  Bexxar is given to patients by physicians and 


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staff with experience in handling radioactive compounds, usually in the Nuclear Medicine 
Department of a hospital.  Most patients receive this treatment as an outpatient.  However, 
because the radioactivity of Bexxar lasts for several days, you will have to follow some 
precautions for several days to avoid exposing others to radiation.  You will receive instruction 
on these precautions before treatment but they include sleeping in a separate bed and avoiding 
close, prolonged contact with children and pregnant women.  The risk to others is very low. 
 
BEAM-  BEAM is a mixture of several chemotherapy drugs that interfere with the growth of 
cancer cells and are widely used to treat NHL:   
BCNU (also called carmustine) 
Etoposide (also called VP-16)  
Ara-C (also called cytarabine) 
Melphalan 
 
When you are finished taking these drugs and have received your transplant, you will be watched 
closely.  For this study, you will have the following tests at least twice per week for the first 4 
weeks and then again at 8 weeks, 100 days, six months, one year and two years after 
transplantation: 
 Medical history 
 Physical examination 
 Blood and urine tests  
 
In addition to these tests, you will have blood drawn to test how well your immune system is 
working at 100 days, six months, one year, and two years after your transplant.  Tests of your 
thyroid gland and your lung function will be done at one year and two years after your transplant.  
Your doctor may also require you to have tests of your thyroid gland for more than two years 
after your transplant. 
 
Tests and exams to look at the status of your lymphoma will be done 100 days, 6 months, 1 year 
and 2 years after your transplant.  These will include scans and bone marrow biopsies.  
 
All of these exams, tests or procedures are part of regular medical care after a transplant and may 
be done even if you do not join the study.  The schedule for testing is only for tests required for the 
study.  Some of these tests will be done more frequently than described here if your doctor thinks it 
is necessary for your medical care.   
 
 
How long will I be on this study? 
After your transplant, the study doctor will ask you to visit the office for follow-up exams for 
two years to receive the study tests and procedures described above.  Your doctor will also 
collect information on how you are doing for up to five years after your transplant. 
 
Follow up for your transplant will last as long as you require care.  However, we would like to 
keep track of your medical condition for the rest of your life by contacting you and the doctor 


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providing your regular medical care by phone or mail once a year.  Keeping in touch with you 
and checking on your condition every year helps us look at the long-term effects of the study and 
transplantation in general.  Many transplant centers include this type of long-term follow-up as 
part of their regular medical care.  It is not necessary for you to agree to follow-up for longer 
than 5 years to participate in this study. 
 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell your doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell your doctor if you are thinking about stopping so any risks from the 
medications can be evaluated.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
 
Can the Study Doctor withdraw me from the study? 
You can be taken off the study (with or without your consent) for any of the following reasons: 
 You do not qualify to be in the study because you do not meet the study requirements.  
Ask your doctor if you would like more information about this. 
 You need a medical treatment not allowed in this study. 
 The study doctor decides that continuing in the study would be harmful to you. 
 The study treatments have a bad effect on you. 
 You become pregnant. 
 You are unable to keep appointments or take study drugs as directed. 
 Other study-specific reasons; for example, if the dose of study drug you are taking is 
found to be unsafe. 
 The study is cancelled by the Food and Drug Administration (FDA) or the National 
Institutes of Health (NIH). 


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STUDY CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transplant (Day 0) 
 (You receive your autologous cells) 
Medical follow-up: 
Twice weekly x 4 weeks, then at 
Week 8, Day 100, Month 6, 12 and 24 
after transplant. 
Transplant (Day 0)  
(You receive your autologous cells) 
Medical follow-up: 
Twice weekly x 4 weeks, then at 
Week 8, Day 100, Month 6, 12 and 24 
after transplant. 
Group 2 (Bexxar/BEAM) 
Pretransplant conditioning 
Bexxar  (Day –19, -12) 
BCNU  (Day -6) 
Etoposide  (Days -5 to -2) 
Ara-C (Days -5 to -2) 
Melphalan (Day -1) 
Medical Evaluation 
Randomization (you will be assigned 
to one group or the other) 
Group 1 (Rituxan/BEAM) 
Pretransplant conditioning 
Rituxan (Day –19, -12) 
BCNU  (Day -6) 
Etoposide  (Days -5 to -2) 
Ara-C (Days -5 to -2) 
Melphalan (Day -1) 


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What side effects or risks can I expect from being in the study? 
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious.  Your health care team may give you medicines to help 
lessen side effects.  In some cases, side effects can be serious, long lasting, or may never go 
away.  There is also a risk of death.  Many of these side effects are possible regardless of the type 
of autologous transplant you receive.  It is possible that some of these side effects are increased 
by the drugs used in this study or that these drugs will have new side effects that we don’t know 
about now. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study.  
 
