A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline Therapy for Patients With CD30+ and/or EBV+ Lymphomas
Phase: PHASE1
Conditions: Adult Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Contiguous Stage II Adult Burkitt Lymphoma, Contiguous Stage II Adult Diffuse Large Cell Lymphoma, Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma, Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma, Contiguous Stage II Adult Lymphoblastic Lymphoma, Contiguous Stage II Grade 1 Follicular Lymphoma, Contiguous Stage II Grade 2 Follicular Lymphoma, Contiguous Stage II Grade 3 Follicular Lymphoma, Contiguous Stage II Mantle Cell Lymphoma, Contiguous Stage II Marginal Zone Lymphoma, Contiguous Stage II Small Lymphocytic Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Epstein-Barr Virus Infection, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Noncontiguous Stage II Adult Burkitt Lymphoma, Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma, Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma, Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma, Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma, Noncontiguous Stage II Adult Lymphoblastic Lymphoma, Noncontiguous Stage II Grade 1 Follicular Lymphoma, Noncontiguous Stage II Grade 2 Follicular Lymphoma, Noncontiguous Stage II Grade 3 Follicular Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Noncontiguous Stage II Marginal Zone Lymphoma, Noncontiguous Stage II Small Lymphocytic Lymphoma, Noncutaneous Extranodal Lymphoma, Peripheral T-cell Lymphoma, Post-transplant Lymphoproliferative Disorder, Progressive Hairy Cell Leukemia, Initial Treatment, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Hairy Cell Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage I Adult Burkitt Lymphoma, Stage I Adult Diffuse Large Cell Lymphoma, Stage I Adult Diffuse Mixed Cell Lymphoma, Stage I Adult Diffuse Small Cleaved Cell Lymphoma, Stage I Adult Hodgkin Lymphoma, Stage I Adult Immunoblastic Large Cell Lymphoma, Stage I Adult Lymphoblastic Lymphoma, Stage I Adult T-cell Leukemia/Lymphoma, Stage I Cutaneous T-cell Non-Hodgkin Lymphoma, Stage I Grade 1 Follicular Lymphoma, Stage I Grade 2 Follicular Lymphoma, Stage I Grade 3 Follicular Lymphoma, Stage I Mantle Cell Lymphoma, Stage I Marginal Zone Lymphoma, Stage I Small Lymphocytic Lymphoma, Stage IA Mycosis Fungoides/Sezary Syndrome, Stage IB Mycosis Fungoides/Sezary Syndrome, Stage II Adult Hodgkin Lymphoma, Stage II Adult T-cell Leukemia/Lymphoma, Stage II Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IIA Mycosis Fungoides/Sezary Syndrome, Stage IIB Mycosis Fungoides/Sezary Syndrome, Stage III Adult Burkitt Lymphoma, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Mixed Cell Lymphoma, Stage III Adult Diffuse Small Cleaved Cell Lymphoma, Stage III Adult Hodgkin Lymphoma, Stage III Adult Immunoblastic Large Cell Lymphoma, Stage III Adult Lymphoblastic Lymphoma, Stage III Adult T-cell Leukemia/Lymphoma, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Small Lymphocytic Lymphoma, Stage IIIA Mycosis Fungoides/Sezary Syndrome, Stage IIIB Mycosis Fungoides/Sezary Syndrome, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Small Lymphocytic Lymphoma, Stage IVA Mycosis Fungoides/Sezary Syndrome, Stage IVB Mycosis Fungoides/Sezary Syndrome, T-cell Large Granular Lymphocyte Leukemia, Testicular Lymphoma, Untreated Hairy Cell Leukemia, Waldenström Macroglobulinemia
Sponsor: Northwestern University

Robert H. Lurie Comprehensive Cancer Center
Study Number:  NU 12H09
Northwestern University
CONFIDENTIAL
This material is the property of Northwestern University. Do not disclose or use except as authorized in writing by the study sponsor.
A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline 
Therapy for Patients with Lymphomas Associated with 
Immunosuppression 
Principal Investigator: Barbara Pro, MD
Northwestern University Feinberg School of Medicine
Robert H. Lurie Comprehensive Cancer Center
676 N St. Clair Suite 850
Chicago, IL 60611
Phone:  312-695-6180
Fax:  312-695-6189
barbara.por@northwestern.edu
Sub-Investigator(s)
Leo Gordon, MD
Jane Winter, MD
Shuo Ma, MD, PhD
Amir Behdad, MD
Reem Karmali, MD
Northwestern University
Andreas Klein, MD
Tufts University School of Medicine
800 Washington St
Boston, MA 02111
Phone: 617-636-2694
Fax: 617-636-7060
aklein2@tuftsmedicalcenter.org 
Sonali Smith, MD
The University of Chicago Medicine 
5841 S. Maryland Avenue, MC 2115 
Chicago, IL 60637
Phone: 773-834-2895
Fax: 773-702-3163
smsmith@medicine.bsd.uchicago.edu 
Biostatistician:
Alfred Rademaker, PhD
Study Drug(s):
Brentuximab vedotin
Rituximab
IND Number:
117195
IND Holder Name:
Barbara Pro, MD
Funding Source: 
Seattle Genetics
Version Date:
December 12, 2017 (Amendment 9)
Clinical Research Office
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
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Study Number:  NU 12H09
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS .........................................................................................................................3
STUDY SCHEMA.........................................................................................................................................4
DOSING SCHEMA.......................................................................................................................................4
1.0
BACKGROUND AND RATIONALE................................................................................................7
2.0
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................18
3.0
PATIENT ELIGIBILITY..................................................................................................................20
4.0
TREATMENT PLAN......................................................................................................................23
5.0
STUDY PROCEDURES ................................................................................................................32
6.0
ASSESSMENT OF ENDPOINTS ..................................................................................................34
7.0
ADVERSE EVENTS......................................................................................................................40
8.0
DRUG INFORMATION..................................................................................................................44
9.0
CORRELATIVES/SPECIAL STUDIES .........................................................................................47
10.0
STATISTICAL CONSIDERATIONS..............................................................................................50
11.0
STUDY MANAGEMENT ...............................................................................................................51
REFERENCES ...........................................................................................................................................56
APPENDICES ............................................................................................................................................58
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
LIST OF ABBREVIATIONS
AE
Adverse Event
AIDS
Acquired Immunodeficiency Syndrome
ALT
Alanine Aminotransferase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CRR
Complete Response Rate
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse Large B-Cell Lymphoma
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
EFS
Event-Free Survival
H&P
History & Physical Exam
HRPP
Human Research Protections Program
HIV
Human Immunodeficiency Virus
IV (or iv)
Intravenously
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
NCI
National Cancer Institute
NHL
Non-Hodgkin Lymphoma
ORR
Overall Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
p.o.
per os/by mouth/orally
PR
Partial Response
PRR
Partial Response Rate
RP2D
QOD
Recommended phase II dose
Every other day
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
WBC
White Blood Cells
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
STUDY SCHEMA
-DLT period (Phase I only): 21 days of induction
-Duration of treatment (Phase I and II): one year, or until POD (whichever occurs first)
-Primary objective assessment: toxicity after week 4 treatment (Phase I only); scans after 
induction treatment and/or after consolidation treatment (if applicable) (Phase II only)
DOSING SCHEMA (in weeks, continued for one year total, or until POD)
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Study Number:  NU 12H09
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STUDY SUMMARY
Title
A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline 
Therapy for Patients with Lymphomas of Immunosuppressed States
Version Date
June 14, 2017 (Amendment 8)
Protocol Number
NU 12H09
Phase
I/II
Methodology
Open-label, single-arm
Study Duration
Approximately 30 months
Study Center(s)
Northwestern University, University of Chicago
Objectives
Primary objectives: 
Phase I: Evaluate the safety of brentuximab vedotin and rituximab in 
patients with immunosuppressed lymphoid malignancies and to 
determine the recommended phase II dose (RP2D) of the combination.  
Phase II: Evaluate the efficacy of brentuximab vedotin and rituximab in 
patients with immunosuppressed lymphoid malignancies.
Secondary objectives:
Phase II: 
1.
Further evaluate the frequency and severity of toxicity.
2.
Further evaluate the efficacy as measured by one-year PFS and 
OS.
3.
Determine the effects of the combination of brentuximab vedotin 
and rituximab on markers of EBV activation and proliferation. 
4.
Further evaluate efficacy as measured by time to initiation of 
cytotoxic chemotherapy. 
5.
Further evaluate efficacy as measured by observed rates of graft 
rejection.
Exploratory objectives (Phase I and II):
Correlate response and outcomes with CD30 expression and EBV 
markers and levels.
Number of Subjects
Phase I: 3-9 patients; Phase II: 24 patients
Diagnosis and Main 
Inclusion Criteria
Adult patients with non-Hodgkin’s lymphoma (NHL) related to an 
immunosuppressed state
Study Product(s), Dose, 
Route, Regimen
Brentuximab vedotin 1.2 mg/kg IV once weekly for 3 weeks, then 1.8 
mg/kg IV once every 3 weeks
Rituximab 375 mg/m2 IV once weekly x 4, then once every 6 weeks
Duration of 
administration
1 year
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Study Number:  NU 12H09
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Statistical Methodology
Our null hypothesis is that the combination of rituximab and brentuximab 
vedotin will yield no difference in the ORR as compared to that observed 
with historical treatments.  The historical ORR for both PTLD and EBV-
related lymphoma of the elderly, when treated with rituximab (with or 
without chemotherapy) is estimated at approximately 50% [1, 2].  
Therefore, the optimal two-stage design to test the null hypothesis that P 
= 0.50 versus the alternative that P ≥ 0.70 (the hypothesized ORR to 
rituximab plus brentuximab vedotin) has an expected sample size of 24.  
Under these conditions, if the combination is actually not significantly 
more efficacious, there is a < 0.05 probability (also known as the alpha 
value) of concluding that it is.  If the combination is actually significantly 
more efficacious, there is a < 0.20 probability (also known as the beta 
value) of concluding that it is not.  Early futility may be declared, such 
that if 8 or fewer responses are observed among the first 15 patients 
enrolled, the trial will be stopped and considered no more efficacious 
than therapy with rituximab alone.  
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
1.0
BACKGROUND AND RATIONALE
1.1
Disease Background
It is estimated that in 2010, there were 65,540 cases of NHL in the United States, and 
20,210 deaths from the disease [3].  Diffuse Large B-Cell Lymphoma (DLBCL) is the 
most common sub-type of NHL, with approximately 20,000 new cases in the United 
States each year [3].  Chemo-immunotherapy consisting of rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard first-line 
treatment, and autologous stem cell transplant (ASCT) is generally the preferred second-
line treatment [4].  However, there remain many patients for whom ASCT is not an option, 
or who relapse in spite of this therapy, and approximately one-third of all patients with 
DLBCL will die due to disease relapse [5].  Therefore, additional treatment options are 
urgently needed.  
Chronic immunosuppression significantly increases the risk for a variety of lymphoid 
malignancies, which together are termed post-transplant lymphoproliferative disorder 
(PTLD) [6]).  These immunosuppressed patients face a roughly six-fold lifetime risk of 
lymphoma as their immunocompetent counterparts [7].  Although DLBCL is the most 
common histology, other NHL, as well as Hodgkin’s Lymphoma (HL) and Peripheral T-
Cell Lymphoma (PTCL) have all been reported as PTLD variants.  Up to 86% of PTLD 
cases are EBV-associated [8]; roughly 70% express CD30 [9]; and over 80% of PTLD 
express CD20 [10].  Although the PTLD population is a heterogeneous one, outcomes 
are generally poor, with recent larger studies reporting median overall survival (OS) in the 
range of 2-4 years [11, 12].  Rates of treatment-related mortality (TRM) of 13-50% are 
moreover striking when these patients are treated with early cytotoxic chemotherapy [13-
15], and significant rates of graft rejection have also been reported in this context   
EBV-related lymphoma of the elderly is likewise a variant of aggressive B-cell lymphoma 
[16], and represents up to 10% of cases of DLBCL in adults [17].  In a vain similar to 
PTLD, immuno-senescence (of the elderly) is thought to put patients at risk for these 
tumors, which generally co-express CD20 and CD30.  Prognosis is generally poor, 
including when treated with cytotoxic chemotherapy [18].  Therefore, better and more 
tolerable treatment strategies are needed for PTLD and EBV-related lymphoma of the 
elderly. 
Finally, autoimmune disorders, such as systemic lupus erythematosis (SLE), rheumatoid 
arthritis (RA), and Sjogren’s syndrome (SS) are associated with increased risk of 
development of NHL, whether related to underlying disruption of normal lymphocyte 
function [19], or to pharmacologic immunosupression with cytotoxic agents or TNFα 
inhibitors [20].  Interestingly, studies suggest that about 60% of such cases are indolent 
lymphomas [19, 21], suggesting that anthracycline-based therapy may be unnecessarily 
toxic.  No standard of therapy exists for such types of lymphoma, and treatment is 
generally guided by histologic subtype and the clinical status of the patient.
1.2
Study Agent(s) Background and Associated Known Toxicities 
1.2.1
Brentuximab vedotin
1.2.1.1 Toxicity Summary
Because clinical trials are conducted under widely varying conditions, 
adverse reaction rates observed in clinical trials of a drug cannot be 
directly compared to rates in the clinical trials of another drug and may 
not reflect the rates observed in practice.  Brentuximab vedotin was 
studied as monotherapy in 160 patients in two phase 2 trials. Across 
both trials, the most common adverse reactions (≥20%), regardless of 
causality, were neutropenia, peripheral sensory neuropathy, fatigue, 
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Study Number:  NU 12H09
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nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, 
thrombocytopenia, cough and vomiting.
Brentuximab vedotin was studied in 102 patients with HL in a single arm 
clinical trial in which the recommended starting dose and schedule was 
1.8 mg/kg intravenously every 3 weeks. Median duration of treatment 
was 27 weeks (range, 3 to 56 weeks). The most common adverse 
reactions (≥20%), regardless of causality, were neutropenia, peripheral 
sensory neuropathy, fatigue, upper respiratory tract infection, nausea, 
diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, 
cough, and vomiting. 
Brentuximab vedotin was studied in 58 patients with sALCL in a single 
arm clinical trial in which the recommended starting dose and schedule 
was 1.8 mg/kg intravenously every 3 weeks. Median duration of 
treatment was 24 weeks (range, 3 to 56 weeks). The most common 
adverse reactions (≥20%), regardless of causality, were neutropenia, 
anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, 
diarrhea, and pain. Following IV administration of 1.2 mg/kg brentuximab 
vedotin, both patients with hepatic impairment (Child-Pugh class A-C) 
and patients with severe renal impairment (CrCl ,30 mL/min) exhibited a 
trend toward moderate decreases in ADC exposure and increases in 
MMAE exposure.
In addition, there is an ongoing contemporaneous phase II clinical trial 
using consecutive doses (q 3 weeks 1.8mg/kg) of ‘single-agent’ SGN-35 
for elderly Hodgkin lymphoma patients. As of May 1st 2013, 11 out of 30 
planned patients have been enrolled. Ten of the 11 patients have 
received at least 2 cycles of SGN-35, while 4 patients have received at 
least 6 SGN-35 cycles. Among these patients, there have been 2 SAEs 
identified (grade 3 orthostatic hypotension and weakness in patient with 
pre-existing resected astrocytoma; and grade 3 alkaline phosphatase 
elevated in patient with baseline fatty liver disease and baseline 
abnormal LFTs).
Pancreatitis
Seattle Genetics performed an internal qualitative review of all cases of 
acute pancreatitis received to date. As of June 30, 2013, Seattle Genetics 
has received reports of acute pancreatitis associated with brentuximab 
vedotin resulting in an incidence of 0.27% from clinical trials and 
compassionate use programs, and 0.07% from other patient exposures. 
The occurrence of acute pancreatitis contributed to a fatal outcome in 2 
patient reports. Most of the cases of acute pancreatitis were reported 
within the first or second cycle of dosing. Some of the cases were 
confounded by other possible contributory factors, including concomitant 
administration of medications known to be associated with pancreatitis 
and possible alternate etiologies (including cholelithiasis and pancreatic 
lymphoma progression).
Re-challenge experiences with subsequent dose(s) after resolution of the 
acute pancreatitis were documented in 3 patients. Two of these patients 
did not experience recurrent acute pancreatitis on re-challenge. In the 
third patient, 2 re-challenge doses were administered without an elevation 
in pancreatic enzyme; however, following the third re-challenge dose, the 
patient experienced a recurrence of acute pancreatitis. 
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Study Number:  NU 12H09
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Based on this information, Seattle Genetics considers acute pancreatitis 
to be an important potential risk associated with brentuximab vedotin 
dosing, and will be updating the Investigator’s Brochure accordingly.
Infusion reactions 
Two cases of anaphylaxis were reported in phase 1 trials. There were no 
Grade 3 or 4 infusion-related reactions reported in the phase 2 trials, 
however, Grade 1 or 2 infusion-related reactions were reported for 19 
patients (12%). The most common adverse reactions (≥2%) associated 
with infusion-related reactions were chills (4%), nausea (3%), dyspnea 
(3%), pruritus (3%), pyrexia (2%), and cough (2%).  
Serious adverse reactions 
In the phase 2 trials, serious adverse reactions, regardless of causality, 
were reported in 31% of patients receiving Brentuximab vedotin. The most 
common serious adverse reactions experienced by patients with HL 
include peripheral motor neuropathy (4%), abdominal pain (3%), 
pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), 
pyelonephritis (2%), and pyrexia (2%). The most common serious 
adverse reactions experienced by patients with sALCL were septic shock 
(3%), supraventricular arrhythmia (3%), pain in extremity (3%), and 
urinary tract infection (3%). Other important serious adverse reactions 
reported included one case each of PML, Stevens-Johnson syndrome 
and tumor lysis syndrome. 
Dose modifications 
Adverse reactions that led to dose delays in more than 5% of patients 
were neutropenia (14%) and peripheral sensory neuropathy (11%).
  
