Pilot Study of Rituximab and Brentuximab Vedotin With Deferred BMT for Relapsed Classical Hodgkin Lymphoma
Phase: PHASE1
Conditions: Lymphoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Rituximab and brentuximab vedotin for cHL 
 
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Rituximab and brentuximab vedotin with deferred BMT for relapsed  
classical Hodgkin lymphoma 
 
Principal Investigator:  
 
Nina Wagner-Johnston, MD 
 
 
 
 
 
CRB I, Room 390 
1650 Orleans Street 
 
 
 
 
 
Baltimore, MD 21287 
 
 
 
 
 
Phone: 410-955-8839 
 
 
 
 
 
Fax: 410-955-0960 
 
 
 
 
 
nwagner7@jhmi.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Co-investigators: 
 
 
Richard Ambinder, MD PhD 
 
 
 
 
 
Stephanie Terezakis, MD 
 
 
 
 
 
Harvey Zeissman, MD 
 
 
 
 
 
Lilja Solnes, MD 
 
 
 
 
 
Lode Swinnen, MD 
 
 
 
 
 
Douglas Gladstone, MD 
 
 
 
 
 
Satish Shanbhag, MD 
 
 
 
 
 
Christopher Gocke, MD 
 
 
 
 
 
Richard Jones, MD 
 
 
 
 
 
 
Statisticians:  
 
 
Gary Rosner, ScD 
 
 
 
 
 
Marianna Zahurak, MS 
 
 
 
 
 
Study site: 
 
 
 
Sidney Kimmel Comprehensive Cancer Center  
 
 
 
 
 
at Johns Hopkins 
 
IRB number:  
 
 
NA_00080336 
 
Version date:  
 
 
September 23, 2015 (Amendment 5) 
 
 
Protocol history: 
Original IRB approval (version date 4/23/2013): 6/26/2013 
Amendment 1 approval (version date 11/8/2013): 11/20/2013  
Amendment 2 approval (version date 1/15/2014): 1/22/2014 
Amendment 3 approval (version date 11/6/2014): 12/10/2014 
Amendment 4 approval – PI change only (version date 3/24/15): 4/8/15 
NCT01900496

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INDEX 
 
Schema 
1.0  
Introduction 
1.1 
Study overview 
1.2 
CSCs as therapeutic targets 
1.21  The CSC concept 
1.22 
Evaluating CSC therapies 
1.3 
Targeting B cells in cHL 
 
 
1.31 
The B-cell origin of cHL 
 
 
1.32 
CD20 as a target in cHL 
 
 
1.33 
Circulating clonotypic B cells as cHL biomarkers 
1.4 
Brentuximab vedotin 
1.5 
High-dose therapy in relapsed cHL 
1.6 
Summary of hypotheses and design  
 
 
 
2.0 
Objectives  
 
2.1 
Primary objective 
 
2.2 
Secondary objectives 
3.0 
Selection of Patients 
3.1 
Eligibility criteria 
3.2  
Study interruption or withdrawal 
4.0 
Registration Procedures 
 
4.1 
Projected accrual 
 
4.2 
Registration 
5.0 
Treatment Plan 
 
5.1 
Evaluations and procedures 
 
5.2 
Brentuximab vedotin and rituximab 
 
 
 
5.21 
Eligibility for antibody combination 
 
 
 
5.22 
Brentuximab vedotin 
 
 
 
5.23 
Rituximab 
 
 
 
5.24 
Dose modifications and delays 
 
5.3 
Supportive care 
 
 
 
5.31 
Filgrastim 
 
 
 
5.32 
Hepatitis B infection 
 
5.4 
Other lymphoma therapies 
 
 
 
5.41 
Permitted lymphoma therapies 
 
 
 
5.42 
Radiation therapy 
 
 
 
5.43 
Steroids 
 
5.5 
Correlative studies 
 
5.6 
Follow-up procedures 
 
5.7 
Toxicity grading and reporting 
6.0 
Measurement of Effect 
 
6.1 
Response assessment 
 
6.2 
Disease and survival endpoints 
 
 
 
6.21 
Progression-free survival 
 
 
 
6.22 
Failure-free survival 
 
 
 
6.23 
Event-free survival 
 
 
 
6.24 
Overall survival 
 
 
 
6.25 
Time to tumor progression 
 
6.3 
Dose intensity 
7.0 
  Study Parameters 
7.1 
Core clinical evaluations 

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7.2 
Research blood collections 
8.0 
Drug Information 
 
8.1 
Rituximab 
 
8.2 
Brentuximab vedotin 
9.0 
Statistical Considerations 
 
9.1 
Primary endpoint 
 
 
 
9.11 
Definition of primary endpoint 
 
 
 
9.12  Sample size 
 
9.2 
Early stopping guidelines 
 
 
 
9.21 
Early stopping rules for futility 
 
 
 
9.22 
Early stopping rules for safety 
 
9.3 
Secondary endpoints 
 
 
 
9.31 
Correlative studies of CCBCs 
 
 
 
9.32 
Secondary clinical endpoints 
10.0 
Pathology Review 
11.0 
Records to be Kept 
12.0 
Patient Consent and Peer Judgment 
13.0 
References 
14.0 
Appendix 
 
A. 
18F FDG PET evaluation form 
 
B. 
Radiation therapy guidelines 
 
C. 
Adverse event reporting for rituximab 
 
D. 
Genentech safety reporting fax cover sheet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
Note: A response to 4 cycles of brentuximab vedotin is required to continue study treatment.  
 
1.0 
INTRODUCTION 
 
1.1 
Study overview  
Curative but less toxic regimens are needed for patients with relapsed classical HL (cHL). 
Salvage chemotherapy followed by high-dose therapy with autologous blood or marrow 
transplantation (auto BMT) is the standard approach for first chemosensitive relapse of 
cHL. Although auto BMT in this context is curative in approximately 40% of cases, it carries 
risks of major morbidity, a 5-8% mortality risk, and a nearly 100% risk of infertility. This 
pilot study explores a completely novel platform for the first-line management of 
relapsed cHL, based on a) the concept of targeting cancer stem cells (CSCs) as well 
as tumor bulk, and b) avoidance of high-dose cytotoxic therapy and BMT for 
chemosensitive relapse. 
 
Although Hodgkin/Reed-Sternberg (HRS) cells in cHL usually lack B-cell markers 
including CD20, this disease is now widely recognized to be a B-cell malignancy. Yet, 
single-agent rituximab has clinical activity in cHL, even in the cases where HRS lack CD20 
expression.1  Our group at Johns Hopkins has found that, in patients with cHL, circulating 
clonotypic malignant cells with stem cell properties express CD20. We have shown that 
rare, clonotypic, malignant B cells circulate in the blood of most patients with active cHL, 
including patients with limited-stage disease.2 These clonotypic B-cells have the same 
immunoglobulin gene rearrangements as lymph node-derived HRS cells and hence are 
clonally related. However, unlike HRS cells, these clonotypic cells lack CD30 while 
expressing memory B-cell markers including CD20. These findings potentially explain the 
clinical activity of rituximab in cHL, including cases lacking CD20 expression on HRS 
cells,1,3 and raise the possibility that anti-B-cell therapies represent new approaches for this 
disease.  
A convergence of clinical observations and laboratory-based work on tumor stem 
cells in B lineage malignancies thus suggests a potential role for rituximab in the 
management of cHL.  A rare, distinct B-cell population in cHL with clonogenic capacity has 
been identified. This population, isolated by our group from patients as well as cell lines, is 
phenotypically distinct from HRS cells and expresses B-cell markers including CD20 and 
CD27.2  The possibility that in vivo as in cell lines, cHL is sustained through “CSCs” that 
express B-cell markers including CD20 raises the possibility that rituximab, and perhaps 
other B-cell targeted therapies, may be effective in HL. Furthermore, our work at Johns 
Hopkins has shown that, in select patients with first chemosensitive relapse of cHL, 
prolonged remissions can be achieved with intensive therapy that does not involve auto 

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BMT.4  These findings form the basis of the present trial for relapsed cHL, investigating 
targeted approaches that include anti-B-cell therapy without BMT as first management of 
relapsed chemosensitive cHL. 
 
In a disease such as HL with a substantial cure rate, large studies carried out over 
many years are required to definitively address clinical questions. The size, duration and 
expense of these studies mean that it will be possible to evaluate very few questions 
efficiently in this fashion. Small studies such as this, to shed light on the potential clinical 
activity of new targeted therapies, to help clarify the biology of the tumor and to help identify 
useful tumor markers will be required to optimally define strategies to be evaluated in large 
clinical trials.  
 
 
1.2 
CSCs as therapeutic targets 
 
1.21 
The CSC concept 
At least two distinct functional groups of cells of tumor lineage are recognized in many 
cancers.5,6 It has been appreciated that many cancers, potentially including HL, are 
comprised of cells that may be functionally divided into these two groups: 1) relatively 
differentiated cells that form the bulk of the tumor but that lack significant renewal capacity, 
and 2) cells that may be quite distinct phenotypically but retain the capacity to self-renew 
and produce differentiated progeny.7  The term “CSCs” is used to designate the latter, self-
renewing cells which are biologically distinct from the bulk of the tumor cells and are 
responsible for initiating and sustaining the malignancy. Chronic myeloid leukemia is an 
example of such a tumor, where in the chronic phase mature granulocytes form the bulk of 
the tumor but are terminally differentiated and non-clonogenic.8  Characterizing the CSC 
population profoundly affects the development of new targeted therapies. This is because 
stem cells may differ markedly in phenotype and drug sensitivity from the cells that 
compromise the bulk of the tumor. Although the clinical significance of CSCs remains hotly 
debated, therapies might be more likely to result in long-term remissions if, in addition to 
reducing overall disease bulk, they also inhibit the cells responsible for disease 
maintenance.5  Few clinical trials have investigated CSC targeting. It is hypothesized that 
strategies that target the more apparent, differentiated cells (to reduce tumor bulk) 
combined with strategies that target CSCs represent a new potential approach to improving 
progression-free survival (PFS). 
 
1.22 
Evaluating CSC therapies 
One of the central challenges posed by the stem cell conceptual framework is that as new 
targeted therapies are investigated, remission induction is not necessarily informative in 
terms of cure, and that in some circumstances cure might be achieved before radiographic 
remission is achieved. In HL it has long been recognized that fibrotic tumor masses may 
persist (leading to evidence of disease by conventional radiographic assessment) even in 
patients who have been cured; hence the importance of progression-free survival 
endpoints.  
 
However, fibrosis is not the only potential confounding factor in assessing treatment 
response. Long lived malignant cells that are not stem cells may in theory be detected in a 
variety of laboratory or radiographic tests even after the CSC compartment has been 
ablated. For example, glucose metabolism may persist leading to signal on 18-F-FDG-PET. 
In HL this is even more of an issue than in other tumors because the FDG-PET signal may 
not even originate in tumor lineage cells but may originate in the benign, infiltrating 
lymphocytes that comprise the bulk of the tumor. FDG-PET would seem to be a reliable 
marker so long as CSCs, bulk tumor cells, and cells of the benign inflammatory infiltrate are 
eradicated in concert. That seems to be the case with present chemotherapies, as it has 
been recently appreciated that FDG-PET is remarkably predictive in HL.9  However, as 

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more targeted therapies are explored, this parallel sensitivity may cease to exist; stem cells 
may be targeted more effectively by one therapy while bulk tumor cells are more effectively 
targeted by another. Other approaches to gauging the efficacy of such treatments are 
therefore needed and form a basis for this trial’s correlative studies, wherein the clinical 
utility of CSC assays (frequency of circulating clonotypic B cells) is investigated. Specimens 
from this trial will be used to help begin to assess the clinical value of monitoring 
frequencies of circulating clonotypic B cells in the context of a potential stem cell targeting 
therapy. This is anticipated to provide a framework for evaluating subsequent studies of 
stem cell directed therapies for cHL. 
 
