Clinical trial NCT02483000
Conditions: Burkitt Lymphoma CD20-Positive Neoplastic Cells Present Diffuse Large B-Cell Lymphoma Indolent Non-Hodgkin Lymphoma Mantle Cell Lymphoma Recurrent B-Cell Non-Hodgkin Lymphoma Refractory Mature B-Cell Non-Hodgkin Lymphoma
Sponsor: Fred Hutchinson Cancer Center
Start date: 2017-02-01; Completion date: 2020-09-02
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of anti-cluster of differentiation (CD)20 radioimmunotherapy (RIT), and to see how well it works when given before chemotherapy and stem cell transplant in treating patients with B-cell malignancies that have not responded to treatment or have come back after responding to treatment. CD20 is a protein found on the cells of a type of cancer cell called B-cells. Anti-CD20 RIT attaches radioactive material to a drug that is designed to target CD20, which brings radioactive material to the cancer cells to kill the cells. This may kill more tumor cells while causing fewer side effects to healthy tissue. Adding anti-CD20 to standard chemotherapy and stem cell transplant may be more effective in treating patients with B-cell malignancies.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of 90Y activity that can be delivered via pretargeted radioimmunotherapy (PRIT) using B9E9-fusion protein (B9E9-FP), clearing agent (CA), and radiolabeled tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin when followed by carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and autologous stem cell transplantation.

SECONDARY OBJECTIVES:

I. To assess the overall and progression-free survival of the above regimen in such patients.

II. To evaluate the response rates of the above therapy.

III. To evaluate the toxicity and tolerability of the above therapy.

IV. To evaluate the feasibility of delivering sequential high-dose PRIT and chemotherapy.

TERTIARY OBJECTIVES:

I. Assess biodistribution and pharmacokinetics of B9E9-FP and radiolabeled DOTA-Biotin.

II. Assess ability of the clearing agent (CA) to remove excess B9E9-FP from the serum.

III. Evaluate the impact, if any, of circulating rituximab on biodistributions.

OUTLINE: This is a phase I, dose-escalation study of yttrium Y 90 DOTA-biotin followed by a phase II study.

B9E9-FP INFUSION: Patients receive B9E9-fusion protein intravenously (IV) over a minimum of 2 hours on day -17.

CLEARING AGENT INFUSION: Patients receive clearing agent IV over a minimum of 30 minutes on day -15.

RADIOBIOTIN INFUSION: Patients receive indium In 111-DOTA-biotin IV and yttrium Y 90 DOTA-biotin IV over 2-5 minutes on day -14.

BEAM CHEMOTHERAPY: Patients receive BEAM chemotherapy comprising carmustine IV over 3 hours on day -7; etoposide IV over 2 hours twice daily (BID) and cytarabine IV over 4 hours BID on days -6 to -3; and melphalan IV over 30 minutes on day -2.

STEM CELL INFUSION: Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0 per standard of care.

After completion of study treatment, patients are followed up at 1, 3, 6, and 12 months, and then annually thereafter.

Arms: arm 1: B9E9-FP INFUSION: Patients receive B9E9-fusion protein IV over a minimum of 2 hours on day -17.

CLEARING AGENT INFUSION: Patients receive clearing agent IV over a minimum of 30 minutes on day -15.

RADIOBIOTIN INFUSION: Patients receive indium In 111-DOTA-biotin IV and yttrium Y 90 DOTA-biotin IV over 2-5 minutes on day -14.

BEAM CHEMOTHERAPY: Patients receive BEAM chemotherapy comprising carmustine IV over 3 hours on day -7; etoposide IV over 2 hours BID and cytarabine IV over 4 hours BID on days -6 to -3; and melphalan IV over 30 minutes on day -2.

STEM CELL INFUSION: Patients undergo autologous PBSCT on day 0 per standard of care.
Interventions: intervention 1: Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein intervention 2: Autologous Hematopoietic Stem Cell Transplantation intervention 3: Carmustine intervention 4: Clearing Agent intervention 5: Cytarabine intervention 6: Etoposide intervention 7: Indium In 111-DOTA-Biotin intervention 8: Laboratory Biomarker Analysis intervention 9: Melphalan intervention 10: Peripheral Blood Stem Cell Transplantation intervention 11: Pharmacological Study intervention 12: Yttrium Y 90-DOTA-Biotin
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo autologous PBSCT intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV intervention 8: Correlative studies intervention 9: Given IV intervention 10: Undergo autologous PBSCT intervention 11: Correlative studies intervention 12: Given IV

Protocol documents:
Prot_SAP_000.pdf: 




PROTOCOL 9189 
 
 
Page 3 of 43 
 
TABLE OF CONTENTS 
 
1.0 
INTRODUCTION AND OVERVIEW ................................................................................................. 7 
2.0 
BACKGROUND .............................................................................................................................. 7 
2.1 
Epidemiology and Pathologic Characteristics of Lymphomas ........................................ 7 
2.2 
Current Targeted Therapies for B-NHL ........................................................................... 7 
2.3 
Addition of RIT to Standard BEAM Conditioning Regimens ........................................... 8 
2.4 
Pretargeted RIT Approach .............................................................................................. 9 
2.5 
Clinical PRIT Data ............................................................................................................ 10 
2.6 
Summary ......................................................................................................................... 11 
3.0 
OBJECTIVES .................................................................................................................................. 11 
3.1 
Primary Objective ........................................................................................................... 11 
3.2 
Secondary Objectives ...................................................................................................... 12 
3.2.1 
Clinical ................................................................................................................ 12 
3.2.2 
Correlative ......................................................................................................... 12 
4.0 
PATIENT SELECTION ..................................................................................................................... 12 
4.1 
Inclusions ........................................................................................................................ 12 
4.2 
Exclusions ........................................................................................................................ 12 
5.0 
DONOR SELECTION ...................................................................................................................... 13 
6.0 
EVALUATION AND COUNSELING OF PATIENT .............................................................................. 13 
7.0 
PROTOCOL REGISTRATION ........................................................................................................... 13 
8.0 
PLAN OF TREATMENT .................................................................................................................. 13 
8.1 
Overview ......................................................................................................................... 13 
8.2 
Investigational Product Dosing ....................................................................................... 14 
8.3 
Peripheral Blood Stem Cell Collection ............................................................................ 15 
8.4 
Investigation Product Administration ............................................................................. 15 
8.4.1 
B9E9-FP infusion ................................................................................................ 15 
8.4.2 
Clearing Agent Infusion ...................................................................................... 15 
8.4.3 
Radiolabeled DOTA-biotin infusion ................................................................... 15 
8.4.4 
Management of Toxicities ................................................................................. 16 
8.5 
Assessment of B9E9-FP Levels ........................................................................................ 16 
8.6 
Quantitative Biodosimetry .............................................................................................. 17 
8.7 
Pharmacokinetic (PK) Sample Collection ........................................................................ 17 
8.7.1 
B9E9-FP and CA PK samples ............................................................................... 17 
8.7.2 
Radiolabeled DOTA-biotin PK samples .............................................................. 17 
8.8 
BEAM Chemotherapy...................................................................................................... 17 
8.9 
Stem Cell Infusion ........................................................................................................... 18 
8.10 
Adjunctive Therapy ......................................................................................................... 18 
8.11 
Criteria for Removal from Protocol Treatment .............................................................. 19 
9.0 
EVALUATIONS .............................................................................................................................. 19 
9.1 
Pre-transplant Evaluations .............................................................................................. 19 
9.2 
Post-transplant Evaluations ............................................................................................ 19 
9.3 
Definitions ....................................................................................................................... 19 
9.4 
Measurement of Response ............................................................................................. 20 
9.5 
Long-term Evaluations .................................................................................................... 20 
10.0 
TOXICITIES AND COMPLICATIONS ............................................................................................... 20 
11.0 
PROTOCOL ENROLLMENT AND SPECIAL CONSIDERATIONS ........................................................ 22 


PROTOCOL 9189 
 
 
Page 4 of 43 
 
12.0 
ADVERSE EVENT REPORTING ....................................................................................................... 22 
12.1 
Adverse Event Definitions ............................................................................................... 22 
12.2 
Monitoring and Recordings AEs ...................................................................................... 23 
12.3 
Grading of the Severity of an Adverse Event .................................................................. 24 
12.4 
Attribution of Adverse Event .......................................................................................... 24 
12.5 
Adverse Event Reporting Period ..................................................................................... 24 
12.6 
Adverse Event Reporting Requirements ......................................................................... 25 
12.6.1 Research Site Reporting Requirements ............................................................. 25 
12.6.2 Fred Hutch Sponsor Reporting Requirements ................................................... 26 
12.7 
SAEs Commonly Associated with ASCT ........................................................................... 26 
13.0 
DATA AND SAFETY MONITORING ................................................................................................ 27 
14.0 
DATA MANAGEMENT/CONFIDENTIALITY .................................................................................... 27 
15.0 
STATISTICAL CONSIDERATIONS .................................................................................................... 28 
15.1 
Randomization/Stratification/Descriptive Factors ......................................................... 28 
15.2 
90Y-DOTA-biotin dose escalation ..................................................................................... 28 
15.3 
Evaluation of Efficacy ...................................................................................................... 29 
15.4 
Estimation of Dosimetry ................................................................................................. 30 
15.5 
Stopping Rules ................................................................................................................ 30 
16.0 
TERMINATION OF THE STUDY ...................................................................................................... 30 
17.0 
REFERENCES ................................................................................................................................. 30 
APPENDIX 1:  GRADING OF TOXICITY (BEARMAN SCALE) ......................................................................... 36 
APPENDIX 2:  SUGGESTED POST TREATMENT EVALUATIONS* ................................................................ 37 
APPENDIX 4:  SWOG PERFORMANCE STATUS .......................................................................................... 43 
 


PROTOCOL 9189 
 
 
Page 5 of 43 
 
List of Tables 
TABLE 1: General Treatment Schema* 
TABLE 2: Dose Levels to be Used 
TABLE 3: Management of Infusion Related Reactions/ Infusion Related Adverse Events 
TABLE 4: BEAM Treatment Schedule 
TABLE 5: General Post-transplant Outpatient Monitoring Guidelines 
TABLE 6: Projected Target Accrual/Ethnic and Gender Distribution Chart 
TABLE 7: Site to Sponsor Reporting Requirements for Adverse Events 
TABLE 8: SAEs Commonly Observed Following Autologous Stem Cell Transplant 
 
 
List of Figures 
FIGURE 1.  Overall survival (left) and progression-free survival (right) of patients treated either with high-
dose radioimmunotherapy (HD-RIT) using 131I-tositumomab and autologous hematopoietic stem cell 
transplantation (ASCT) or conventional high-dose therapy (C-HDT) and ASCT6. 
FIGURE 2: Components for PRIT. Schema depicting one-step conventional RIT (A) and multistep PRIT (B). 
PRIT involves infusion of the Ab-SA construct (step 1), followed by injection of a synthetic N-
acetylgalactosamine–containing clearing agent (step 2) designed to facilitate hepatic clearance of excess 
Ab-SA from the bloodstream, and then infusion of the radiolabeled small molecule DOTA–biotin (Step 
3)34. 
FIGURE 3: B9E9-FP serum clearance. Serum B9E9-FP concentration data from patients in cohort A (n = 3) 
generated from 186Re counting or ELISA shown as percent of injected dose (mean ± SD). 
FIGURE 4: Tumor targeting of known sites of disease. Images obtained 20 minutes, 3 hours, and 44 
hours after the administration of 111In(5 mCi)/90Y(15 mCi/m2)-DOTA-biotin. Gamma camera whole-body 
scans of patient no. 1 (anterior views) obtained at 20 minutes, 3 hours, and 44 hours after infusion of 
111In/90Y-DOTA-biotin. Arrows show radionuclide localization to known sites of tumor involvement. 
FIGURE 5: Study Schema 
 
 
 
 


PROTOCOL 9189 
 
 
Page 6 of 43 
 
 Acronyms 
Ab 
antibody 
AE 
Adverse Event 
ASCT  
autologous stem cell transplantation 
B-NHL 
B-cell non-Hodgkin’s lymphoma 
C-HDT  
conventional high-dose therapy  
CA 
clearing agent 
CFR 
case report forms 
CR 
complete response 
DLBCL 
diffuse large B-cell  
DLT 
dose limiting toxicity 
DOTA-biotin  
radiobiotin  
DSMC 
Data Safety Monitoring Committee 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
Fred Hutch or FHCRC 
Fred Hutchinson Cancer Research Center 
FL 
follicular  
FLIPI 
Follicular Lymphoma International Prognostic Index 
HAMA  
human anti-mouse antibody  
HASA  
human anti-streptavidin antibody  
HCT  
hematopoietic cell transplantation  
HD-RIT  
high-dose radioimmunotherapy  
IND 
investigational new drug 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
MCL  
mantle cell  
MoAb  
monoclonal antibody  
MTD  
maximally tolerated dose  
MZL 
marginal zone lymphoma 
NHL 
non-Hodgkin’s lymphoma 
OS 
overall survival  
PBSC  
peripheral blood stem cells  
PFS 
progression free survival  
PK 
Pharmacokinetic 
PRIT 
Pretargeted radioimmunotherapy 
RIT 
radioimmunotherapy 
SA  
streptavidin  
SAE 
Serious Adverse Event 
SCCA 
Seattle Cancer Care Alliance 
SCT 
stem cell transplant 
SLL 
small lymphocytic 
SRC 
Scientific Review Committee 
UW 
University of Washington 
UWMC 
University of Washington Medical Center 
 