Discontinuations 
Adverse reactions led to treatment discontinuation in 21% of patients. 
Adverse reactions that led to treatment discontinuation in 2 or more 
patients with HL or sALCL were peripheral sensory neuropathy (8%) and 
peripheral motor neuropathy (3%).   
1.2.1.2 Mechanism of Action
Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate 
(ADC).  The antibody is a chimeric IgG1 directed against CD30.  The 
small molecule, MMAE, is a microtubule disrupting agent.  MMAE is 
covalently attached to the antibody via a linker.  Nonclinical data suggest 
that the anticancer activity of Brentuximab vedotin is due to the binding 
of the ADC to CD30-expressing cells, followed by internalization of the 
ADC-CD30 complex, and the release of MMAE via proteolytic cleavage.  
Binding of MMAE to tubulin disrupts the microtubule network within the 
cell, subsequently inducing cell cycle arrest and apoptotic death of the 
cells.
1.2.1.3 Pharmacodynamics
The effect of brentuximab vedotin (1.8 mg/kg) on the QTc interval was 
evaluated in an open label, single-arm study in 46 evaluable patients 
with CD30-expressing hematologic malignancies.  Administration of 
brentuximab vedotin did not prolong the mean QTc interval > 10 ms from 
baseline.  Small increases in the mean QTc interval (< 10 ms) cannot be 
excluded because this study did not include a placebo arm and a positive 
control arm.
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Study Number:  NU 12H09
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1.2.1.4 Pharmacokinetics
The pharmacokinetics of brentuximab vedotin were evaluated in phase I 
trials and in a population pharmacokinetic (PK) analysis of data from 314 
patients.  The pharmacokinetics of 3 analytes were determined: the 
ADC, MMAE, and total antibody.  Total antibody had the greatest 
exposure and had a similar PK profile as the ADC.  Hence, data on the 
PK of the ADC and MMAE have been summarized.
1.2.1.5 Absorption
Maximum concentrations of ADC were typically observed close to the 
end of infusion.  A multiexponential decline in ADC serum concentrations 
was observed with a terminal half-life of approximately 4 to 6 days.  
Exposures were approximately dose proportional from 1.2 to 2.7 mg/kg.  
Steady-state of the ADC was achieved within 21 days with every 3-week 
dosing of brentuximab vedotin, consistent with the terminal half-life 
estimate.  Minimal to no accumulation of ADC was observed with 
multiple doses at the every 3-week schedule.  The time to maximum 
concentration for MMAE ranged from approximately 1 to 3 days.  Similar 
to the ADC, steady-state of MMAE was achieved within 21 days with 
every 3 week dosing of brentuximab vedotin. MMAE exposures 
decreased with continued administration of brentuximab vedotin with 
approximately 50% to 80% of the exposure of the first dose being 
observed at subsequent doses.
1.2.1.6 Distribution
In vitro, the binding of MMAE to human plasma proteins ranged from 68-
82%. MMAE is not likely to displace or to be displaced by highly protein-
bound drugs. In vitro, MMAE was a substrate of P-gp and was not a 
potent inhibitor of P-gp.
In humans, the mean steady state volume of distribution was 
approximately 6-10 L for ADC.
1.2.1.7 Metabolism
In vivo data in animals and humans suggest that only a small fraction of 
MMAE released from brentuximab vedotin is metabolized.  In vitro data 
indicate that the MMAE metabolism that occurs is primarily via oxidation 
by CYP3A4/5.  In vitro studies using human liver microsomes indicate 
that MMAE inhibits CYP3A4/5 but not other CYP isoforms.  MMAE did 
not induce any major CYP450 enzymes in primary cultures of human 
hepatocytes.
1.2.1.8 Elimination
MMAE appeared to follow metabolite kinetics, with the elimination of 
MMAE appearing to be limited by its rate of release from ADC.  An 
excretion study was undertaken in patients who received a dose of 1.8 
mg/kg of brentuximab vedotin.  Approximately 24% of the total MMAE 
administered as part of the ADC during an brentuximab vedotin infusion 
was recovered in both urine and feces over a 1-week period.  Of the 
recovered MMAE, approximately 72% was recovered in the feces and 
the majority of the excreted MMAE was unchanged.
1.2.1.9 Effects of Gender, Age and Race
Based on the population PK analysis, gender, age and race do not have 
a meaningful effect on the PK of brentuximab vedotin.
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1.2.1.10 Clinical studies
1.2.1.10.1
Hodgkin’s Lymphoma
The efficacy of brentuximab vedotin in patients with HL who 
relapsed after ASCT was evaluated in one open-label, 
single-arm, multicenter trial of 102 patients treated with 1.8 
mg/kg of brentuximab vedotin IV over 30 minutes every 3 
weeks.  An independent review facility performed efficacy 
evaluations which included overall response rate (ORR = 
complete remission [CR] + partial remission [PR]) and 
duration of response as defined by clinical and radiographic 
measures including computed tomography (CT) and 
positron-emission tomography (PET) [in accordance with the 
2007 Revised Response Criteria for Malignant Lymphoma 
(modified)].  The 102 patients ranged in age from 15-77 
years (median, 31 years) and most were female (53%) and 
white (87%). Patients had received a median of 5 prior 
therapies including ASCT.
1.2.1.10.2
Systemic Anaplastic Large Cell Lymphoma (sALCL)
The efficacy of brentuximab vedotin in patients with relapsed 
sALCL was evaluated in one phase II open-label, single-arm, 
multicenter trial.  This trial included patients who had sALCL 
that was relapsed after prior therapy.  Fifty-eight patients 
were treated with 1.8 mg/kg of brentuximab vedotin 
administered IV over 30 minutes every 3 weeks.  An 
independent review facility performed efficacy evaluations 
which included ORR (CR + PR) and duration of response as 
defined by clinical and radiographic measures as defined by 
the 2007 Revised Response Criteria for Malignant 
Lymphoma (modified).  The 58 patients ranged in age from 
14-76 years (median, 52 years) and most were male (57%) 
and white (83%).  Patients had received a median of 2 prior 
therapies; 26% of patients had received prior ASCT. Fifty 
percent (50%) of patients were relapsed and 50% of patients 
were refractory to their most recent prior therapy. Seventy-
two percent (72%) were anaplastic lymphoma kinase (ALK)-
negative.
1.2.1.10.3
Relapsed/refractory CD30+ malignancies
The safety and efficacy of weekly dosing of brentuximab 
vedotin was also evaluated in patients with relapsed and 
refractory CD30+ hematologic malignancies [21].  The agent 
was administered intravenously on Days 1, 8, and 15, of 
each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg, 
with doses escalated in increments of 0.2 mg/kg until dose-
limiting toxicity (DLT) was observed. The MTD was 1.2 
mg/kg. The most common adverse events were peripheral 
sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, 
and pyrexia; and the majority of events were mild to 
moderate in severity. Tumor regression occurred in 85% of 
patients and the overall objective response rate was 59% (n 
= 24), with 34% (n = 14) complete remissions.  We are using 
this data as rationale for weekly induction therapy of 
brentuximab vedotin.
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Study Number:  NU 12H09
Initial Version: November 8, 2012
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Amendment 9: December 12, 2017
1.2.2
Rituximab
1.2.2.1 Toxicity Summary
The following serious adverse reactions were observed in patients 
treated with Rituximab, when used either alone or with other agents:
· Infusion reactions
· Tumor lysis syndrome
· Mucocutaneous reactions
· Progressive multifocal leukoencephalopathy 
· Hepatitis B reactivation with fulminant hepatitis
· Infections
· Cardiac arrhythmias
· Renal toxicity
· Bowel obstruction and perforation
The most common adverse reactions of rituximab (incidence ≥ 25%) 
observed in clinical trials of patients with NHL were infusion reactions, 
fever, lymphopenia, chills, infection, and asthenia.  The most common 
adverse reactions of rituximab (incidence ≥ 25%) observed in clinical 
trials of patients with CLL were: infusion reactions and neutropenia.  
Because clinical trials are conducted under widely varying conditions, 
adverse reaction rates observed in the clinical trials of a drug cannot be 
directly compared to rates in the clinical trials of another drug and may 
not reflect the rates observed in clinical practice.
1.2.2.2 Mechanism of Action
Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-
restricted differentiation antigen, Bp35), a hydrophobic transmembrane 
protein with a molecular weight of approximately 35 kD located on pre-B 
and mature B lymphocytes.  The antigen is expressed on approximately 
90% of B-cell NHL, but the antigen is not found on hematopoietic stem 
cells, pro-B-cells, normal plasma cells or other normal tissues.  CD20 
regulates n early step(s) in the activation process for cell cycle initiation 
and differentiation, and possibly functions as a calcium ion channel.  
CD20 is not shed from the cell surface and does not internalize upon 
antibody binding.  Free CD20 antigen is not found in the circulation.  
Twenty [22] of 38 B cells are believed to play a role in the pathogenesis 
of rheumatoid arthritis (RA) and associated chronic synovitis. In this 
setting, B cells may be acting at multiple sites in the 
autoimmune/inflammatory process, including through production of 
rheumatoid factor (RF) and other autoantibodies, antigen presentation, 
T-cell activation, and/or proinflammatory cytokine production.  The Fab 
domain of rituximab binds to the CD20 antigen on B lymphocytes, and 
the Fc domain recruits immune effector functions to mediate B-cell lysis 
in vitro.  Possible mechanisms of cell lysis include complement-
dependent cytotoxicity [23] and antibody-dependent cell mediated 
cytotoxicity (ADCC).  The antibody has been shown to induce apoptosis 
in the DHL-4 human B-cell lymphoma line.  Rituximab binding was 
observed on lymphoid cells in the thymus, the white pulp of the spleen, 
and a majority of B lymphocytes in peripheral blood and lymph nodes.  
Little or no binding was observed in the non-lymphoid tissues examined.
1.2.2.3 Pharmacodynamics
In NHL patients, administration of rituximab resulted in depletion of 
circulating and tissue-based B cells.  Among 166 patients in Study 1, 
circulating CD19-positive B cells were depleted within the first 3 weeks 
with sustained depletion for up to 6 to 9 months post treatment in 83% of 
patients.  B-cell recovery began at approximately 6 months and median 
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B-cell levels returned to normal by 12 months following completion of 
treatment.  There were sustained and statistically significant reductions 
in both IgM and IgG serum levels observed from 5 through 11 months 
following rituximab administration; 14% of patients had IgM and/or IgG 
serum levels below the normal range.
1.2.2.4 Pharmacokinetics
PKs were characterized in 203 NHL patients receiving 375 mg/m2 
rituximab weekly by IV infusion for 4 doses. Rituximab was detectable in 
the serum of patients 3 to 6 months after completion of treatment. The 
PK profile of rituximab when administered as 6 infusions of 375 mg/m2 in 
combination with 6 cycles of CHOP chemotherapy was similar to that 
seen with rituximab alone.  Based on a population PK analysis of data 
from 298 NHL patients who received rituximab once weekly or once 
every three weeks, the estimated median terminal elimination half-life 
was 22 days (range, 6.1 to 52 days).  Patients with higher CD19-positive 
cell counts or larger measurable tumor lesions at pretreatment had a 
higher clearance. However, dose adjustment for pretreatment CD19 
count or size of tumor lesion is not necessary.  Age and gender had no 
effect on the PK of rituximab.  PKs were characterized in 21 patients with 
CLL receiving rituximab according to the recommended dose and 
schedule.  The estimated median terminal half-life of rituximab was 32 
days (range, 14 to 62 days).
1.2.2.5 Clinical Studies
Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-
Cell NHL
The safety and effectiveness of rituximab in relapsed, refractory CD20+ 
NHL were demonstrated in 3 single-arm studies enrolling 296 patients.
1.2.2.5.1
Study 1
A multicenter, open-label, single-arm study was conducted in 
166 patients with relapsed or refractory, low-grade or 
follicular, B-cell NHL who received 375 mg/m2 of rituximab 
given as an IV infusion weekly for 4 doses.  Patients with 
tumor masses greater than 10 cm or with more than 5000 
lymphocytes/uL in the peripheral blood were excluded from 
the study.  The median time to onset of response was 50 
days.  Disease-related signs and symptoms (including B-
symptoms) resolved in 64% (25/39) of those patients with 
such symptoms at study entry.
1.2.2.5.2
Study 2
In a multicenter, single-arm study, 37 patients with relapsed 
or refractory, low-grade NHL received 375 mg/m2 of 
rituximab weekly for 8 doses.
1.2.2.5.3
Study 3
In a multicenter, single-arm study, 60 patients received 375 
mg/m2 of rituximab weekly for 4 doses.  All patients had 
relapsed or refractory, low-grade or follicular, B-cell NHL and 
had achieved an objective clinical response to rituximab 
administered 3.8-35.6 months (median 14.5 months) prior to 
retreatment with rituximab.  Of these 60 patients, 5 received 
more than one additional course of rituximab.
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1.2.2.5.4
Bulky Disease
In pooled data from studies 1 and 3, 39 patients with bulky 
(single lesion greater than 10 cm in diameter) and relapsed 
or refractory, low-grade NHL received 375 mg/m2 of 
rituximab weekly for 4 doses.
The safety and effectiveness of rituximab in previously 
untreated, low-grade or follicular, CD20+ NHL were 
demonstrated in 3 randomized, controlled trials enrolling 
1,662 patients.
1.2.2.5.5
Study 4
A total of 322 patients with previously untreated follicular 
NHL were randomized (1:1) to receive up to eight 3-week 
cycles of CVP chemotherapy alone (CVP) or in combination 
with 375 mg/m2 rituximab (R-CVP)  on Day 1 of each cycle in 
an open-label, multicenter study.  The main outcome 
measure of the study was progression-free survival (PFS) 
defined as the time from randomization to the first of 
progression, relapse, or death.  Twenty-six percent (26%) of 
the study population was over 60 years of age, 99% had 
Stage III or IV disease, and 50% had an International 
Prognostic Index [24] score greater than 2.  The PFS results 
based on investigator assessment of progression were 
similar to those obtained by the independent review 
assessment. 
1.2.2.5.6
Study 5
An open-label, multicenter, randomized (1:1) study was 
conducted in 1,018 patients with previously untreated 
follicular NHL who achieved a response (CR or PR) to 
rituximab in combination with chemotherapy. Patients were 
randomized to rituximab as single-agent maintenance 
therapy, 375 mg/m2 every 8 weeks for up to 12 doses or to 
observation. Rituximab was initiated at 8 weeks following 
completion of chemotherapy.  The main outcome measure of 
the study was PFS, defined as the time from randomization 
in the maintenance/observation phase to progression, 
relapse, or death, as determined by independent review.  Of 
the randomized patients, 40% were over 60 years of age, 
70% had Stage IV disease, 96% had ECOG performance 
status 0-1, and 42% had FLIPI scores of 3–5.  Prior to 
randomization to maintenance therapy, patients had 
received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 
71% had a complete or unconfirmed complete response and 
28% had a partial response. PFS was longer in patients 
randomized to rituximab as single agent maintenance 
therapy (HR: 0.54, 95% CI: 0.42, 0.70).  The PFS results 
based on investigator assessment of progression were 
similar to those obtained by the independent review 
assessment.
1.2.2.5.7
Study 6
A total of 322 patients with previously untreated low-grade, 
B-cell NHL who did not progress after 6 or 8 cycles of CVP 
chemotherapy were enrolled in an open-label, multicenter, 
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randomized trial.  Patients were randomized (1:1) to receive 
rituximab, 375 mg/m2 IV infusion, once weekly for 4 doses 
every 6 months for up to 16 doses or no further therapeutic 
intervention.  The main outcome measure of the study was 
PFS defined as the time from randomization to progression, 
relapse, or death.  Thirty-seven percent (37%) of the study 
population was over 60 years of age, 99% had Stage III or IV 
disease, and 63% had an IPI score of 2 or greater.  There 
was a reduction in the risk of progression, relapse, or death 
(hazard ratio estimate in the range of 0.36 to 0.49) for 
patients randomized to rituximab as compared to those who 
received no additional treatment.
Diffuse Large B-Cell NHL (DLBCL)
The safety and effectiveness of rituximab were evaluated in 3 
randomized, active-controlled, open-label, multicenter studies with a 
collective enrollment of 1854 patients.  Patients with previously untreated 
DLBCL received rituximab in combination with cyclophosphamide, 
doxorubicin, vincristine, and prednisone [25] or other anthracycline-
based chemotherapy regimens.
1.2.2.5.8
Study 7
A total of 632 patients age ≥ 60 years with DLBCL (including 
primary mediastinal B-cell lymphoma) were randomized in a 
1:1 ratio to treatment with CHOP or R-CHOP.  Patients 
received 6 or 8 cycles of CHOP, each cycle lasting 21 days.  
All patients in the R-CHOP arm received 4 doses of 
rituximab 375 mg/m2 on Days -7 and -3 (prior to Cycle 1) and 
48-72 hours prior to Cycles 3 and 5.  Patients who received 
8 cycles of CHOP also received rituximab prior to Cycle 7.  
The main outcome measure of the study was PFS, defined 
as the time from randomization to the first of progression, 
relapse, or death.  Responding patients underwent a second 
randomization to receive rituximab or no further therapy.  
Among all enrolled patients, 62% had centrally confirmed 
DLBCL histology, 73% had Stage III-IV disease, 56% had IPI 
scores ≥ 2, 86% had ECOG performance status of ≤ 2, 57% 
had elevated LDH levels, and 30% had two or more 
extranodal disease sites involved.  Analysis of results after 
the second randomization in Study 7 demonstrates that for 
patients randomized to R-CHOP, additional rituximab 
exposure beyond induction was not associated with further 
improvements in progression-free survival or overall survival.
1.2.2.5.9
Study 8
A total of 399 patients with DLBCL, age ≥ 60 years, were 
randomized in a 1:1 ratio to receive CHOP or R-CHOP.  All 
patients received up to eight 3-week cycles of CHOP 
induction; patients in the R-CHOP arm received rituximab 
375 mg/m2 on Day 1 of each cycle.  The main outcome 
measure of the study was event-free survival, defined as the 
time from randomization to relapse, progression, change in 
therapy, or death from any cause.  Among all enrolled 
patients, 80% had Stage III or IV disease, 60% of patients 
had an age-adjusted IPI ≥ 2, 80% had ECOG performance 
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status ≤ 2, 66% had elevated LDH levels, and 52% had 
extranodal involvement in at least 2 sites.
1.2.2.5.10
Study 9
A total of 823 patients with DLBCL, aged 18-60 years, were 
randomized in a 1:1 ratio to receive an anthracycline-
containing chemotherapy regimen alone or in combination 
with rituximab. The main outcome measure of the study was 
time to treatment failure, defined as time from randomization 
to the earliest of progressive disease, failure to achieve a 
complete response, relapse, or death.  Among all enrolled 
patients, 28% had Stage III-IV disease, 100% had IPI scores 
of ≥ 1, 99% had ECOG performance status of ≤ 2, 29% had 
elevated LDH levels, 49% had bulky disease, and 34% had 
extranodal involvement. 
1.3
Rationale
CD20 is expressed in NHL of B-cell origin, as well as in normal B-lymphocytes ([16].  
Although its precise function is not fully elucidated, it appears to be important to B-cell 
development and proliferation [26].  The function of CD30 is likewise incompletely 
understood, though is known to have a role in stimulation and selection of T-lymphocytes 
[27].  CD30 expression is nearly universal in cHL and Anaplastic Large Cell Lymphoma 
(ALCL) [28], occurs commonly in PTLD (as noted above) [9], and is found in other virus-
associated lymphoid malignancies, such as Adult T-cell Leukemia/Lymphoma [29] and 
Primary Effusion Lymphoma [28].  Importantly, CD30 is upregulated in cases of infection 
with EBV and Human T-lymphotropic Virus (HTLV) [30], and EBV in particular has been 
shown to induce CD30 expression in B-lymphocytes [31, 32].        
Rituximab, a chimeric monoclonal antibody [33] against CD20, has gained regulatory 
approval for use in NHL, with robust data supporting its use in both the upfront and 
relapse/refractory disease settings [34].   Brentuximab vedotin, on the other hand, is an 
anti-CD30 mAb conjugated to the antitubulin agent monomethyl auristatin E (MMAE).  It 
was recently FDA-approved for use in relapsed/refractory HL and ALCL [35].  After 
demonstrating an 86% ORR in a phase I study [36], similar ORR was achieved in phase 
II trials of HL (N=102) and ALCL (N=58) [35].  Both mAb’s are well-tolerated, with side 
effect profiles that compare favorably to those of cytotoxic chemotherapy [34, 35].      
As noted above, up-front use of aggressive cytotoxic chemotherapy has been plagued by 
early TRM and graft rejection, and further clinical experience has suggested that a 
delayed introduction of aggressive chemotherapy may significantly reduce risks of TRM.  
For instance, a European cooperative group experience demonstrated the apparent 
advantage of a rituximab-based risk-stratified sequential treatment (RSST) strategy for 
PTLD patients [1].  In this model, all patients with a new diagnosis of PTLD are treated 
with 4 doses of weekly rituximab, followed by re-staging.  Those with a complete 
response (CR) then receive an additional four doses of weekly rituximab, followed by 
observation, while those with any other response receive four cycles of R-CHOP-21.  
Among the first 40 patients treated, there was a 93% ORR, with 32% of patients able to 
avoid cytotoxic chemotherapy, and perhaps most notably, with rates of TRM (1/40 
patients) that compare very favorably to historical rates.  The potential clinical 
advantages to limiting exposure to cytotoxic chemotherapy have also been recognized in 
pediatric PTLD [37].Also as noted above, most cases of non-transplant autoimmune-
related lymphoma are indolent histology [19].  There is little or no data to establish R-
CHOP as frontline therapy for such patients, and anthracycline is potentially “over-
treatment” for indolent lymphomas in non-immunocompromised hosts [38]. 
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We therefore hypothesize that brentuximab vedotin and rituximab, used together for the 
upfront treatment of EBV-related lymphoid malignancies, would optimize efficacy as 
compared to historical controls by A) improving response rates as compared to single-
agent rituximab; B) reducing exposure to cytotoxic therapy, and thereby reduce rates of 
TRM; and C) ultimately improving PFS and OS.  We propose a RSST strategy, similar to 
that described above, such that those patients failing to achieve a PR or CR to combined 
brentuximab vedotin and Rituximab therapy can then be treated with cytotoxic 
chemotherapy, with or without additional mAb therapy.  Whereas we predict that EBV 
positivity may predict for response to anti-CD30 therapy, and that targeting of CD20 will 
serve to effectively deplete the EBV reservoir, tumor samples need express neither in 
order to enroll.
Based upon this hypothesis, we propose to conduct a Phase I/II trial combining 
Brentuximab vedotin with rituximab in patients with newly-diagnosed lymphoid 
malignancies that are CD30+ and/or EBV+ (as defined by evidence of EBV in either the 
tumor biopsy specimen, or by positive EBV viral load at time of diagnosis).  Phase I will 
aim to establish the RP2D (which will be defined as the MTD; it is expected that the 
combination dose of each agent will be identical to that when each is used alone).  Phase 
II will aim to evaluate the efficacy of this regimen as measured by response rates.  As we 
expect the majority of patients to have a history of significant immunosuppression (based 
upon observed patterns in our patient population), we do not plan to stratify patients 
based upon transplant history status (ie, those with history of solid organ transplant, 
versus those without).  However, exploratory analyses of this factor may eventually be 
considered.
In light of the potentially aggressive course of some cases of PTLD and other EBV-
related malignancies, we propose a weekly dosing of each agent before transitioning to a 
treatment schedule of every 3 weeks.  Of note, the safety and efficacy of weekly 
induction has been shown for both brentuximab vedotin and rituximab when used as 
single agents [21, 39].
It would perhaps be reasonable to have concerns about offering the treatment proposed 
in this study as frontline therapy to eligible young, otherwise-healthy patients who could 
also be candidates for other accepted, well-established, frontline therapies with outcomes 
that are reasonably well-described.  However, it is our contention that the TRM 
associated with early aggressive therapy, makes alternative treatments, such as that 
offered in this trial, a very attractive means of attempting to reduce risk of early TRM, and 
that this alone warrants its evaluation as a front-line regimen.  Moreover, this trial 
specifically recommends early cessation of treatment protocol, in favor of more 
aggressive chemotherapy, for those patients who fail to achieve adequate response, per 
the discretion of the treating investigator.  We believe that this introduces a safety 
mechanism necessary to the treatment of this patient population that will have a variety of 
potential clinical acuity.   
The acuity of specific patients that are eligible for this trial should be considered at all 
times by the local treating investigator, and it is the responsibility of the treating 
investigator to factor in appropriate clinical decisions regarding whether a given patient 
would be best treated as part of this clinical trial, as opposed to with multi-agent cytotoxic 
chemotherapy.  Because of the very wide variety of patient circumstances, we are unable 
to precisely define clinical features, other than those specified in sections 3.1 and 3.2, 
that should result in choosing to enroll, or not enroll, in this trial.
1.4
Correlative Studies
In addition to the overall goals of this study, we plan to assess whether and to what 
extent immunohistochemical biomarkers might correlate with efficacy and outcome in this 
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population. We will also plan to collect and store whole blood samples (phase II patients 
only) for future, unspecified use.
1.4.1
A tissue microarray (TMA) of paraffin-embedded lymphoid tissue biopsies of all 
patients (enrolled in both Phase I and Phase II) will be created and analyzed by 
Dr. Amir Behdad, hematopathologist and sub-investigator.  This TMA will quantify 
expression of CD30, markers of EBV proliferation, and other markers known to 
be of prognostic significance in lymphoma (eg, Ki-67 and C-Myc), in order to 
determine how such markers correlate with clinical outcome.
2.0
STUDY OBJECTIVES AND ENDPOINTS
2.1
Primary Objectives 
2.1.1
Phase I:  To evaluate the safety of brentuximab vedotin and rituximab in patients 
with immunosuppressed lymphoid malignancies, and to determine the RP2D of 
the combination.
2.1.2
Phase II:  To evaluate the efficacy, as measured by response rates, of 
brentuximab vedotin and rituximab in patients with immunosuppressed lymphoid 
malignancies.
2.2
Secondary Objectives (Phase II only) 
2.2.1
To further evaluate the frequency and severity of toxicity. 
2.2.2
To further evaluate the clinical efficacy of the combination of brentuximab vedotin 
and rituximab, as measured by PFS and OS at one year after the end of 
treatment.
2.2.3
To evaluate the best response to therapy.
2.2.4
To determine the effects of the combination of brentuximab vedotin and rituximab 
on markers of EBV activation and proliferation.  
2.2.4
Further evaluate efficacy as measured by time to cytotoxic chemotherapy.
2.2.5
Further evaluate efficacy as measured by observed rates of graft rejection.
2.3
Primary Endpoints
2.3.1
The primary endpoint for phase I, dose-limiting toxicity (DLT) will be defined as 
the occurrence of toxicity as detailed in section 4.2 (using CTCAE v 4.03), 
experienced during the first 3 weeks of study treatment.  The MTD, which 
constitutes the RP2D, will be defined as described in Section 11 (Study Design).
2.3.2
The primary endpoint for phase II, response after induction or 
induction/consolidation, will be defined as the detection of SD, PR, or CR by CT 
or PET/CT, and/or resolution of marrow-only involvement.  CR and PR will each 
be assessed according to the Revised Response Criteria for Malignant 
Lymphoma.  Assessments will be performed after induction and/or consolidation 
treatment (if applicable).
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2.4
Secondary Endpoints: 
2.4.1
Adverse events will be defined as those included in CTCAE v 4.03.  The 
occurrence and severity of each will be recorded. 
2.4.2
PFS will be defined as the time elapsed between treatment initiation and tumor 
progression or death from any cause (whichever occurs first), with censoring of 
patients who are lost to follow-up.  OS will be defined as freedom from death by 
any cause.
2.4.3
Best response will be assessed by CT or PET/CT according to the Revised 
Response Criteria for Malignant Lymphoma after induction and/or consolidation 
(if applicable) and every 12 weeks during maintenance treatment. 
2.4.4
EBV activation and proliferation will be measured by viral loads as measured at 
time of enrollment and monthly thereafter in all enrolled patients, until completion 
of study therapy.
2.4.5
Time to initiation of cytotoxic chemotherapy will be defined as the time elapsed 
between treatment initiation, and time of first non-targeted cytotoxic 
chemotherapy.
2.4.6
Graft rejection will be defined as any of the following: documentation of new or 
progressive rejection by tissue biopsy of the graft; re-transplantation due to graft 
rejection; clinical diagnosis of new or progressive graft rejection, since start of 
treatment on protocol, as given by the patient’s transplant physician.  Escalation 
of intensity of immunosuppression will not, by itself, be considered evidence of 
graft rejection. (Note: patients with clinically active graft rejection will not be 
excluded from trial enrollment, but will not be considered to have treatment-
emergent graft rejection unless progression of rejection is documented.)
2.5
Exploratory Objectives
The objectives of the correlative studies are to determine:
2.5.1
whether and to what extent CD30 expression predicts for response and outcome
2.5.2
whether and to what extent expression of EBV markers predicts for response and 
outcome
2.5.3
whether changes in serum levels of EBV correlate with response and subsequent 
loss of response to therapy
2.5.4
Collect and store peripheral blood samples for future, unspecified use (phase II 
patients only).
2.6
Exploratory Endpoints
Levels of CD30 expression, EBV proliferation, and tumor proliferation (ie, Ki-67), all 
obtained from TMAs performed on pre-treatment tissue samples, will be correlated with 
ORR, as well as with EFS at one year.  Quantitative serum EBV levels will be monitored 
for the duration of treatment, and change in levels correlated with ORR, duration of 
response, and progression of disease.  
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3.0
PATIENT ELIGIBILITY
The target population for this study is patients with CD20+ lymphoid malignancies related to an 
immunosuppressed state. This will be a multi-center trial conducted at Northwestern University 
and University of Chicago. Northwestern will serve as the lead site and coordinating center for 
this study. Participating sites will include Tufts University.
A total of up to 33 subjects will be needed for this trial. Approximately 2 potentially eligible 
patients are seen per month, and it is anticipated that at least 5 patients will be accrued each 
month. Potential patients may be referred to the Principal Investigator (PI) at Northwestern 
University, Dr. Barbara Pro at (312) 695-6180.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to section 11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a histologically confirmed CD20+ lymphoproliferative disease 
that is related to an immunosuppressed state (e.g., PTLD, DLBCL of the elderly, 
iatrogenic immunodeficiency-associated LPD) and for which rituximab 
monotherapy would be considered to be appropriate frontline therapy. 
3.1.2
In cases of lymphoproliferative disease arising in patients who are 
pharmacologically immunosuppressed, reduction of immunosuppression (RI) 
must be attempted prior to or in conjunction with enrollment, with the exception of 
those for whom RI would pose excessive threat of clinically significant graft 
rejection (as judged by local investigator).
NOTE: Patients who are otherwise immunosuppressed (for reasons such as 
immune dysregulation related to autoimmune conditions, in the absence of 
pharmacological immunosuppression) may be eligible if, in the opinion of the 
treating investigator, the risk of immediate treatment with R-CHOP outweighs the 
benefit for these patients.
3.1.3
Patients must have bi-dimensionally measurable disease (at least 1 cm). 
NOTE: Patients with fully resected disease are eligible, and will be evaluable for 
all toxicity and efficacy endpoints except objective response.
3.1.4
Patients must be ≥ 18 years of age.
3.1.5
Patients must have an ECOG performance status ≤ 2.
3.1.6
Patients must have adequate organ and marrow function as defined below 
(documented within 28 days of registration):
- absolute neutrophil count
≥ 750/mcL
- platelets
≥ 50,000/mcl
- total bilirubin
≤ 2 X institutional upper limit of normal (ULN)
- AST(SGOT)/ALT(SPGT)
≤ 3 X institutional ULN
- creatinine
≤ 2 X institutional ULN
NOTE:  Patients who do not meet the above criteria because of disease 
involvement of the organ in question, or because of acute systemic illness due to 
lymphoma, may enroll with permission of the study PI and approval from the 
Data Monitoring Committee.  We propose that this flexibility be allowed due to 
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the heterogeneity of the patient population, the wide range of complications seen 
in the initial presentation of EBV-related malignancy, and the frequent difficulty 
encountered in attempting to clearly document that organ dysfunction is the 
result of an underlying lymphoproliferative disorder.
In addition, patients with abnormal renal function may be included if the abnormal 
function is due to allograft dysfunction resulting from diagnosis of PTLD, or from 
reduction/cessation of immunosuppression aimed at treatment of PTLD.
3.1.7
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 90 days following 
completion of therapy.  Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately.
3.1.9.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy; or

Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months).
3.1.8
Patients must be free of any prior malignancies for ≥1 year.  
NOTE:  The exception to this would be currently treated squamous cell and basal 
cell carcinoma of the skin, carcinoma in situ of the cervix, breast, or bladder, or 
surgically removed melanoma in situ of the skin (stage 0) with histologically 
confirmed free margins of excision.  In addition, it is well-recognized that patients 
at highest risk for EBV-related lymphoma (ie, those with chronic 
immunosupression) are also at high risk for various malignancies, both invasive 
and non-invasive. Therefore, exceptions may also be granted on a case-by-case 
basis, at the discretion of the PI with approval from the Data Monitoring 
Committee, for those patients with good clinical control of active malignancy, if 
the EBV-related lymphoma is considered to be a more immediate threat to the 
subject’s health and/or life.
3.1.9
Patients must have the ability to understand and the willingness to sign a written 
informed consent.  All patients must have signed, witnessed informed consent 
prior to registration. 
3.2
Exclusion Criteria
3.2.1
Patients who have received prior treatment for lymphoma are not eligible. 
NOTE: Patients may have received corticosteroids for lymphoma for 10 or fewer 
days at any dose (no washout period required). 
NOTE: Patients may have received up to 1 prior dose of rituximab before 
registration. In this case, patients will only receive 3 doses of rituximab on study, 
as specified in section 4 1.1.2.1.
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Amendment 9: December 12, 2017
3.2.2
Patients who have received chemotherapy (including monocolonal antibodies) or 
radiotherapy, administered for any condition, within 4 weeks prior to registration 
are not eligible.
NOTE: Patients may have received one dose of rituximab prior to enrollment. In 
such cases, patients will only continue with 3 doses of rituximab during induction 
(4 total doses). 
3.2.3
Patients who have had prior surgical intervention for lymphoma, unless 
performed for the sake of tissue diagnosis or on an urgent basis for disease-
related threat to life, limb, or organ function, are not eligible.
3.2.4
Patients with incomplete recovery from adverse events due to agents 
administered more than 4 weeks prior to registration are not eligible.
3.2.5
Patients must not have ongoing treatment with any other investigational agents ≤ 
14 days prior to registration.
3.2.6
Patients must not have known CNS involvement of lymphoma.
3.2.7
Patients must not have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to brentuximab vedotin and/or rituximab.
3.2.8
Patients must not have an uncontrolled intercurrent illness including, but not 
limited to, ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
3.2.9
Patients must not have known HIV infection.
3.2.10
Patients must not have known JC virus infection and/or progressive multifocal 
leukoencephalopathy (PML).
3.2.11
Patients are not eligible who have clinically active hepatitis B (tested at 
screening) or known hepatitis A or C infections.  
NOTE:  Patients with chronic HCV or HBV infection may enroll if other laboratory 
criteria are met.  Those with HBV surface antigen positivity may enroll only if 
maintained on appropriate suppressive antiviral therapy, per treating 
investigator’s discretion, for the duration of enrollment in the trial. 
3.2.12
Pregnancy or active nursing of an infant is not permitted.
3.2.13
Patients with a prior history of documented pancreatitis are not eligible.
3.2.14
Patients with severe renal impairment (CrCL <30 mL/min) are not eligible. A 
calculated CrCl is acceptable.
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
4.0
TREATMENT PLAN
Patients will be treated with combination treatment consisting of brentuximab vedotin and 
rituximab infusions as detailed below.  All patients will receive Induction treatment, and those who 
achieve response (PR or CR) may have an optional cycle of Consolidation treatment, identical to 
Induction. Maintenance will then continue for up to one year from the first dose of study 
treatment.
TABLE 1: Dosing Summary
Induction
(1 cycle = 4 weeks)
Consolidation*
(1 cycle = 4 weeks)
Maintenance
(1 cycle = 3 weeks)
Brentuximab 
Vedotin dosing
1.2 mg/kg IV over 30 mins
Weekly x3
1.2 mg/kg IV over 30 mins
Weekly x3
1.8 mg/kg IV over 30 mins 
Once every 3 weeks
Rituximab 
dosing
375 mg/m2 IV weekly x4
375 mg/m2 IV weekly x4
375 mg/m2 IV once every 6 
weeks
*Optional for patients who achieve PR/CR during induction. See section 4.1.3 for stipulations 
regarding SD.
4.1
Treatment Dosage and Administration
NOTE: A baseline weight and height should be obtained on the first day of treatment for 
all patients, and weights should be checked at least once per cycle.  Treatment dosages 
will be based upon most recent weight and BSA (preferably from that day of treatment).  
Dosing is to be subsequently modified if subject weight has changed by more than 10% 
or the BSA has changed more than 5%.
NOTE: The cycle lengths are as follows:
Induction: 
4 weeks (28 days)
Consolidation: 4 weeks (28 days)
Maintenance: 
3 weeks (21 days)
4.1.1
Phase I and II dosage:
Because both drugs are well-tolerated and carry low risks of clinically significant 
toxicity, patients in phase I were treated initially at the most commonly used 
doses of each drug according to the schedules outlined below. NOTE:  The dose 
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for patients with a weight of >100 kg should be calculated for 100 kg (please refer 
to Section 8.1.6 for details):
The RP2D was established for Phase II on 3/12/2014, and dosing for both Phase 
I and Phase II is outlined below.
 