1.3 
Targeting B cells in cHL 
 
1.31 
The B-cell origin of cHL 
The B-cell origin of cHL has only relatively recently been widely appreciated. It was long 
obscured by the peculiar architecture of the involved nodes with their dense polymorphous 
infiltrates, the absence of surface immunoglobulin (Ig) gene expression on HRS cells, as 
well as the paucity of surface B-cell markers on the HRS cells. Ig gene rearrangement 
studies importantly suggest that RS cells in cHL represent a monoclonal expansion of a 
germinal center B-cell.10,11  B-cell antigens therefore represent potential new therapeutic 
targets for this disease, including CD20 as discussed below.  
 
1.32 
CD20 as a target in cHL 
In contrast to lymphocyte-predominant HL, most of the tumor in cHL is comprised of a 
benign inflammatory infiltrate including B cells and activated T cells, with relatively few 
interspersed RS cells. Notably, although a minority of malignant cells in cHL express CD20,  
rituximab can produce clinical responses even when HRS cells lack CD20 expression.1 In a 
pilot study for multiply relapsed cHL conducted by the MD Anderson, single agent rituximab 
(375 mg/m2 weekly for 6 weeks) produced objective responses in 22% of patients, 
irrespective of HRS cell CD20 expression; the median response duration was nearly 8 
months (range 3-15 months).1  It has been proposed that rituximab might work in cHL by 
depleting benign supporting B cells from the tumor microenvironment.1,12 
 
Alternatively, we propose that rituximab might target neoplastic cHL stem cells or a 
B-cell population clonally related to these stem cells.2 Our group at Johns Hopkins recently 
reported that within cHL cell lines, a small population, unlike HRS cells, has a memory B 
cell phenotype including CD20 and surface immunoglobulin (Ig) expression, lacks CD15 
and CD30 expression, and is enriched for the stem cell marker aldehyde dehydrogenase 
(ALDH).2 Moreover, these rare B cells appear to generate and sustain the growth of HRS 
cells.2 In cHL pts we have also recently reported the existence of a rare, distinct clonotypic 
B-cell population that is phenotypically compatible with the presumed stem cell fraction 
identified in cHL cell lines .2 These rare, clonotypic, malignant B cells circulate in the blood 
of most pts with newly diagnosed cHL, including most pts with limited-stage disease.  
Although the circulating CD19+ cells (as well as the CD19+ ALDHlow cells) displayed a 
normal ratio of CD27 and Ig light chain restriction, the CD19+ ALDHhigh cells were a virtually 
pure population of light-chain restricted, CD27+ CD30– B cells that represented a median of 
0.2% (range 0-2.4%) of the total circulating CD19+ cells. Furthermore, these clonotypic B 
cells have the same Ig gene rearrangement as lymph node-derived HRS cells and hence 
are clonally related.2 Clonality was confirmed by Ig CDR3 length restriction and by DNA 
sequencing.2 Their surface Ig expression is plausible given that, in most EBV– tumors, HRS 
cells have functional Ig rearrangements that appear to be epigenetically silenced.13 
 
Interestingly, morphologically distinct subpopulations were similarly described within 
a human cHL cell line over 20 years ago.14 Clonogenic potential appeared to be largely 
limited to rare CD19+ mononuclear cells that were phenotypically distinct from HRS cells.14 

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There was considerable heterogeneity in this clonal cell line; some cells were capable of 
sustaining tumor growth whereas others had limited clonogenic potential.14  Interestingly, 
the cells with clonogenic potential (which might now be regarded as “CSCs”) were 
phenotypically distinct from the "RS-like" cells. The cells with clonogenic potential were 
smaller and expressed B-cell markers.  Therapeutic implications were not readily apparent 
at that time, but may in fact exist in light of the growing recognition of the stem cell biology 
of many cancers including cHL. 
The clinical data with rituximab in cHL, including why clinical responses may occur 
in the absence of CD20 expression on HRS cells, may thus be interpreted in several ways. 
Depletion of B-cells from tumor masses may lead to apparent shrinkage of the tumor mass 
without any impact on cells of the malignant clone. Rituximab may potentiate the effects of 
cytotoxic chemotherapy, perhaps in part by depleting benign B-cells (and hence cytokines 
and intercellular signals) from the tumor microenvironment.3  Alternatively, rituximab may 
target the neoplastic H/RS cell. The above findings therefore lend support to the possibility 
that HL arises from malignant stem cells that express B cell markers and that are 
phenotypically distinct from classic RS cells or their Hodgkin's variants. This possibility is of 
interest because of its direct therapeutic relevance, and provides further rationale for the 
study of rituximab and possibly other B-cell targeted therapies as potential “stem cell 
inhibitors” in cHL. 
 
1.33 
Circulating clonotypic B cells as cHL biomarkers 
Whether circulating clonotypic B cells (CCBCs) in cHL represent “CSCs” or a molecularly 
related population not critical for tumor maintenance or progression is unknown. However, 
preliminary data from our recently published study of rituximab-ABVD suggest these 
CCBCs might track with disease status and might have prognostic significance15. Based on 
the above data, our group at Johns Hopkins developed a multicenter, translational phase 2 
study of rituximab-ABVD for newly diagnosed, stage II-IV cHL.15 Of 49 pts, 69% had stage 
IIB-IV disease; 8% had CD20+ HRS cells. Rituximab-ABVD was generally well-tolerated 
with encouraging efficacy, similar to findings from a concurrently published phase 2 study of 
rituximab-ABVD by the MD Anderson.12 As these were nonrandomized studies, further 
clinical trials are needed to define the utility of rituximab in cHL.  
 
In the Johns Hopkins study of rituximab-ABVD, a secondary goal was to assess the 
behavior of CCBCs clinically. Of the 24 evaluable pts, most (88%) had detectable clonal, 
surface Ig+, CD27+ ALDHhigh B cells at baseline representing a median of 0.3% of total 
circulating CD19+ cells. After rituximab-ABVD, 0/15 pts whose clone disappeared have 
relapsed vs. 3/6 pts who had persistence or documented reemergence of the clone (P = 
0.015). This was the first investigation of CCBCs as prognostic markers in HL. Further 
defining their clinical significance in cHL and the utility of their monitoring is warranted. 
 
 
1.4 
Brentuximab vedotin 
The malignant HRS cells in cHL characteristically have strong CD30 expression, whereas 
normal tissues have limited, restricted expression of CD30. In contrast to earlier generation 
anti-CD30 therapies,16 brentuximab vedotin, a monoclonal anti-CD30 antibody-drug 
conjugate, is highly active in relapsed cHL17 as well as anaplastic large cell lymphoma.18 It 
is an anti-CD30 chimeric monoclonal antibody (cAC10) covalently linked, through an 
enzyme-cleavable linker, to the anti-tubulin agent MMAE and is FDA approved for relapsed 
cHL or anaplastic large cell lymphoma. In a pivotal phase 2 study of cHL patients who 
relapsed after auto BMT, brentuximab vedotin (1.8 mg/kg IV at 3 week intervals, maximum 
16 cycles) produced a 75% overall response rate (34% CR rate), with a median time to 
objective response of 5.7 weeks (range 5.1-56 weeks) and a median time to CR of 12 
weeks.17 This was a heavily pretreated cohort, of whom approximately half did not respond 
to their most recent systemic therapy.17 Brentuximab vedotin was associated with a median 

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response duration of 6.7 months overall, and 20.5 months those who achieved CR. The 
median PFS was 5.6 months (95% CI, 5.0 – 9.0 months), and the estimated 1-year overall 
survival (inclusive of patients who received subsequent therapy) was notably 89% (95% CI, 
83-95%). 
 
Brentuximab vedotin carried generally manageable toxicities, with the most common 
including (generally reversible) peripheral neuropathy (mostly sensory) and gastrointestinal 
side effects.17 Of the grade > 3 toxicities, 8% were from peripheral sensory neuropathy and 
the majority were hematologic (including 6% grade 4 neutropenia) though without any 
episodes of febrile neutropenia.17 The median time to onset of grade 2 peripheral 
neuropathy was 27.3 weeks (38.0 weeks for grade 3 peripheral neuropathy). Improvement 
or resolution of neuropathy occurred in 80% of patients. Frontline regimens incorporating 
brentuximab vedotin are under investigation. 
 
1.5 
High-dose therapy in relapsed cHL 
In cHL that relapses after frontline therapy, multiagent salvage chemotherapy, followed by 
high-dose therapy with auto BMT, is the widely adopted standard, provided that the relapse 
is chemosensitive. Auto BMT in this setting produces a 1-year FFS of ~70%, a 3-year FFS 
of ~50%,19,20 and a significantly better FFS than standard-dose chemotherapy alone.19 
However, a statistically significant overall survival advantage to auto BMT in cHL has not 
been demonstrated.19,21 Auto BMT also carries a 5-8% mortality risk, a risk of major 
morbidity, and a nearly 100% risk of infertility. Furthermore, the finding that cHL “CSCs” 
may circulate even in early-stage disease heightens concern that autograft contamination 
contributes to relapse.  
 
Given the need for curative but less toxic regimens for relapsed cHL, we conducted 
a 30-patient pilot study for patients with relapsed chemosensitive cHL and no prior BMT, 
involving rituximab, high-dose cyclophosphamide without BMT, and an allogeneic, GM-CSF 
producing cancer vaccine.4 Patients having primary refractory disease or prior BMT were 
excluded. On preliminary analysis, with median 3.1 year follow-up, the estimated PFS was 
70% at 1 year and 61% at 3 years; the estimated overall survival was 91% at 3 years. In 
patients who had relapsed within 1 year of first-line therapy completion (a poor-risk feature), 
the estimated PFS was 59%. The regimen was generally well-tolerated. Although late-onset 
neutropenia (presumably secondary to rituximab) was common, it carried no or no major 
clinical consequence. All patients who subsequently relapsed were able to proceed to auto 
or allo BMT. Thus this study had promising results that appear comparable to what would 
be expected with auto BMT, and significantly, demonstrates that a clear subset of patients 
with relapsed chemosensitive cHL could achieve durable remissions with less intensive 
therapies that do not involve BMT.  
 
1.6 
Summary of hypotheses and design 
Although the clinical utility of rituximab in cHL requires furthers study, and the data 
regarding cHL stem cell biology and targeting are preliminary, our present CCBC data 
suggest that brentuximab vedotin and rituximab are likely to target different cellular 
compartments in cHL. Brentuximab vedotin, which targets the CD30+ HRS cells would not 
be expected to target the CD30- clonotypic B-cell population in cHL whereas anti-CD20 
therapies such as rituximab might. This study is based upon the hypothesis that, by 
targeting different cellular compartments, the combination of anti-CD20 therapy (targeting 
cHL CSCs) and anti-CD30 therapy (targeting HRS cells and tumor bulk) may be 
complementary in cHL. Given the impressive activity of brentuximab vedotin as salvage in 
the post-transplant setting and the potential for rituximab to target the cHL CSCs, it is also 
hypothesize that such an antibody combination alone could be sufficient for patients with 
first chemosensitive relapse of cHL, allowing high-dose therapy and auto BMT, and the 
associated major risks, to be avoided.  