Potential Side Effects 
 
Rituxan 
Likely 
Less Likely 
Rare but Serious 
 
Shaking chills 
 
Fever 
 
Itching  
 
Low blood pressure 
 
Shortness of breath 
 
Rash 
 
Nausea/vomiting 
 
Diarrhea 
 
Headache 
 
Throat irritation 
 
Night sweats 
 
High blood sugar 
level 
 
Low blood counts 
 
Tiredness 
 
Pain from areas of 
lymphoma 
 
Cardiac arrhythmia 
 
Chest pain 
 
Renal failure 
 
Angioedema 
 
Angina 
 
Progressive 
Multifocal 
Leukoencephalopathy 
(PML) 
GCSF (Filgrastim) 
Likely 
Less Likely 
Rare but Serious 
 Muscle pain 
 Bone pain 
 Fluid retention 
 Fluid around the heart  
 Pain and swelling at 
the injection site 
 Allergic reactions 
 Spleen swelling 
 Spleen rupture 
 Difficulty breathing 
 


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Bexxar 
Likely 
Less Likely 
Rare but Serious 
 Low blood counts 
 Allergic reaction 
 Nausea/vomiting 
 Abdominal pain 
 Diarrhea 
 Low thyroid hormone 
 Constipation 
 Anorexia 
 High blood pressure 
 Headache 
 Itching 
 Sweating 
 Skin rash 
 Cough 
 Fever, shaking chills 
  Low blood pressure 
 Difficulty breathing 
 Abnormal bone 
marrow 
 Second cancers, 
including MDS and 
leukemia 
 Human Anti-Mouse 
Antibodies 
 
BEAM 
Likely 
Less Likely 
Rare but Serious 
 Low blood counts 
 Nausea/vomiting 
 Mouth sores 
 Sores in esophagus 
 Abdominal 
pain/diarrhea 
 Difficulty eating 
 Hair loss 
 Fatigue 
 Liver problems 
 Lung problems 
 Low blood pressure 
 High levels of uric 
acid 
 Skin rash 
 Chills 
 Liver failure 
 Severe lung problems 
 Severe allergic 
reactions 
 Second cancers, 
including MDS and 
leukemia 
 Life-threatening 
infection 
 Disease of the 
peripheral nervous 
system 
 Sterility 
 
 
 
Reproductive Risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 
this study.  Check with your study doctor about what kind of birth control methods to use and 
how long to use them.  Some methods might not be approved for use in this study.  Some of the 
drugs used in the study may make you unable to have children in the future. 
 


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Hepatitis B Reactivation:  In people who have ever been infected with hepatitis B virus, there is 
a risk that the virus can flare up during treatment with drugs that affect your immune system, 
such as Rituxan.  This could lead to liver failure or even death.  The risk of hepatitis B virus 
flaring up may continue for several months after you stop taking Rituxan.  If you become 
jaundiced (yellowing of the skin and eyes) or develop viral hepatitis while taking Rituxan or 
after stopping treatment, you should tell your study doctor immediately.  Your study doctor will 
discuss this risk with you and explain what testing is recommended to check for hepatitis. 
 
Progressive Multifocal Leukoencephalopathy (PML):  In the past, the FDA has reported a 
very rare case of two deaths that were reported after patients had been treated with Rituxan for 
systemic lupus erythematosus (SLE).  These deaths have been caused by a viral infection of the 
brain called progressive multifocal leukoencephalopathy (PML).  In rare cases, you may 
encounter problems with speech or movement, or in very rare cases death.  Please notify your 
doctor immediately if you have any new or worsening memory loss, trouble thinking, difficulty 
walking, or changes in vision. 
 