PROTOCOL 9189 
 
 
Page 7 of 43 
 
1.0 
INTRODUCTION AND OVERVIEW 
High dose chemoradiotherapy followed by autologous stem cell transplantation (ASCT) has become the 
standard of care for patients with relapsed or refractory intermediate or high grade non-Hodgkin’s 
lymphoma (NHL) 1,2 and has also been shown to prolong survival in patients with relapsed indolent 
lymphomas or mantle cell lymphoma in first remission.3,4 Despite the potential to improve outcomes, 
the majority of patients with aggressive B-NHL and nearly all patients with indolent or mantle cell 
lymphoma are likely to relapse as well as most with relapsed aggressive B-NHL that has failed rituximab-
chemotherapy.3,4,5 Based on the exquisite radiosensitivity of B-NHL, we have conducted phase I & II 
studies of directly radiolabeled anti-B-cell antibodies and have demonstrated improved outcomes when 
compared to non-randomized controls. 6,7 Though these results appear better than historical standards, 
many patients will still not be cured of their disease. Some of this may be due to the fact that the ratio 
of absorbed radiation dose to tumor sites vs normal organs with this approach is at best 2:1. Pretargeted 
radioimmunotherapy (PRIT) has been shown in preclinical and clinical non-transplant models to be able 
to improve this ratio up to 20:1.8-15 This trial builds on our and other’s extensive expertise and 
experience in this area to develop a myeloablative PRIT conditioning regimen to augment standard 
BEAM chemotherapy with the ultimate goal to improve remission durations and cure rates in patients 
with B-NHL.    
2.0 
BACKGROUND 
2.1 
Epidemiology and Pathologic Characteristics of Lymphomas 
Each year in the United States over 75,000 individuals will be newly diagnosed with lymphoma, resulting 
in over 20,000 deaths annually. 16 The vast majority are B-NHL with the most common histologic entities 
including diffuse large B-cell (DLBCL), follicular (FL), mantle cell (MCL), small lymphocytic (SLL), and 
marginal zone lymphoma (MZL). These lymphomas express many similar surface antigens including 
CD19, CD20, and CD45.  
2.2 
Current Targeted Therapies for B-NHL 
B-cell lymphomas are the first group of malignancies to have benefited from the development of 
targeted monoclonal antibody (MoAb) therapies. Rituximab, a MoAb that targets the pan-B-cell antigen 
CD20, has contributed to the first major improvement in the treatment of many B-cell malignancies in 
decades.17-21 Despite its activity, most patients that receive rituximab alone achieve only partial 
responses and remission durations are limited. The addition of radionuclides such as Iodine-131 (131I) or 
Yttrium-90 (90Y) to anti-CD20 antibodies exploits the exquisite radiosensitivity of NHLs. This has resulted 
in improved rates of response and longer remission durations. 22,23 One approach to further improve 
outcomes, pioneered by our group and others, involves escalating the dose of CD20 targeted RIT 
combined with autologous stem cell rescue to support hematopoiesis. We have previously 
demonstrated that this approach delivers approximately twice the absorbed radiation dose to tumor 
sites as compared to the critical normal organ that received the highest radiation exposure, and ten 
times more radiation to tumors than is delivered to the whole body.  Our data have confirmed that 
escalating the absorbed dose of RIT correlates with improved progression free survival (PFS).6-8,23,24 


PROTOCOL 9189 
 
 
Page 8 of 43 
 
These phase II clinical trials demonstrated that high-dose anti-CD20 RIT yields response rates of >90% in 
heavily pre-treated B-NHL patients;8 and, when compared to concurrent non-randomized controls 
treated with conventional conditioning regimens, RIT-based conditioning yielded improved overall 
survival (OS) and PFS  (Figure 1). 
FIGURE 1.  Overall survival (left) and progression-free survival (right) of patients 
treated either with high-dose radioimmunotherapy (HD-RIT) using 
131I-
tositumomab and autologous hematopoietic stem cell transplantation (ASCT) or 
conventional high-dose therapy (C-HDT) and ASCT6.  
The efficacy and tolerability of high-dose anti-CD20 RIT and ASCT is further supported by our recent data 
suggesting that this approach can safely extend potentially curative therapies to adults into their mid-
70s. Collectively, our studies have repeatedly demonstrated the feasibility, safety, and efficacy of 
delivering high-dose CD20-directed RIT and hematopoietic cell transplantation (HCT) for B-NHL. 
However, despite the promising outcomes using single step RIT, the absorbed radiation doses to tumor 
sites are at best twice that is delivered to non-target organs. 8,23,24 We hypothesize that improving this 
ratio and thereby increasing the absorbed dose to target sites we will be able to reduce relapse rates 
and improve long-term outcomes.  
2.3 
Addition of RIT to Standard BEAM Conditioning Regimens 
In an effort to improve on one of the most commonly employed autologous transplant conditioning 
regimens for lymphoma, anti-CD20 RIT with 131I-tositumomab or 90Y-ibritumomab tiuxetan has been 
added to a variety of high-dose chemotherapy regimens prior to ASCT. 7,25-33  Generally, these reports 
demonstrate little additive toxicity attributable to RIT, considering the often-substantial toxicity seen 
from the myeloablative chemotherapy backbones to which it was added.  However, there have been 
relatively few randomized controlled trials comparing myeloablative preparative regimens with or 
without RIT.  In one study from Israel, the addition of 90Y-ibritumomab tiuxetan to BEAM for relapsed 
DLBCL yielded superior 2-year overall survival compared to BEAM alone (91% vs 62%, respectively; P = 
0.05).7,31  However, a larger study comparing BEAM plus either rituximab or 131I-tositumomab for 
relapsed DLBCL showed no difference in overall or progression-free survival between the two arms.7,29  
These studies primarily used the standard low doses of 131I-tositumomab or 90Y-ibritumomab tiuxetan.  
Thus, it is possible that RIT was not sufficiently dose-intensified to achieve maximum efficacy.  To 


PROTOCOL 9189 
 
 
Page 9 of 43 
 
achieve this objective, Winter and colleagues escalated the dose of radiation delivered to critical organs 
by 90Y-ibritumomab tiuxetan in combination with BEAM in patients with relapsed/refractory B-NHL.7,27  
They estimated the maximally tolerated dose (MTD) to be 15 gray (Gy), though they conceded that most 
of the toxicities observed were similar to those typically seen with BEAM alone (e.g., infections, 
pulmonary and hepatic toxicity, etc.).  They also observed relatively promising clinical outcomes in this 
cohort of generally high-risk (i.e., heavily pre-treated, non-remission) patients.  
One current approach (protocol 2728) utilizing 90Y-anti-CD45 RIT in addition to BEAM chemotherapy and 
auto transplant and has shown that absorbed doses to non-target sites (primarily liver) up to 16 Gy can 
be delivered without evidence of dose limiting toxicities. There has also been no indication that 
engraftment has been impacted despite the use of standard single-step radioimmunotherapy. Though 
dose escalation continues with this approach, and combination of high-dose RIT with BEAM 
chemotherapy is clearly feasible, we recognize that with single-step RIT, at best the tumor to normal 
organ ratios of absorbed radiation dose will be 2:1 likely limiting our ability to maximally escalate the 
exposure of target sites to ionizing radiation. We plan to build on this experience with a PRIT-BEAM 
combination as described below.  
2.4 
Pretargeted RIT Approach 
Another strategy to further improve the ability to selectively deliver targeted radiation to desired sites 
and limit exposure to normal organs is PRIT.  
FIGURE 2: Components for PRIT. Schema depicting one-step conventional RIT (A) and multistep PRIT 
(B). PRIT involves infusion of the Ab-SA construct (step 1), followed by injection of a synthetic N-
acetylgalactosamine–containing clearing agent (step 2) designed to facilitate hepatic clearance of 
excess Ab-SA from the bloodstream, and then infusion of the radiolabeled small molecule DOTA–
biotin (Step 3)34.   
With traditional RIT, the slow clearance of unbound radiolabeled antibody (Ab) from the circulation and 
the resultant high levels of background radioactivity are major obstacles to the optimal implementation 
since these pharmacokinetic features limit the tumor-to-normal organ ratios of absorbed radiation that 
can be achieved.7,35-37  PRIT approaches offer a potential to further reduce the toxicity and improve the 
sub-optimal therapeutic index (target to non-target ratio) currently achievable with conventional RIT 
methodologies.  We have investigated a PRIT strategy that utilizes the high affinity streptavidin (SA)-
biotin system in which the Ab-SA conjugate and the radioactive biotin are administered separately 


PROTOCOL 9189 
 
 
Page 10 of 43 
 
(Figure 2).7,35,36,38-42 The localization of the Ab-SA component to tumor is relatively slow and an unbound 
portion of the conjugate remains in circulation.  However, because no radionuclide is attached, there are 
no toxic consequences due to the non-tumor bound unlabeled Ab-SA conjugate.  The radiolabeled small 
molecule is delivered after maximal accumulation of Ab-SA conjugate in targeted tissues (e.g., after 24-
48 hours) and after clearance of unbound Ab-SA from the blood. The natural clearance of the unbound 
Ab-SA conjugate prevents it from complexing with the radiolabeled small molecule in the 
circulation.7,15,43-49 The clearance of unbound Ab-SA in the blood can be further enhanced by the use of a 
synthetic N-acetylgalactosamine–containing clearing agent that removes excess antibody from the 
bloodstream.11 Therapeutic radiobiotin, due to its small size, is able to penetrate tumor sites rapidly and 
attach to the pretargeted Ab-SA conjugate bound specifically to tumor cells.  If the tumor-bound Ab-SA 
does not capture this small radioactive molecule, the kidney rapidly excretes it.  This PRIT approach has 
been shown to improve the ratios of radiation delivered to tumors compared to normal organs in both 
preclinical and clinical models.7,15,43-47,50-58 Our group has recently demonstrated reduced toxicity and 
markedly enhanced efficacy using a pretargeted anti-CD20 Ab-SA conjugate compared to the directly 
labeled anti-CD20 Ab in mouse xenograft studies.7,15  We have further shown that results using either 
pretargeted anti-CD45 or anti-CD20 Ab-SA conjugates are comparable in murine preclinical NHL 
models.7,51  
2.5 
Clinical PRIT Data 
Two pilot non-ablative PRIT Phase I clinical trials using anti-CD20 Ab-SA have been reported and 
preliminary results suggest that the use of this reagent is safe and that the pretargeted RIT approach is 
feasible.7,57,58 These studies demonstrated rapid tumor localization and urinary excretion of Yttrium-90 
(90Y)-labeled biotin with resulting tumor-to-blood ratios of 65:1 and minimal toxicity.7,57 The second 
phase I trial evaluated 2 doses of anti-CD20 antibody-streptavidin B9E9[scFv]4SA fusion protein (B9E9-
FP) (160 mg/m2 and 320 mg/m2) finding them both to be pharmacokinetically similar. The same trial also 
demonstrated that a molar excess of clearing agent (CA) (45 mg/m2) administered at either 48 or 72 
hours later highly effectively removed >95% of unbound B9E9-FP from the circulation (Figure 3).  This 
was then followed by radiobiotin (DOTA-biotin) labeled with both 90Y for therapeutic purposes and 
Indium-111 (111In) for concurrent imaging/dosimetry. Importantly, this group was able to clearly 
demonstrate targeting to tumor sites (Figure 4) and resultant objective responses despite the phase I 
nature of this trial. The only clinically significant but expected adverse events observed in this trial were 
transient hematologic toxicity of ≥ grade 3 in 2 of 14 patients, all of whom were treated at the 15 
mCi/m2 dose. With this approach in mind, we have repeatedly been able to administer much higher 
myeloablative doses of radioisotopes followed by hematopoietic stem cell transplantation to abrogate 
the expected hematologic toxicity of high-dose radioimmunotherapy in published6,59,60 or ongoing 
clinical trials (protocols 2238, 2361, 2728, 2398) with no impairment of engraftment or long-term 
cytopenias. 