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 This is a single-arm pilot study for first management of relapsed cHL, with 1-year 
failure-free survival (FFS) as the primary endpoint. This study uniquely investigates the 
combination of rituximab and brentuximab vedotin to potentially target cHL CSCs and HRS 
cells, respectively, and uniquely avoids auto BMT (and its associated toxicities) in those 
patients who have chemosensitive disease. The study aims to investigate the no-BMT 
intervention only in patients with chemosensitive disease, defined as a response to 4 lead-
in doses of single-agent brentuximab vedotin. Responding patients then receive 
combination brentuximab vedotin plus rituximab, with BMT reserved for treatment failure, 
whereas patients who do not respond to the brentuximab vedotin lead-in go off-study.  
We anticipate that with the rituximab-brentuximab vedotin combination, a significant 
subset of chemosensitive pts will achieve durable remissions without BMT and that this 
combination is potentially curative. We also anticipate that, should the combination fail, 
efficacy of standard salvage regimens will not be compromised, as the mechanism of action 
of these monoclonal antibodies differs from that of salvage regimens standardly used in this 
setting (e.g., ifosfamide, carboplatin, etoposide). For similar reasons, hematopoietic stem 
cell mobilization is unlikely to be impaired. We also expect this approach to be generally 
well-tolerated with manageable toxicities. Because these patients are not heavily 
pretreated, and because brentuximab vedotin cycles are capped with mandated 
adjustments for grade > 2 peripheral neuropathy, the incidences of prohibitive neuropathy 
and neutropenia17 are expected to be low. Based on previous experiences with rituximab-
associated late-onset neutropenia,22,23 idiopathic late-onset neutropenia is anticipated but 
should carry no or no major clinical consequence. 
As a key secondary endpoint, frequencies of CCBCs (the putative cHL CSC 
population) will be serially quantified, so as to investigate the potential impact of this 
approach on cHL CSCs, further characterize the clinical significance of these clonotypic B-
cells, and serve as a platform for future studies of cHL CSC targeting. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary objective 
 
In patients with chemosensitive relapse of cHL, estimate the probability of 1-year FFS 
with the combination of brentuximab vedotin and rituximab without high-dose therapy. 
 
 
 
2.2 
Secondary objectives 
 
Evaluate circulating clonotypic B cells as potential biomarkers in cHL:  
 
Through serial measurements, characterize the impact of the study treatment on 
the presence and frequency of CCBCs. 
 
Characterize the relationship between clonotypic B cell detection and clinical 
outcome, so as to begin to evaluate CCBC frequencies as potential biomarkers 
for classification (progression) and risk assessment (PFS) in cHL. 
 
Describe tolerability, relative delivered dose intensity, and safety including frequency 
and significance of grade > 3 infections and grade > 3 late-onset neutropenia. 
 
Estimate objective response rate (overall response rate, PR, CR) and median times to 
objective response, best response, and duration of response.  
 
Estimate probabilities of 1-year and longer-term progression-free, event-free and overall 
survival, and longer-term FFS. 
 
Describe disease outcomes according to duration of initial remission.  
 
Describe disease and survival outcomes with salvage therapy following combination 
brentuximab vedotin and rituximab, including the probability of freedom from next 
progression.  
 
Describe the association between the post-cycle 2 PET result and PFS. 
 
Descriptively compare FFS with combination brentuximab vedotin and rituximab to FFS 

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after most recent prior treatment. 
 
3.0 
SELECTION OF PATIENTS 
 
3.1 
Eligibility criteria 
 
Age > 16 years 
 
Biopsy-proven diagnosis of cHL (regardless of HRS cell CD20 expression) per the 
World Health Organization classification criteria24; lymphocyte predominant histology is 
excluded 
 
Untreated relapse of cHL (with the exception of steroids) as follows: 
a. HL that relapsed > 3 months after completion of first-line chemotherapy or 
combined modality therapy, and has not yet been treated with salvage 
chemotherapy 
b. Stage I-II HL that relapsed > 3 months after first-line chemotherapy, then 
relapsed after radiation therapy delivered with curative intent, and has not yet 
been treated with salvage chemotherapy 
 
Radiographically measurable disease (> 1 focus of lymphoma measuring > 1.5 cm) 
 
No primary induction failure, defined as failure to achieve CR with first-line 
chemotherapy or chemoradiation, disease progression during first-line chemotherapy or 
chemoradiation, or progression or biopsy-proven disease persistence within 8 weeks of 
first-line therapy completion 
 
No prior brentuximab vedotin  
 
If rituximab previously given, lymphoma must have relapsed > 12 months after last 
rituximab dose 
 
No grade > 2 peripheral neuropathy 
 
No HIV infection, active hepatitis B infection, or active hepatitis C infection 
 
No receipt of a live vaccine within 4 weeks prior to registration 
 
Baseline laboratories:  
a. ANC > 1000/uL and platelets > 75,000/uL, unless due to bone marrow 
involvement by lymphoma 
b. Serum creatinine < 2.0 mg/dL 
c. Total bilirubin < 2.0 mg/dL (excluding Gilbert’s syndrome), unless due to 
lymphoma 
 
ECOG performance status 0, 1 or 2.  
 
No NYHA class III or IV heart disease. 
 
No active concurrent malignancy with the exception of superficial non-melanoma skin 
cancer and cervical carcinoma in situ. 
 
Not pregnant or breast feeding; women of childbearing potential and sexually active 
men must agree to use an accepted and effective method of birth control. 
 
Signed informed consent. 
 
3.2 
Study interruption or withdrawal 
Potential reasons for interruption or discontinuation of protocol therapy include: 
 
Serious or intolerable adverse reaction to treatment.  
 
No response to 4 lead-in doses of single-agent brentuximab vedotin. 
 
Protocol violation. 
 
Withdrawal of consent. 
 
4.0 
REGISTRATION PROCEDURES 
4.1 
Projected accrual 
Up to 35 patients will be treated and additional patients may be screened and registered, in 

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order to identify up to 25 patients who are eligible to receive combination brentuximab 
vedotin and rituximab (those who respond to 4 lead-in cycles of brentuximab vedotin alone) 
and hence are considered evaluable for the primary endpoint (per Statistical 
Considerations, Section 9.0). Participation of women and minorities is encouraged. 
 
4.2 
Registration  
To register a patient at Johns Hopkins, the following documents must be completed and the 
patient then registered in CRMS: 
 
Study-specific registration form  
 
Signed and dated informed consent 
 
Eligibility checklist  
A registration may be cancelled in writing provided that the subject has not begun protocol 
therapy.  
 
5.0 
TREATMENT PLAN 
 
5.1   
Evaluations and procedures 
Required evaluations are designated in Section 7.0. 
 
5.2 
Brentuximab vedotin and rituximab 
 
5.21 
Eligibility for antibody combination 
Only patients who have an adequate response to the first 4 cycles of single-agent 
brentuximab vedotin are eligible to proceed with the combination of brentuximab vedotin 
and rituximab. A response is considered a) PR or CR per anatomic (CT-based) but not 
metabolic criteria from the 2007 IWG criteria,25 or b) stable disease anatomically, with a 
“negative” PET result by Deauville criteria,25 per Section 6.1.  
 
If an adequate response is not achieved to 4 cycles of single-agent brentuximab vedotin, 
the patient will go off study and will be regarded as inevaluable for the primary endpoint and 
secondary survival endpoints. That patient will, however, be evaluable for the correlative 
blood work, having a maximum of 3 research blood collections: two at baseline and one at 
the post-cycle 4 assessment (per Section 7.2).  
 
5.22 
Brentuximab vedotin 
Brentuximab vedotin, 1.8 mg/kg IV over 30 minutes (weight capped at 100 kg), is given for 
up to 10 doses (cycles), with a cycle length of 21 days. Brentuximab vedotin is first given on 
day 1 of cycles 1, 2, 3, and 4 as a single agent (weeks 0, 3, 6, and 9, respectively). Four 
cycles are chosen because of the 12-week median time to CR in the pivotal phase 2 trial of 
brentuximab vedotin after autologous BMT for HL.17 
 
Responding patients (per Section 5.21) then receive brentuximab vedotin on day 1 of 
cycles 5 through 10 (~weeks 12, 15, 18, 21, 24, and 27, respectively) in combination with 
rituximab as designated in Section 5.23. Any other therapy for lymphoma with the exception 
of consolidative radiation therapy (RT) is reserved for treatment failure, including BMT. 
 
The designated time points for brentuximab vedotin are +/- 1 day for the first 6 doses of 
brentuximab vedotin, and +/- 3 days for the remaining doses of brentuximab vedotin.  
 
Brentuximab vedotin is dosed according to actual body weight unless the patient weighs 
>100 kg, in which case the dose will be calculated based on a 100 kg weight. 
Premedication for brentuximab vedotin is not routinely administered before the first dose. 

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Should the patient develop an infusion reaction, premedication with acetaminophen (650 
mg p.o) and diphenhydramine (25 mg p.o. or IV, or 50 mg p.o.) at least 30 minutes before 
subsequent doses should be given. 
 
5.23  Rituximab 
Rituximab 375 mg/m2 IV (may be rounded to the nearest 100 mg) is given for up to 8 
“induction” doses: day 1 of week 12, 13, 14, and 15, then day 1 of week 18, 21, 24, and 27. 
This is followed by rituximab “maintenance” (375 mg/m2 IV once every 3 months x 2 doses) 
to complete a ~ 1 year total course of therapy.  
 
The designated time points for rituximab are +/- 1 day for the first 4 doses, +/- 3 days for the 
next 4 doses of rituximab, and +/- 1 week for the remaining two doses given as 
maintenance. 
 
Rituximab is dosed according to actual body weight. The rituximab dose may be split over 2 
days in the case of significant infusion reaction. 
 
Rituximab is initially given in 1 week intervals with the intent of maximizing B-cell depletion 
early in the treatment course. Maintenance rituximab is given with the intent of facilitating 
CSC targeting after reduction in tumor bulk.  
 
 
5.24 
Dose modifications and delays 
The dose of rituximab is never adjusted. Dose reductions in brentuximab vedotin may be 
required as outlined below. 
 
1) Dose modifications for hematologic toxicities 
The dose of rituximab is never adjusted, though may be split over 2 days in the case of 
significant infusion reaction. Should grade 4 neutropenia occur despite growth factor 
support and not resolve by 7 days, brentuximab vedotin is to be reduced to 1.2 mg/kg, or if 
already at 1.2 mg/kg, then to 0.9 mg/kg. Should grade 4 neutropenia occur despite these 
measures and be accompanied by grade > 3 infection, continuation with study treatment 
shall be discussed with the PI and a decision rendered on a case-to-case basis. 
 
For grade 4 thrombocytopenia not attributable to bone marrow involvement by lymphoma or 
another cause, brentuximab vedotin is to be reduced to 1.2 mg/kg, or if already at 1.2 
mg/kg, then to 0.9 mg/kg. Should grade 4 thrombocytopenia occur despite these measures, 
and not be adequately supported by platelet transfusion, continuation with study treatment 
shall be discussed with the PI and a decision rendered on a case-to-case basis. 
 
There will be no dose modifications or delays for anemia. 
 