Potential Allergic Reactions to Murine Proteins:  Bexxar is a mouse (murine) protein 
antibody.  You should notify your physician if you know that you have received a product 
containing mouse antibodies.  Some patients that have previously been exposed to products 
containing mouse antibodies may develop their own antibodies against mouse proteins.  This 
may happen to you after you receive Bexxar.  These are called human anti-mouse antibodies or 
HAMA.  The presence of HAMA may possibly make a person more likely to develop an allergic 
reaction to mouse proteins, but this is not proven.  Unfortunately, there is no well-accepted test 
for measuring HAMA and it is not known whether the presence of HAMA would let us know if 
you would have an allergic reaction to mouse proteins.  Therefore, we will not be testing for 
HAMA in this study.  In the event that you do have an allergic reaction, epinephrine (a drug used 
for cardiac arrest) and antihistamines (drugs used for allergic reactions) will be available at your 
bedside during the administration of Bexxar. 
 
This study is designed to help persons who are suffering from Non-Hodgkin’s Lymphoma 
(NHL).  A risk remains, however, that neither treatment arm will be successful in curing or 
improving your illness. 
 
After you have recovered from your stem cell transplantation, your doctor may consider 
additional radiation to areas where you have had lymphoma.  If so, your doctor will review with 
you the rationale and potential side effects at that time. 
 
For more information about risks and side effects, ask your study doctor. 
 
 


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Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  This research study is 
comparing two pre-transplant conditioning regimens.  At this time doctors do not know if one 
conditioning regimen has better results than the other, or if they both have the same results.  We 
do know that the information from this study will help doctors learn more about transplantation 
for NHL.  This information could help future patients with NHL. 
 
 
What other choices do I have if I do not take part in the study? 
Your other choices may include: 
 Treatment with other drugs or a combination of drugs without a transplant.  
 An autologous stem cell transplant that is not part of the study or another type of 
transplant. 
  No therapy directed against your lymphoma at this time. 
 
Talk to your doctor about your treatment choices before you decide if you will take part in this 
study. 
 
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
The company that manufactures Bexxar will provide this drug at no cost.  All other costs of your 
care including the chemotherapy drugs and costs associated with administration of them will 
need to be paid by you and/or your health plan/insurance company.  All of the medical tests, 
evaluations and procedures in this study are considered part of standard medical care. 
 
The companies that make the drugs used in this study did not plan or design this clinical trial.  
They will also not have a part in analyzing the results of this study. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
 


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What happens if I am injured because I took part in this study? 
It is important that you tell your doctor, __________________ [investigator's name(s)], if you 
feel that you have been injured because of taking part in this study.  You can tell the doctor in 
person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.  
 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.  
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
 
 
Will my 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.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
The National Marrow Donor Program and the Center for International Blood and Marrow 
Transplant Research, organizations involved in research on blood and marrow 
transplantation and in the coordination of this study 
 
The EMMES Corporation, a research organization that is helping to coordinate this study 
 
Members of the Blood and Marrow Transplant Clinical Trials Network, which is 
conducting this study 
 
The National Heart Lung and Blood Institute (NHLBI), the National Cancer Institute 
(NCI) and other government agencies, like the Food and Drug Administration (FDA), 
involved in keeping research safe for people  
 
Southwest Oncology group (SWOG), clinical trials cooperative group 
 


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Information about the results of this study will also be provided to the GlaxoSmithKline 
Company (which makes Bexxar) but without any identifying information. 
 
 
HIPAA1 authorization to use and disclose individual health information for research 
purposes 
 
a. Purpose:  As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my individual health information for the purpose of 
conducting the research study entitled Phase III Rituxan/BEAM vs. Bexxar/BEAM with 
Autologous Hematopoietic Stem Cell Transplantation (ASCT) for Persistent or Relapsed 
Chemotherapy Sensitive Diffuse Large B-cell Non-Hodgkin’s Lymphoma. 
 
b. Individual Health Information to be Used or Disclosed: My individual health information 
that may be used or disclosed to conduct this research includes: demographic information 
(e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with 
prior treatment), physical examination findings, and laboratory test results obtained at the 
time of work up and after transplantation (e.g., blood tests, biopsy results).  
 
c. Parties Who May Disclose My Individual Health Information: The researcher and the 
researcher’s staff may obtain my individual health information from: 
(list hospitals, clinics or providers from which health care information can be requested) 
 