PROTOCOL 9189 
 
 
Page 11 of 43 
 
 
 
FIGURE 3: B9E9-FP serum clearance. Serum B9E9-FP 
concentration data from patients in cohort A (n = 3) 
generated from 186Re counting or ELISA shown as 
percent of injected dose (mean ± SD).  
FIGURE 4: Tumor targeting of known 
sites of disease. Images obtained 20 
minutes, 3 hours, and 44 hours after the 
administration of 
111In(5 mCi)/90Y(15 
mCi/m2)-DOTA-biotin. Gamma camera 
whole-body scans of patient no. 1 
(anterior views) obtained at 20 minutes, 
3 hours, and 44 hours after infusion of 
111In/90Y-DOTA-biotin. 
Arrows 
show 
radionuclide localization to known sites 
of tumor involvement.  
2.6 
Summary 
We and others have demonstrated the feasibility and potential improved efficacy of high-dose RIT-
based conditioning as a single agent or in combination with high-dose chemotherapy, but recognize the 
hypothetical limitations with this approach. Extensive preclinical data indicate that PRIT can further 
intensify the absorbed radiation dose to target sites while limiting dose to non-target normal organs. We 
have successfully piloted the high-dose PRIT strategy using CD45 targeting in the setting of AML. Prior 
clinical data indicate that the B9E9 anti-CD20 PRIT strategy is feasible, safe and has anti-tumor activity at 
low doses without the use of stem cell support. In this protocol, we will perform a phase I trial escalating 
the 90Y activity delivered using a PRIT strategy to myeloablative doses along with BEAM chemotherapy 
prior to ASCT for patients with high-risk B-NHL. The B9E9-FP will be generated in the Fred Hutchinson 
Cancer Research Center (“Fred Hutch”) Biological Production Facility, the Cluster Clearing Agent-16-
Biotin (CA) will be produced in the Memorial Sloan Kettering Cancer Center Organic Synthesis Core 
Facility, and the radiolabeling and final product release testing of the radiolabeled DOTA-biotin will 
occur in a controlled environment at the University of Washington (UW) Nuclear Medicine Radiolabeling 
Laboratory, room BB030. 
3.0 
OBJECTIVES 
3.1 
Primary Objective 


PROTOCOL 9189 
 
 
Page 12 of 43 
 
To estimate the MTD of 90Y activity that can be delivered via PRIT using B9E9-FP, CA, and radiolabeled 
DOTA-biotin when followed by BEAM chemotherapy and autologous stem cell transplantation.  
3.2 
Secondary Objectives  
3.2.1 
Clinical 
a. To assess the overall and progression-free survival of the above regimen in such patients.  
b. To evaluate the response rates of the above therapy.  
c. To evaluate the toxicity and tolerability of the above therapy.  
d. To evaluate the feasibility of delivering sequential high-dose PRIT and chemotherapy. 
3.2.2 
Correlative 
a. Assess biodistribution and pharmacokinetics of B9E9-FP and radiolabeled DOTA-Biotin. 
b. Assess ability of the CA to remove excess B9E9-FP from the serum. 
c. Evaluate the impact, if any, of circulating rituximab on biodistributions. 
4.0 
PATIENT SELECTION  
Evaluations done as part of the standard clinical work-up for patients undergoing autologous 
transplantation may be used for determination of eligibility if performed within 30 days of enrollment 
(PET-CT may be used if performed within 56 days prior to treatment). 
4.1 
Inclusions 
1) Patients must have a histologically confirmed diagnosis of lymphoma expressing the CD20 antigen 
and generally must have failed at least one prior standard systemic therapy.  The exception will be 
MCL patients, who may be enrolled while in first CR as well as other select high-risk lymphomas 
(e.g., Burkitt’s, double hit DLBCL, transformed indolent B-NHL, etc.) in accordance with current 
transplant standard of care for these patients. 
2) Patients must have normal renal function (Cr <2.0) and normal hepatic function (bilirubin <1.5 
mg/dL), with the exception of patients thought to have Gilbert’s syndrome, who may have a total 
bilirubin above 1.5 mg/dL. 
3) All patients eligible for therapeutic study must have (≥2x106 CD34/kg) autologous hematopoietic 
stem cells harvested and cryopreserved. 
4) Patients must have an expected survival of >60 days and must be free of major infection. 
5) Patients of childbearing potential must agree to abstinence or the use of effective contraception.  
4.2 
Exclusions 
1) Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled 90Y therapy 
dose 
2) Inability to understand or give an informed consent 
3) Prior radiation >20 Gy to any critical normal organ (e.g., lung, liver, spinal cord, both kidneys) within 
1 year of the treatment date 


PROTOCOL 9189 
 
 
Page 13 of 43 
 
4) Active central nervous system lymphoma 
5) Other serious medical conditions considered to represent contraindications to BMT (e.g., 
abnormally decreased cardiac ejection fraction, DLCO<50% predicted, patient on supplemental 
oxygen, AIDS, etc.) 
6) Age < 18 years 
7) Pregnancy or breast feeding 
8) Prior bone marrow or stem cell transplant 
9) SWOG performance status ≥ 2.0 (Appendix 4) 
10) Known sensitivity to kanamycin and other aminoglycosides. Patients with known hypersensitivity to 
kanamycin or any other aminoglycoside antibiotic will be excluded. 
5.0 
DONOR SELECTION 
Not Applicable. This protocol employs autologous transplantation, utilizing the patient’s own 
hematopoietic stem cells obtained from either the peripheral blood or bone marrow. 
6.0 
EVALUATION AND COUNSELING OF PATIENT 
This protocol should be discussed thoroughly with the patient and family (if appropriate), and all known 
risks and hazards to the patient should be described.  The stem cell transplant procedure of this protocol 
as well as possible and alternative forms of therapy should be reviewed as objectively as possible.  
Consent will be obtained using forms approved by the Fred Hutch Institutional Review Board (IRB).  A 
summary of the conference should be dictated for the medical record detailing what was covered. 
7.0 
PROTOCOL REGISTRATION  
Patients will be assigned and registered utilizing the institution’s standard procedures. 
8.0 
PLAN OF TREATMENT  
8.1 
Overview 
Each patient will undergo concurrent therapy based on mCi/m2 dosing of 90Y and flat (5-10 mCi) dosing 
of 111In along with concurrent imaging and dosimetry for correlative and safety purposes. The sequence 
of events is summarized in Table 1 and Figure 5. The therapy/biodistribution dose will be given 
approximately 7 days prior to initiation of BEAM chemotherapy and approximately 2 weeks prior to 
ASCT.  The 90Y activity will be escalated to estimate a maximally tolerated dose when combined with 
BEAM chemotherapy.  
TABLE 1: General Treatment Schema* 
Day 
Event 
-17 
B9E9-FP administration  
-15** 
Clearing Agent (CA) administration 
-14 
111In-DOTA-biotin (~5-10 mCi) trace-labeled infusion  


PROTOCOL 9189 
 
 
Page 14 of 43 
 
Day 
Event 
 
90Y-DOTA-biotin therapeutic infusion 
Gamma Camera Imaging 
-14 -7 
 Gamma Camera Imaging 
-7 
BEAM Chemotherapy 
0 
PBSC infusion 
*   Following the infusion of radiobiotin, the remainder of the treatment will be considered standard of care and can be 
adjusted as per standard of care at the discretion of the treating provider. The exact dates of the gamma scans can be 
adjusted +/- 3 days based on the patient schedule and the guidance of the nuclear medicine team for that given patient. 
  
**  CA may be given up to 3 days after B9E9-FP if needed due to scheduling or clinical reasons and all other days will need 
to be shifted accordingly.  
 
 
FIGURE 5: Study Schema 
 
 
8.2 
Investigational Product Dosing 
Doses of the investigational reagents should be as follows: 
 
B9E9-FP: 160 mg/m2 
 
CA: 100 mg 
 
DOTA-biotin: 1.3 mg/m2 
 
In-111: 10+/-5 mCi 
 
Y-90: (see dose escalation schema in Table 2) 
 
 


PROTOCOL 9189 
 
 
Page 15 of 43 
 
TABLE 2: Dose Levels to be Used (See 15.2 for further explanation of dose escalation): 
Dose 
level 
B9E9-FP 
(mg/m2) 
Clearing Agent 
(mg) 
DOTA-biotin 
(mg/m2) 
In-111 
(mCi) 
Y-90 
(mCi/m2) 
1 
160 
100 
1.3 
~10 
30 
2 
160 
100 
1.3 
~10 
40 
3 
160 
100 
1.3 
~10 
50 
4 
160 
100 
1.3 
~10 
60 
5 
160 
100 
1.3 
~10 
70 
6 
160 
100 
1.3 
~10 
80 
7 
160 
100 
1.3 
~10 
90 
8 
160 
100 
1.3 
~10 
100 
9 
160 
100 
1.3 
~10 
110 
10 
160 
100 
1.3 
~10 
120 
11 
160 
100 
1.3 
~10 
130 
12 
160 
100 
1.3 
~10 
140 
8.3 
Peripheral Blood Stem Cell Collection  
Peripheral blood stem cell collection is not part of this protocol, however, prior to the B9E9-FP infusion, 
peripheral blood stem cells (PBSC) will need to be collected by serial leukaphereses per standard of care. 
8.4 
Investigation Product Administration 
8.4.1 
B9E9-FP infusion 
 
 
Premedications:  Premedications are not required for B9E9-FP infusion based on prior experience 
utilizing this agent without premedications. However, standard premeds may be used at the 
discretion of the treating team.  
 
Vital signs: Vital signs should be obtained prior to infusion, at the completion of the infusion, and as 
clinically needed during the infusion. 
 
Infusion rate: B9E9-FP will be infused at a dose of 160 mg/m2 IV over a minimum of 2 hours. 
8.4.2 
Clearing Agent Infusion 
 
Premedications: Premedications are not required for the CA infusion based on prior experience 
utilizing this agent without premedications. However, standard premeds may be used at the 
discretion of the treating team. 
 
Vital signs: Vital signs should be obtained prior to infusion, at the completion of the infusion, and as 
clinically needed during the infusion. 
 
Infusion rate: The clearing agent will be administered at a dose of 100 mg over a minimum of 30 
minutes.  
8.4.3 
Radiolabeled DOTA-biotin infusion 
 
IV Fluids, pre and post radiolabeled DOTA-biotin infusion: IV hydration of physician/provider’s 
choice at ≥ 200 ml/hr starting prior to the infusion, continuing throughout the radiolabeled DOTA-
biotin infusion, and post infusion for a total volume as clinically indicated. 


PROTOCOL 9189 
 
 
Page 16 of 43 
 
 
Premedications: Premedications are not required for the radiolabeled DOTA-biotin infusion based 
on prior experience utilizing this agent without premedications. However, standard premeds may be 
used at the discretion of the treating team. 
 
Vital signs: Vital signs will be obtained prior to administration and afterwards and as clinically 
needed thereafter.   
 
Infusion rate: DOTA-biotin will be administered at a total dose of approximately 1.3 mg/m2. The 
radiolabeled (111In/90Y)-DOTA-biotin infusions may be administered concurrently over 2 to 5 minutes 
or serially over 2 to 5 minutes each. All appropriate shielding and radiation safety precautions will 
be followed during the administration.   
 
Inpatient hospital admission: Patients may be admitted for up to 3 days (more typically 1 day) as 
inpatients at University of Washington Medical Center (UWMC) for monitoring or longer if clinically 
required. 
8.4.4 
Management of Toxicities 
Management of infusion reactions following any of the investigational agents are outlined in Table 3  
TABLE 3: Management of Infusion Related Reactions/ Infusion Related Adverse Events 
Infusion Reaction 
Suggested Medication 
Fever 
Acetaminophen 650 mg PO every 4 hours PRN 
Rigors 
Meperidine ≤ 25-50 mg IV every 2-4 hours PRN 
Pruritus 
Diphenhydramine ≤ 25 mg every 2 hours or ≤50 mg every 4 hours PO or IV 
PRN 
Nausea 
Lorazepam 0.5-2 mg IV every 4 hours PRN 
Diphenhydramine ≤ 25 mg every 2 hours or ≤ 50 mg every 4 hours IV PRN 
Prochlorperazine ≤ 5-10 mg IV/PO every 4 hours PRN 
Ondansetron 8 mg IV every 8 hours PRN  
Cough, chest, or throat tightness or wheezing 
Diphenhydramine ≤ 25 mg every 2 hours or ≤ 50 mg every 4 hours IV or 
PO PRN  
Hydrocortisone 100 mg IV every 2 hours PRN 
Albuterol by nebulizer 2.5–5 mg up to every 1 hours PRN 
Low blood pressure 
Up to 500 ml Normal Saline Bolus given IV over 30 min.  May repeat x 1 
PRN 
Hypoxemia 
Supplemental oxygen PRN to keep Oxygen saturation within normal limits 
Anaphylaxis 
Cessation of investigational product and alert the Code Team or Rapid 
Response Team or patient’s inpatient team for additional orders 
8.5 
Assessment of B9E9-FP Levels 
Blood levels of B9E9-FP will be assessed at specified time points (see Section 8.7.1) post infusion to 
confirm a decrease of at least 50% concentration from completion of infusion before administration of 


PROTOCOL 9189 
 
 
Page 17 of 43 
 
radiolabeled DOTA-biotin.  This demonstration of clearance from the circulation will provide assurance 
that the majority of the radiolabeled DOTA-biotin will clear the bloodstream rapidly as it homes to the 
B9E9-FP, thereby supporting the goal of limiting radiation exposure throughout the circulation.    
8.6 
Quantitative Biodosimetry 
In order to estimate the localization of radioisotopes to normal organs and tumor sites to potentially 
correlate with antitumor response and toxicity planar gamma camera imaging and optional SPECT/CT 
and PET/CT imaging as previously published. OLINDA dosimetry software will be utilized for internal 
dosimetry estimation.61 Gamma scans will be done at the following time points: prior to infusion 
(attenuation), immediately following infusion, and up to 4 additional time points over the following 7 
days. Optional core bone marrow (at 24-48 hours) and lymph node biopsies (at 48-96 hours) can occur 
over this time frame to further refine absorbed dose estimates to these sites.   
8.7 
Pharmacokinetic (PK) Sample Collection 
The following PK samples will be obtained from a minimum of three patients: 
8.7.1 
B9E9-FP PK samples 
Blood: 2-5 cc in purple top tubes taken immediately post B9E9-FP infusion, immediately prior to CA 
infusion, immediately post CA infusion, and immediately prior to radiolabeled DOTA-biotin infusion. 
8.7.2 
Radiolabeled DOTA-biotin PK samples 
Blood: 2-5 cc in purple top tubes taken prior to treatment, and then after treatment at approximately 15 
and 30 minutes, and approximately 2, 4, 8, 24, 48 and 72 hours (some variation in time points is 
allowable due to logistics of patient visits and sample collection in the collection of up to 8 PK blood 
sample post infusion). 
Urine: may be collected as 24-hour samples by taking aliquots from total volume of first void after 
treatment, next void-24 hours, 24-48 hours, and 48-72 hours; or may be collected as aliquots from 
individual voids during the first 3 days following infusion. 
8.8 
BEAM Chemotherapy 


PROTOCOL 9189 
 
 
Page 18 of 43 
 
Approximately 7 days after the radiobiotin infusion, BEAM chemotherapy will be initiated according to 
Seattle Cancer Care Alliance (SCCA)’s standard pharmacy guidelines.  In general, BEAM will be given as 
per Table 4, but doses of individual agents may be adjusted at the discretion of the attending physician 
as per standard of care.  *If at any time the SCCA develops Standard Practice Guidelines for BEAM, then 
this protocol’s administration schedule and dosage will change to concur with the SCCA Guidelines. 
 