2) Dose delays for hematologic toxicities 
Should neutropenia occur, the next dose of study drug(s) must be delayed until the ANC is 
> 1000/uL unless the neutropenia is attributable to bone marrow involvement by lymphoma. 
Should grade 4 thrombocytopenia occur that is not attributable to bone marrow involvement 
by lymphoma, the next dose of study drug(s) must be delayed until the thrombocytopenia is 
< grade 4, without platelet transfusion in the preceding 3 days. Anemia or 
thrombocytopenia should be managed per institutional guidelines and transfusion 
considered as necessary. Study drug(s) may be delayed as appropriate for grade > 3 
infection or as otherwise deemed medically necessary. 
 

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3) Dose modifications and delays for neuropathy 
In the case of grade 2 peripheral neuropathy, reduce brentuximab vedotin to 1.2 mg/kg IV 
and resume treatment without delay; or, if at 0.9 mg/kg IV when grade 2 neuropathy occurs, 
continue dosing at that level. 
 
For grade 3 peripheral neuropathy, hold brentuximab vedotin until the toxicity is < grade 2, 
then reduce to 0.9 mg/kg IV and resume treatment. If already at 0.9 mg/kg, discontinue 
brentuximab vedotin. 
 
For grade 4 peripheral neuropathy, brentuximab vedotin must be discontinued. Decisions to 
continue on study will be made on a case-by-case basis with the PI.  
 
 
 
4) Treatment should hepatitis B virus reactivate 
Should HBV reactivate during study treatment, immediately and permanently discontinue 
rituximab and institute antiviral treatment (see Section 5.32). Further decisions regarding 
study participation will be made on a case-by-case basis.  
 
 
5) Combination therapy and correlative studies during treatment delays 
Should brentuximab vedotin be delayed due to toxicity, the first 4 weekly doses of rituximab 
begun with Cycle 5 should continue on schedule (provided above hematologic criteria are 
met). Subsequent doses of rituximab that are due to be given concurrently with 
brentuximab vedotin (e.g., originally weeks 18, 21, 24, and 27) and may be delayed up to 
10 days, beyond which rituximab and brentuximab vedotin may be given on separate days. 
Any correlative blood draws (for CSC assays) due at the time a treatment is delayed, will be 
coupled with the new schedule of rituximab. 
 
5.3 
Supportive care   
Supportive care including but not limited to antiemetics, antibiotic prophylaxis, infection 
management and transfusion support shall be delivered according to good medical practice 
and institutional standards.  
 
5.31 
Filgrastim 
The use of growth factors for neutropenia management is left to the discretion of the 
treating physician and will be tracked.  
 
5.32 
Hepatitis B infection 
All patients must be screened for HBV infection, per Section 7.0, before initiating study 
treatment. For patients having evidence of prior HBV infection, consult with a specialist 
regarding monitoring and consideration of antiviral therapy. 
 
Monitor patients with prior HBV infection for clinical and laboratory signs of hepatitis or HBV 
reactivation during, and for several months following, rituximab therapy. HBV reactivation 
has been reported up to 24 months following therapy completion. 
 
In patients who develop reactivation of HBV while on study, immediately discontinue 
rituximab and institute appropriate treatment. Insufficient data exist regarding the safety of 
resuming rituximab in patients who develop HBV reactivation. 
 
5.4 
Other lymphoma therapies 
 
5.41 
Permitted lymphoma therapies 
With the exception of consolidative RT and, if medically necessary, steroids, no other 

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treatment for lymphoma is permitted on study in the absence of treatment failure or 
an event that leads to study withdrawal. 
 
5.42 
Radiation therapy 
Consolidative RT is permitted for relapse that has been localized, after completion of the full 
planned combination of brentuximab vedotin-rituximab (i.e., through cycle 10) and 
associated responsive assessment and research blood draws. RT may then be given, 
either prior to or concurrently with maintenance rituximab. RT records (including summary 
of fields, dose, technique) will be obtained and toxicities during RT tracked as they may 
related to the study drugs. Guidelines for consolidative RT are provided in the Appendix. 
 
5.43 
Steroids  
Steroids are permitted if medically necessary, for short-term use in lymphoma treatment (in 
urgent situations only; no longer-term use) or otherwise as medically necessary. Their use 
will be tracked. 
 
5.5 
Correlative studies 
Blood will be collected for correlative studies on cHL CSC biology (i.e. frequencies of 
circulating clonotypic B cells) per Section 7.2. These correlative blood draws are required. 
The assays will be performed in the Jones laboratory at Johns Hopkins, based on 
previously published methods.2 Specimens will be banked for future related research on 
cHL stem cell biology and biomarkers.  
 
5.6 
Follow-up procedures 
The minimum follow-up for study purposes is specified in Section 7.0. Standard monitoring, 
consisting of an exam and indicated diagnostic studies is suggested at these or more 
frequent intervals according to good medical practice.  
 
Should disease progression occur despite combination brentuximab vedotin-rituximab, 
information that will be tracked includes but is not limited to the following unless patient 
consent is withdrawn: frequency of circulating clonotypic B cells, type of salvage regimen(s) 
including hematopoietic BMT, freedom from next progression, overall survival and all-cause 
mortality. Copies of relevant medical records will be obtained.  
 
5.7 
Toxicity grading and reporting 
Toxicities are graded according to the National Cancer Institute (NCI) Common Toxicity 
Criteria, version 4.0 and attribution to study treatment designated. Toxicities will be reported 
in accordance with IRB, federal, and sponsor-specified requirements. 
 
In those cases where the NCI criteria do not apply, intensity will be defined as: 
Mild: awareness of symptom or sign, but easily tolerated 
Moderate: discomfort is enough to cause interference with normal activities 
Severe: inability to perform normal daily activities 
Life threatening: immediate risk of death from the reaction as it occurred 
 
Specific adverse event grading and reporting requirements for rituximab are designated in 
Appendix C. 
 
6.0 
MEASUREMENT OF EFFECT 
 
6.1 
Response assessment  
Response assessment is based on the 2007 revised IWG criteria for lymphoma25 and the 

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Deauville criteria26,27 as follows (see 18F FDG PET evaluation form, Appendix).  
 
Post-cycle 10 (or last cycle) response assessment and subsequent assessments utilize the 
2007 revised IWG criteria for lymphoma.25 
 
Post-cycle 4 (interim) response assessment utilizes the CT-based but not metabolic criteria 
from the 2007 revised IWG criteria for lymphoma, as these metabolic criteria were not 
developed for interim scans.25  In addition, the interim and post-cycle 10 (or last cycle) 
metabolic imaging is evaluated with the Deauville criteria26,27 (“negative” = score of 1, 2, or 
3; “positive” = score of 4 or 5).  
 
Up to two expert radiologists will be assigned to interpret these and potentially other 
imaging results for study purposes.  
 
For exploratory purposes only, characterization of the intensity of FDG uptake using 
semiquantitative methods is planned (e.g., delta SUVmax,28 PERCIST29).  
 
6.2 
Disease and survival endpoints 
 
6.21 
Progression-free survival (PFS) is defined as the interval from treatment initiation 
to the date of first objective disease progression or relapse, death from any cause, 
or last patient evaluation. Patients who have not progressed, relapsed or died will be 
censored at the last date they were assessed. 
 
6.22 
Failure-free survival (FFS) is defined as the interval from treatment initiation to the 
date of first objective disease progression or relapse; documented failure to achieve 
CR by the time of post-cycle 8 assessment; death from any cause; or last patient 
evaluation. Patients without treatment failure will be censored at the last date they 
were assessed and deemed failure-free. 
 
6.23 
Event-free survival (EFS) is defined as the interval from treatment initiation to any 
treatment failure (per Section 6.22), discontinuation of specified treatment due to 
any reason (e.g., toxicity, patient or physician preference, initiation of alternative 
treatment without documented treatment failure), death from any cause, or last 
patient evaluation. Patients without an event will be censored at the last date they 
were assessed. 
 
6.24 
Overall survival (OS) is defined as the interval from protocol-specified treatment 
initiation to the date of death from any cause or last patient contact. Surviving 
patients will be censored at the date they were last known to be alive. 
 
6.25 
Time to tumor progression (TTP) is defined as the interval from the date the 
patient was last found to be progression-free, to the date of first objective disease 
progression. 
 
6.3 
Dose intensity 
The delivered relative dose intensity of brentuximab vedotin and rituximab will be calculated 
per standard published methods.30  If the patient does not complete 8 cycles of therapy, the 
projected duration of 8 cycles will be regarded as the reference time.  
 
7.0 
STUDY PARAMETERS 
The tables in Sections 7.1 and 7.2 below summarize the minimum evaluations required for 

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study purposes in the absence of subsequent relapse/progression. This does not include all 
assessments indicated as standard of care, the results of which may be collected and used 
for study purposes.  
 
7.1 
Core clinical evaluations 
 
 a Baseline scans must be performed within 3 weeks prior to start of treatment; remaining 
baseline evaluations must be performed within 4 weeks, except for bone marrow biopsy 
which is within 8 weeks. Standard-of-care assessments that were performed before 
registration may be used for protocol purposes. Include start and stop dates for prior 
lymphoma therapy, if available, and type of therapy.  
b Including tumor EBV status and HRS cell CD20 expression, both designated as present or 
absent. 
c With bidimensional tumor measurements. Add neck CT if clinically indicated.  
d Including additional, dedicated contrast-enhanced CT (omit iodinated IV contrast if 
contraindicated). 
e Prior to any RT or maintenance rituximab. Should 10 cycles not be completed, then ~3-4 
weeks after last protocol-specified therapy, prior to any RT or maintenance rituximab.  
f Measured from post-cycle 10 evaluation (includes required assessment prior to each dose 
of maintenance rituximab). Designated time points are +/- 1 week. 
g If involved with lymphoma at baseline.  
h Chemistry panel includes BUN, creatinine, AST, ALT, total bilirubin, alkaline phosphatase. 
i Serum or urine HCG in females of childbearing potential. 
j  It is preferred that PET/CT scans be done at the same facility. Baseline, post Cycle 4, and 
post cycle 10 (or last cycle) CT and PET/CT scans, if performed elsewhere, must be 
submitted for Johns Hopkins review. 
k HBsAg, anti-HBc, and anti-HBs. For patients with risk factors or prior hepatitis B infection, 
add e-antigen. If hepatitis B infection screen is positive, monitor viral load and consult with 
specialist (Section 5.32). 
 
Required clinical evaluations 
 
 
Baseline a  
0-5 d 
before 
each cycle  
0-5 d 
before 
C5 
0-5 d 
before C7 
and C9 
3-4 weeks 
after C10 e 
Q3 mo x 1 y, 
then Q6 mo  
x 3 y f 
 
History & physical 
X 
X 
 
 
X   
X  
Pathology review b 
X 
 
 
 
  
 
CBC with differential 
X  
X 
 
 
 X 
X 
Chemistry panel h 
X 
X 
 
 
 X 
X 
HIV antibody 
X 
 
 
 
 
 
Hepatitis B testing k 
X 
 
 
 
 
 
Hepatitis C antibody 
X 
 
 
 
 
 
Pregnancy test i 
X  
 
 
 
 
 
Bone marrow biopsy  
X 
 
 
 
 X g 
 
18F FDG PET-CT c, d, j 
X  
 
X   
 
 X   
 
CT chest-abd-pelvis c, j    
 
 
X 
 
X 

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7.2 
Research blood collections  
 
Required research blood draws 
 
Time Point a, b 
Sample Type Amount 
1-4 weeks before study treatment 
Heparin 
SST 
Seven 10 mL tubes 
One 7 mL tube 
D1 C1 of BV  
Heparin 
SST 
Five 10 mL tubes 
One 3 mL tube 
D1 of C5, C7, and C9   
Heparin 
SST 
Five 10 mL tubes 
One 3 mL tube 
3-4 weeks after C10 c 
 
Heparin 
SST 
Seven 10 mL tubes 
One 3 mL tube 
Prior to each maintenance rituximab  
Heparin 
SST 
Five 10 mL tubes 
One 3 mL tube 
Every 6 months x 2, following last 
maintenance rituximab 
Heparin 
SST 
Five 10 mL tubes 
One 3 mL tube 
Upon next relapse/progression d  
Heparin 
SST 
Five 10 mL tubes 
One 3 mL tube 
 
a Research labs must be drawn 0-3 days prior to any scheduled treatment up through C9; 
with maintenance rituximab, the window is 0-5 days prior. 
b Patients who relapse/progress will have measurements up to and including the time of 
relapse/progression. 
c Prior to consolidative radiation therapy or maintenance rituximab; or should 10 cycles not 
be completed, then ~3-4 weeks after last protocol-specified therapy, prior to any RT or 
maintenance rituximab.  
d When feasible. 
 