4.1.1.1 Brentuximab vedotin 
Induction: 1.2 mg/kg IV infusion over 30 minutes, weekly x 3 (1 cycle = 4 
weeks; no brentuximab vedotin is given during the fourth week)
Consolidation (optional): Identical to Induction.  Those patients who 
achieve response (PR or CR) after the Induction course may receive an 
additional treatment of the same (termed Consolidation).  In addition, any 
patients achieving CR to induction, in whom avoidance of Maintenance 
therapy is sought, can receive consolidation as their final planned 
therapy. See section 4.1.3 for stipulations regarding stable disease.
Maintenance: 1.8 mg/kg IV infusion over 30 minutes once every 3 weeks 
(1 cycle = 3 weeks), for a total of one year from the first induction dose or 
until progression of disease.  
4.1.1.2 Rituximab 
Induction: 375 mg/m2 IV infusion per standard protocol, once weekly for 
4 weeks (1 cycle = 4 weeks)
Consolidation (optional): Identical to Induction.  Those patients who 
achieve response (PR or CR) after the Induction course may receive an 
additional treatment of the same (termed Consolidation).  In addition, any 
patients achieving CR to induction, in whom avoidance of Maintenance 
therapy is sought, can receive consolidation as their final planned 
therapy. See section 4.1.3 for stipulations regarding stable disease.
Maintenance: 375 mg/m2 IV infusion per standard protocol, once every 6 
weeks for a total of one year from the first induction dose or until 
progression of disease. 
4.1.1.2.1
Pre-Registration Rituximab
Patients may receive one dos of rituximab prior to 
registration as specified in 3.1.3. In such cases, the patient 
will receive a total of four rituximab doses during Induction, 
with only 3 doses given as part of Induction treatment 
(weekly, along with brentuximab vedotin).
4.1.1.3
It is intended that all treatments will be administered on an outpatient 
basis.  However, treatment can be initiated during hospitalization (i.e., 
for newly-diagnosed patients), and can continue during unforeseen 
hospitalizations, but only at the discretion of the local PI.
4.1.1.4
When both agents are to be administered on the same day, rituximab 
will be given immediately before brentuximab vedotin.  No specific time 
interval is required between dosing of the agents (for either Phase I or 
Phase II).  In other words, one can be given immediately after the other.
4.1.2
Phase I treatment plan:
The DLT detection period will be the first 21 days of treatment, starting on day 1 
of induction.  The first three patients enrolled on the study will be treated as a 
single cohort at the doses described above. If none of these first three (0/3) 
patients experience a DLT (defined below), this will constitute the RP2D.  
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In the event of 1 DLT among the first 3-patient cohort (1/3), an expansion cohort 
of an additional three patients will be treated at the same dose.  Of the second 3 
patients treated, if no additional patients experience DLT (ie, DLT in 1/6 patients), 
RP2D will not be changed. 
In the event of 2 or 3 DLT among the first 3-patient cohort, or in the event that an 
expansion cohort is required and results in 2 or more DLT among the 6 patients 
(≥ 2/6) treated in the first and expansion cohorts, dose de-escalation will be 
explored. De-escalation will consist of brentuximab vedotin at 0.8 mg/kg, with the 
schedule otherwise unchanged, and with rituximab dose and schedule 
unchanged.  
This dose de-escalation will be studied in a cohort of 3 patients, and if no DLT 
are observed, the study will commence at this lower dose. In the event that 1 or 
more DLT are observed at this dose reduction, enrollment will be held and the 
protocol reviewed. 
4.1.3
Phase II treatment:
Treatment will be at the RP2D (see section 4.1.1), as determined by the means 
described above.  
Induction: 1.2 mg/kg IV infusion over 30 minutes, weekly x 3 (1 cycle = 4 weeks; 
no brentuximab vedotin is given during the fourth week)
After First Re-Staging:
Patients achieving PD at first re-staging should be taken off treatment and 
treated with R-CHOP or similar chemotherapy at the discretion of the local 
treating investigator.
Patients achieving SD should likewise be taken off treatment and treated as 
above. However, at the discretion of the treating investigator, such patients may 
receive an additional treatment of the same termed “Consolidation”. 
Consolidation treatment is identical to Induction. If, after Consolidation treatment, 
these patients achieve CR or PR, they should proceed to Maintenance (see 
below for description). If, however, these patients are still SD or have progressed 
to PD, they should be taken off treatment and treated with R-CHOP or similar 
chemotherapy at the discretion of the local treating investigator.
Patients achieving CR or PR after the Induction course may receive an additional 
treatment of the same termed “Consolidation”. Consolidation treatment is 
identical to Induction. For patients achieving CR after Induction, in whom 
avoidance of maintenance therapy is sought, Consolidation may be given as their 
final planned therapy. Patients who achieve CR after Induction may proceed 
directly to Maintenance therapy at the discretion of the treating investigator (for 
instance, if they are not likely to tolerate Consolidation therapy given the toxicity 
they experienced during Induction). 
Following Consolidation, patients will proceed to Maintenance: 1.8 mg/kg IV 
infusion over 30 minutes once every 3 weeks (1 cycle = 3 weeks), for one year 
from starting induction or until progression of disease.  At the discretion of the 
treating investigator, patients may discontinue brentuximab vedotin after 10 
maintenance doses.
4.1.4
Dose escalation on a per-patient basis (for both Phase I and Phase II):
For any patient treated with a brentuximab vedotin dose of 0.8 mg/kg for 2 or 
more 21-day cycles without DLT, subsequent doses can be increased to 1.2 
mg/kg, but only at the discretion of the treating investigator.  NOTE:  the 
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Amendment 9: December 12, 2017
basis for escalation, or lack thereof, should be clearly documented in the 
Treatment eCRF.
4.1.5
Recommended treatment off study in the event of progressive disease or 
loss of response: 
Clinical suspicion of progressive disease (PD) or loss of response should be 
investigated radiographically, and if confirmed, will result in removal from active 
therapy (though any such patient will remain in study follow up; see 4.5, Duration 
of Therapy).  In this case, it is strongly recommended that investigators consider 
early initiation R-CHOP or similar chemoimmunotherapy (off trial). 
4.1.6
Administration details
Table 2 below summarizes the administration of both agents.
TABLE 2:  Regimen Detail
Agent
Premedications*
Dose
Route
Schedule^
Duration
375 mg/m2
IV per 
standard 
protocol (see 
below)
Weekly x 4
4 weeks¥
Rituximab 
375mg/m2
IV per 
standard 
protocol (see 
below)
Every 6 
weeks 
1 year or 
until POD
1.2 mg/kg¥ 
IV over 30 
min¥ 
Weekly x 3 
(4th week off)¥
3 weeks¥
Brentuximab 
vedotin
30 min prior:
Tylenol 650 mg PO
Benadryl 50 mg IVPB
PRN for infusion 
reactions:
Solumedrol 125 mg 
IV over 15 min
1.8 mg/kg
IV over 30 
min
Every 3 
weeks 
1 year or 
until POD
*Premedication protocol is the same regardless of which drug is used, and will be used only once 
when both drugs are administered on the same day, unless ≥ 4 hours passes between 
start of rituximab infusion and that of brentuximab vedotin, in which case the same 
premedication protocol can be administered again prior to the start of the second study 
agent, at the discretion of the treating investigator.
¥The parameters specified in the shaded boxes represent the Induction phase and the optional 
Consolidation phase, the latter of which is optional (see sections 4.1.1.1 and 4.1.1.2). 
The non-shaded boxes represent the maintenance phase.
^During Induction and the optional Consolidation phase, 1 cycle = 4 weeks; during maintenance 
therapy, 1 cycle = 3 weeks
4.1.6.1 Rituximab Administration Guidelines:
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. Premedicate 
before each infusion.  Administer only as an IV infusion.
4.1.6.1.1
First Infusion: 
Initiate infusion at a rate of 50 mg/hr.  In the absence of 
infusion toxicity, increase infusion rate by 50 mg/hr 
increments every 30 minutes, to a maximum of 400 mg/hr.
4.1.6.1.2
Subsequent Infusions: 
Initiate infusion at a rate of 100 mg/hr.  In the absence of 
infusion toxicity, increase rate by 100 mg/hr increments at 
30-minute intervals, to a maximum of 400 mg/hr.  Interrupt 
the infusion or slow the infusion rate for infusion reactions. 
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Amendment 9: December 12, 2017
Continue the infusion at one-half the previous rate upon 
improvement of symptoms.
At the discretion of the treating investigator, rapid rituximab 
infusion is allowable after the first dose, if the initial dose was 
well-tolerated.
4.2
Dose-Limiting Toxicity (DLT) and Maximally Tolerated Dose (MTD):
For Phase I, DLT evaluation will occur weekly during the first 21 days of induction.  
(Adverse events, however, will continue to be collected for the duration of treatment).  In 
general, a non-hematologic DLT is defined as any Grade ≥ 3 toxicity, and a hematologic 
DLT is defined as any Grade ≥ 4 toxicity, both by CTCAE v4.03 criteria.  In addition, the 
following criteria and exceptions apply:
4.2.1
ANC < 500/mm3 for > 14 days despite GCSF support is a DLT.
4.2.2
Platelet count < 20,000/mm3 that is considered drug-related is a DLT.
4.2.3
For nausea, vomiting, or diarrhea, patients must have Grade 3 or 4 toxicity that 
persists at this level despite use of optimal symptomatic treatment, in order for 
these to be considered a DLT.
4.2.4
Grade 3 thromboembolic events are not considered DLT.
4.2.5
Any Grade 3 rash that resolves to Grade ≤ 2 within a 10 day period (including 
with symptomatic treatment) will not be considered a DLT.
4.2.6
Cases involving hyperbilirubinemia that is primarily indirect, and considered not 
reflective of underlying liver disease (ie, resulting from transfusion of red blood 
cells), will not be considered a DLT.
4.3
Toxicities and Dosing Delays/Dose Modifications
All patients receiving at least one treatment on this protocol will be evaluable for toxicity. 
Each patient will be assessed for the development of toxicity according to the Time and 
Events Table (See Section 6.4).  Toxicity will be assessed according to the CTCAE v 
4.03, and pre-dose lab values must be assessed prior to dosing at each treatment visit.  
Dose adjustments should be made according to the system showing the greatest degree 
of toxicity. 
Treatment modifications and dosing delays are to follow in Tables 3 and 4 below.  For the 
phase I component, those events constituting a DLT also warrant treatment/modification 
as outlined below.  In the event that both study agents could be responsible for a given 
toxicity, the treating investigator should first modify only the dose of the most likely 
offending agent; brentuximab vedotin should be adjusted before that of rituximab, as 
most toxicities are more common with this agent. Study treatment should not be delayed 
but rather, skipped & not be made up. Cycles should not be extended, if possible. If the 
dose of brentuximab vedotin is skipped or decreased due to toxicity, the dose may be 
restarted or increased for that individual patient in the event that the toxicity resolves 
completely (at the treating investigator’s discretion).
Please also refer to sections of this protocol that contain more detailed information on the 
potential adverse events and risks associated with each agent (Sections 1.2.1.1 and 
1.2.2.1). Any patient missing more than 3 consecutive administrations due to toxicity 
must be removed from the study.  Doses reduced per protocol due to occurrence of 
adverse events are not counted as missed doses.
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Amendment 9: December 12, 2017
TABLE 3a:  Drug-Related Hematological Toxicity Dose Reductions for Brentuximab vedotin - ANC
ANC
Action
≥ 1,500/L
None.
1000-1499/L
-1st Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. 
Do not replace missed doses. Restart next treatment at previous dose. 
-2nd Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Do not replace missed doses. Restart next treatment at 50% previous dose. 
-3rd Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. 
Do not replace missed doses. Restart next treatment at 25% previous dose.
-4th Occurrence: Discontinue protocol therapy.
500-999/L
-1st Occurrence: Notify treating investigator. Withhold current dose until ANC ≥ 1,500/L 
and platelets ≥ 100,000/L. Do not replace missed doses. Restart next treatment at 50% 
previous dose.
 -2nd Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Do not replace missed doses. Restart next treatment at 25% previous dose.
-3rd Occurrence: Discontinue protocol therapy.
<500/L
-1st Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 100,000/L. 
Restart next treatment at 25% previous dose.
-2nd Occurrence: Discontinue protocol therapy. 
*G-CSF (Filgrastim), including Neulasta® , may be added for low ANC while a dose reduction is instituted 
at treating physician’s discretions. 
TABLE 3b:  Drug-Related Hematological Toxicity Dose Reductions for Brentuximab vedotin - 
Platelets
Platelets
Action
100,000/L
None.
75,000-99,000/L
-1st Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Do not replace missed doses. Restart next treatment at previous dose. 
-2nd Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Do not replace missed doses. Restart next treatment at 50% previous 
dose. 
-3rd Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Do not replace missed doses. Restart next treatment at 25% previous 
dose.
-4th Occurrence: Discontinue protocol therapy.
50,000-74,000/L
-1st Occurrence: Notify treating investigator. Withhold  current dose  until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not replace missed doses. Restart next 
treatment at 50% previous dose.
 -2nd Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Do not replace missed doses. Restart next treatment at 25% previous 
dose.
-3rd Occurrence: Discontinue protocol therapy.
<50,000/L
-1st Occurrence: Withhold current dose until ANC ≥ 1,500/L and platelets ≥ 
100,000/L. Restart next treatment at 25% previous dose.
-2nd Occurrence: Discontinue protocol therapy. 
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TABLE 4 Drug-Related Non-Hematological Toxicity Dose Reductions for Brentuximab vedotin & 
Rituximab 1
CTCAE v 4.03
Grade
Brentuximab vedotin
Rituximab
0-2
No change from original 
starting dose
No change from original 
starting dose
3-4
Skip treatment until 
resolved to < Grade 2, 
then reduce by 33%
May continue if toxicity is 
clinically attributed to 
brentuximab vedotin. 
Otherwise, skip 
treatment until resolved 
to ≤Grade 2, then 
resume at same dose
Second episode of 
grade 3 or 4 toxicity
Skip treatment until 
resolved to < Grade 2, 
then reduce by 33%
May continue if toxicity is 
clinically attributed to 
brentuximab vedotin. 
Otherwise, skip 
treatment until resolved 
to ≤ Grade 2, then 
resume at same dose
Third episode of 
grade 3 or 4 toxicity
Remove subject from 
trial
Remove subject from 
trial
1 This table should be followed for all non-hematological toxicities EXCEPT peripheral neuropathy, 
hyperamylaseemia, and pacreatitis, which should be managed as outlined below. In cases 
involving hyperbilirubinemia that is primarily indirect, and considered not reflective of underlying 
liver disease (ie, resulting from transfusion of red blood cells), treating investigators may consider 
avoiding protocol-specified dose reductions, after consultation with principal investigator.
Management of peripheral neuropathy:

For new or worsening Grade 2 or 3 peripheral neuropathy, brentuximab vedotin should be 
withheld until neuropathy improves to Grade 1 or baseline and then restarted at a dose of 1.2 
mg/kg. Missed doses will not be made up.

For grade 4 peripheral neuropathy, discontinue treatment with brentuximab vedotin.
Dose modifications regarding hyperamylaseemia and pancreatitis

Asymptomatic elevated amylase and lipase (for patients with amylase elevation >3x upper 
limit of normal, but no abdominal pain): 
o
Grade 1 – continue at same dose level
o
Grade 2 – continue at same dose level
o
Grade 3 – withhold treatment until toxicity resolves to ≤ Grade 2 and then resume 
treatment at the same dose level. Missed doses will not be made up. 
o
Grade 4 – withhold treatment  until toxicity resolves to ≤ Grade 2 and then resume 
treatment at reduced dose level or discontinue at the discretion of the treating 
investigator

Mild to moderate pancreatitis (hyperamylasemia syndrome – characterized by abdominal 
pain of <72 hours duration with amylase and/or lipase elevation): Withhold  brentuximab 
vedotin. May consider resuming, with 1 dose level reduction, when signs, symptoms and 
laboratory values (i.e., amylase and lipase) return to baseline/normalize. If a 2nd episode of 
mild to moderate pancreatitis occurs, brentuximab vedotin must be permanently 
discontinued. Missed does will not be made up. 

Severe pancreatitis (abdominal pain of 72 hours and amylase elevation of 3x normal for > 72 
hours duration): Permanently discontinue brentuximab vedotin.
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4.4
Concomitant Medications/Treatments
4.4.1
Required concomitant medications
4.4.1.1 Tylenol (acetaminophen) 650 mg PI 30 minutes prior to each infusion or 
equivalent as per standard practice.
4.4.1.2 Benadryl (diphenhydramine) 50 mg IVPB 30 minutes prior to each 
infusion or equivalent as per standard practice.
4.4.2
Allowed concomitant medications
4.4.2.1 Solumedrol 125 mg IV over 15 minutes as needed for infusion reactions.
4.4.2.2 Symptomatic treatment as needed for nausea, vomiting, and/or diarrhea, 
including 5-HT3 antagonists, corticosteroids, benzodiazepines, and anti-
motility agents.
4.4.2.3 Topical and systemic treatment for rash, including corticosteroids. 
4.4.2.4 Hormonal birth control medications.
4.4.2.5 Concurrent antiviral therapy for HBV surface antigen positivity. 
4.4.2.6 G-CSF (Filgrastim), including Neulasta® , may be added for low ANC 
while any requisite dose reduction in study agent is instituted, at treating 
physician’s discretion. 
4.4.3
Concomitant medications and treatments NOT allowed
4.4.3.1 Concurrent chemotherapy, radiotherapy within 28 days prior to 
registration, or other investigational agents within 14 days prior to 
registration.
4.5
Other Modalities or Procedures
No other treatment modalities or procedures are required as part of the study treatment.  
Any patient receiving radiation therapy and/or surgery related to progression of 
malignancy will be removed from protocol therapy.  In addition, any patient that 
subsequently undergoes stem cell transplant will be removed from protocol therapy.
4.6
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue for 
one year or until:
4.6.1
Disease progression
4.6.2
Inter-current illness that prevents further administration of treatment
4.6.3
Unacceptable adverse event(s)
4.6.4
Patient decides to withdraw from the study, OR
4.6.5
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.
Please also refer to Section 4.8 for additional information regarding off-treatment and off-
study criteria.
4.7
Duration of Follow Up
Once patients are off treatment (whether treatment is completed or they are withdrawn 
for any reason) patients will be followed with at least one clinic visit every three months, 
for up to one year from discontinuation of treatment, then every six months up to 3 years 
from discontinuation of treatment, or until death, whichever occurs first.  Patients 
removed from treatment for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. 
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4.8
Removal of Subjects from Treatment and/or Study
Patients can be removed from the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral, or administrative reasons. The reason(s) for discontinuation must be 
documented and may include:
5.5.1
Patient voluntarily withdraws from treatment (follow-up permitted); 
5.5.2
Patient withdraws consent (termination of treatment and follow-up);
5.5.3
Patient is unable to comply with protocol requirements;
5.5.4
Patient demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator);
5.5.5
Patient experiences toxicity that makes continuation in the protocol unsafe;
5.5.6
Treating physician judges continuation on the study would not be in the patient’s 
best interest;
5.5.7
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event);
5.5.8
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study;
5.5.9
Patient is lost to follow-up. If a research subject cannot be located to document 
survival during the follow-up period (up to 3 year after starting study treatment), 
the subject may be considered “lost to follow-up.” All attempts to contact the 
subject during the follow-up period must be documented and approved by the 
Data Monitoring Committee.
4.9
Patient Replacement
During Phase I, all three patients enrolled at the starting dose level must be observed for 
one cycle (21 days), at which point the study will be temporarily suspended for toxicity 
evaluation, before which it may either be reopened for an additional cohort (at either the 
same dose or a lower dose), or proceed to Phase II (as outlined in sections 4.1.2 and 
4.1.3).  Any DLT noted at any point after treatment begins (up till the end of the DLT 
evaluation period) shall count toward the total number of DLT, and patients are not 
replaced.  An exception will be made for those patients who are enrolled but, for 
whatever reason, never receive treatment; such patients should be replaced.  If a patient 
is withdrawn from the study within 21 days of starting therapy, for whatever reason, but 
without experiencing a DLT prior to withdrawal, an additional patient may be added to 
that dose level. Patients missing more than three weeks’ worth of doses due to toxicity 
will not be replaced since these patients will be considered to have experienced a dose 
limiting toxicity.
During Phase II, any patient who is enrolled but not treated on the study, or who 
completes fewer than two total cycles of therapy and is withdrawn for any reason except 
POD or toxicity, shall be replaced.
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5.0
STUDY PROCEDURES
5.1
Table 5: Time and Events Table
Maintenance7    
 (1 cycle = 21 days) 
± 3 days
PROCEDURES/
ASSESSMENTS
Baseline/ 
screening1
Induction
(1 cycle = 28 days) 
± 3 days
Consolidation7
(1 cycle = 28 days) 
(Optional12)
± 3 days
Off 
Treatment10
Follow-
up11
Weeks13
1
2
3
4
5
6
7
8
C1D1 
+Odd 
cycles 
C2D1 
+Even 
cycles 
Informed consent 
X
H&P  and vital 
signs
X
X
X
X
X
X
X
Review of 
eligibility
X
Performance 
status
X
X9
X
X
Toxicity (include 
DLT) evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Scans2 
X2
X2
X2
X2
X
CBC and serum 
chemistries3
X
X
X
X
X
X
X
X
X
X
X
Serum amylase4
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
TMA 
X5
Serum EBV viral 
load
X
X
X
X
X
Hepatitis B9
X
Peripheral Blood 
Banking6
X
X6
X6
X6
Brentuximab 
vedotin7
X
X
X
X
X
X
X
X
Rituximab8
X
X
X
X
X
X
X
X
X
1 All screening procedures should be completed within 28 days of registration
2Tumor assessment will be by means of PET/CT at screening, after induction (after fourth dose of induction rituximab and prior 
to starting consolidation) and after consolidation if applicable (after fourth dose of consolidation rituximab and prior to 
starting maintenance; patients with a CR after induction do not need to repeat a scan after consolidation). NOTE: 
Although PET/CT is preferred, patients may be assessed by CT alone at any time point. During maintenance, patients 
will have CT with contrast every 12 weeks (4 cycles), within 7 days prior to Day 1 of Cycle 1, 5, 9 etc… During the 
Maintenance phase, the treating physician may assess with CT or PET/CT at his/her discretion. In addition, an End of 