 
 
 
d. Parties Who May Receive or Use My Individual Health Information: The individual 
health information disclosed by parties listed in item c and information disclosed by me 
during the course of the research may be received and used by the following parties: 
 Members of the BMT CTN Data and Coordinating Center and 0401 Protocol 
Team 
 National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer 
Institute (NCI), both of the National Institutes of Health (NIH), study sponsors  
 Southwest Oncology group (SWOG), clinical trials cooperative group 
 U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research 
Protections (OHRP) 
                                                   
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


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 U.S. government agencies that are responsible for overseeing public health 
concerns such as the Centers for Disease Control (CDC) and federal, state and 
local health departments 
 Other: 
 
 
 
 
e. Right to Refuse to Sign this Authorization: I do not have to sign this Authorization.  If I 
decide not to sign the Authorization, I will not be allowed to participate in this study or 
receive any research-related treatment that is provided through the study.  However, my 
decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
f. Right to Revoke:  I can change my mind and withdraw this authorization at any time by 
sending a written notice to the Principal Investigator to inform the researcher of my 
decision.  If I withdraw this authorization, the researcher may only use and disclose the 
protected health information already collected for this research study.  No further health 
information about me will be collected by or disclosed to the researcher for this study. 
g. Potential for Re-disclosure: My individual health information disclosed under this 
authorization may be subject to re-disclosure outside the research study and no longer 
protected.  Examples include potential disclosures for law enforcement purposes, 
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities 
and public health measures. 
h. This authorization does not have an expiration date. 
 
************************************************ 
About Using Blood for Research 
Please note: This section of the informed consent form is about future research studies that 
will be done using blood samples from people who are taking part in the main study described 
above.  You may give blood samples for these future research studies if you want to.  You can 
still be a part of the main study even if you say 'no' to giving blood samples for future research 
studies.  You can say "yes" or "no" to giving blood samples for future research studies.  
Please mark your choice at the end of this section.  
 
We would like to have a blood sample for future research.  If you agree, 1 tablespoon (10 mL) of 
blood will be obtained at the time other blood samples are drawn at the beginning of the study 
and will be kept and may be used in research to learn more about cancer and other diseases.  
When the sample is given to investigators for research, no information about name, address, 
phone number of other information that will let the researcher know who you are will be 
provided. 
 


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The sample collected for research purposes will be sent to the National Heart, Lung, and Blood 
Institute (NHLBI) sample repository in Maryland.  The sample will be labeled with unique codes 
that do not contain information that could identify you.  A link to this code does exist.  The link 
is stored at the Data Coordinating Center for the Blood and Marrow Transplant Clinical Trials 
Network (BMT CTN).  The staff at the repository where your sample is being stored does not 
have a link to this code.  Your sample will be stored at this repository until the entire sample has 
been used for the research tests or until the end of the study.  Any research performed on this 
sample must first be approved by an advisory panel at the NHLBI. 
 
The research that may be done with your blood is not designed specifically to help you.  It might 
help people who have cancer and other diseases in the future.  
 
Reports about research done with your blood will not be given to you or your doctor.  These 
reports will not be put in your health record.  The research will not have an effect on your care.  
 
Things to Think About: The choice to let us have a blood sample for future research is up to 
you.  No matter what you decide to do, it will not affect your care.  
 
If you decide now that your blood can be kept for research, you can change your mind at any 
time.  Just contact your study doctor and let him or her know that you do not want us to use your 
blood sample.  Then any blood that remains will no longer be used for research.  
 
In the future, people who do research on these blood samples may need to know more about your 
health.  While the study doctor or others involved in running this study may give the researchers 
reports about your health, it will not give them your name, address, phone number, or any other 
information that will let the researchers know who you are.  
 
Sometimes blood is used for genetic research (about diseases that are passed on in families).  
Even if your blood is used for this kind of research, the results will not be put in your health 
records.  
 
Your blood will be used only for research and will not be sold.  The research done with your 
blood may help to develop new products in the future.  
 
Benefits: The benefits of research using blood include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.  
 
Risks: The greatest risk to you is the release of information from your health records.  We will 
do our best to make sure that your personal information will be kept private.  The chance that 
this information will be given to someone else is very small.  
 
Making Your Choice: Please read each sentence below and think about your choice.  After 
reading each sentence, please indicate your choice below.  If you have any questions, please talk 
to your doctor or nurse, or call our research review board at ___________________.  
 