8.0 
DRUG INFORMATION 
 
8.1 
Rituximab 
Other names 
IDEC-C2B8, Rituxan. 
Classification 
 
Monoclonal antibody.  
Mode of action 
This chimeric mouse/human anti-CD20 antibody binds human complement and causes 
lysis of B-cells. It has significant activity in assays for antibody dependent cellular 
cytotoxicity. 
Storage and stability 
Stored at 2-80 C. Reconstituted antibody is stable for 24 hours upon refrigeration followed 
by 12 hours at room temperature. 
Preparation 
Diluted with normal saline to a concentration of 1 - 4 mg/mL. Shaking can cause 

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aggregation and precipitation of the antibody and should be avoided. 
Administration and infusion reactions 
Intravenous infusion. The initial dose rate should be 50 mg/hour for the first hour. If no 
toxicity is seen, the dose rate may be escalated gradually to a maximum of 400 mg/hour. 
Subsequent doses have required much less infusion time. If the first dose of rituximab is 
well tolerated, the starting flow rate for subsequent doses is 100 mg/hour, then increased 
gradually (e.g., 100 mg/hour increments at 30-minute intervals) not to exceed 400 mg/hour. 
Alternatively, subsequent doses (but not the first rituximab dose) may be given as a rapid 
infusion in accordance with institutional standards (e.g., 20% of total dose over 30 minutes, 
followed by 80% of total dose over 60 minutes), provided there was no severe reaction to 
the previous dose of rituximab. 
 
Patients may experience infusion reactions. When these occur, the antibody infusion should 
be temporarily discontinued or slowed. When symptoms improve, the infusion should be 
resumed, initially at half the previous rate. Following the antibody infusion, the intravenous 
line should be kept open for medications, as needed. If there are no complications, the 
intravenous line may be discontinued after one hour of observation. 
 
Oral premedication (acetaminophen and diphenhydramine hydrochloride) may be 
administered 30 to 60 minutes prior to starting each infusion of rituximab. Steroid 
premedication is permitted in the case of prior infusion reaction. Since transient 
hypotension may occur during rituximab infusion, consideration should be given to 
withholding antihypertensive medications 12 hours prior to rituximab infusion. 
 
Availability  
Commercially available in 10 mL (100 mg) and 50 mL (500 mg) single-use vials at a 
concentration of 10 mg /mL.  
 
Incompatibilities 
Do not mix or dilute rituximab with other drugs. No incompatibilities between rituximab and 
polyvinylchloride or polyethylene bags have been observed. 
 
Side effects of rituximab include: 
1. Infusion related symptoms: Fevers, chills, rigors, hypotension, anaphylaxis or 
hypersensitivity reactions, arrhythmia, dyspnea, bronchospasm and angioedema. In rare 
cases (0.04-0.07%), severe and fatal cardiopulmonary events, including hypoxia, 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, and 
cardiogenic shock, have occurred, nearly all in association with the first infusion. Patients 
with preexisting cardiac conditions, including arrhythmia and angina, have had recurrences 
of these cardiac events during rituximab infusions. 
 
2. Gastrointestinal: Nausea, vomiting. 
 
3. Hematologic: Leukopenia, anemia, thrombocytopenia. In clinical trials, NCI CTC Grade 3 
and 4 cytopenias were reported in 48% of patients treated with rituximab, including 
lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and 
thrombocytopenia (2%). In addition, prolonged pancytopenia, marrow hypoplasia, and late-
onset grade 3 and 4 neutropenia23 have occurred. The late-onset neutropenia may be 
GCSF responsive. 
 

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4. Dermatologic: Rash, pruritus, urticaria, and rarely severe mucocutaneous reactions. 
 
5. Infectious: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections 
can occur during and following the completion of rituximab-based therapy.  Infections have 
been reported in some patients with prolonged hypogammaglobulinemia (defined as 
hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral 
infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster 
virus, West Nile virus, and hepatitis B and C. Discontinue rituximab for serious infections 
and institute appropriate anti-infective therapy. Hepatitis B virus (HBV) reactivation, in 
some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in 
patients treated with drugs classified as CD20-directed cytolytic antibodies, including 
rituximab. Cases have been reported in patients who are hepatitis B surface antigen 
(HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core 
antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to 
have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B 
surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in 
HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of 
HBsAg in a person who was previously HBsAg negative and anti-HBc positive. 
Reactivation of HBV replication is often followed by hepatitis. The median time to the 
diagnosis of hepatitis was approximately four months after the initiation of rituximab and 
approximately one month after the last dose.  
 
JC virus infection resulting in Progressive multifocal leukoencephalopathy (PML) 
and death can occur in rituximab-treated patients with hematologic malignancies or with 
autoimmune diseases. The majority of patients with hematologic malignancies diagnosed 
with PML received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or 
concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 
12 months of their last infusion of rituximab. Consider the diagnosis of PML in any patient 
presenting with new-onset neurologic manifestations.  Evaluation of PML includes, but is 
not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.  
Discontinue rituximab and consider discontinuation or reduction of any concomitant 
chemotherapy or immunosuppressive therapy in patients who develop PML. 
 
6. Renal and electrolyte: Renal toxicity has occurred in patients with high numbers of 
circulating malignant cells (>25,000/mm2) or high tumor burden who experience tumor lysis 
syndrome. Although rare, tumor lysis syndrome has been reported in postmarketing 
studies and is characterized in patients with a high number of circulating malignant cells 
(>25,000 ul) by rapid reduction in tumor volume, renal insufficiency, hyperkalemia, 
hypocalcemia, hyperuricemia, and hyperphosphatemia 
 
7. Other: Headache, asthenia. The following immune serious adverse events have been 
reported to occur rarely (<0.1%) in patients following completion of rituximab infusions: 
arthritis, disorders of blood vessels (vasculitis, serum sickness and lupus-like syndrome), 
lung disorders including pleuritis and scarring of the lung (bronchiolitis obliterans), eye 
disorders (uveitis and optic neuritis), and severe bullous skin reactions (including toxic 
epidermal necrolysis and pemphigus) that may result in fatal outcomes. Patients may have 
these symptoms alone or in combination with rash and polyarthritis 
 
8.2 
Brentuximab vedotin  
Other names 
 
Adcentris TM, SGN-35 

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Classification 
 
Antibody-drug conjugate 
 
 
 
Mode of action 
Brentuximab vedotin is an antibody-drug conjugate consisting of a CD30 targeted chimeric 
monoclonal antibody (cAC10) covalently linked, via an enzyme-cleavable linker, to the anti-
tubulin agent MMAE. cAC10 has a typical structure of the human IgG1 subclass.  
Storage and stability 
Vials must be stored under refrigeration at 2-8°C. Chemical and physical stability of the 
reconstituted brentuximab vedotin drug product has been demonstrated for 24 hours at 2-
8°C and 25°C. However, brentuximab vedotin does not contain preservatives; therefore, 
from a microbiological standpoint, opened and reconstituted vials should be used 
immediately. If not used immediately, the in-use storage should not be longer than 24 hours 
under refrigeration at 2–8°C. It is recommended that brentuximab vedotin vials and 
solutions be protected from direct sunlight until the time of use. 
 
 
Preparation 
Brentuximab vedotin is a sterile, preservative-free, white to off-white lyophilized cake or 
powder, supplied in single-use vials. Each vial contains brentuximab vedotin, trehalose, 
sodium citrate, and polysorbate 80. Brentuximab vedotin drug product is reconstituted with 
Sterile Water for Injection. The pH of reconstituted product is approximately 6.6. 
The reconstituted brentuximab vedotin drug product is a clear to slightly opalescent, 
colorless solution with no visible particulate matter. The reconstituted solution is 
subsequently diluted in sterile 0.9% Sodium Chloride for Injection, USP, 5% Dextrose 
Injection USP, or Lactated Ringer’s Injection USP, for IV administration. 
Administration and infusion reactions 
Administered as an IV infusion over 30 minutes. Infusion-related reactions may occur 
during or soon after brentuximab vedotin treatment. Symptoms include chills, nausea, 
cough, itching, and shortness of breath. Serious allergic reaction (including wheezing, 
difficulty breathing, hives, itching, swelling) that requires immediate medical attention and 
treatment discontinuation is possible. Premedication is not routinely given with the first dose 
of brentuximab vedotin, but is advised (e.g., diphenhydramine, acetaminophen) for 
subsequent doses should an infusion-related reaction occur. 
 
Potential drug interactions 
Evidence in humans suggests brentuximab vedotin and MMAE are neither inhibitors nor 
inducers of CYP3A4. Data indicate that MMAE is a substrate of CYP3A4. No dose 
adjustment should be necessary based on co-administration of a CYP3A4 inducer. Patients 
receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be 
closely monitored for AEs.  
 
Distribution, metabolism and excretion 
The distribution of brentuximab vedotin when administered intravenously at standard doses 
is primarily limited to the vascular space. The primary route of excretion of MMAE is fecal, 
whereas urinary excretion is moderate, with data suggesting a low propensity for 
metabolism-based biotransformation.  

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Side effects of brentuximab vedotin 
The table below is adapted from Comprehensive Adverse Event and Potential Risks 
(CAEPR) list of reported and/or potential AEs associated with brentuximab vedotin. Other 
toxicities may occur, and brentuximab vedotin in combination with other agents could 
exacerbate AEs or cause AEs not previously reported with either agent.  
 
 Adverse Events with Possible  
 Relationship to Brentuximab Vedotin 
 (CTCAE 4.0 Term) 
[n= 249] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Constipation 
 
 
Diarrhea 
 
 
 
Nausea 
 
 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Chills 
 
 
 
Edema 
 
 
Fatigue 
 
 
 
Fever 
 
 
 
 
Infusion related 
reaction 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
 
Upper respiratory 
infection 
 
 
INVESTIGATIONS 
 
Neutropenia 2 
 
 
 
 
Thrombocytopenia 
 
 
 
Leukopenia 2 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
 
Tumor lysis syndrome  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
Myalgia 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 

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 Adverse Events with Possible  
 Relationship to Brentuximab Vedotin 
 (CTCAE 4.0 Term) 
[n= 249] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Headache 
 
 
 
 
Other nervous system 
disorders (PML) 
 
 
Peripheral motor 
neuropathy 
 
 
Peripheral sensory 
neuropathy 
 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Cough 
 
 
 
Dyspnea 
 
 
 
 
Pneumonitis1 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
Pruritus 
 
 
 
Rash (maculopapular)  
 
 
 
Stevens-Johnson 
syndrome 
 
1Elevated risk of pulmonary toxicity (e.g., pneumonitis) has been observed in patients 
treated with brentuximab vedotin in combination with bleomycin. 
2 Thus may increase the risk of infection, including severe infection.  
 