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Treatment scan will be performed 3-4 weeks after the last dose of study treatment.
3  CBC and Chemistry panels must be resulted prior to dosing to assess the need for dose delays or modifications. 
4 Serum amylase levels may be drawn up to 72 hours prior to the dosing of brentuximab vedotin. If amylase level is elevated, 
lipase must also be drawn. See Section 4.3 regarding dose modifications for hyperamylasemia (with or without 
pancreatitis).
5 Procurement of tissue and completion of TMA may be done prior to or upon enrollment, but are not required for 
registration/eligibility purposes.
6Phase II patients only: One red top tube and one green top tube will be drawn at baseline OR day 1 of induction, and day 1 of 
the first 3 maintenance cycles. Blood products will be frozen and stored in the Pathology Core Facility for future, 
unspecified use.
7 Brentuximab vedotin will be given intravenously over approximately 30 minutes at the specified time points. The dose will be 
1.2mg/kg during induction and optional consolidation (see section 4.1) and 1.8mg/kg during maintenance. Lab values 
for CBC and Chemistry panels must be resulted prior to dosing to assess for dose delays or modifications. 
Consolidation treatment should start 7-21 days after the fourth induction dose of rituximab. Maintenance treatment 
should start 7-21 days after the fourth consolidation dose of rituximab.
8 Rituximab will be given intravenously at a dose of 375mg/m2 at the specified time points. Rituximab should be given 
immediately before brentuximab vedotin on days when both drugs are administered. See section 4.1 for more details. 
Lab values for CBC and Chemistry panels must be resulted prior to dosing to assess for dose delays or modifications.9 
Hepatitis testing at screening will include HepBsAg and HepBcAb within 4 months prior to registration. 10 The End of 
Treatment visit should take place 21-28 days after the patient’s last dose of study drug.
11 Patients will be followed every three months for one year following discontinuation of study treatment, then every six months 
for a total of three years following discontinuation of study treatment, or until death, whichever comes first. 
12 Consolidation treatment is optional for patients who achieve response (PR or CR; see section 4.1.3 regarding SD) after 
induction. In addition, any patients achieving CR to induction, in whom avoidance of Maintenance therapy is sought, can 
receive consolidation as their final planned therapy. 
13 Treatment and assessments will take place on Day 1 of each Week

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6.0
ASSESSMENT OF ENDPOINTS
6.1
Toxicity Definitions
6.1.1
Evaluable for toxicity. 
All patients will be evaluable for toxicity from the time of their first treatment with 
study drug. This includes the primary endpoint of safety and the secondary 
endpoint of toxicity.
6.1.2
Safety/tolerability
Analyses will be performed for all patients having received at least one dose of 
study drug. The study will use the CTCAE version 4.03 for reporting of non-
hematologic adverse events (http://ctep.cancer.gov/reporting/ctc.html) and 
modified criteria for hematologic adverse events.
6.2
Efficacy Definitions
6.2.1
Response and progression will be evaluated in Phases I and II using 2007 
Revised Response Criteria for Malignant Lymphoma (modified).
6.2.1.1 Evaluable for objective response. 
Only those patients who have measurable disease (at least 1cm) present 
at baseline, have received at least three doses of brentuximab vedotin, 
and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to 
the definitions stated below. (Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
6.2.1.2 Evaluable for Survival
All patients who have had at least one dose of study treatment will be 
evaluable for PFS and OS.
6.2.1.3 Evaluable for Other Endpoints

Time to cytotoxic chemotherapy will be evaluated in all patients who 
receive at least one dose of study treatment. 

Effect on EBV markers will be evaluated in all patients who receive 
at least one dose of study treatment and have an evaluable TMA 
collected at baseline.

Rates of graft rejection will be evaluatd in all patients who receive at 
least one dose of study treatment 
6.2.2
Antitumor Effect
6.2.2.1 Response Criteria
Response criteria will be those specified by Cheson, et al [19] as the 
Revised Response Criteria for Malignant Lymphoma.  Please refer to 
Table 6 for a tabular summary of the below definitions.
6.2.2.1.3
Complete Remission (CR): 
The designation of CR requires the following (Table 6): 
1. Complete disappearance of all detectable clinical evidence 
of disease and disease-related symptoms, if present before 
therapy. 
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2a. A post-treatment residual mass of any size is permitted 
as long as it is PET negative. 
2b. If a pretreatment PET scan was negative, all lymph 
nodes and nodal masses must have regressed on CT to 
normal size (≤1.5 cm in their greatest transverse diameter for 
nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their long axis and more than 1.0 
cm in their short axis before treatment must have decreased 
to ≤ 1.0 cm in their short axis after treatment. 
3. The spleen and/or liver, if considered enlarged before 
therapy on the basis of a physical examination or CT scan, 
should not be palpable on physical examination and should 
be considered normal size by imaging studies, and nodules 
related to lymphoma should disappear. However, 
determination of splenic involvement is not always reliable 
because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reﬂect 
variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or causes other than 
lymphoma. 
 
6.2.2.1.4
Partial Response (PR): 
The designation of PR requires all of the following: 
1. At least a 50% decrease in sum of the product of the 
diameters (SPD) of up to six of the largest dominant nodes or 
nodal masses. These nodes or masses should be selected 
according to all of the following: they should be clearly 
measurable in at least 2 perpendicular dimensions; if 
possible they should be from disparate regions of the body; 
and they should include mediastinal and retroperitoneal 
areas of disease whenever these sites are involved. 
2. No increase should be observed in the size of other nodes, 
liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥50% in their 
SPD or, for single nodules, in the greatest transverse 
diameter. 
4. With the exception of splenic and hepatic nodules, 
involvement of other organs is usually assessable and no 
measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of 
a PR if the sample was positive before treatment. However, if 
positive, the cell type should be specified (eg, large-cell 
lymphoma or small neoplastic B cells). Patients who achieve 
a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement, will be considered 
partial responders. When the bone marrow was involved 
before therapy and a clinical CR was achieved, but with no 
bone marrow assessment after treatment, patients should be 
considered partial responders. 
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6. No new sites of disease should be observed. 
7. If the PET scan was positive before therapy, the post-
treatment PET should be positive in at least one previously 
involved site. 
8. If the pretreatment PET scan was negative, CT criteria 
should be used.
6.2.2.1.5
Stable Disease (SD):
Stable disease (SD) is defined as the following: 
1. A patient is considered to have SD when he or she fails to 
attain the criteria needed for a CR or PR, but does not fulfill 
those for progressive disease (see “Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD],” below). 
2. The PET should be positive at prior sites of disease with 
no new areas of involvement on the post-treatment CT or 
PET. 
3. If the pretreatment PET was negative, there must be no 
change in the size of the previous lesions on the post-
treatment CT scan.
6.2.2.1.6
Relapsed Disease (after CR)/Progressive Disease (after PR, 
SD) 
Lymph nodes should be considered abnormal if the long axis 
is more than 1.5 cm regardless of the short axis. If a lymph 
node has a long axis of 1.1 to 1.5 cm, it should only be 
considered abnormal if its short axis is more than 1.0. Lymph 
nodes ≤ 1.0 x ≤ 1.0 cm will not be considered as abnormal 
for relapse or progressive disease. 
1. Appearance of any new lesion more than 1.5 cm in any 
axis during or at the end of therapy, even if other lesions are 
decreasing in size. Increased FDG uptake in a previously 
unaffected site should only be considered relapsed or 
progressive disease after confirmation with other modalities. 
In patients with no prior history of pulmonary lymphoma, new 
lung nodules identified by CT are mostly benign.  Thus, a 
therapeutic decision should not be made solely on the basis 
of the PET without histologic confirmation. 
2. At least a 50% increase from nadir in the SPD of any 
previously involved nodes, or in a single involved node, or 
the size of other lesions (eg, splenic or hepatic nodules). To 
be considered progressive disease, a lymph node with a 
diameter of the short axis of less than 1.0 cm must increase 
by ≥ 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm 
in the long axis. 
3. At least a 50% increase in the longest diameter of any 
single previously identified node more than 1 cm in its short 
axis. 
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4. Lesions should be PET positive if disease lesions were 
PET positive before therapy, unless the lesion is too small to 
be detected with current PET systems (<1.5 cm in its long 
axis by CT). Measurable extranodal disease should be 
assessed in a manner similar to that for nodal disease. For 
these recommendations, the spleen is considered nodal 
disease. Disease that is only assessable (eg, pleural 
effusions, bone lesions) will be recorded as present or absent 
only, unless, while an abnormality is still noted by imaging 
studies or physical examination, it is found to be 
histologically negative.
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Table 6

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6.2.2.2
Evaluation of Best Overall Response
The best overall response is the best response recorded from 
the start of the treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.
Target 
Lesions
Non-
Target 
Lesions
New Lesions
Overall 
Response
Best 
Response for 
this Category 
Also 
Requires:
CR
CR
No
CR
>4 wks. 
confirmation
CR
Non-
CR/Non-
PD
No
PR
PR
Non-PD
No
PR
>4 wks. 
confirmation
SD
Non-PD
No
SD
documented at 
least once >4 
wks. from 
baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
no prior SD, 
PR or CR
*
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
Note:
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment.
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery.
6.2.3
Duration of Response
6.2.3.1 Duration of overall response: 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is 
objectively documented.
6.2.3.2 Duration of stable disease: 
Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest 
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measurements recorded since the treatment started. 
6.2.3
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression.  PFS will be documented based on clinical 
follow-up.  Results of imaging studies conducted for clinical purposes will be 
documented, but the nature (eg, PET vs. CT) and frequency is at the discretion 
of the treating physician (apart from PET/CT obtained after Induction and 
Consolidation phases, which are mandatory).
6.2.4
Overall Survival
Overall survival (OS) is defined as the duration of time from start of treatment to 
time of death, up to three years from the start of study treatment.
6.2.5
Time to first cytotoxic chemotherapy
Time to first cytotoxic chemotherapy (TTFCC) is defined as the time from start of 
study treatment to time of first dose of antineioplastic cytotoxic chemotherapy 
that is administered to treat lymphoma.  This does not include corticosteroids, 
antivirals, or chemotherapeutic agents used for either non-neoplastic diseases or 
other malignant processes (not lymphoma).
7.0
ADVERSE EVENTS
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents.  Adverse events are reported in a 
routine manner at scheduled times during a trial.  All adverse events will be reported on 
the appropriate eCRF (as outlined in the guidelines in NOTIS).  Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal monitoring 
of patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until: 
7.1.1
the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 
7.1.2
any abnormal laboratory values have returned to baseline; 
7.1.3
there is a satisfactory explanation other than the study drug for the changes 
observed; or
7.1.4
death.
7.2
Definitions
7.2.1
Definition of Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
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7.2.2
Severity of Adverse Events
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4.03 is available at http://ctep.cancer.gov/reporting/ctc.html.
If no CTCAE grading is available, the severity of an AE is graded as follows:
7.2.2.1 Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities.
7.2.2.2 Moderate (grade 2): the event causes discomfort that affects normal 
daily activities.
7.2.2.3 Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status.
7.2.2.4 Life-threatening (grade 4): the patient was at risk of death at the time of 
the event.
7.2.2.5 Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events
All SAEs, regardless of attribution, occurring during the study or within 30 days of 
the last administration of study drug must be reported to the PI upon discovery or 
occurrence.  Additional expedited or routine reporting may be required, 
depending on the nature of the SAE (as outlined in 7.4.1 below).  A “serious” 
adverse event is defined in regulatory terminology as any untoward medical 
occurrence that:
7.2.3.1 Results in death.
If death results from (progression of) the disease, the disease 
should be reported as event (SAE) itself.
7.2.3.2 Is life-threatening.
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it 
were more severe).
7.2.3.3 Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.
7.2.3.4 Results in persistent or significant disability or incapacity.
7.2.3.5 Is a congenital anomaly/birth defect
7.2.3.6 Is an important medical event
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment 
in an emergency room or at home; convulsions that may not result 
in hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs)
A UPIRSO includes events that are unanticipated in terms of nature, severity, or 
frequency, place the research subject or others at a different or greater risk of 
harm, and are deemed to be related or possibly related to participation in the 
study.  
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7.3
Steps to Determine If an Adverse Event Requires Expedited Reporting
7.3.1
Step 1: Identify the type of adverse event using the NCI CTCAE v 4.03. 
7.3.2
Step 2: Grade the adverse event using the NCI CTCAE v 4.03.
7.3.3
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:
7.3.3.1 Definite – The AE is clearly related to the study treatment.
7.3.3.2 Probable – The AE is likely related to the study treatment.
7.3.3.3 Possible – The AE may be related to the study treatment.
7.3.3.4 Unrelated – The AE is clearly NOT related to the study treatment.
Note: This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last dose 
of treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly.
7.3.4
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity 
of the event is not listed in:
7.3.4.1 the current known adverse events listed in the Agent Information Section 
of this protocol;
7.3.4.2 the drug package insert;
7.3.4.3 the current Investigator’s Brochure
7.4
Reporting Requirements for Adverse Events
7.4.1
Expedited Reporting of SAEs
7.4.1.1 Reporting to the QAM/DMC:
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form is 
required.   The completed form should assess whether or not the event 
qualifies as a UPIRSO.  The report should also include:

Protocol description and number

Patient’s Identification Number

Description of event, severity, treatment, and outcome if
known

Supportive laboratory results and diagnostics

Hospital Discharge Summary (if available)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.Reporting to the NU IRB
Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the 
Northwestern University IRB within 24 hours of notification.
The following SAEs will be reported to the NU IRB within 10 working 
days of notification:

Death of a non-NU subject that is unanticipated in nature 
and at least possibly related to study participation.