BCNU (Carmustine): administered on day -7.  Dose: 300 mg/m2 IV  in D5W 250 ml over 3 hours (one 
day only)  
 
Etoposide (VP-16, Vepesid): administered on days -6, -5, -4 & -3.  Dose: 100 mg/m2 IV in D5W per 
Pharmacy standard over 2 hours BID x 4 days (or 200 mg/m2 total daily dose x 4 days) 
 
Ara-C (Cytarabine): administered on days -6, -5, -4 & -3.  Dose: 100 mg/m2 IV in D5W 250 ml over 4 
hours BID x 4 days (or 200 mg/m2 total daily dose x 4 days) 
 
Melphalan: administered on day -2.  Dose: 140 mg/m2 IV in NS 250 ml over 30 minutes (one day 
only) 
 
TABLE 4: BEAM Treatment Schedule 
Medication 
Day 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
BCNU (300 mg/m2 IV x 1 d) 
X 
 
 
 
 
 
 
 
Etoposide (100 mg/m2 IV BID x 4 days or 200 mg/m2 total 
daily dose x 4 days) 
 
X 
X 
X 
X 
 
 
 
Ara-C (100 mg/m2 IV BID x 4 days or 200 mg/m2 total daily 
dose x 4 days) 
 
X 
X 
X 
X 
 
 
 
Melphalan (140 mg/m2 IV x 1 day) 
 
 
 
 
 
X 
 
 
Day of REST (optional- see Section 8.9) 
 
 
 
 
 
 
X 
 
Autologous Stem Cell Infusion 
 
 
 
 
 
 
 
X 
NOTE: The above dates are to be used as a general timeframe.  The precise days of initiation for BEAM 
relative to the date of stem cell infusion can be adjusted +/- 1 day if necessary to accommodate 
clinic/hospital scheduling. 
 
8.9 
Stem Cell Infusion 
PBSC will be thawed and infused per standard practice approximately 14 days after the 90Y therapy dose. 
*Stem cells should not be infused within 24 hours of melphalan infusion if a day of rest is not taken 
(Table 4). 
8.10 
Adjunctive Therapy 
Adjunctive therapy will follow standard practice guidelines. 


PROTOCOL 9189 
 
 
Page 19 of 43 
 
8.11 
Criteria for Removal from Protocol Treatment 
Patients will be removed from protocol treatment for the following reasons: 
 
Patient request 
 
Unacceptable toxicity 
 
Treating physician or investigator request to prevent unacceptable risk to the patient. 
9.0 
EVALUATIONS 
9.1 
Pre-transplant Evaluations 
Patients will undergo a pre-transplant work-up as per standard practice for patients undergoing 
autologous transplantation, including standard clinical staging assessments for lymphoma (e.g., CT scans 
of chest, abdomen, and pelvis, and neck at the discretion of treating MD or investigator; PET-CT within 
56 days prior to treatment is strongly recommended for patients with aggressive B-NHL; bone marrow 
biopsy if indicated; etc.), and standard clinical workup for transplant including pulmonary function 
testing and assessment of cardiac ejection fraction (usually by echocardiogram or MUGA scan, 
performed commonly per standard practice but not required in all instances). In addition, the following 
assessments will be performed: 
 
Testing for presence of HAMA and HASA 
 
Serum rituximab level will be measured at baseline (prior to any study-related treatment) to 
evaluate the potential impact of the presence of rituximab on CD20 targeting. 
 
Measurement of organ volumes (obtained from imaging studies used for pre-transplant staging) for 
purposes of dosimetry when possible. 
 
Tumor volumes may be measured when possible from pre-transplant imaging.  
9.2 
Post-transplant Evaluations 
Patients will routinely be followed within the general institutional guidelines and based on the patient’s 
clinical condition. Common follow-up guidelines used when patients are followed on an outpatient basis 
until engraftment are summarized in Table 5 below. All hospitalized patients have daily clinical 
assessments.  Initial response assessments will be conducted approximately 1 month post-transplant as 
described below. 
TABLE 5: General Post-transplant Outpatient Monitoring Guidelines 
Assessment 
Interval 
When ANC<500 or PLT<20 
When ANC≥500 and PLT≥20K 
CBC 
Daily 
Weekly 
Electrolytes 
Weekly 
Weekly 
Liver Function Tests 
Weekly 
Weekly 
Clinical assessment 
Weekly 
Weekly 
9.3 
Definitions 


PROTOCOL 9189 
 
 
Page 20 of 43 
 
 
Measurable Disease: Bidimensionally measurable lesions with clearly defined margins by physical 
examination (e.g., adenopathy), plain x-ray with one diameter 0.5 cm or greater, or CT/MRI (both 
diameters must be greater that the distance between the cuts of the imaging study). 
 
 
Evaluable Disease: Unidimensional measurable lesions, masses with margins not clearly defined, 
lesion with both diameters less than 0.5 cm, or lesions on scans with both diameters smaller than 
the distance between cuts. 
 
 
Non-Evaluable Disease: Pleural effusions, ascites, or disease documented only by indirect evidence 
(e.g., by lab values). 
9.4 
Measurement of Response   
Response will be interpreted by investigator review of radiographic findings along with MD assessed 
physical findings and bone marrow or blood reports and will follow the revised lymphoma response 
criteria established by an international working group.62  Disease response is not a primary endpoint in 
this dose-finding study; however, response will be assessed using standard criteria. 
9.5 
Long-term Evaluations 
After the primary endpoint is reached for each patient (Day 30 toxicity) patients will be followed 
primarily for serious adverse events/toxicity, disease progression and survival.  Patients with progressive 
disease will only be followed for survival and development of myelodysplasia or secondary malignancies. 
Follow-up evaluations (outlined in Appendix 2) will be within the standard of care for lymphoma 
patients following transplant. Data and samples provided by outside locations will be accepted for study 
evaluation purposes, and the Principal Investigator will continue to assess disease response objectively 
based on the data received. In addition we will specifically request renal function (BUN, creatinine) and 
hepatic function (transaminases, bilirubin, alkaline phosphatase) for all patients until 5 years after 
transplant or until the initiation of additional anti-neoplastic therapy. We will request these laboratory 
data approximately every three months for the first year, then every 6 months through the second year 
then annually through 5 years. 
10.0 TOXICITIES AND COMPLICATIONS 
1) Toxicity attributable to foreign mouse proteins 
Allergic reactions to administration of foreign mouse proteins may include fever, urticaria, 
bronchospasm, anaphylaxis, Arthus reaction, vasculitis and serum sickness.  In addition, infusion of 
foreign mouse proteins may produce pulmonary, renal or hepatic toxicity as a result of lysis or 
agglutination of circulating cells.  Management of infusion toxicities are described in Table 3.  
2) Radiation Toxicity:   
Severe bone marrow suppression was expected during the course of 90Y dose escalation.  It is 
anticipated that bone marrow suppression will occur 7-14 days after radiobiotin infusion, but will be 
rescued by the planned stem cell transplantation.  Other organs that may receive significant radiation 


PROTOCOL 9189 
 
 
Page 21 of 43 
 
doses and thus experience toxicity include liver, lung, gastrointestinal tract, kidney and thyroid.  Late 
effects of radiation may include hypothyroidism, pulmonary fibrosis, cataracts, renal insufficiency, 
growth retardation, sterility and carcinogenesis.  
3) BEAM Toxicity: 
BCNU (Carmustine) – a nitrosourea derivative/alkylating agent: 
Adverse Effects: The most serious and frequent adverse effect is delayed hematologic toxicity, which is 
cumulative and usually occurs weeks after administration.  Nausea and vomiting occur frequently after 
IV administration.  Pulmonary toxicity, which can be rapidly progressive and fatal, is characterized by 
pulmonary infiltrates and hypoxia.  Most of the cases have occurred in patients receiving total doses 
exceeding 1400 mg/m2, although pulmonary fibrosis has occurred with lower total doses.  
Hepatotoxicity (reported in up to 26% of patients) is generally mild and reversible.  Progressive azotemia 
and renal failure have occurred in patients who have received large cumulative doses, and occasionally 
in patients after lower doses. 
 
Etoposide (VP-16, Vepesid) – a semi-synthetic podophyllotoxin: 
Adverse Effects: Reversible myelotoxicity has been uniformly observed to be the major toxicity of 
Etoposide and represents the only clinically significant side effect.  Transient, modest nausea, usually 
without vomiting, is common.  Occasional alopecia is reported, as well as occasional hypotension, 
anaphylaxis or fever. 
 
Ara-C (Cytarabine) – a synthetic pyrimidine nucleoside and pyrimidine antagonist antimetabolite: 
Adverse Effects: The major adverse event is myelosuppression.  Nausea and vomiting may occur more 
frequently in patients receiving rapid IV infusion of the drug.  Other reported adverse effects include 
fever, rash, alopecia, skin ulceration, conjunctivitis, chest pain, urinary retention, renal dysfunction, 
dizziness, somnolence, neuritis or neurotoxicity, and reactions at the injection site including pain, 
inflammation, thrombophlebitis, or cellulitis.  A cytarabine syndrome manifested as fever, myalgia, bone 
pain, maculopapular rash, conjunctivitis, malaise and occasionally chest pain has been reported.  If 
symptoms of the syndrome require treatment, administration of corticosteroids should be considered. 
 
Melphalan (L-phenylalanine mustard) – an alkylating agent: 
Adverse Effects: The most common side effect is bone marrow suppression. Gastrointestinal 
disturbances such as nausea, vomiting, diarrhea and oral ulceration occur infrequently. Other reported 
adverse reactions include pulmonary fibrosis and interstitial pneumonitis, skin hypersensitivity, 
vasculitis, alopecia, hemolytic anemia and allergic reaction. 
 


PROTOCOL 9189 
 
 
Page 22 of 43 
 
4) Transplant related toxicities: 
It is expected that patients will frequently require admission during the first 30 days post-transplant for 
transplant-related toxicities, often due to neutropenic fever, infections, or mucositis causing severe pain 
and/or interfering with food and fluid intake.  
11.0 PROTOCOL ENROLLMENT AND SPECIAL CONSIDERATIONS 
 
All patients will require placement of a double lumen central venous catheter prior to the 
therapeutic infusion; for the biodistribution infusion, alternative devices (e.g., peripherally-inserted 
central catheter [PICC] or port) are permitted.  
 
All blood and tissue samples containing radioisotopes should be clearly identified as such.  Samples 
containing high levels of activity (>50 µCi) should be transported in appropriate containers.  All 
samples should be processed by personnel trained in the use of radioisotopes and sample volumes 
submitted to clinical laboratories will be as small as possible. 
 
Potential alternative therapies will be discussed with all patients including observation alone, 
conventional chemotherapy and radiation therapy, and marrow transplantation with conventional 
conditioning regimens for which the patients are eligible. 
 
Neither gender nor ethnicity is criteria for enrollment on this study.  Based on previous enrollment 
experience at FHCRC/UW the expected gender and ethnicity distribution is shown in Table 6. 
TABLE 6: Projected Target Accrual/Ethnic and Gender Distribution Chart 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
17 
24 
41 
Ethnic Category: Total of All Subjects * 
18 
26 
44 
Racial Categories 
American Indian/Alaska Native 
0 
1 
1 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander  
1 
1 
2 
Black or African American  
1 
1 
2 
White 
15 
22 
37 
Racial Categories: Total of All Subjects * 
18 
26 
44 
12.0 ADVERSE EVENT REPORTING 
12.1 
Adverse Event Definitions 
 
Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product; the event does not necessarily have a causal relationship with 


PROTOCOL 9189 
 
 
Page 23 of 43 
 
study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
 
Serious Adverse Event  
A serious adverse event (SAE) is defined as an untoward medical occurrence that results in any of 
the following outcomes: 
o Death. 
o Life-threatening situation (i.e., with an immediate risk of death from the event as it occurred but 
not including an event that, had it occurred in a more serious form, might have caused death). 
o In-patient hospitalization or prolongation of existing hospitalization. Inpatient hospitalization 
comprises formal admission to a hospital for medical reasons, for any length of time, whether or 
not hospitalization extends overnight. However, hospital admissions for administration of the 
study drug, procedures required by the study protocol, or tumor-related diagnostic procedures 
are not considered serious. 
o Persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
normal life functions. 
o Congenital anomaly/birth defect. 
o An important medical event that requires intervention to prevent one of the above outcomes. 
 
Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or frequency that 
is not consistent with the applicable investigator brochure.  “Unexpected,” as used in this definition, 
refers to an adverse drug experience that has not been previously observed and reported rather 
than an experience that has not been anticipated based on the pharmacological properties of the 
study drug. 
12.2 
Monitoring and Recordings AEs 
All adverse events will be assessed by the investigator or qualified designee and recorded in the CRFs. 
The investigator should attempt to establish a diagnosis of the event on the basis of signs, symptoms 
and/or other clinical information. In such cases, the diagnosis should be documented as the adverse 
event and/or serious adverse event and not described as the individual signs or symptoms. The 
following information should be recorded: 
 
Description of the adverse event using concise medical terminology 
 
Description as to whether or not the adverse event is serious  
 
The start date (date of adverse event onset) 
 
The stop date (date of adverse event resolution) 
 
The severity (grade) of the adverse event  
 
A description of the potential relatedness of the adverse event to study drug or a study procedure  
 
The action taken due to the adverse event 
 
The outcome of the adverse event. 
 


PROTOCOL 9189 
 
 
Page 24 of 43 
 
12.3 
Grading of the Severity of an Adverse Event 
All AEs will be graded in severity according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). If a CTCAE criterion does not exist, 
the investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life-threatening), or Grade 5 (fatal) to describe the maximum intensity of the adverse 
event. However, the Bearman Scale of Regimen-Related Toxicity will be used for decisions regarding 
dose escalation/ de-escalation and invocation of stopping rules.   
 
12.4 
Attribution of Adverse Event 
Association or relatedness to the study agent will be assessed by the investigator as follows: 
• 
Definite:  The event follows a reasonable temporal sequence from exposure to the investigational 
agent, has been previously described in association with the investigational agent, and cannot 
reasonably be attributed to other factors such as the patient’s clinical state, other therapeutic 
interventions or concomitant medications; AND the event disappears or improves with withdrawal 
of the investigational agent and/or re-appears on re-exposure (e.g., in the event of an infusion 
reaction). 
• 
Probable:  The event follows a reasonable temporal sequence from exposure to the investigational 
agent and has been previously been described in association with the investigational agent OR 
cannot reasonably be attributed to other factors such as the patient’s clinical state, other 
therapeutic interventions or concomitant medications. 
• 
Possible:  The event follows a reasonable temporal sequence from exposure to the investigational 
agent, but could be attributable to other factors such as the patient’s clinical state, other 
therapeutic interventions or concomitant medications. 
• 
Unlikely:  Toxicity is doubtfully related to the investigational agent(s).  The event may be attributable 
to other factors such as the patient’s clinical state, other therapeutic interventions or concomitant 
medications. 
• 
Unrelated:  The event is clearly related to other factors such as the patient’s clinical state, other 
therapeutic interventions or concomitant medications. 
 
For general AE assessment, an AE is considered related if it is assessed as definitely, probably, or 
possibly related; unrelated if it is assessed as unlikely related or unrelated. For determination of IND 
safety reporting, AE attribution will be assessed according to the suspected adverse reaction definition 
described in 21 CFR 312.32 as an AE for which there is a reasonable possibility that the drug caused the 
adverse event where “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the AE. Suspected adverse reactions that are both serious and unexpected will be 
reported to the FDA as an IND safety report, in accordance with regulations under 21 CFR 312.32. 
12.5 
Adverse Event Reporting Period 
AEs will be monitored and recorded in study-specific case report forms (CRFs). From the time of first 
exposure to an investigational agent (i.e., the start of the B9E9-FP infusion) through the start of BEAM 


PROTOCOL 9189 
 
 
Page 25 of 43 
 
chemotherapy treatment all SAEs and all grades of adverse events will be captured. From the start of 
BEAM chemotherapy through day +30 post-transplant non-hematologic adverse events of ≥ grade 3, 
and all serious adverse events will be captured.  Beyond day +30 after transplant/discharge from the 
transplant service until day +100, only SAEs and grade 4 and 5 toxicities will be collected.  Beyond day 
+100, disease progression, development of myelodysplasia or secondary malignancies, and survival only 
will be collected. AEs with an onset date prior to the first exposure to an investigational product will not 
be recorded, except in the case of clinically significant worsening of the AE during the specified 
monitoring time frame. A subject withdrawn from the study because of an adverse event must be 
followed until the clinical outcome from the adverse event is determined.  
 
The following events are not identified as AEs in this study: 
 
Disease progression or relapse.  However, clinical events associated with progression/relapse may 
be reportable as AEs. 
 
Hospitalization for the purpose of facilitating stem cell transplant is not considered an AE.  Any AE 
requiring prolongation of this hospitalization will be recorded and subject to applicable SAE 
reporting. 
 
Medical or surgical procedures in and of themselves, including those that require hospitalization 
(e.g., surgery, endoscopy, biopsy procedures) are not considered AEs.  However, an event or 
condition requiring such procedures may be an AE. 
12.6 
Adverse Event Reporting Requirements 
12.6.1 Research Site Reporting Requirements 
Classification of an event as serious or non-serious (see Section 12.1) determines the reporting 
procedures to be followed by the site for reporting the event to the Sponsor which are outlined in Table 
7. The investigator must report events to the Fred Hutch IRB in accordance with the policies of the IRB. 
TABLE 7: Site to Sponsor Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Contact Information 
Serious 
Adverse 
Event (SAE) 
Fatal or life-
threatening 
Within 24 hours of research 
team awareness 
Email notification to 
Sponsor’s Medical Monitor & 
ISIOC Administrator 
Medical Monitor email: 
tillb@fredhutch.org 
ISIOC email: 
ISIOC@fredhutch.org 
All SAEs 
Within 2 business days of 
research team awareness 
Submit completed 
Institution-Sponsored IND 
SAE Reporting Form signed 
by PI or designated sub-
Investigator 
ISIOC Fax: 
206-667-6068 
ISIOC email: 
ISIOC@fredhutch.org 
Non-serious Adverse Event 
Per CRF completion 
guidelines 
Record information on 
appropriate CRFs 
N/A 
*Research team is defined as the individuals listed on the delegation of authority log. Physicians listed on the study’s delegation 
of authority log as transplant service attending physicians delegated authority to administer informed consent will not be 
considered part of the research team unless additional responsibilities related to the conduct of the study have been delegated 
to them by the Principal Investigator.  


PROTOCOL 9189 
 
 
Page 26 of 43 
 
The information in the Institution-Sponsored IND SAE Reporting Form must match or be reconciled with 
the information recorded in the adverse events section of the CRF and study database. For example, the 
same adverse event term should be used on both forms. 
The investigator must report events to the Fred Hutch IRB in accordance with the policies of the IRB. The 
sponsor assumes responsibility for IND safety reporting to the FDA and participating investigators, in 
accordance with regulations under 21 CFR 312.32.  
12.6.2 Fred Hutch Sponsor Reporting Requirements 
The sponsor assumes responsibility for IND safety reporting to the FDA and participating investigators, in 
accordance with regulations under 21 CFR 312.32. 
Each serious adverse event report received from the investigator will be evaluated by the Medical 
Monitor who will assess the seriousness of the event (see Section 12.1), the expectedness of the event 
(see Section 12.1), and the relationship to participation in the study (see Section 12.4). For regulatory 
reporting purposes, the Sponsor will determine expectedness relating to the investigational product 
using safety information specified in the Investigator Brochure. An event will be classified as related if 
either the investigator or the Sponsor determines that the event may be related to the study drug. 
 
The Sponsor or its designee will provide all investigators with a safety letter notifying them of an event 
that meets FDA IND Safety Reporting criteria. Investigators will be requested to provide written 
notification of safety report to the Fred Hutch IRB as soon as is practical, consistent with IRB 
requirements. 
12.7 
SAEs Commonly Associated with ASCT 
Certain events that are commonly observed as SAEs following ASCT are outlined in Table 8. SAEs that 
are identified as routinely experienced in the autologous transplant setting will be assessed as unrelated 
to the radioimmunotherapy regimen used in this protocol.  All of the SAEs listed in Table 8 will 
nevertheless be collected and graded.  
TABLE 8: SAEs Commonly Observed Following Autologous Stem Cell Transplant 
CTCAE Category 
Toxicity 
Blood and lymphatic system 
disorders 
As noted above, all patients undergoing HCT are expected to have ≤ Grade 4 
pancytopenia as an intended therapeutic effect.  These hematologic adverse events will 
be tracked and recorded only as time to recovery of blood counts/engraftment. 
Febrile neutropenia 
General disorders and 
administration site conditions 
Fatigue 
Fever 
Rigors, chills 
Gastrointestinal 
Diarrhea 
Dysphagia 
Esophagitis 
Mucositis/Stomatitis 
Nausea 
Vomiting 
Hemorrhage/Bleeding 
Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia 


PROTOCOL 9189 
 
 
Page 27 of 43 
 
CTCAE Category 
Toxicity 
Infections and infestations 
Infections may be associated with neutropenia following HCT 
Metabolism and nutrition 
disorders 
Anorexia 
Dehydration 
Hypokalemia (e.g., potassium < 2.5 can result from wasting induced by HCT related 
medications) 
Reproductive system and 
breast disorders 
Reproductive system and breast disorders – Other: Sterility/infertility 
 
13.0 DATA AND SAFETY MONITORING  
This is a single institution trial where all patients are followed closely by the investigators.  Additionally, 
the trial design provides rules for dose escalation depending upon the rate of development of Grade 
III/IV RRT (Bearman Scale).  This design mandates ongoing review of the outcome of previous patients 
treated on study so that the appropriate Dose Level for the current patient can be assigned. The 
principal investigator, primary research nurse, and study data communicate routinely (typically weekly) 
to review recently acquired data, stopping rules, and adverse events.  The data recorded within the 
research charts and protocol database is compared with the actual data that is available from the 
medical record and/or clinical histories.  Data detailed in the research case report forms includes the 
nature and severity of all significant toxicities, which are also reported as described above.  All 
investigators on the protocol have received formal training in the ethical conduct of human research.  
Institutional support of trial monitoring will be in accordance with the FHCRC/University of Washington 
Cancer Consortium Institutional Data and Safety Monitoring Plan (DSMP).  Under the provisions of this 
plan, FHCRC Clinical Research Support coordinates data and compliance monitoring conducted by 
consultants, contract research organizations, or FHCRC employees unaffiliated with the conduct of the 
study.  Independent monitoring visits occur at specified intervals determined by the assessed risk level 
of the study and the findings of previous visits per the institutional DSMP.  
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety 
Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the FHCRC/University of 
Washington Cancer Consortium Institutional Review Board (IRB).  The review committees evaluate 
accrual, adverse events, stopping rules, and adherence to the applicable data and safety monitoring plan 
for studies actively enrolling or treating patients.  The IRB reviews the study progress and safety 
information to assess continued acceptability of the risk-benefit ratio for human subjects.  Approval of 
committees as applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and other 
institutional, state and federal guidelines. 
14.0 DATA MANAGEMENT/CONFIDENTIALITY 
The investigator will ensure that data collected conform to all established guidelines. Each subject is 
assigned a unique subject number to assure subject confidentiality. Subjects will not be referred to by 


PROTOCOL 9189 
 
 
Page 28 of 43 
 
this number, by name, or by any other individual identifier in any publication or external presentation. 
The licensed medical records department, affiliated with the institution where the subject receives 
medical care, maintains all original inpatient and outpatient chart documents. Additional clinical data 
may be made available from the Fred Hutch core database (Gateway), which is managed and verified 
independent of the research group.   
The research team will maintain Case Report Forms (CRF) and associated research documentation for 
each patient treated under the protocol.  This documentation includes both clinical data and study-
specific documents for each patient.  Additional study-specific documents and radiologic data are 
maintained by the UW Division of Nuclear Medicine.  The Principal Investigator or a designee will verify 
completed CRFs against source documentation on an ongoing basis as they are completed for individual 
patients.  CRFs should be complete and data entered into the study database within 120 days of 
transplant. Data required for analysis of patients treated on this protocol will be maintained in a 
password-protected study-specific database. Data from the CRFs are keyed directly into the database by 
authorized research staff and verified on an ongoing basis.   
15.0 STATISTICAL CONSIDERATIONS 
15.1 
Randomization/Stratification/Descriptive Factors 
1) Randomization-none 
2) Stratification-none 
3) Descriptive factors- Histological subtype by WHO classification should be supplied. Patients will be 
classified as chemo-responsive if they achieve at least a partial response with their most recent 
chemotherapy (e.g., cytoreductive or mobilization chemotherapy). Patients that have never 
achieved at least a PR will be categorized as primary refractory. Other patients will be categorized as 
chemo-resistant (i.e., patients that have previously achieved at least a PR, but have not responded 
to their most recent chemotherapy) .Patients’ disease stage should be recorded both at the time of 
diagnosis and the time of treatment. International Prognostic Index (IPI) or Follicular Lymphoma 
International Prognostic Index (FLIPI) score, as appropriate, will be calculated and recorded directly 
on case report forms.63, 64 
15.2 
90Y-DOTA-biotin dose escalation 
The primary objective of this study is to estimate the MTD of 90Y-biotin that can be delivered in a pre-
targeted fashion prior to BEAM chemotherapy and ASCT in patients with relapsed/refractory lymphoma. The 
MTD is defined as the dose that is associated with a true dose-limiting toxicity (DLT) rate of 25%, where a 
DLT is defined as a grade III or IV Bearman (transplant) toxicity within 30 days of transplant 65. Dose 
escalation/de-escalation will be conducted by a modification of the “two-stage” approach introduced by 
Storer 66. The starting dose level will be level 1 (30 mCi/m2). In the first stage, up to two patients will be 
treated at escalating doses in 20 mCi/m2 increments (Table 2) until a DLT is observed. Once a DLT is 
observed, the second stage will begin at the next lower dose level and patients will be treated in cohorts of 