Note: Patients who are pregnant or breastfeeding should not receive brentuximab vedotin 
because of potential risk to the fetus or nursing baby. 
 
8.2 
Toxicity grading and reporting 
Toxicities are graded according to the National Cancer Institute (NCI) Common Toxicity 
Criteria, version 4.0 and attribution to study treatment designated. Toxicities will be reported 
in accordance with IRB requirements. 
 
In those cases where the NCI criteria do not apply, intensity will be defined as: 
Mild: awareness of symptom or sign, but easily tolerated 
Moderate: discomfort is enough to cause interference with normal activities 
Severe: inability to perform normal daily activities 
Life threatening: immediate risk of death from the reaction as it occurred 
 
9.0  
STATISTICAL CONSIDERATIONS  
 
9.1 
Primary endpoint 
 
9.11 
Definition of primary endpoint 
This is a single-arm pilot study with 1-year FFS as the primary efficacy measure and 
endpoint. A failure is defined as relapse/progression, lack of CR by completion of 
brentuximab vedotin + rituximab “induction” (post-cycle 10 assessment), or death. Overall 

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hazard rate estimates and 95% confidence intervals (CIs) as well as non-parametric 
Kaplan-Meier estimates will be used to estimate FFS, and the 1-year FFS reported with 
95% CI. The design includes interim analyses for futility.  
 
 
9.12 
Sample size 
Based in part on projected accrual, up to 25 patients eligible to receive combination 
brentuximab vedotin-rituximab, as determined after 4 cycles of single-agent brentuximab 
vedotin, will be accrued and considered evaluable for the primary efficacy measure. Up to 
35 may begin treatment with single-agent brentuximab vedotin to identify those eligible for 
the antibody combination, as not all patients are expected to respond to brentuximab 
vedotin. Only those patients who receive the antibody combination will be considered 
evaluable for the primary endpoint. 
 
The 1-year FFS will be compared to a reference of 40% (hazard rate = 
0.916/person-year, i.e. median of 9.08 months). In patients with first chemosensitive 
relapse of cHL, a 1-year FFS of 70% is a reasonable benchmark for what one could expect 
with BMT. However, because this study aims to avoid BMT and its associated toxicities, a 
1-year FFS of 60% (hazard rate = 0.51/person-year, median of 16.3 months) would be 
considered promising and is the benchmark for this study. Assuming exponential survival, 
accrual of ~8 evaluable (chemosensitive) patients per year, minimum 1 year of additional 
follow-up and a two-sided alpha of 0.10, the sample size of 25 will have 83% power to 
detect a hazard ratio of 0.55.  
  
9.2  
Early stopping guidelines 
 
 
 
9.21 
Early stopping rules for futility 
The operating characteristics of design are demonstrated by simulations, carried out with 
exponential survival and staggered patient entry. The design assumes a sample size of 25 
evaluable patients and the above accrual period and additional follow up. The null 1-year 
FFS is 40%. We have designed the study to stop early only if the posterior probability of 1-
year FFS being less than the null is 80% or higher.  
 
Interim analyses begin once 10 evaluable patients have been entered and occur 
after groups of 5 patients thereafter up to a maximum of 25. The interim analysis estimates 
of 1-year FFS are based on analyses with an underlying Dirichlet process prior. We 
approximate the posterior distribution, which is actually a mixture of Beta distributions, the 
mixture depending on the amount of censoring, with a single Beta distribution. The 
parameters of this posterior Beta distribution are based on the number of failures and the 
effective sample size at one year, combined with the parameters of the prior.  
 
The following table summarizes the operating characteristics of the futility stopping 
rule under various scenarios for the underlying exponential FFS, based on 1000 
simulations. For futility monitoring we optimistically characterize the uncertainty of the 1-
year FFS estimate with the prior: beta(3,2). This implies that our prior guess at the 1-year 
FFS in this study is 60% and there is 90% certainty that the 1-year FFS is between 25% 
and 90%.  

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Characteristics of futility stopping rule with N of 25 
1-y FFS 
Prob Stop 
for Futility 
Avg N 
Estimated  
1-y FFS 
lo 95% 
Post Int'l 
hi 95% Post 
Int'l 
Prob H0 
Rejected  
0.10 
1.00 
10 
0.10 
0.00 
0.30 
0.00 
0.20 
1.00 
10 
0.20 
0.00 
0.40 
0.00 
0.30 
0.98 
11 
0.28 
0.00 
0.47 
0.01 
0.40 
0.84 
14 
0.37 
0.10 
0.60 
0.10 
0.50 
0.59 
17 
0.45 
0.20 
0.68 
0.30 
0.60 
0.27 
22 
0.57 
0.30 
0.76 
0.66 
 
9.22 
Early stopping rules for safety 
If it becomes evident that the proportion of patients who develop grade 4 infection (up 
through 6 months following completion of study-specified treatment) convincingly exceeds 
10%, the study will be halted for a safety consultation. Only patients who receive 
combination brentuximab vedotin-rituximab will be considered evaluable for this safety 
stopping rule, with censoring for this toxicity upon treatment of subsequent 
relapse/progression. The stopping rule will hold enrollment if the posterior probability of this 
toxicity more than 0.10 is 75% or higher. The prior for this monitoring rule is beta(1,9). This 
means that our prior guess at the proportion with grade 4 infection is 10%, and there is 90% 
probability that this proportion is between 0.57% and 28.3%.  
 
The following table shows the resulting stopping rule. For example, the rule will call 
for stopping the study if 3 out of the first 9 evaluable patients experience a grade 4 
infection. The next shows the percent of the time that the stopping rule will terminate the 
study under different hypothetical risks of grade 4 infections, along with the average sample 
size at time of stopping (based on 5000 simulations).  
 
Stopping rule for grade 4 infection 
Study paused if:  
2 AEs 
3 AEs 
4 AEs 
And number of patients between: 
2 - 8  
9 - 16 
17 - 25 
 
 
The next table shows the percent of the time that the stopping rule will terminate the 
study under different hypothetical risks of grade 4 infections, along with the average sample 
size at time of stopping (based on 5000 simulations).  
Operating characteristics of safety stopping rule 
based on 5000 simulations 
True Risk 
Prob. Stopping 
Avg. N 
0.02 
1.1% 
24.8 
0.05 
8.6% 
23.7 
0.10 
34.0% 
20.2 
0.15 
62.2% 
16.1 
0.20 
81.6% 
12.5 
0.25 
92.0% 
9.9 
0.30 
98.0% 
7.7 
 
9.3 
Secondary endpoints 
 
 
9.31 
Correlative studies of CCBCs 
A key secondary objective, through serial measurements of CCBC frequencies, is to 
characterize the impact of the study treatment on the presence and frequency of CCBCs, 

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and to investigate the clinical utility of CCBC assays in cHL. Specifically, the study begins to 
evaluate CCBCs as potential biomarkers for classification (progression) and risk 
assessment (PFS) in cHL. It is hypothesized that CCBC assays could be useful as a 
classification biomarker (their persistence might increase the probability of progression) and 
risk assessment biomarker (their persistence might correlate with inferior PFS). 
 
It is expected that 90% of patients will have detectable CCBCs at baseline and 
therefore our projected sample size for correlative endpoints is 22. The following analyses 
are planned: 
 
1)Trends in CCBC frequencies 
Changes in CCBC frequencies will be displayed for each patient (baseline to post-cycle 4 
brentuximab vedotin and subsequent changes with rituximab-brentuximab vedotin 
treatment) and trends assessed with descriptive summary statistics of raw, transformed 
continuous and binary (proportion with clearance) data. A regression line with the estimated 
slope for log CCBC values may be calculated individually and an overall mean slope 
reported. The exact analytic plan may vary depending of the results of serial CCBC 
measurements, but patients will be categorized as having CCBC decline (clearance) or 
CCBC increase (persistence). If changes occur gradually over the duration of study 
treatment for most patients and appear linear, the slope from simple linear regression 
models will be used to evaluate CCBC changes. If clearance is early and complete for a 
proportion of patients, regression analyses will not be necessary. If the decline in CCBCs 
extends past the period of combination treatment, a second binary indicator will be 
considered.  
 
2) Classification biomarkers for progression 
Sensitivity and specificity of CCBC changes for relapse/progression will be estimated: 
a) To evaluate more immediate effects on disease status, we will construct tables indicating 
presence or absence of progression within a given time period, relate this to preceding 
categorical changes in CCBCs, test these associations with Fisher’s exact tests and 
estimate sensitivity, specificity and positive and negative likelihood ratios.  
 
b) To evaluate longer-range effects, a linear regression (or simple difference) will estimate 
each patient’s CCBC changes during rituximab-brentuximab vedotin, with pts then grouped 
according to sign of the slope (positive or negative). The proportion progressing by 1 y and 
2 y will be estimated and compared using a Fisher’s exact test. Congruence of CCBC 
changes and ultimate clinical outcome will also be itemized on a case-by-case basis, with 
the proportion of congruent cases (CCBC clearance and remission, or CCBC persistence 
and relapse) and non-congruent cases reported with 95% CIs.  
 
Implications of sample size for estimating sensitivity and specificity 
With an N of 22, with a binary predictor for progression and 50% progression rate, 
sensitivity and specificity could be estimated with a 95% CI of +/- 0.3; likelihood 
ratios for combinations of sensitivity and specificity are shown in the table below. 
 
Likelihood ratios with N of 22  
and 50% progression rate 
Sens. 
Spec. 
LR+ (95% CI) 
LR- (95% CI) 
60% 
60% 
1.50 (0.63-3.58) 
0.67 (0.28-1.59) 
70% 
70% 
2.33 (0.87-6.23) 
0.43 (0.16-1.14) 
80% 
80% 
4.00 (1.18-13.53) 0.25 (0.07-0.85) 
 
 

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Implications of sample for a Chi-square test  
If there are approximately equal numbers of patients with clearance of CCBCs 
compared to the number of patients with persistence, and our hypotheses are 
correct, we could expect large differences in the probability of progression between 
these groups. If the expected proportion of patients that progress with complete 
clearance is very low, 5%, and if the expected proportion of patients that progress 
with persistence or increasing CCBCs is large, 50%, a sample size of 22 (11 per 
group) with a two-sided 0.10 Chi-square test would provide 84% power to detect this 
45 % difference (0.05 vs 0.50).  
 
3) Risk assessment biomarkers for PFS   
Even if CCBCs do not have high sensitivity and specificity for the classification of patients at 
risk for progression, we expect that CCBCs may be useful as a risk assessment biomarker. 
Patients with persistence of CCBCs would be expected to have shorter durations of PFS. 
As in correlative analysis 2b, patients will be grouped by CCBC changes and Kaplan-Meier 
curves for PFS generated, to evaluate any potential association between CCBC 
persistence and shorter PFS.  
 