Other UPIRSOs
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The following SAEs will be reported to the NU IRB at the time of 
continuing review:

All deaths of NU subjects that were not previously reported

All deaths of non-NU subjects that are deemed to be 
unanticipated in nature and unrelated to participation

All other SAEs not previously reported to the NU IRB as 
UPIRSOs
In addition, participating sites should follow local guidelines for reporting 
of SAEs to their IRB as required.
7.4.1.2 Reporting to the FDA:
The QAM will notify FDA will be notified within 7 calendar days of any 
SAE that is associated with study treatment, is unexpected, and is fatal 
or life-threatening. In these instances, an FDA MedWatch Form will be 
completed.
7.4.1.3 Reporting to Seattle Genetics:
Any SAE that occurs in a study subject must be reported to Seattle 
Genetics Drug Safety within 24 hours of first awareness of the event.  
Notification should be via fax to either 425-527-4308 or 866-333-6627.  
The NU CRO SAE Form is an acceptable method of reporting.  The 
Principal Investigator will assist Seattle Genetics in investigating any 
SAE and will provide any follow-up information reasonably requested by 
Seattle Genetics.
7.4.2
Routine Reporting
All other adverse events, such as those that are expected, or are unlikely or 
definitely not related to the study participation, are to be reported on a regular 
basis to the assigned QAM for the study in accordance with the Robert H. Lurie 
Comprehensive Cancer Center’s Data Safety Monitoring Plan (DSMP).  These 
will be reviewed by the DMC on an on-going basis.  The QAM will notify the FDA 
within 15 calendar days of any SAE that is associated with the study treatment, 
unexpected, and serious but not fatal or life-threatening. This includes any 
previous SAEs that were not initially deemed reportable, but are later determined 
to meet the criteria for reporting (i.e. by the DMC).  A summary of all these 
events will be reported annually to the NU IRB as part of the continuing review 
process.
7.5
Stopping Rules 
As noted in Section 5.0, the study will be terminated in the event that ≥ 2/3 patients 
experience toxicity in cohort -1 (1.2 mg/kg brentuximab vedotin) during Phase I.  
Likewise, the study will be stopped after the first stage of Phase II if, among the first 15 
patients treated, four or fewer patients have a CR or PR, as this will be considered 
evidence of inadequate efficacy.  In addition, the Data Safety Monitoring Committee will 
monitor the study in accordance with the DSMP and may suspend or close the study to 
accrual at any point if required, as out lined in the DSMP.
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8.0
DRUG INFORMATION
8.1
Brentixumab vedotin
8.1.1
Other names for the drug(s): ADCETRIS®
8.1.2
Classification – type of agent
Antibody-drug conjugate; the antibody is a chimeric IgG1 directed against CD30 
and the small molecule, MMAE, is a microtubule disrupting agent.
8.1.3
Mode of actionThe ADC binds to CD30-expressing cells, followed by 
internalization of the ADC-CD30 complex, and the release of MMAE via 
proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule 
network within the cell, subsequently inducing cell cycle arrest and apoptotic 
death of the cells.
8.1.4
How supplied/Storage and handling 
8.1.4.1 How Supplied 
ADCETRIS® (brentuximab vedotin) for Injection is supplied as a sterile, 
white to off-white preservative-free lyophilized cake or powder in 
individually-boxed single-use vials: 
• NDC (51144-050-01), 50 mg brentuximab vedotin. 
8.1.4.2 Storage 
Store vial at 2-8˚C (36-46˚F) in the original carton to protect from light.  
8.1.4.3 Special Handling 
Procedures for proper handling and disposal of anticancer drugs should 
be considered. Several guidelines on this subject have been published, 
and are available in the manufacturer’s prescribing information insert. 
Each study site will be responsible for regular inventory checks and 
disposing of expired drug in a timely manner
8.1.5
Protocol dose: 
1.2 mg/kg IV weekly x 3, then 1.8 mg/kg IV every 3 weeks.
NOTE: A baseline weight and height should be obtained on the first day of 
treatment for all patients, and weights should be checked at least every three 
weeks (once per cycle).  Treatment dosages will be based upon most recent 
weight and BSA (preferably from that day of treatment).  Dosing is to be 
subsequently modified if subject weight has changed by more than 10% or the 
BSA has changed more than 5%. 
8.1.6
Instructions for Preparation and Administration 
Procedures for proper handling and disposal of anticancer drugs should be 
considered. Several guidelines on this subject have been published (see 
manufacturer’s prescribing information insert). Use appropriate aseptic technique 
for reconstitution and preparation of dosing solutions. 
8.1.6.1 Reconstitution 
Calculate the dose (mg) and number of vials of ADCETRIS® required. 
The dose for patients with a weight of >100 kg should be calculated for 
100 kg. Reconstitute each 50 mg vial of ADCETRIS® with 10.5 mL of 
Sterile Water for Injection, USP, to yield a single-use solution containing 
5 mg/mL brentuximab vedotin. Direct the stream toward wall of vial and 
not directly at the cake or powder. Gently swirl the vial to aid dissolution. 
DO NOT SHAKE. Inspect the reconstituted solution for particulates and 
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discoloration. The reconstituted solution should be clear to slightly 
opalescent, colorless, and free of visible particulates. Following 
reconstitution, dilute immediately into an infusion bag, or store the 
solution at 2-8˚C (36-46˚F) and use within 24 hours of reconstitution. DO 
NOT FREEZE. Discard any unused portion left in the vial. 
8.1.6.2 Dilution 
Calculate the required volume of 5 mg/mL reconstituted ADCETRIS® 
solution needed and withdraw this amount from the vials. The dose for 
patients with a weight of >100 kg should be calculated for 100 kg. 
Immediately add the reconstituted solution to an infusion bag containing 
a minimum volume of 100 mL to achieve a final concentration of 0.4 
mg/mL to 1.8 mg/mL brentuximab vedotin. ADCETRIS® can be diluted 
into 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated 
Ringer's Injection. Gently invert the bag to mix the solution. ADCETRIS® 
contains no bacteriostatic preservatives. Following dilution, infuse the 
ADCETRIS® solution immediately, or store the solution at 2-8˚C (36-
46˚F) and use within 24 hours of reconstitution. DO NOT FREEZE. 
8.1.7
Route of administration for this study
Intravenous infusion.
8.1.8
Incompatibilities: 
Brentuximab vedotin is not to be mixed with, or administered as an infusion with, 
other medicinal products.  (The only exception is that it may be co-administered, 
but not mixed with, rituximab, when administered as part of this clinical trial.) 
8.1.9
Availability
Brentuximab vedotin will be supplied by the study supporter, Seattle Genetics.  
This drug may be ordered by completing the Investigational Drug 
Request/Shipment Record Form (see Appendix B), which then may be faxed or 
emailed as directed on the Form.
8.1.10
Side effects: 
The most common adverse reactions (≥20%), regardless of causality, were 
neutropenia, peripheral sensory neuropathy, fatigue, nausea,, upper respiratory 
tract infection, diarrhea, pyrexia, and vomiting.
Less commonly progressive multifocal leukoencephalopathy (PML), Stevens-
Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), tumor lysis 
syndrome (TLS), acute pancreatitis, pulmonary toxicity, and hepatotoxicity.
NOTE: Current safety data are based on oncology studies (see section 1.2.1).    
As a result, 1.8mg/kg is the recommended dose for approved indications. 
8.1.11
Return and Retention of Study Drug
It is NOT expected that excess drug will be returned to the manufacturer, and it is 
asked that sites destroy drug remaining at the end of the study per their local 
policy.  The manufacturer will provide memos with lot number and expiration 
dates, and expired drug may also be destroyed per local policy.
8.1.12
Nursing/patient implications
•Avoid use in patients with severe renal impairment
•Avoid use in patients with moderate or severe hepatic impairment (Child-Pugh B 
or C). .
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8.2
Rituximab
8.2.1
Other names for the drug(s)
IDEC-C2B8, Rituximab, NSC# 68745
8.2.2
Classification - type of agent
Chimeric murine-derived monoclonal antibody 
8.2.3
Mode of action
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal antibody 
(Chinese hamster ovary [CHO] transfectoma).  It recognizes the CD20 antigen 
expressed on normal B cells and most malignant B-cell lymphomas.  It binds with 
high affinity to CD20-positive cells, performs human effector functions in vitro, 
and depletes B cells in vivo.  The Fab domain of rituximab binds to the CD20 
antigen on  B-lymphocytes and the Fc domain recruits immune effector functions 
to mediate B-cell lysis in vitro. The biological effect is manifested by B-cell 
depletion in peripheral blood, lymph nodes, and bone marrow. 
8.2.4
Storage and stability
Rituximab vials are stored at refrigerated temperatures 2° to 8°C (36° to 46°F).  
Protect vials from direct sunlight.  Diluted drug product at a concentration of 0.5 
to 4 mg/ml in polyvinylchloride or polyolefin IV bags containing normal saline or 
dextrose 5% can be stored for up to 24 hours at 2° to 8°C, and at room 
temperature for an additional 12 hours
8.2.5
Protocol dose
Rituximab will be administered the standard dose of 375 mg/m2 IV weekly for the 
first 4 weeks then every 6 weeks thereafter.
8.2.6
Preparation
Withdraw the necessary amount of rituximab and dilute to a final concentration of 
1-4 mg/ml into an infusion bag containing either 0.9% Sodium Chloride or 5% 
Dextrose in Water.  Gently invert the bag to mix the solution.  Caution should be 
taken during the preparation of the drug, as shaking can cause aggregation and 
precipitation of the antibody
8.2.7
Route of administration for this study
Intravenous infusion (see Section 5 for detailed administration instructions).
8.2.8
Incompatibilities
Do not mix or dilute rituximab with other drugs.  No incompatibilities between 
rituximab and polyvinylchloride or polyethylene bags have been observed.
8.2.9
Availability
Rituximab is commercially available and will not be provided by the study.
8.2.10
Side effects
Adverse events with an incidence > 5% include: fever, chills, rigors, asthenia, 
headache, angioedema, hypotension, myalgia, dizziness, fatigue, throat irritation, 
abdominal pain, nausea, abdominal pain, nausea, vomiting, leukopenia, 
thrombocytopenia, neutropenia, rhinitis, broncospasm, pruritus, rash, utricaria.
8.2.11
Return and Retention of Study Drug
Rituximab will be prescribed to all patients on study.  No investigational supply 
will be purchased or stored for study purposes.
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9.0
CORRELATIVES/SPECIAL STUDIES
9.1
The objectives of the correlative studies are to determine:
9.1.1
the frequency of expression of both CD30, and markers of EBV (EBER, LMP-1, 
and EBNA-2), in NHL and solid tumors
9.1.2
whether and to what extent CD30 expression, and expression of EBV markers, 
predict for response and outcome on this prospective trial
9.1.3
whether a multivariate model of outcome in PTLD can be prospectively validated, 
and whether expression of CD30 and EBV markers can be incorporated into a 
multi-factorial prognostic model for PTLD:
9.1.4
whether changes in serum levels of EBV correlate with response and subsequent 
loss of response to therapy
9.1.5
Bank whole blood samples for future, unspecified use (phase II patients only).
9.2
Background and Rationale
The Epstein Barr Virus (EBV) is implicated in the pathogenesis not only of multiple 
lymphoid malignancies, including Hodgkin and Burkitt lymphoma [32], PTLD [9], 
peripheral T-cell lymphoma (PTCL) [40], but also of various solid tumors, such as 
nasopharyngeal carcinoma [41] and possibly breast and gastric cancers [42].  Many 
of these diseases carry poor prognoses, and even among those with generally good 
prognoses (eg, HL and BL), there are significant subsets of patients who die due to 
relapsed or refractory disease.
The membrane glycoprotein CD30 is a tumor necrosis factor receptor, was first 
identified as a marker of Reed–Sternberg (RS) cells in HL [43], and is universally 
expressed in this disease.  It is also frequently expressed in PTCL and PTLD [9], and 
in virus-infected lymphocytes and activated T-cells [44].  Increased levels of both 
membrane-bound CD30, and the soluble form (sCD30), which is generated by 
proteolytic cleavage of the extracellular component of the molecule, are found in 
patients infected with EBV and HIV [45].  Increased expression of sCD30 is 
associated with poor outcome in HIV, ALCL and HL [45-47].  In fact, in both ALCL 
and HL, levels of sCD30 decrease with treatment and subsequently rise with 
recurrence [46], [47].  Whereas CD30 expression is not routinely evaluated in other 
types of non-Hodgkin lymphoma (NHL), nor in solid tumors, it is unclear to what 
extent such tumors might express CD30. 
Taken together, these data highlight interesting questions that have yet to be 
answered.  For instance, it remains unclear to whether and to what extent CD30 
expression, and its localization, might predict for response to SGN-35.  It is also 
unknown whether markers of EBV expression and/or proliferation, when associated 
with malignancy, might predict for response to SGN-35, in correlation with, or 
irrespective to, CD30 expression.  
Prognostication for patients with PTLD has not been well studied.  In a large cohort of 
patients with PTLD, Evens, et al, evaluated primarily clinical features of disease, and 
reported a multivariate model of PFS and OS, which relied upon the presence vs 
absence of normal albumin levels, CNS involvement, and bone marrow involvement 
[12].  This model has not been prospectively validated. 
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9.2.1
Objective 1.  Determine the frequency of expression of both CD30, and markers 
of EBV (EBER, LMP-1, and EBNA-2), in NHL and solid tumors:
Pre-treatment biopsy samples, obtained from pathology archives at NMH, will 
be identified by a search of corresponding pathological diagnoses in 
approximately the following numbers:
Non-Hodgkin lymphoma (excluding ALCL)  N=100
Diffuse large B-cell lymphoma (DLBCL) N=30
      
Burkitt lymphoma (BL) N=20
      
Follicular lymphoma (FL) N=30
Other B-cell lymphoma (mantle cell, marginal zone lymphomas)  
N=20
    
Nasopharyngeal carcinoma N=20
     
Gastric adenocarcinoma N=20
Each sample will be evaluated by IHC with respect to expression of CD30 
and EBV markers (EBER, LMP-1, and EBNA-2).  Percentage of positivity will 
be estimated by an experienced hematopathologist, with values (0-100%) 
reported both for the malignant lymphoid cells, and for the stromal cells. 
This will be a descriptive analysis of the rates of expression of these markers 
in various disease states, and no formal statistical analysis is planned.
9.2.2
Objective 2.  Determine whether and to what extent CD30 expression, and 
expression of EBV markers, predict for response and outcome on this 
prospective trial:
As described in Objective 1, each sample will be evaluated by IHC with 
respect to expression of CD30 and EBV markers (EBER, LMP-1, and EBNA-
2).  Percentage of positivity will be estimated by an experienced 
hematopathologist, with values (0-100%) reported both for the malignant 
lymphoid cells, and for the stromal cells. 
In univariate and multivariate analyses, these percentages will be correlated 
with response (CR/PR vs SD/PD), and PFS.
9.2.3
Objective 3. Determine whether a multivariate model of outcome in PTLD can be 
prospectively validated, and whether expression of CD30 and EBV markers can 
be incorporated into a multi-factorial prognostic model for PTLD:
We will evaluate the model described above [12] in the patients treated as part of 
this trial.  We will additionally incorporate CD30 expression and markers of EBV 
into a multivariate analysis to determine whether a more precise clinicopatholo 
model of prediction is possible. 
9.2.4
Objective 4. Determine whether changes in serum levels of EBV correlate with 
response and subsequent loss of response to therapy:
Serum EBV levels will be followed as standard of care, and will be evaluated as a 
dichotomous variable (undetectable vs detectable).  Loss of detectable EBV will 
be correlated with response (CR/PR vs SD/PD), and emergence of detectable 
EBV will likewise be correlated with loss of response.
9.2.5
Objective 5. Peripheral blood samples will be collected will be collected from 
patients at baseline, day 1 of induction, and day 1 of the first 3 maintenance 
cycles. This will be stored for future, unspecified use.
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9.3
Sample Collection Guidelines
Original paraffin-embedded pathology samples will be collected for all enrolled subjects 
and reviewed centrally for correlative studies. Core size to be obtained from these 
samples will be at the discretion of the Dr. Amir Behdad.. NOTE:  This is not needed prior 
to enrollment or treatment initiation for eligibility purposes.  Prior to or upon enrollment, all 
specimens are to be sent to the Pathology Department at Northwestern Memorial 
Hospital at the following address:
Amir Behdad,, MD 
Professor of Pathology           
Northwestern Memorial Hospital
Feinberg 7-210     
Chicago, IL  60611
Tissue samples will be received in the Pathology Department and reviewed centrally.  
The Pathology Core Facility at Northwestern University will then arrange pick-up of the 
samples for construction of the TMA.  
Phase II Patients Only
Peripheral blood samples will be collected at the time points noted below and banked for 
future, unspecified use.  One red top and one green top tube will be drawn at each time 
point (see section 5.4), and can be drawn before or after any treatment scheduled for that 
same day. Samples will be picked up by and stored by the Clinical Trials Pathology 
Office.