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No matter what you decide to do, it will not affect your care. 
 
 Yes, I agree to have blood drawn for future research. 
 
 No, I do not agree to have blood drawn for future research. 
 
 ____________________________________   _____________________________  
Signature 
Date 
 
************************************************ 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Rituxan/BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
B-16 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study. 
Contact your study doctor __________________ [name(s)] at ______________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the __________[name of 
center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
 
 
SIGNATURE 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
 
Participant ________________________________ 
 
 
Date _____________________________________ 
 
 
Witness __________________________________ 
 
 
Date_____________________________________ 
 
 
As a representative of this study, I have explained the purpose, the procedures, the benefits, and 
the risks that are involved in this research study: 
 
 
 
 
 
 
 
 
 
 
 
Signature of person conducting informed consent   
 
 
__________________________________________ 
Date 
 
 


BMT CLINICAL TRIALS NETWORK 
 
Rituxan/BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
 
APPENDIX C 
 
LABORATORY PROCEDURES 


BMT CLINICAL TRIALS NETWORK 
 
Rituxan/BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
1. PATHOLOGY/CYTOGENETICS STUDIES 
 
Unilateral bone marrow biopsies and aspirates are required for pathology analysis and bone 
marrow aspirates are required for cytogenetic analysis prior to the conditioning therapy.  Other 
bone marrow assessments as summarized in the schedule of evaluations (Chapter 4) do not 
require the inclusion of bone marrow pathology/cytogenetics unless the original diagnostic 
marrow or the baseline marrow documented abnormal pathology/cytogenetics. 
 
Pathology and cytogenetic studies will be conducted per institutional guidelines. 
 
 
2. MEASUREMENTS OF POST-TRANSPLANT IMMUNE RECONSTITUTION 
 
Background and Rationale: Following peripheral blood stem cell transplantation, total B-cells 
(CD19+) are reconstituted to normal levels within 2-4 months [1-3]. T-cell recovery typically 
demonstrates relatively normal to elevated numbers of CD8+ cells, with CD4+ numbers 
remaining low for a year or longer, resulting in a persistently inverted CD4+/CD8+ ratio. 
CD45+RO+ memory cell numbers usually exceed CD45+RA+ naïve T-cell numbers during the 
first year, suggesting that T-cell recovery represents the expansion of mature T cells and a 
limited T-cell repertoire. NK cells recover early post transplant, and may reach normal values 
within one month. 
 
The effect of post-autologous peripheral blood stem cell transplant adjuvant rituximab on 
immune reconstitution, as measured by lymphocyte subsets and quantitative immunoglobulins, 
has been reported by Horwitz et al [4].  In a prospective study of weekly rituximab for 4 to 8 
doses beginning post-transplant Day 42, B-cell recovery was delayed in all patients and 
suppressed immunoglobulin G (IgG) levels and pneumococcus antibody titers in a subset.   
B-cell counts, measured by CD20+ and CD19+ cells, were low in absolute number in the 
majority of patients at study entry, and declined to zero in all patients receiving rituximab.  
Recovery occurred from 18-24 months after transplant.  Mean CD3+ numbers were only mildly 
depressed during the 24 months post transplant; whereas, mean CD4+ cell numbers were 
decreased throughout the first year but recovered by 24 months.  Natural killer cells were present 
in normal quantities throughout the study period.  
 
A depletion of or a substantial drop in CD20-positive peripheral blood cells was observed in 47 
of 59 patients shortly after treatment with 131I tositumomab (Bexxar) for relapsed or refractory  
B-cell non-Hodgkin's lymphoma [5].  The median time to B-cell recovery (defined as a return to 
the normal range of the absolute number of CD20-expressing cells) was 3.6 months (95% CI: 
3.2-6.6).  No significant effect on T-cell counts was observed. 
 


BMT CLINICAL TRIALS NETWORK 
 
Rituxan/BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
C-2 
Assays:  Blood for flow cytometry will be taken at the following time points: prior to the 
initiation of the Day -19 Bexxar or Rituxan (baseline), at Day + 100, and yearly for 2 years.  The 
two year post-ASCT assay is not required unless the results from the one year post-ASCT assay 
were abnormal.  The following tests will be performed: CD2, CD3, CD4, CD8, CD19, 
CD3/CD25, CD45 RA/RO, CD56+/CD3-, and quantitative immunoglobulins (IgM, IgG and 
IgA).  These tests will be performed per institutional guidelines. 
 