Implications for a sample size of 22 for the hazard ratio 
In evaluating CCBCs as a risk assessment biomarker for PFS, the sample size 
calculations are based on using a binary predictor, assuming exponential survival, 
and varying proportions of patients in the group with persistent or increasing CCBCs 
(and thus an expected worse prognosis). If Group 1 indicates patients with 
persistent or increasing CCBCs and Group 2 indicates patients with CCBC 
clearance, the table below shows the power for a minimum detectable effect (HR; 
G1/G2) of 4.0 at the end of 3 years. G1 and G2 event rates of 1.0 and 0.25 per 
person-year (HR 4.0), corresponding to median PFS times of 8.35 and 33 months, 
3-y accrual and 1-y additional follow-up were assumed. 
 
Power to detect HR for PFS 
N 
% G1  
(n1/n2) 
HR  
(G1/G2) 
Power  
(3-y) 
Power 
(4-y) 
22 
0.27 (6/16) 
4.0 
0.71 
0.78 
22 
0.50 (11/11) 4.0 
0.84 
0.88 
22 
0.73 (16/6) 
4.0 
0.81 
0.85 
 
 
 
 
9.32 
Secondary clinical endpoints 
1) The frequencies of toxicities by type and grade will be described by tabulation and 
reported with exact 95% binomial CI’s. These include but are not limited to grade ≥ 2 
peripheral neuropathy, grade ≥ 3 infection and grade ≥ 3 hematologic toxicities 
including late-onset neutropenia. Duration, GCSF responsiveness, and clinical 
consequence of late-onset neutropenia will be described.  
Delivered relative dose intensity of brentuximab vedotin and rituximab will be 
summarized with the mean, median, minimum and maximum values and interquartile 
range.  
2) Objective response rates (CR+PR, CR, PR) and median times to response, best 
response, and duration of response will be reported, with appropriate estimates and 
95% CIs. 
3) One year and longer term failure-free, progression-free, event-free and overall survival 
will be reported using non-parametric KM estimates and 95% CIs.  
4) Disease outcomes will be described separately for patients who relapsed < 1 year or > 

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1 year after completion of first-line chemotherapy or chemoradiation.  
5) Disease outcomes will be reported according to the post-cycle 4 PET scan result 
(negative vs. positive) using the Kaplan Meier method and 95% CI. 
6) Descriptive statistics will be used: proportions, mean (std), median (range) and Kaplan-
Meier estimates to describe disease and survival outcomes with salvage therapy 
following rituximab- brentuximab vedotin, including the probability of freedom from next 
progression.  
7) For comparison of FFS with brentuximab vedotin-rituximab to FFS after most recent 
prior treatment, landmark analyses will be used for each of these endpoints separately 
and the median FFS reported for both.  
11.0 
RECORDS TO BE KEPT 
Records to be filed include the following:  
1. Patient consent form 
2. Registration form 
3. Case report forms  
4. Adverse event report form(s) 
5. Follow-up assessments 
 
The principal investigator will routinely review case report forms. Case report forms will be 
supported by primary source documents. All parties will maintain reports and all related 
documentation (or true copies of these documents) for a time period required by the 
applicable laws and regulations in the territories for which they are responsible, taking into 
account the minimum archiving period worldwide.  
 
It is recommended to retain all documentation of adverse events, records of trial drug 
receipt and dispensation, and all IRB correspondence for at least 2 years after the 
investigation is completed.  
 
12.0 
PATIENT CONSENT AND PEER JUDGMENT 
Current federal, NCI, state and institutional regulations regarding informed consent will be 
followed. 
 
13.0  REFERENCES  
1. 
Younes A, Romaguera J, Hagemeister F, et al. A pilot study of rituximab in patients with 
recurrent, classic Hodgkin disease. Cancer. 2003;98(2):310-314. 
2. 
Jones RJ, Gocke CD, Kasamon YL, et al. Circulating clonotypic B cells in classic Hodgkin 
lymphoma. Blood. 2009;113(23):5920-5926. 
3. 
Younes A, McLaughlin P, Goy A, et al. Rituximab plus ABVD therapy for newly diagnosed 
patients with classical Hodgkin's disease: a novel combination program targeting the cancer cells 
and the microenvironment. Blood (ASH Annual Meeting Abstracts). 2003;102:abstract 83. 
4. 
Kasamon YL, Jones RJ, Levitsky HI, et al. High-dose cyclophosphamide (Cy), rituximab, 
and a cancer vaccine for relapsed classical Hodgkin's lymphoma (cHL). Blood (ASH Annual 
Meeting Abstracts). 2010;116:abstract 3954. 
5. 
Jones RJ, Matsui WH, Smith BD. Cancer stem cells: are we missing the target? J Natl 
Cancer Inst. 2004;96(8):583-585. 
6. 
Huff CA, Matsui W, Smith BD, Jones RJ. The paradox of response and survival in cancer 
therapeutics. Blood. 2006;107(2):431-434. 
7. 
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. 
Nature. 2001;414(6859):105-111. 
8. 
Bedi A, Zehnbauer BA, Collector MI, et al. BCR-ABL gene rearrangement and expression 
of primitive hematopoietic progenitors in chronic myeloid leukemia. Blood. 1993;81(11):2898-2902. 

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9. 
Hutchings M, Loft A, Hansen MT, et al. FDG-PET after two cycles of chemotherapy predicts 
treatment failure and progression-free survival in Hodgkin Lymphoma. Blood. 2005. 
10. 
Marafioti T, Hummel M, Foss HD, et al. Hodgkin and reed-sternberg cells represent an 
expansion of a single clone originating from a germinal center B-cell with functional 
immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood. 
2000;95(4):1443-1450. 
11. 
Kanzler H, Kuppers R, Hansmann ML, Rajewsky K. Hodgkin and Reed-Sternberg cells in 
Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) 
germinal center B cells. J Exp Med. 1996;184(4):1495-1505. 
12. 
Younes A, Oki Y, McLaughlin P, et al. Phase 2 study of rituximab plus ABVD in patients 
with newly diagnosed classical Hodgkin lymphoma. Blood. 2012;119(18):4123-4128. 
13. 
Ushmorov A, Ritz O, Hummel M, et al. Epigenetic silencing of the immunoglobulin heavy-
chain gene in classical Hodgkin lymphoma-derived cell lines contributes to the loss of 
immunoglobulin expression. Blood. 2004;104(10):3326-3334. 
14. 
Newcom SR, Kadin ME, Phillips C. L-428 Reed-Sternberg cells and mononuclear 
Hodgkin's cells arise from a single cloned mononuclear cell. Int J Cell Cloning. 1988;6(6):417-431. 
15. 
Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical 
Hodgkin lymphoma. Blood. 2012;119(18):4129-4132. 
16. 
Kasamon YL, Ambinder RF. Immunotherapies for Hodgkin's lymphoma. Crit Rev Oncol 
Hematol. 2008;66(2):135-144. 
17. 
Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab 
vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 
2012;30(18):2183-2189. 
18. 
Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or 
refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 
2012;30(18):2190-2196. 
19. 
Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared 
with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed 
chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359(9323):2065-2071. 
20. 
Akpek G, Ambinder RF, Piantadosi S, et al. Long-term results of blood and marrow 
transplantation for Hodgkin's lymphoma. J Clin Oncol. 2001;19(23):4314-4321. 
21. 
Schmitz N, Haverkamp H, Josting A, et al. Long term follow up in relapsed Hodgkin's 
disease (HD): updated results of the HD-R1 study comparing conventional chemotherapy (cCT) to 
high-dose chemotherapy (HDCT) with autologous haemopoetic stem cell transplantation (ASCT) of 
the German Hodgkin Study Group (GHSG) and the Working Party Lymphoma of the European 
Group for Blood and Marrow Transplantation (EBMT). J Clin Oncol. 2005;23(16S):abstract 6508. 
22. 
Kasamon YL, Jones RJ, Brodsky RA, et al. Immunologic recovery following autologous 
stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell 
lymphoma. Ann Oncol. 2010;21(6):1203-1210. 
23. 
Nitta E, Izutsu K, Sato T, et al. A high incidence of late-onset neutropenia following 
rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: a 
single-institution study. Ann Oncol. 2007;18(2):364-369. 
24. 
Jaffe ES, Harris NL, Stein H, Vardiman JW eds. World Health Organization Classification of 
Tumours: Pathology and Genetics of Tumours of Haematolpoietic and Lymphoid Tissues. Lyon: 
IARC Press; 2001. 
25. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007;25(5):579-586. 
26. 
Biggi A, Gallamini A, Chauvie S, et al. International Validation Study for Interim PET in 
ABVD-Treated, Advanced-Stage Hodgkin Lymphoma: Interpretation Criteria and Concordance 
Rate Among Reviewers. J Nucl Med. 2013. 

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27. 
Barrington SF, Qian W, Somer EJ, et al. Concordance between four European centres of 
PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med 
Mol Imaging. 2010;37(10):1824-1833. 
28. 
Lin C, Itti E, Haioun C, et al. Early 18F-FDG PET for prediction of prognosis in patients with 
diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med. 
2007;48(10):1626-1632. 
29. 
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving 
Considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S-150S. 
30. 
Longo DL, Duffey PL, DeVita VT, Jr., Wesley MN, Hubbard SM, Young RC. The calculation 
of actual or received dose intensity: a comparison of published methods. J Clin Oncol. 
1991;9(11):2042-2051. 
 

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APPENDIX A: 18F FDG PET evaluation form 
 
Patient Name:       _____________________ 
 
Medical Record # _____________________ 
 
 
 
 
Date of imaging study  ____/____/____ 
Date of most recent chemotherapy ____/____/____ 
 
Timing of PET scan: 
 After Cycle 4  
 After Cycle 10 
 Other ____________________ 
 
 
 
Overall PET Result (for the presence of active tumor), based on 2007 IWG response 
criteria25: 
 Negative 
 Positive 
Overall PET Result based on Deauville criteria27: 
 Negative 
 Positive 
Deauville criteria (for foci believed to represent tumor): evaluate maximum activity in tumor using 
mediastinal blood pool and normal liver as reference activity: 
Negative 
 1 no abnormal activity (tumor cold compared with background) 
 2 minimal activity (tumor < mediastinal blood pool) 
 3 equivocal (tumor > mediastinal blood pool but < normal liver) 
_____________________________________________ 
       Positive 
 4 moderate activity (tumor moderately > normal liver) 
 5 strong activity (tumor markedly > normal liver or disease progression) 
 
Additional foci of activity 
Complete for scans other than baseline scan: 
 Are there new foci of FDG activity?  
 Yes  
 No 
 Are these judged to represent lymphoma?  Yes  
 No 
 
Comments:____________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
_____________________________________________ 
 
___________________________________  
 
 ____/____/____ 
Signature of radiologist 
 
 
 
 
 
       Date 

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APPENDIX B:  Radiation Treatment Guidelines 
 
The following are general guidelines for consolidative radiation therapy. The dose, schedule, and 
extent of radiation are at the discretion of the radiation oncologist. 
 
Radiation Schedule 
Fractionation and start time 
It is suggested that involved field radiation therapy consist of 30.6 Gy in 17 fractions of 1.8 Gy per 
day. Treatment is given daily, 5 days per week. Treatment should begin no later than 6 weeks after 
the last cycle, provided hematologic parameters are adequate.  
 
Treatment beaks and blood counts 
Treatment breaks are discouraged. However, radiation should be held if ANC < 500/uL or platelets 
< 25,000/uL and resumed upon adequate hematologic recovery.  
 
Equipment 
Modality 
Photon radiation should be used. In certain situations where a superficial lymph node is being 
treated, an electron beam may be used. IMRT is allowed on this study. 
 
Energy 
Megavoltage radiation should be used with accelerator beams with a nominal energy of at least 6 
MV.  
 