PROTOCOL 9189 
 
 
Page 29 of 43 
 
4 with 10 mCi/m2 increments according to the following rules (if the first of the two patients has a DLT, the 
second patient will not be treated at this dose and the second stage will commence at the next lower dose 
level). If no DLT is observed in a cohort of 4 the next cohort will be treated at a dose that is one dose level 
higher; if 1 of 4 experiences a DLT the next group will be treated at the same dose; if 2 DLTs are seen among 
4 (or fewer) in a cohort, the next group of 4 will be treated at a dose that is  one dose level lower, and no 
further testing will be done with the dose at which 2 DLTs were observed. This algorithm will continue until 
24 patients are treated in the second stage. Following the completed observation of the final patient, a two-
parameter logistic model will be fit to the data, thereby generating a dose-toxicity curve based on the 
observed DLT rate at the various dose levels visited.  Based on this fitted model, the MTD is estimated to be 
the dose that is associated with a DLT rate of 25%.  
It is possible that a patient will be entered on the protocol before the prior patient (in the first stage) or all 
patients in a cohort (in the second stage) have been followed sufficiently long to evaluate toxicity.  Such 
patients will be treated at the current dose level and will be used for purposes of fitting the dose-toxicity 
curve.  These patients will not be used for purposes of dose-modification, however, nor will they be counted 
towards the total of 24 patients on the second stage for completion of the dose-adjustment phase of the 
trial. A maximum of 2 additional patients may be added to a given dose level while the initial patients are 
completing the DLT period. It is important to note that the overall sample size of this trial cannot be 
completely predicted as this will be determined by observed DLTs and timing of accruals. 
15.3 
Evaluation of Efficacy 
After completing sufficient enrollment to estimate the MTD of this approach, patients will be enrolled into a 
second cohort to evaluate its efficacy in terms of overall response rate, overall survival, and progression-free 
survival (PFS).  A secondary endpoint of this study will be to estimate the rate of PFS at 1 year from ASCT 
when conditioned with pretargeted 90Y-biotin + BEAM, which we will compare to a historical control.  This 
study will not necessarily exclude patients that are traditionally felt to have poor outcomes from standard 
myeloablative conditioning (e.g., DLBCL failing to achieve remission after first salvage) .5,67  Furthermore, this 
study will enroll a variety of B-NHL histologies.  Thus, finding an accurate comparison to use as a historical 
control is challenging.  Based on other reports, we will use the following benchmarks for 1-year PFS for each 
of these unfavorable-risk subgroups: for example, 10% for DLBCL that relapsed within 1 year of diagnosis 
(following a rituximab-based induction regimen); 30% for relapsed/refractory MYC+ DLBCL; 60% for 
rituximab-refractory FL. We’ll assume that our proposed treatment will have roughly the same impact across 
these various histologies, and the ultimate benchmark that we’ll use to assess potential efficacy will be a 
weighted average of these individual benchmarks, with the weights derived from the proportion of patients 
with each histology enrolled on the trial.  For the current purposes, we’ll assume that the overall benchmark 
to be used will be 30%.  If the true 1-year PFS rate using the proposed approach is 54%, then 24 patients will 
provide 80% power to detect a statistically significant increased rate of PFS from the fixed rate of 30%, 
based on a one-sample chi-square test with one-sided significance level of 5%.  We will include patients who 
were treated at the MTD in the dose-adjustment phase of the trial in this efficacy sample.  Thus, the number 
of patients to be enrolled in this phase of the trial will be 24-n, where n is the number treated at the MTD in 
the Phase 1 portion of the trial. 


PROTOCOL 9189 
 
 
Page 30 of 43 
 
Based on current referral patterns, dose escalation/de-escalation rules, and competing protocols, we 
anticipate entering 1 patient per month to this phase I protocol which we project will take up to 4 years 
to complete.  Secondary endpoints will include descriptive statistics on the number and percent 
toxicities and responses will be calculated.   
15.4 
Estimation of Dosimetry  
We will also describe the estimated dose to normal organs and tumor sites based on the tumor to normal 
organ ratios derived from dosimetry estimates coupled with the absorbed dose to normal organs based on 
the administered activity of 90Y. This evaluation will be made among all patients and among those treated at 
the estimated MTD. 
15.5 
Stopping Rules 
Since the patients enrolled on this trial would be expected to have a poor outcome from a standard 
autologous transplant, we will accept a progression rate of up to 80% of patients experiencing 
progression at day 30 following transplantation.  If the observed progression rate exceeds 80% by day 30 
after transplant, the study will be suspended for lack of efficacy, pending a detailed review by an ad hoc 
safety committee comprised of individuals with appropriate clinical and research expertise who are 
independent of this research program, and/or by the Fred Hutch/UW Cancer Consortium Data and 
Safety Monitoring Committee (DSMC).  In addition, rules will be in place for suspending the study due to 
an excess of late toxicities, as defined by grade III/IV Bearman toxicity that occurs prior to progressive 
disease or additional antineoplastic therapy.  If there is ever sufficient evidence to suggest that the true 
probability of late toxicity exceeds 25%, then the study will be suspended pending review by an ad hoc 
safety committee or DSMC as described above.  Sufficient evidence will be taken to be any proportion of 
late toxicities to patients treated whose lower one-sided 80% confidence limit exceeds 0.25.  Any of the 
following ratios would satisfy this: 2/2-3, 3/4-6, 4/7-9, 5/10-12, 6/13-16, 7/17-19, 8/20-23, 9/24-26, 
10/27-30, 11/31-33, 12/34-35.  If the true probability of late toxicity is 0.15, then the probability of 
suspending the trial after 20 or 30 patients is approximately 0.10 and 0.11, respectively.  If the true 
probability of late toxicity is 0.40, these probabilities are approximately 0.80 and 0.90, respectively 
(estimated from 5,000 simulated trials).  Each of these rules will be evaluated among all patients, 
regardless of the dose delivered.   
16.0 TERMINATION OF THE STUDY 
The study will be terminated upon complete accrual of patients, when toxicity criteria noted above are 
met, or at the discretion of the PI or sponsor. 
17.0 REFERENCES  
1. 
Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared 
with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma [see 
comments]. N Engl J Med. 1995;333(23):1540-1545. 
2. 
Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared 
with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. The 
New England journal of medicine. 1995;333(23):1540-1545. 


PROTOCOL 9189 
 
 
Page 31 of 43 
 
3. 
Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and 
survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP 
trial. J Clin Oncol. 2003;21(21):3918-3927. 
4. 
Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy 
followed by autologous stem cell transplantation in first remission significantly prolongs 
progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the 
European MCL Network. Blood. 2005;105(7):2677-2684. 
5. 
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for 
relapsed large B-cell lymphoma in the rituximab era. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2010;28(27):4184-4190. 
6. 
Gopal AK, Gooley TA, Maloney DG, et al. High-dose radioimmunotherapy versus conventional high-
dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-
Hodgkin lymphoma: a multivariable cohort analysis. Blood. 2003;102(7):2351-2357. 
7. 
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 
lymphomas. Blood. 2000;96(9):2934-2942. 
8. 
Press OW, Eary JF, Appelbaum FR, et al. Radiolabeled-antibody therapy of B-cell lymphoma with 
autologous bone marrow support [see comments]. N Engl J Med. 1993;329(17):1219-1224. 
9. 
Breitz HB, Weiden PL, Beaumier PL, et al. Clinical optimization of pretargeted radioimmunotherapy 
with antibody-streptavidin conjugate and 90Y-DOTA-biotin. Journal of nuclear medicine : official 
publication, Society of Nuclear Medicine. 2000;41(1):131-140. 
10. Forero A, Weiden PL, Vose JM, et al. Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted 
radioimmunotherapy for B-cell non-Hodgkin lymphoma. Blood. 2004;104(1):227-236. 
11. Weiden PL, Breitz HB, Press O, et al. Pretargeted radioimmunotherapy (PRIT) for treatment of non-
Hodgkin's lymphoma (NHL): initial phase I/II study results. Cancer biotherapy & 
radiopharmaceuticals. 2000;15(1):15-29. 
12. Knox SJ, Goris ML, Tempero M, et al. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-
10 antibody/streptavidin in patients with metastatic colon cancer. Clinical cancer research : an 
official journal of the American Association for Cancer Research. 2000;6(2):406-414. 
13. Pagel JM, Orgun N, Hamlin DK, et al. A comparative analysis of conventional and pretargeted 
radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in 
combinations. Blood. 2009;113(20):4903-4913. 
14. Park SI, Shenoi J, Frayo SM, et al. Pretargeted radioimmunotherapy using genetically engineered 
antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 2011;17(23):7373-
7382. 
15. Press OW, Corcoran M, Subbiah K, et al. A comparative evaluation of conventional and pretargeted 
radioimmunotherapy of CD20-expressing lymphoma xenografts. Blood. 2001;98(8):2535-2543. 
16. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 
2014;64(1):9-29. 


PROTOCOL 9189 
 
 
Page 32 of 43 
 
17. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone 
in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242. 
18. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal 
antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 
1997;90(6):2188-2195. 
19. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line 
treatment for advanced follicular lymphoma. Blood. 2005;105(4):1417-1423. 
20. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody 
therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment 
program. J Clin Oncol. 1998;16(8):2825-2833. 
21. van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of 
relapsed/resistant follicular non-Hodgkin's lymphoma, both in patients with and without rituximab 
during induction: results of a prospective randomized phase III intergroup trial. Blood. 2006. 
22. Witzig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan 
radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma. J 
Clin Oncol. 2003;21(7):1263-1270. 
23. 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. 2001;19(19):3918-3928. 
24. Press OW, Eary JF, Appelbaum FR, et al. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with 
autologous stem cell transplantation for relapsed B cell lymphomas. Lancet. 1995;346(8971):336-
340. 
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 
lymphomas. Blood. 2000;96(9):2934-2942. 
26. Nademanee A, Forman S, Molina A, et al. A phase 1/2 trial of high-dose yttrium-90-ibritumomab 
tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous 
stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood. 
2005;106(8):2896-2902. 
27. Winter JN, Inwards DJ, Spies S, et al. Yttrium-90 ibritumomab tiuxetan doses calculated to deliver 
up to 15 Gy to critical organs may be safely combined with high-dose BEAM and autologous 
transplantation in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol. 
2009;27(10):1653-1659. 
28. Decaudin D, Mounier N, Tilly H, et al. (90)Y ibritumomab tiuxetan (Zevalin) combined with BEAM (Z 
-BEAM) conditioning regimen plus autologous stem cell transplantation in relapsed or refractory 
low-grade CD20-positive B-cell lymphoma. A GELA phase II prospective study. Clin Lymphoma 
Myeloma Leuk. 2011;11(2):212-218. 
29. Vose JM, Carter SL, Burns LJ, et al. Randomized Phase III Trial of 131iodine-Tositumomab 
(Bexxar)/Carmustine, Etoposide, Cytarabine, Melphalan (BEAM) Vs. Rituximab/BEAM and 
Autologous Stem Cell Transplantation for Relapsed Diffuse Large B-Cell Lymphoma (DLBCL): No 
Difference in Progression-Free (PFS) or Overall Survival (OS). Blood (ASH Annual Meeting). Atlanta: 
American Society of Hematology; 2011:Abstract 661. 


PROTOCOL 9189 
 
 
Page 33 of 43 
 
30. Gopal AK, Gooley T, Rajendran J, et al. A Phase I Study of Myeloablative I-131-Anti CD-20 
(Tositumomab) Radioimmunotherapy with Escalating Doses of Fludarabine Followed by Autologous 
Hematopoietic Stem Cell Transplantation (ASCT) for Adults 60 Years of Age with High-Risk or 
Relapsed/Refractory B-Cell Lymphoma. Blood (ASH Annual Meeting). Atlanta: American Society of 
Hematology; 2011:Abstract 663. 
31. Shimoni A, Avivi I, Rowe JM, et al. A randomized study comparing yttrium-90 ibritumomab tiuxetan 
(Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen 
before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 
2012;118(19):4706-4714. 
32. Jo JC, Yoon DH, Kim S, et al. Yttrium-90 ibritumomab tiuxetan plus busulfan, cyclophosphamide, 
and etoposide (BuCyE) versus BuCyE alone as a conditioning regimen for non-Hodgkin lymphoma. 
Korean J Hematol. 2012;47(2):119-125. 
33. Vose JM, Bierman PJ, Loberiza FR, et al. Phase II trial of 131-Iodine tositumomab with high-dose 
chemotherapy and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma. 
Biol Blood Marrow Transplant. 2013;19(1):123-128. 
34. Green DJ, Orgun NN, Jones JC, et al. A preclinical model of CD38-pretargeted radioimmunotherapy 
for plasma cell malignancies. Cancer research. 2014;74(4):1179-1189. 
35. Goodwin DA, Meares CF, Osen M. Biological properties of biotin-chelate conjugates for pretargeted 
diagnosis and therapy with the avidin/biotin system. J Nucl Med. 1998;39(10):1813-1818. 
36. Rosebrough SF. Pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin and 
biotin. Nucl Med Biol. 1993;20(5):663-668. 
37. Paganelli G, Malcovati M, Fazio F. Monoclonal antibody pretargetting techniques for tumour 
localization: the avidin-biotin system. International Workshop on Techniques for Amplification of 
Tumour Targetting. Nucl Med Commun. 1991;12(3):211-234. 
38. Paganelli G, Chinol M, Maggiolo M, et al. The three-step pretargeting approach reduces the human 
anti-mouse antibody response in patients submitted to radioimmunoscintigraphy and 
radioimmunotherapy. Eur J Nucl Med. 1997;24(3):350-351. 
39. Paganelli G, Magnani P, Zito F, et al. Three-step monoclonal antibody tumor targeting in 
carcinoembryonic antigen-positive patients. Cancer Res. 1991;51(21):5960-5966. 
40. DeNardo DG, Xiong CY, Shi XB, DeNardo GL, DeNardo SJ. Anti-HLA-DR/anti-DOTA diabody 
construction in a modular gene design platform: bispecific antibodies for pretargeted 
radioimmunotherapy. Cancer Biother Radiopharm. 2001;16(6):525-535. 
41. Boerman OC, van Schaijk FG, Oyen WJ, Corstens FH. Pretargeted radioimmunotherapy of cancer: 
progress step by step. J Nucl Med. 2003;44(3):400-411. 
42. Gautherot E, Rouvier E, Daniel L, et al. Pretargeted radioimmunotherapy of human colorectal 
xenografts with bispecific antibody and 131I-labeled bivalent hapten. J Nucl Med. 2000;41(3):480-
487. 
43. Axworthy DB, Reno JM, Hylarides MD, et al. Cure of human carcinoma xenografts by a single dose 
of pretargeted yttrium-90 with negligible toxicity. Proc Natl Acad Sci U S A. 2000;97(4):1802-1807. 
44. Goldenberg DM, Sharkey RM, Paganelli G, Barbet J, Chatal JF. Antibody pretargeting advances 
cancer radioimmunodetection and radioimmunotherapy. J Clin Oncol. 2006;24(5):823-834. 