 
3. RESEARCH SPECIMENS 
 
BMT CTN research samples will be given unique bar code designations that cannot be linked 
back to the donor or the recipient.  All research samples will become property of the NHLBI 
after conclusion of the BMT CTN Protocol #0401 study.  An NHLBI Biologic Specimen 
Repository Utilization Committee will advise NHLBI on requests for samples to perform 
research with these anonymous samples.  If the committee approves an Investigator’s request for 
these samples, the NHLBI may provide a panel of the specimens requested using unique code 
numbers.  Laboratory test results, clinical information, etc., associated with the coded samples 
are provided to the Investigator only after completion of the main protocol.  Samples sent to 
researchers cannot be linked with any remaining sample at the repository. 
 
For All Patients:  Peripheral blood (10mL nucleated cell sample) will be collected for future 
testing at the time of disease staging and shipped quarterly to the Repository in compliance with 
the shipping procedures specified in the BMT CTN MOP. 


BMT CLINICAL TRIALS NETWORK 
  
Rituxan/BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
C-3 
SCHEDULE OF LABORATORY EVALUATIONS 
 
 
Type of Sample 
Type of Storage 
Dates Samples Obtained 
Shipping Specifications 
Test 
Location 
Flow Cytometry 
for analysis of 
CD2, CD3, CD4, 
CD8, CD19, 
CD3/CD25, CD45 
RA/RO, and 
CD56+/CD3- 
Per institutional 
guidelines 
Store according 
to institutional 
practice 
At baseline and at Day 100, 1year, and 2 years 
post-transplant1 
N/A 
Transplant 
Center 
Quantitative 
Immunoglobulins 
(IgM, IgG and 
IgA) 
Per institutional 
guidelines 
Store according 
to institutional 
practice 
At baseline and at Day 100, 1year, and 2 years 
post-transplant1 
N/A 
Transplant 
Center 
Patient Research 
Specimen 
Nucleated Cells 
from Peripheral 
Blood  
10 mL peripheral 
blood 
Obtain white 
blood cell pellet 
(by ficoll) and 
freeze in cryovial 
at -70° 
Prior to initiation of the ASCT conditioning 
therapy 
Frozen shipment 
quarterly to Repository in 
compliance with shipping 
procedures specified in 
the BMT CTN MOP 
TBD 
1 Immune reconstitution assays are not required at two years post-ASCT, unless results from the one year post-ASCT assays are abnormal. 
 


BMT CLINICAL TRIALS NETWORK 
  
BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
 
C-4 
 
REFERENCES IN APPENDIX C 
 
1. Ashihara E, Shimazaki C, Yamagata N, Hirata T, Okawa K, Oku N, Goto H, Inaba T, 
Fujita N, Nakagawa M.  Reconstitution of lymphocyte subsets after peripheral blood stem 
cell transplantation: two-color flow cytometric analysis.  Bone Marrow Transplant 
1994;13:377-381. 
2. Steingrimsdottir H, Gruber A, Bjokholm M, Svensson A, Hansson M.  Immune 
reconstitution after autologous hematopoietic stem cell transplantation in relation to 
underlying disease, type of high-dose therapy and infectious complications.  
Haematologica 2000;85:832-838. 
3. Schlenke P, Sheikhzadeh S, Weber K, Wagner T, Kirchner H.  Immune reconstitution 
and production of intracellular cytokines in T lymphocyte populations following 
autologous peripheral blood stem cell transplantation.  Bone Marrow Transplant 
2001;28:251-257. 
4. Horwitz SM, Negrin RS, Blume KG, Breslin S, Stuart MJ, Stockeri-Goldstein KE, 
Johnston LJ, Wong RM, Shizuru JA, Horning SJ.  Rituximab as adjuvant to high-dose 
therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin 
lymphoma.  Blood 2004;103:777-783. 
5. Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, Regan D, Fisher S, 
Gutierrez J, Kroll S, Stagg R, Tidmarsh G, Wahl R.  Radioimmunotherapy with iodine 
131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated 
results and long-term follow-up of the University of Michigan experience.  Blood 
2000;96:1259-1266. 
 