Geometry 
The distance from the radiation source to the prescription point should be no less than 80 cm. 
 
Calibration 
All therapy units used in this protocol should have calibrations verified by the Radiological Physics 
Center. 
 
Treatment Fields and Techniques 
The following target volumes are based on the International Commission on Radiation Units and 
Measurements (ICRU-50 and 62). 
 
Gross Tumor Volume (GTV) is defined as all known areas of gross disease determined from CT 
and/or PET after chemotherapy (e.g., brentuximab vedotin). It will include any lymph node 
measuring > 1.5 cm in a single axis as defined on CT.  If no disease is present following therapy 
(i.e., CR) then the GTV does not exist. 
 
Clinical Target Volume (CTV) is defined as all areas of gross tumor (GTV) and involves initial 
lymph node volume before chemotherapy. It takes into account the initial location and extent of 
disease and will be defined based on the anatomic compartments defined below. 
 
Planning Target Volume (PTV) is the CTV with an additional 0.5 to 1.0 cm margin to account for 
daily treatment set up, patient positioning, and internal organ motion. This expansion may be 
modified at the discretion of the treating radiation oncologist. 
 
Beam Orientation 
Treatment should be delivered through equally weighted AP/PA parallel opposed fields, though 
certain exceptions may exist and IMRT is allowed on this protocol. 
 

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Treatment Position 
Patients should be treated in the supine position with other positioning recommendations listed in 
the appropriate site-specific section below.  
 
Additional recommendations at simulation 
IV contrast is strongly recommended for accurate identification of the vessels. 
 
Anatomic compartments: 
Unilateral neck 
The neck region includes both the cervical and supraclavicular lymph nodes. The involved side of 
the neck should be treated alone with the neck in the hyperextended position. The superior border 
should be 1-2 cm above the lower tip of the mastoid process and the inferior border should be 2 
cm below the clavicle. The lateral border should include the medial 2/3 of the clavicle. The medial 
border is defined based on whether there is involvement of the supraclavicular nodes. If the 
supraclavicular nodes are not involved, the lateral border should be placed at the tip of the 
ipsilateral transverse process. If the supraclavicular nodes (or other medial nodes) are involved, 
then the lateral border should be placed at the contralateral transverse process.  
 
Bilateral neck 
Both sides of the neck are treated with the same head position, shielding, and superior and inferior 
borders as described in the unilateral neck section above. 
 
Unilateral axilla 
Arms should preferably be placed above the head to pull the axillary lymph nodes from the chest to 
allow for additional lung blocking. The superior border should be placed at the C5-C6 interspace or 
2 cm above the pre-chemotherapy extent of disease. The inferior border should be placed at the tip 
of the scapula or 2 cm below the lowest axillary lymph node. The lateral border should flash the 
axilla. The medial border is defined based on involvement of supraclavicular lymph nodes. If there 
are no supraclavicular lymph nodes involved, then the medial border should be placed at the 
ipsilateral transverse process. If there is supraclavicular lymph node involvement, include the entire 
vertebral body. 
 
Mediastinum +/- hila 
The mediastinal region includes the mediastinum, bilateral hila, and bilateral supraclavicular lymph 
nodes. Arms should be placed akimbo or at the sides. Due to the risk of secondary breast cancer 
in female patients, the breast should be positioned laterally away from the field and taped for 
immobilization. The breast can also be outlined with a wire during simulation for better visualization 
and avoidance during treatment planning. The superior border should be placed at the C5-C6 
interspace or the top of the larynx if the supraclavicular lymph nodes are involved. This border 
should be at least 2 cm above the pre-chemotherapy extent of disease. The inferior border should 
be 5 cm below the carina or 2 cm below the pre-chemotherapy extent of disease. The lateral 
border should be a 1.5 cm margin on the post-chemotherapy extent of disease. A 1 cm margin 
should be place around the hilar region if not initially involved; otherwise, a 1.5 cm margin should 
be used. 
 
Para-aortic lymph nodes 
The superior border should be placed at the top of T11 and at least 2 cm above the pre-
chemotherapy extent of disease. The inferior border should be placed at the bottom of L4 and at 
least 2 cm below the pre-chemotherapy extent of disease. The lateral borders should include the 
edge of the transverse processes and at least a 2 cm lateral to the post-chemotherapy volume. 
The spleen should only be treated if suggestive of disease involvement initially and is treated with 
a 1.5 cm margin around the post-chemotherapy volume. Both kidneys should be contoured on CT 

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simulation, identified for avoidance, and shielded as appropriate. When it is necessary to include 
one or both kidneys in the treated volume, keep the mean bilateral kidney dose to < 15 Gy. 
Testicles should be shielded in men with a clamshell and consider oophoropexy for reproductive 
age women. 
 
Pelvic lymph nodes 
The pelvic region includes the external iliac, femoral, and inguinal lymph nodes. Patients should be 
simulated in a “frog-leg” position to separate the leg from the external genitalia and flatten any 
inguinal skin folds to minimize any potential skin reactions. The superior border should be at the 
middle of the sacroiliac joint or 2 cm above the pre-chemotherapy extent of disease. The inferior 
border should be below the pre-chemotherapy volume or 5 cm below the lesser trochanter. The 
medial border should be at least 2 cm medial to the pre-chemotherapy volume or may extend to 
include the medial border of the obturator foramen. The lateral border should be at least 2 cm 
lateral to the pre-chemotherapy volume or may extend to include the greater trochanter. If common 
iliac lymph nodes are involved, the superior border should be extended to the L4-L5 interspace 
with at least a 2 cm margin above the pre-chemotherapy lymph node volume. Testicles should be 
shielded in men with a clamshell and consider oophoropexy for reproductive age women. 
 
Dose calculations 
Dose definition 
The suggested total dose to the prescription point is 30.6 Gy in 17 fractions of 1.8 Gy (180 cGy). 
Patients with residual disease following chemotherapy might receive an additional boost of 5.4 Gy 
in 3 fractions of 1.8 Gy for a total dose of 36 Gy. 
 
Prescription points 
For AP/PA parallel opposed beams, the prescription point is defined as a point along the central 
axis that is midway between the beam entrance and exit points. 

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APPENDIX C:  Adverse Event Reporting for Rituximab 
 
In addition to protocol Section 5.7, the following safety assessment and reporting guidelines apply 
to rituximab (RITUXAN), as specified by Genentech, Inc.: 
 
ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to RITUXAN, all events of death, and any study 
specific issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
This includes the following: 
 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Hodgkin lymphoma that were 
not present prior to the AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the investigator 
to have worsened in severity or frequency or changed in character during the protocol-specified AE 
reporting period. 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.) 
 
It requires or prolongs inpatient hospitalization. 
 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to the IMP. 
 
It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
one of the outcomes listed above). 
 
 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in 

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accordance with CFR 312.32 (IND Safety Reports).  
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment and ends 6 months following the last administration of 
study treatment or study discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the RITUXAN 
(see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
RITUXAN, and the AE cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to RITUXAN; 
and/or the AE abates or resolves upon discontinuation of RITUXAN or dose reduction and, if 
applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than the RITUXAN (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to RITUXAN administration (e.g., cancer diagnosed 2 days after 
first dose of RITUXAN). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator 
Brochure (I.B.) or not identified. This includes adverse events for which the specificity or severity is 
not consistent with the description in the P.I. or I.B. For example, under this definition, hepatic 
necrosis would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. 
 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be adopted. 
Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?”  
Specific Instructions for Recording Adverse Events 

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Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid 
colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is ok to report the 
information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, will 
be reported to the appropriate parties. When recording a death, the event or condition that caused 
or contributed to the fatal outcome should be reported as the single medical concept. If the cause 
of death is unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death”. 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass surgery, 
record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study or 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
e. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior RITUXAN exposure. If the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female subject who participated in the study, this should be reported as an SAE.  
f. 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will 
agree to the reconciliation periodicity and format, but agree to exchange quarterly line listings of 
cases received by the other party. If discrepancies are identified, the Sponsor and Genentech will 

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cooperate in resolving the discrepancies. The responsible individuals for each party shall handle 
the matter on a case-by-case basis until satisfactory resolution. 
g.  
SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. The 
completed Medwatch/case report should be faxed immediately upon completion to Genentech 
Drug Safety at: 
(650) 225-4682 
OR 
(650) 225-5288 
 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available. 
 
Serious AE reports that are related to RITUXAN will be transmitted to Genentech within 
fifteen (15) calendar days of the Awareness Date. 
 
Serious AE reports that are unrelated to RITUXAN will be transmitted to Genentech within 
thirty (30) calendar days of the Awareness Date. 
 
Additional Reporting Requirements to Genentech include the following: 
 
Any reports of pregnancy following the start of administration with RITUXAN will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness Date.  
h. 
Non-Serious AE Reporting 
All non-serious Adverse Events originating from the Study will be forwarded, in a quarterly report to 
Genentech.  
 
Note: Investigators should also report events to their IRB as required. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to the 
correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom and adverse event was reported. For questions regarding SAE 

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reporting, you may contact the Genentech Drug Safety representative noted above or the MSL 
assigned to the study. Relevant follow-up information should be submitted to Genentech Drug 
Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the FDA apply 
in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the investigator to be possibly related to the use of RITUXAN. An 
unexpected adverse event is one that is not already described in the RITUXAN Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar 
days of first learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of RITUXAN. An unexpected adverse event is one that is not already described 
in the RITUXAN investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the event. 
The FDA prefers these reports on a Medwatch 3500 form, but alternative formats are acceptable 
(e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed 
to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-5288 
And to the Site IRB: 
Fax:  (410) 955-4367 or (443) 287-5353 

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For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. Copies of such reports should be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study report). 
Additionally, any literature articles that are a result of the study should be sent to Genentech. 
Copies of such reports should be mailed to the assigned Clinical Operations contact for the study: 
 
Rituxan Clinical Operations Group 
Fax: 650-745-7373 
Email: rituxan-gsur@gene.com 
 
SAFETY REPORTING REQUIREMENTS FOR IND EXEMPT STUDIES 
For Investigator Sponsored IND Exempt Studies, there are some reporting requirements for the 
FDA in accordance with the guidance set forth in 21 CFR 314.80. 
 
Postmarketing 15-Day “Alert Report”: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of 
Rituximab. An unexpected adverse event is one that is not already described in the Investigator 
Brochure. Such reports are to be submitted to the FDA (2 copies) at the following address: Central 
Document Room, 12229 Wilkins Avenue, Rockville, MD 20852. 
 
All Postmarketing 15-Day “Alert Reports” submitted to the FDA by the Sponsor-Investigator must 
also be faxed to:  
 
Genentech Drug Safety  
Fax: 
(650) 225-4682 or (650) 225-4683  
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission. Also provided on Rituxan CD-ROM) 
 
For questions related to safety reporting, contact: 
Genentech Drug Safety 
Tel: 
1-888-835-2555 
         Or 
Fax: 
(650) 225-4682 or (650) 225-4683 
(Please use the safety reporting fax cover sheet attached to this document for your fax 
transmission) 

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APPENDIX D:   
 
 
 
 
   SAFETY REPORTING FAX COVER SHEET 
                                      Genentech Supported Research 
 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
(DD/MON/YYYY) 
       ____ / ____ /____ 
Follow-up Report Date 
(DD/MON/YYYY) 
       ____ / ____ /____ 
 
Subject Initials 
(Please enter a dash if patient has no 
middle name) 
          ___ / ___ /___ 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
 
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