PROTOCOL 9189 
 
 
Page 34 of 43 
 
45. Pagel JM, Lin Y, Hedin N, et al. Comparison of a tetravalent single-chain antibody-streptavidin 
fusion protein and an antibody-streptavidin chemical conjugate for pretargeted anti-CD20 
radioimmunotherapy of B-cell lymphomas. Blood. 2006;108(1):328-336. 
46. Pantelias A, Pagel JM, Hedin N, et al. Comparative biodistributions of pretargeted 
radioimmunoconjugates targeting CD20, CD22, and DR molecules on human B-cell lymphomas. 
Blood. 2007;109(11):4980-4987. 
47. Schultz J, Lin Y, Sanderson J, et al. A tetravalent single-chain antibody-streptavidin fusion protein 
for pretargeted lymphoma therapy. Cancer Res. 2000;60(23):6663-6669. 
48. Theodore L, Axworthy D. Cluster clearing agents. US Patent 6 172 045. 2001. 
49. Pagel JM, Pantelias A, Hedin N, et al. Evaluation of CD20, CD22, and HLA-DR targeting for 
radioimmunotherapy of B-cell lymphomas. Cancer Res. 2007;67(12):5921-5928. 
50. Subbiah K, Hamlin DK, Pagel J, et al. Comparative immunoscintigraphy, toxicity, and efficacy of 
conventional and pretargeted radioimmunotherapy in a CD20-expressing human lymphoma 
xenograft model. J Nucl Med. 2003;44(3):437-445. 
51. Pagel J, Hedin N, Subbiah K, et al. Comparison of anti-CD20 and anti-CD45 antibodies for 
conventional and pretargeted radioimmunotherapy of B-cell lymphomas. Blood. 2003;101(6):2340-
2348. 
52. Axworthy DB, Fritzberg AR, Hylarides MD, et al. Preclinical evaluation of an anti-tumor monoclonal 
antibody/streptavidin conjugate for pretargeted Y-90 radioimmunotherapy in a mouse xenograft 
model. J Immunother. 1994;16(158). 
53. Knox SJ, Goris ML, Tempero M, et al. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-
10 antibody/streptavidin in patients with metastatic colon cancer. Clin Cancer Res. 2000;6(2):406-
414. 
54. Yao Z, Zhang M, Axworthy DB, et al. Radioimmunotherapy of A431 xenografted mice with 
pretargeted B3 antibody-streptavidin and (90)Y-labeled 1,4,7,10-tetraazacyclododecane-
N,N',N",N"'-tetraacetic acid (DOTA)-biotin. Cancer Res. 2002;62(20):5755-5760. 
55. Graves SS, Dearstyne E, Lin Y, et al. Combination Therapy with Pretarget CC49 
Radioimmunotherapy and Gemcitabine Prolongs Tumor Doubling Time in a Murine Xenograft 
Model of Colon Cancer More Effectively Than Either Monotherapy. Clin Cancer Res. 
2003;9(10):3712-3721. 
56. Waldmann TA, White JD, Carrasquillo JA, et al. Radioimmunotherapy of interleukin-2R alpha-
expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac. Blood. 1995;86(11):4063-4075. 
57. Weiden PL, Breitz HB, Press O, et al. Pretargeted radioimmunotherapy (PRIT) for treatment of non-
Hodgkin's lymphoma (NHL): initial phase I/II study results. Cancer Biother Radiopharm. 
2000;15(1):15-29. 
58. Forero A, Weiden PL, Vose JM, et al. A Phase I trial of a novel anti-CD20 fusion protein in 
pretargeting radioimmunotherapy for B cell non-Hodgkin's lymphoma. Blood. 2004;(in press). 
59. Gopal AK, Rajendran JG, Gooley TA, et al. High-dose [131I]tositumomab (anti-CD20) 
radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults > or = 60 
years old with relapsed or refractory B-cell lymphoma. J Clin Oncol. 2007;25(11):1396-1402. 


PROTOCOL 9189 
 
 
Page 35 of 43 
 
60. Gopal AK, Gooley TA, Rajendran JG, et al. Myeloablative I-131-tositumomab with escalating doses 
of fludarabine and autologous hematopoietic transplantation for adults age >/= 60 years with B cell 
lymphoma. Biology of blood and marrow transplantation : journal of the American Society for Blood 
and Marrow Transplantation. 2014;20(6):770-775. 
61. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software 
for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46(6):1023-1027. 
62. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin 
Oncol. 2007;25(5):579-586. 
63. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's 
Lymphoma Prognostic Factors Project [see comments]. N Engl J Med. 1993;329(14):987-994. 
64. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 
2004;104(5):1258-1265. 
65. Bearman SI, Appelbaum FR, Back A, et al. Regimen-related toxicity and early posttransplant survival 
in patients undergoing marrow transplantation for lymphoma. J Clin Oncol. 1989;7(9):1288-1294. 
66. Storer BE. An evaluation of phase I clinical trial designs in the continuous dose-response setting. 
Stat Med. 2001;20(16):2399-2408. 
67. Moskowitz C. Diffuse large B cell lymphoma: how can we cure more patients in 2012? Best practice 
& research Clinical haematology. 2012;25(1):41-47. 
68. Phipps C, Gopal AK, Storer BE, et al. Autologous transplant for relapsed follicular lymphoma: impact 
of pre-transplant rituximab sensitivity. Leukemia & lymphoma. 2014:1-5. 
69. Cuccuini W, Briere J, Mounier N, et al. MYC+ diffuse large B-cell lymphoma is not salvaged by 
classical R-ICE or R-DHAP followed by HDT/ASCT. A bio-CORAL report. Blood. 2012. 
 
 


PROTOCOL 9189 
 
 
Page 36 of 43 
 
APPENDIX 1:  GRADING OF TOXICITY (BEARMAN SCALE) 
 
 
Parameter 
I (mild) 
II (moderate) 
III (severe) 
IV (life threatening) 
 
 
 
 
 
Allergic 
Pruritus, rash 
Generalized  
Anaphylaxis 
Fatal 
 
 
Urticaria 
 
 
Renal 
 
 
 
 
Creatinine 
1.5-2x 
>2x increase 
Dialysis 
Fatal 
 
increase 
No dialysis 
 
 
 
 
 
 
 
Pulmonary 
Dyspnea 
Interstitial 
Ventilatory 
Fatal 
 
 
pneumonia 
support or 
 
 
 
 
F102 >50% 
 
 
 
 
 
 
Cardiac 
Mild CHF 
Moderate CHF 
Severe CHF 
Fatal 
 
No therapy needed 
Diuretics 
needed 
Ejection Fraction 
<30% 
 
 
 
 
 
 
Hepatic 
 
 
 
 
Bilirubin 
2-6 mg/L 
6-2 mg/L 
>20 mg/dL 
Fatal 
SGOT 2- 
5 x increase 
>5 x increase 
Encephalopathy 
 
Ascites 
Ascites <100 ml 
Ascites >100 ml 
 
 
 
 
 
 
 
CNS 
Transient 
Somnolence 
Seizure 
Fatal 
 
somnolence 
>36 hr 
or coma 
 
 
 
 
 
 
Stomatitis 
Ulcerations 
IV opiates 
Intubation 
Fatal 
 
 
 
or aspiration 
 
 
 
 
pneumonia 
 
 
 
 
 
 
GI 
Watery stools 
Stools>2L/day 
Hemorrhagic 
Fatal 
 
0.5-2 L/d 
Subileus 
enterocolitis 
 
 
 
 
NG suction 
 
 
 
 
 
 
Bladder 
Macroscopic 
Macroscopic 
Sclerosing agents 
Fatal 
 
Hematuria 
hematuria 
or surgery needed 
 
 
<7 days 
>7 days 
 
 


PROTOCOL 9189 
 
 
Page 37 of 43 
 
  
 
APPENDIX 2:  SUGGESTED POST TREATMENT EVALUATIONS*  
 
 
EVALUATION 
TIME (MONTHS)1 
1 
3 
6 
12 
18 
24* 
(annually until relapse/progression or 
initiation of additional anti-neoplastic 
therapy.) 
CBC 
X 
X 
X 
X 
 
X 
Chemistries2 
X 
X 
X 
X 
X 
X 
Bone Marrow Biopsy3 
X 
 
 
X 
 
X 
Bone Marrow Aspirate3 
X 
 
 
X 
 
X 
SPEP4 
 
 
 
X 
 
X 
CT/MRI5 
X 
X 
X 
X 
 
X 
PET-CT6 
X 
X 
X 
X 
 
X 
Pulmonary Function Testing 
 
 
 
X 
 
 
 
1 
Timepoints for these assessments are relative to the date of stem cell infusion. 
 
2 
Chemistries = BUN, creatinine, LDH, transaminases, bilirubin, and alkaline phosphatase. 
 
3 
Only when clinically indicated, BM biopsy/aspirate PCR (only patients that had prior positive PCR 
studies), flow cytometry, cytogenetics as performed at baseline per standard practice. 
 
4 
Only patients with a prior documented monoclonal protein are required to undergo follow up SPEP 
testing 
 
5 
CT/MRI = chest, abdomen and pelvis. 
 
6 
Post-treatment PET-CT scan at 1 month is strongly recommended (but is not required by the study) 
if baseline scan was positive.  Subsequent PET-CT scans are to be considered (but are not required 
by the study) until complete treatment response has been documented by a negative PET-CT. 
 
*Following relapse or disease progression, patients will be followed annually for survival and development of 
secondary malignancies.  Following other significant diagnoses and/or therapies that would confound assessment 
of the relationship between the study treatment and adverse events (e.g., further therapy intended to maintain 
disease remission), patients will be followed annually for disease status, survival, and development of secondary 
malignancies. Follow up will in general mirror the current standard of care.  
 