BMT CLINICAL TRIALS NETWORK 
  
BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
 
 
APPENDIX D 
 
HUMAN SUBJECTS


BMT CLINICAL TRIALS NETWORK 
  
BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
 
D-1 
APPENDIX D 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The Principal Investigator or 
another designated physician will conduct the conference.  All potential risks associated with the 
use of rituximab, chemotherapy agents, BEAM or Bexxar should be discussed as objectively as 
possible.   
 
The consent document should be reviewed with the patient and family prior to proceeding to 
autologous HSCT. 
 
Informed consent from the patient will be obtained using a form approved by the Institutional 
Review Board of the institution enrolling the patient.  
 
 
2. 
Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code relaying the patient’s identity with the ID code will be kept separately 
at the center.  The ID code will be transmitted to the BMT CTN Data Coordinating Center upon 
enrollment. 
 
 
3. 
Participation of Women and Minorities and Other Populations 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the IBMTR and from published data on incidence of DLCL in 
these groups.  Centers will be notified if their rates differ significantly from those expected and 
asked to develop appropriate recruitment strategies. 
 


BMT CLINICAL TRIALS NETWORK 
  
BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
 
 
APPENDIX E 
 
STUDY DRUG (BEXXAR) ORDER FORM


BMT CLINICAL TRIALS NETWORK 
  
BEAM vs Bexxar/BEAM – Protocol 0401 
 
 
Version 8.0 dated September 20, 2010 
 
E-1 
GSK Protocol #105918  
Study Drug Order Form 
Phase III Rituxan/BEAM vs. Bexxar/BEAM with Autologous Hematopoietic Stem Cell 
Transplantation (ASCT) for Persistent or Relapsed Chemotherapy Sensitive Diffuse Large B-cell 
Non-Hodgkin’s Lymphoma 
 (BMT CTN Protocol 0401) 
 
Patient Identification Number:  
 
 
 
 
 
 
 
 
 
Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
Date: 
 
 
 
 
 
Study/Site Coordinator: 
 
 
 
 
 
 
 
 
 
Street Address:  
 
 
 
 
 
 
 
 
 
 
City, State, Zip Code: 
 
 
 
 
 
 
 
 
 
 
Phone #: 
 
 
 
 
 
Fax #:  
 
 
  
 
 
Radiopharmacy Contact Information 
Contact Person:  
 
 
 
 
 
 
 
 
 
 
Street Address:  
 
 
 
 
 
 
 
 
 
 
City, State, Zip Code: 
 
 
 
 
 
 
 
 
 
 
Phone #: 
 
 
 
 
 
Fax #:  
 
 
  
 
 
Nuclear Medicine/Radiation Oncology Contact Information 
Prescribing Physician Name (Authorized User):  
 
 
 
 
 
 
 
Prescribing Physician Signature:  
 
 
 
 
 
 
 
 
 
Contact Person:  
 
 
 
 
 
 
 
 
 
 
Street Address:  
 
 
 
 
 
 
 
 
 
 
City, State, Zip Code: 
 
 
 
 
 
 
 
 
 
 
Phone #: 
 
 
 
 
 
Fax #:  
 
 
  
 
 
Dosimetric:  
Date: 
 
Time:  
Therapeutic: 
Date: 
 
Time:  
 
 
 
Dx Alternate: Date(s): 
 
 
Tx Alternate: Date(s): 
 
 
 
 
 
Site Name Where the Tositumomab will be administered:  
 
 
 
 
 
 
Contact Person:  
 
 
 
 
 
 
 
 
 
 
Street Address:  
 
 
 
 
 
 
 
 
 
 
City, State, Zip Code: 
 
 
 
 
 
 
 
 
 
 
Phone #: 
 
 
 
 
 
Fax #:  
 
 
  
 
 
To complete Drug order placement: 
1. Fax completed form to your radiopharmacy. 
2. Have your radiopharmacy place order by faxing form to (877) 279-1512.  Your 
Radiopharmacy can call the BEXXAR Service Center (877) 423-9927 if additional 
scheduling requirements are needed. 
3. If you have any questions regarding the order process please contact the Bexxar 
Service Center at (877) 423-9927. 
 
 
August 29, 2005 
 
 
 
 
 
Bexxar Drug Order Form, Version 1.0