PROTOCOL 9189 
 
 
Page 38 of 43 
 
Appendix 3:  Methods Used to Estimate Radiation Absorbed Doses  
 
The calculation of radiation absorbed dose to internal organs, tissues, the whole-body, and tumor 
tissues is a fundamentally important aspect of successfully achieving the desired clinical objectives of 
radiopharmaceutical therapy.  The use of radiopharmaceuticals for cancer treatment requires detailed, 
patient-specific dosimetry and dose planning for assessments of absorbed dose to both normal tissues 
and tumors.  Dosimetry serves two primary goals:  (a) to ascertain the maximally achievable radiation 
doses to cancerous tumors and lesions for complete disease eradication, and (b) at the same time and 
under the same circumstances, to ensure that radiation doses to critical normal organs and tissues do 
not exceed maximally tolerated levels.   
a. Scientific Basis for Internal Dosimetry Calculations 
Direct measurements of organ or tissue radioactivity must account for the geometry and density of the 
source organ or tissue, organ size and mass, potential overlap, thickness of tissue between the organ 
and the detector, and the spatial distribution of activity with a tissue.  Measurements are corrected for 
background, photon attenuation, and photon scatter that may influence the accuracy of direct counting.  
For any radionuclide, the Information needed to calculate absorbed dose includes: the total activity 
administered to the patient and time of infusion, the fraction of the administered activity that is taken 
up by each major source organ or tissue, and the time-dependent retention and clearance of activity in 
each major source organ through complete radiological decay. 
Radiation absorbed doses will be calculated for each patient’s normal organs and tissues, the whole 
body, and for imageable tumors using methods recommended by the Medical Internal Radiation Dose 
(MIRD) Committee of The Society of Nuclear Medicine (Loevinger et al., 1991).  The MIRD methods 
account for both the penetrating gamma and the non-penetrating beta radiation (electrons) emitted by 
radioactivity distributed throughout the body.  In the MIRD schema, dosimetry calculations are based on 
a series of direct measurements of the organ biodistribution of radiolabeled antibody in individual 
patients.  These include gamma-camera images and quantitative activity measurements of the 
radionuclide used (111In as a tracer for yttrium-90-labeled-biotin) in the major imageable source organs, 
tumor tissue, red marrow, and the total body at various time-points post-infusion.  Radiation doses to 
red marrow may be determined by direct measurement of radioactivity in distinct spaces such as 
acetabulum and sacrum, or by a combination of direct imaging and marrow tissue biopsy.  When 
available, the patient-specific organ masses are used for internal dose calculations rather than generic 
model values. The mathematical foundations for application of these methods to critical organs in high-
dose radioimmunotherapy are well-established (Fisher 1994, 2000; Fisher et al. 2009).  Fully 
implemented, the MIRD formalism accounts for all source regions and all target organs, all source-target 
geometries, and all radioactive emissions contributing to absorbed dose.   
b. Rationale for the Use of Indium-111 to Predict Yttrium-90 Biodistribution. 
Because 90Y is a pure beta-emitter, it cannot be imaged accurately or conveniently in the patient.  Based 
on prior studies, we assume that the biodistribution of the trace-labeled 111In-biotin faithfully represents 
the biodistribution of the 90Y-labeled-therapeutic conjugate in the cancer patient.   Preclinical studies 


PROTOCOL 9189 
 
 
Page 39 of 43 
 
show that the biodistribution of 111In-labeled-biotin usually correlates well with 90Y-labeled-biotin 
biodistribution (Fisher et al. 2009).   Therefore, it is common practice in nuclear medicine to use 111In-
conjugates measurement data to predict the biodistribution of 90Y-conjugate. We have found two 
exceptions:  If the indium-111 or yttrium-90 disassociates from the protein, (1) free (unbound) 90Y may 
deposit on bone surfaces, and (2) free 111In may preferentially deposit in the testes due to natural 
uptake of indium by germ cells.  During radiolabeling, quality control usually allows less than 2% 
unbound 111In.  We will not measure the unbound fraction in serum after injection.  For dosimetry 
calculations, however, we will assume that the biodistributions of 111In and 90Y labeled antibody are 
equivalent, recognizing the exceptions that without further correction this assumption may lead to 
underestimates of 90Y dose to bone surfaces and red marrow, and to overestimates of 90Y dose to the 
testes. 
c. Direct Measurements in Patients 
In planar imaging, the geometric mean of counts obtained from anterior and posterior views is 
determined.  The counts obtained in an organ or tissue region of interest must be converted to units of 
radioactivity using appropriate measurement methods and calibration standards, including: daily quality 
assurance, patient positioning, patient-thickness measurements, background subtraction, attenuation 
correction, and scatter correction.   
(i) Conjugate Views 
Conjugate-view quantitative planar imaging with anterior and posterior measurements is the most 
widely used method for assessing source-organ activity in patients.   The conjugate view method does 
not require knowing the depth of the source region and does not depend on assumptions inherent in 
single-view phantom simulations, but does incorporate correction for background, scatter, and photon 
attenuation.  
(ii) Biodistribution Imaging 
After a tracer quantity of 111In (usually 111 to 222 MBq or 3 to 6 mCi) labeled to DOTA-biotin is 
administered, the patient is imaged using collimated anterior and posterior planar gamma-camera 
imaging.  Biodistribution imaging begins immediately after infusion of 111In trace-labeled DOTA-biotin on 
day 0.  A nuclear medicine camera with a medium energy collimator, with photopeak settings at 171 and 
245 keV, and a symmetric 15% window around each photopeak, is used for imaging.  Images include 
chest with upper humeri and thyroid, abdomen, and pelvis with upper femurs.  Regions of interest are 
typically selected for the major source organs that visualize above background, which may include, but 
are not limited to, the liver, spleen, heart volume, red marrow space, lungs, kidneys, thyroid, and testes.  
Normal organs and tumors are visualized when concentrations of 111In antibody in the organ or tumor 
are greater than in the surrounding tissue.  Background regions are drawn for each organ/region similar 
to the methods described above. In addition, attenuation correction factors are determined for the 
chest and abdomen using the methods described below.  We image tumor sites that have well-defined 
uptakes and retention of 111In-radiopharmaceuticals, allowing us to determine the percent of 
administered activity per gram of tumor tissue for all tumors selected for dose assessment.  Imaging of 


PROTOCOL 9189 
 
 
Page 40 of 43 
 
selected tumors may be conducted for various time points, and time-activity curves can be constructed 
and integrated for tumor dose assessments. 
Measurements are also made of representative background tissue and of an imaging standard without 
the patient in the camera field-of-view.  The outlines for the regions of interest are drawn by a 
technologist from the acquired images, and counts are obtained from the selected regions.  The counts 
are decay-corrected to the 111In imaging standard.  The geometric mean of the anterior and posterior 
counts is obtained for each region of interest.  Counts are then corrected for attenuation, decay, and 
background. Total-body measurements are obtained using whole-body gamma camera images in both 
anterior and posterior projections, to quantify the total 111In activity remaining in the patient, over time, 
as a fraction of the total administered activity.  
 (iii)  Attenuation 
Prior to antibody infusion, all patients will have measurement made of their abdomen attenuation by 
transmission scans.  A fluid filled sheet source, large enough to cover the entire useful field of view of 
the camera, is loaded with approximately 0.7 mCi of 111In.  Uniform distribution of the isotope 
throughout the sheet source is ensured.  The source is placed on the lower detector, and with the 
patient on the scanning table and their abdomen in the field of view, the upper detector is lowered into 
place.  A five-minute transmission image is acquired.  Without moving the detectors and with the 
scanning table alone between them, another five minute image (flood) is acquired.  The observed ratio 
of counts in the flood source activity counted with and without the patient overlying is the attenuation 
correction factor for the various organs of interest. 
(iv)  Sampling Times 
Selecting an appropriate number of counting times requires trade-offs between obtaining sufficient 
data, economizing the imaging costs, and minimizing patient inconvenience.  The objective is to select 
the fewest time points that will provide a reasonable description of the activity-time curve.  Three to 
five data measurement points will typically be required for 111In-DOTA-biotin imaging.  Imaging includes 
one measurement at or as close as possible to time zero (time of radiopharmaceutical infusion), plus 
additional measurements on the day of infusion and on subsequent days post-infusion.  On Days 1 and 2 
post infusion, patients will have a total of at ideally two sessions of gamma camera images (for example, 
in the morning of Day 1 and the afternoon of Day 2 post infusion).  The final imaging time point should 
ideally be on Days 4 to 6 post-infusion.  Analyses of time-activity functions provide an estimate of the 
fraction of the administered activity that resides in each source organ and in the total body at each 
measurement time point. 
d. Time-Activity Curves 
The sequential measurement data are plotted to determine the cumulated activity and residence times 
for each source organ.  Separately for each organ or tissue, we plot the fraction of the total 
administered activity observed at each measurement time point in the organ. We then identify an 
appropriate mathematical function to represent the data by curve-fitting and least-squares regression 
analysis.  These functions may be single-exponentials, bi-exponentials, or mathematical equations of 
other forms.  Time-activity curves are constructed from the measurement data and are integrated to 


PROTOCOL 9189 
 
 
Page 41 of 43 
 
infinite time to determine the time-integrated activity coefficient (, hours), or area-under-curve for 
each source organ, tumor, the red marrow, and the whole body.  An estimate of the long-term tail of the 
time-activity curve may be made by fitting an exponential function to the last two points. We plot the 
effective fractions present (as measured), rather than the values that were decay-corrected from a 
radionuclide standard, because internal doses are calculated from the integral areas under the effective 
time-activity curves.   Standard mathematical software packages are used to fit the measurement points 
to representative equations.   
e. Time-integrated Activity Coefficients 
The time-integrated activity coefficient (previously known as “residence time” (Bq-sec/Bq or Ci-hr/Ci 
administered) for a source organ is the fraction of the administered activity in an organ or tissue over 
time to complete decay, obtained by integrating the time-activity curve.  The coefficient is the basic 
input value to dosimetry software packages (such as OLINDA-EXM, Vanderbilt University, Nashville, 
Tennessee) that implement the MIRD dosimetry schema.  We will use OLINDA-EXM for this project.   
The cumulated activity, Ã h, and time-integrated activity coefficient,  h, are determined by integrating 
the area under the activity-time curves for the clinical measurement data for each source organ and the 
remainder tissues.  The integrations are carried to infinity for accuracy and simplicity.   
f. 
Patient-specific Dosimetry 
Since organ dose is approximately proportional to the inverse of target mass, a correction should be 
made for patient weight and organ mass when actual organ weights are known from CT-imaging.   
Actual patient weights and organ sizes vary, but OLINDA corrects for those differences when actual 
masses are known.  The correction involves recalculating the S values for each of the source-target 
combinations where patient-specific organ volumes are used.  The recalculated S values account for 
both the gamma component specific absorbed fraction of energy and the mass over which the beta 
component is averaged.  For most radionuclides, the beta self-irradiation dose in a source organ is the 
greater contributor to total organ dose (usually more than 90 percent of the total).  For yttrium-90, 
which emits no gamma rays, this self-irradiation component is essentially 100%.  
g. Estimate of Dose to Testes 
In male patients with significant testicular uptake of 111In, we estimate the 90Y dose to testes with 
corrections for 111In disassociation and thickness of tissue due to their superficial position in anterior 
scans.  Regions may be drawn around the testicular uptake on serial anterior gamma camera 
images.  Care is taken to separate the penile activity by instructing the patient to physically move the 
penis away from the testes during each scanning session.  A suitable background is used to correct the 
counts, but no attenuation correction factor are used because the testes are positioned to the anterior 
view without any significant attenuating tissues.   
h. Estimate of Dose to the Bone Marrow:  
Red marrow dosimetry is challenging because it is difficult to assess 1) the highly variable concentration 
of radioactivity in marrow by anatomical location, and 2) the mass of red marrow in the patient.  
Common approaches to marrow dosimetry often rely on unreliable estimates of radiolabeled antibody 


PROTOCOL 9189 
 
 
Page 42 of 43 
 
concentration in red marrow or in red marrow relative to the concentration in circulating blood or blood 
plasma.  Rather than measure blood plasma activity and make uncertain assumptions, we employ 
quantitative imaging of defined marrow spaces (acetabulum, sacrum, femoral head, or lumbar 
vertebrae) by repetitive direct counting.  These measurements provide data for evaluating the red 
marrow time-activity curve.   The sacrum is assumed to contain exactly 9.9 percent of total body marrow 
(Siegel et al., 1989).  One may then assume that total-body marrow activity is directly proportional to 
the concentration measured in the sacrum to obtain the time-integrated activity coefficient for red 
marrow (Siegel et al., 1989).  Alternatively, a marrow time-activity function may be normalized through 
a marrow biopsy measurement (radioactivity per gram), if a biopsy measurement is available. 
i.  Dosimetry Results.  Results of radiation dose calculations for individual patients are summarized and 
reported back to the University of Washington, Division of Nuclear Medicine.  The report includes the 
gamma camera measurement data (percent administered activity in each major source organ and the 
whole body), the calculated time-integrated activity coefficients, values of Ao (an estimate of initial 
organ uptake immediately following radiolabeled antibody infusion, the effective and biological 
retention half-times, and the correlation coefficients applicable to the mathematical retention equations 
used.  The report also includes the calculated radiation absorbed doses (cGy) to each of the listed organs 
and tissues of the body, plus the whole-body, per unit administered activity (milliCuries). 
 
REFERENCES:  
 
Loevinger R, Budinger TF, Watson EE et al.  MIRD Primer for Absorbed Dose Calculations (revised).  
New York: The Society of Nuclear Medicine, 1991. 
 
Fisher DR.  "Radiation Dosimetry for Radioimmunotherapy:  An Overview of Current Capabilities and 
Limitations."  Cancer 73(3Suppl):905-911; 1994. 
 
Fisher, DR.  “Internal Dosimetry for Systemic Radiation Therapy.”  Sem. in Rad. Oncol. 10(2):123-132; 
2000. 
 
Fisher DR, Meredith RF, and Shen S.  “MIRD Dose Estimate Report No. 20: Radiation Absorbed Dose 
Estimates for 111In- and 90Y-Ibritumomab Tiuxetan (ZevalinTM).”   J Nucl Med.  44(3):465-474; 2009. 
 
Rajendran JG, Fisher DR, Gopal AK, Durack LD, Press OW, and Eary JF.  “High-dose 131I-Tositumomab 
(anti-CD20) Radioimmunotherapy for non-Hodgkin's Lymphoma: adjusting radiation absorbed dose 
to actual organ volumes.”  J. Nucl. Med.  45(6):1059-1064; 2004. 
 
Siegel JA, Lee RE, Pawlyk A, Horowitz JA, Sharkey RM, and Goldenberg DM. “Sacral scintigraphy for   
bone marrow dosimetry in radioimmunotherapy.”  Int J Radiat Appl Instrument., Part B., Nucl Med 
Biol. 16(6):553-339; 1989. 
 
 


PROTOCOL 9189 
 
 
Page 43 of 43 
 
APPENDIX 4:  SWOG PERFORMANCE STATUS 
 
 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g. light housework, office work  
(Karnofsky 70-80) 
2 
Ambulatory and capable of self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours  
(Karnofsky 50-60%) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours  
(Karnofsky 30-40%) 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or 
chair 
(Karnofsky 10-20 %) 
5 
Dead