Baseline (within 28 days prior to start of study treatment) OR day 1 of induction 
therapy.

Day 1 of the first 3 maintenance therapy cycles

If patient misses/skips any of the first 3 maintenance cycles, every 
attempt will be made to collect the samples at the next cycle initiation 
(day 1 of X cycle) for a total of three maintenance samples.
9.3.1
Blood Processing & Shipping:
Red Top Tube:
a.
Red top tube should sit upright after the blood is drawn at 
room temperature for a minimum of 30 minutes to a 
maximum of 60 minutes to allow the clot to form. 
b.
Centrifuge the blood sample at the end of the clotting time 
for 15 minutes at room temperature at 1500g. If the blood is 
not centrifuged immediately after the clotting time, the tubes 
should be refrigerated (4 degrees Celsius) for no longer than 
4 hours
c.
Pipette serum into the labeled cryovials, Close caps on the 
vials tightly. 
Note: Be careful not to pick up red blood cells when aliquoting. This can be 
done by keeping the pipet above the red blood cell layer and leaving a 
small amount of serum in the tube
d.
Place all aliquots upright in a specimen box or rack in an -
80C or colder freezer. All specimens should remain at -80C 
prior to shipping. The samples should not be thawed prior to 
shipping.
Green Top Tube:
a.
Transfer/aliquot whole blood from green top tube into 2 cryovials or falcon tubes. 
Close caps on the vials tightly. 
b.
Place all aliquots upright in a specimen box or rack in an -80C or colder freezer. All 
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specimens should remain at -80C prior to shipping. The samples should not be 
thawed prior to shipping.
Samples are to be labeled with the study participant’s study ID number. The 
following parameters must be recorded for each specimen collection:

Date and time of blood draw

Time of specimen processing

Time specimen was frozen
Frozen samples and associated paperwork should be shipped to the Robert H. 
Lurie Comprehensive Cancer Center Patchcore Facility Clinical Trials Unit (PCF-
CTU). Specimens must be shipped via overnight FedEx on dry ice. Email PCF-
CTU staff with details of shipment using the email listed below. It is important that 
samples do not thaw, therefore all packages should be sent Monday-Thursday 
only; batch shipping of specimens is allowable. All packages should be sent 
to:
Robert H. Lurie Comprehensive Cancer Center of
Northwestern University
Clinical Trial Pathology Office
Attention: NU 12H09
Olson 8-412
710 North Fairbanks Court
Chicago, IL 60611
312-908-0603
PCF-CTU@northwestern.edu
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints/Data Analysis
10.1.1
Phase I (also refer to section 4.1.2)
The first three patients enrolled on the study will be treated as a single cohort. If 
none of these first three patients experience a dose-limiting toxicity (DLT; defined 
below), Phase II of the study will subsequently commence at the same dose.  
In the event of one DLT among the first three-patient cohort, an expansion cohort 
of an additional three patients will be treated at the same dose.  Of the second 
three patients treated, if no additional patients experience DLT, Phase II of the 
study will commence at the same dose. 
In the event of two or three DLT among the first three-patient cohort, or in the 
event of two or more DLT among the six patients treated in the first and 
expansion cohorts, dose de-escalation will be studied, with Brentuximab vedotin 
at 1.2 mg/kg, with the schedule otherwise unchanged, and with Rituximab dose 
and schedule unchanged.  This dose de-escalation will be studied in a cohort of 
three patients, and if no DLT are observed, the study will commence at this dose 
schedule. 
In the event that one or more DLT are observed at this dose reduction, 
enrollment will be held and the protocol reviewed. 
10.1.2
Phase II
Our null hypothesis is that the combination of rituximab and brentuximab vedotin 
will yield no difference in the rate of ORR as compared to that observed with 
historical treatments.  The historical ORR for both PTLD and EBV-related 
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lymphoma of the elderly, when treated with rituximab (with or without 
chemotherapy is estimated at approximately 50% [1, 2].  Therefore, the optimal 
two-stage design to test the null hypothesis that P=0.50 versus the alternative 
that P>=0.70 (the hypothesized ORR to rituximab plus brentuximab vedotin) has 
an expected sample size of 24.  Under these conditions, if the combination is 
actually not significantly more efficacious, there is a <0.05 probability (also known 
as the alpha value) of concluding that it is.  If the combination is actually 
significantly more efficacious, there is a <0.20 probability (also known as the beta 
value) of concluding that it is not.  Early futility may be declared, such that if eight 
or fewer responses are observed among the first 15 patients enrolled, the trial 
will be stopped and considered no more efficacious than therapy with rituximab 
alone.  
10.2
Sample Size and Accrual
For Phase I, we anticipate enrolling either three or six patients, depending on whether 
one or two cohorts are opened.  For Phase II, we plan to enroll 24 patients. This results in 
a total of 27-33 patients.  Under current conditions at our centers, we anticipate being 
able to successfully accrue patients to this protocol at an average rate of 1.5 per month, 
resulting in a target time frame of approximately 2-2.5 years for completion of Phases I 
and II.
11.0
STUDY MANAGEMENT
11.1
Conflict of Interest
All investigators will follow the Northwestern University conflict of interest policy.
11.2
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.3
Required Documentation (for multi-site studies)
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office.

A copy of the official IRB approval letter for the protocol and informed consent

IRB membership list
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
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study

Form FDA 1572 appropriately filled out and signed with appropriate documentation 
[48]

A copy of the IRB-approved consent form

CAP and CLIA Laboratory certification numbers and institution lab normal values

Executed clinical research contract
11.4
Registration Procedures
Patients may not begin protocol treatment prior to registration.  All patient registrations 
will be registered centrally through the Clinical Research Office (CRO) at Northwestern 
University before enrollment to study.  Please contact the assigned QAM or email the 
CRO’s QA Department at croqualityassurance@northwestern.edu for questions 
regarding patient registration.  
11.4.1
Access to NOTIS 
Eligible patients will be registered to the study via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which can be found 
at: https://notis.nubic.northwestern.edu.  Please note that a username and 
password is required to use this program, and will be provided during site 
activation prior to training on the NOTIS system.
11.4.2
Registering a Patient for the Phase I Portion of the Study
For potential patients for the phase I portion of this study, please email the QA 
department at NU (croqualityassurance@northwestern.edu) prior to consenting a 
patient to determine whether a slot is available on the current cohort.  Slots may 
be reserved according to the Slot Reservation Procedure (see appendix D). An 
email confirming the reservation and expiration date will be sent by the QAM. In 
order for registrations to be processed efficiently, study teams are asked to 
inform the QAM of the date and time that the patient will need to be registered. 
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive a subject identification number: 

Eligibility eCRF (complete in NOTIS)

Eligibility checklist (signed and dated by the treating physician – upload 
in NOTIS)

Signed and dated informed consent document (upload in NOTIS)

Pathology Report (upload in NOTIS)
Affiliates sites are required to de-identify, scan, and e-mail the following
source documents in order to confirm eligibility prior to registration for phase I 
patients:

Complete medical and surgical history, current medications, history of 
clinically significant infections, and physical exam [including weight, 
height, ECOG PS, vital signs (pulse, temperature, respiratory rate, blood 
pressure, oxygen saturation)] 

Lab results (ANC,  platelets, bilirubin, AST/ALT, creatinine)

Negative pregnancy test (if applicable) 

Copy of baseline PET/CT report
For Northwestern University (NU) study teams are NOT required to submit a 
separate email for NU participants, provided that the required documentation 
listed above is readily available in the patient’s electronic medical record (EMR), 
a separate e-mail submission is NOT required.  However, any information that is 
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not available in the EMR must be de-identified and emailed to the QAM.  
The QAM will review all source documentation required to confirm eligibility. 
Once the QAM confirms the patient is eligible, he or she will register the patient, 
assign a subject identification number, provide a cohort assignment, and send a 
confirmation of registration to involved personnel. Registration will then be 
complete and the patient may begin study treatment.  
11.4.3
Registering a Patient to the Phase II Portion of the Study
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive a subject identification number: 

Eligibility eCRF (complete in NOTIS)

Eligibility checklist (signed and dated by the treating physician – upload 
in NOTIS)

Signed and dated informed consent document (upload in NOTIS)

Pathology Report (upload in NOTIS)
The QAM will review the registration, register the patient, assign an identification 
number, and send a confirmation of registration to involved personnel. 
Registration will then be complete and the patient may begin study treatment. 
11.5
Data Management and Monitoring/Auditing
This study will be monitored as a high risk study, which requires high intensity monitoring, 
as outlined in the Lurie Cancer Center’s DSMP.  Please refer to NOTIS for more specific 
details on the monitoring plan and data submission guidelines. All participating sites are 
responsible for entering data in the timeframe outlined in the data submission guidelines.   
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, a IRB modification form 
must be completed within five [22] business days of making the change. 
11.6.2
Other Protocol Deviations
According to the IRB, a protocol deviation is any unplanned variance from an IRB 
approved protocol that: 

Is generally noted or recognized after it occurs

Has no substantive effect on the risks to research participants

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected 

Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
variance protocol deviation is considered an instance of Promptly Reportable 
Non-Compliance (PRNC) if the variance:
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
Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
Protocol Deviations: Study personnel will report all deviations to the NU QAM 
Deviations d be summarized and reported to the IRB at the time of continuing 
review.
PRNC: Study personnel should report instances of PRNC within one [22] week of 
the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems. 
11.7
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required. 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. 
11.8
Record Retention
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study.
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study.
11.9
Obligations of Investigators
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
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Amendment 9: December 12, 2017
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data.
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
REFERENCES
1.
Trappe R, e.a., Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD: 
Results from a Multicenter Phase II Trial. Proc Amer Society Hematology 2009. Abstract 100.
2.
Huang, G., et al., Human cytomegalovirus in neoplastic cells of Epstein-Barr virus negative 
Hodgkin's disease. Int J Oncol, 2002. 21(1): p. 31-6.
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Howlader N, N.A., Krapcho M, (eds). , SEER Cancer Statistics Review, National Cancer Institute. 
Bethesda, MD 1975-2008.
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Zelenetz A, A.J., Advani RH, et al. , Clinical Practice Guidelines in Oncology for Non-Hodgkin 
Lymphoma. J Natl Compr Canc Netw 2011. 9: p. 484-560.
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Sehn, L.H., et al., The revised International Prognostic Index (R-IPI) is a better predictor of 
outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-
CHOP. Blood, 2007. 109(5): p. 1857-61.
6.
Penn, I., The role of immunosuppression in lymphoma formation. Springer Semin Immunopathol, 
1998. 20(3-4): p. 343-55.
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Gan, Y.J., et al., A defective, rearranged Epstein-Barr virus genome in EBER-negative and 
EBER-positive Hodgkin's disease. Am J Pathol, 2002. 160(3): p. 781-6.
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Meij, P., et al., Antibody responses to Epstein-Barr virus-encoded latent membrane protein-1 
(LMP1) and expression of LMP1 in juvenile Hodgkin's disease. J Med Virol, 2002. 68(3): p. 370-7.
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Haque, T., et al., Soluble CD30: a serum marker for Epstein-Barr virus-associated 
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Mitarnun, W., et al., Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, 
Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and 
molecular analysis. J Med Assoc Thai, 2002. 85(5): p. 552-9.
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Caussinus, E., et al., Simultaneous occurrence of Epstein-Barr virus associated Hodgkin's 
disease and HHV-8 related multicentric Castleman's disease: a fortuitous event? J Clin Pathol, 
2001. 54(10): p. 790-1.
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Evens, A.M., et al., Multicenter analysis of 80 solid organ transplantation recipients with post-
transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J 
Clin Oncol, 2010. 28(6): p. 1038-46.
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Mamzer-Bruneel, M.F., et al., Durable remission after aggressive chemotherapy for very late 
post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center. J 
Clin Oncol, 2000. 18(21): p. 3622-32.
14.
Elstrom, R.L., et al., Treatment of PTLD with rituximab or chemotherapy. Am J Transplant, 2006. 
6(3): p. 569-76.
15.
Choquet, S., et al., CHOP-21 for the treatment of post-transplant lymphoproliferative disorders 
(PTLD) following solid organ transplantation. Haematologica, 2007. 92(2): p. 273-4.
16.
Swerdlow SH, C.E., Harris NL, et al. (Eds), World Health Organization Classification of Tumours 
of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2008: p. 262-8.
17.
Krieger, N., et al., Breast cancer, birth cohorts, and Epstein-Barr virus: methodological issues in 
exploring the "hygiene hypothesis" in relation to breast cancer, Hodgkin's disease, and stomach 
cancer. Cancer Epidemiol Biomarkers Prev, 2003. 12(5): p. 405-11.
18.
Massarweh, S., et al., HIV-related Hodgkin's disease with central nervous system involvement 
and association with Epstein-Barr virus. Am J Hematol, 2003. 72(3): p. 216-9.
19.
Ekstrom Smedby, K., et al., Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: 
a pooled analysis within the InterLymph Consortium. Blood, 2008. 111(8): p. 4029-38.
20.
Mariette, X., et al., Lymphoma in patients treated with anti-TNF: results of the 3-year prospective 
French RATIO registry. Ann Rheum Dis, 2010. 69(2): p. 400-8.
21.
Gandhi M, e.a., Immunosuppression related lymphoma: solid organ transplant & autoimmune 
conditions. Ninth Annual Lewis Landsberg Research Day, 2013(April 2013).
22.
http://seer.cancer.gov/csr/1975_2008/results_single/sect_01_table.01.pdf.
23.
CDC, HIV/AIDS Surveillance Report, Rev ed. Atlanta: U.S. Department of Health and Human 
Services, 2007. 17: p. 1-54.
24.
Gregory, C.D., et al., Isolation of a normal B cell subset with a Burkitt-like phenotype and 
transformation in vitro with Epstein-Barr virus. Int J Cancer, 1988. 42(2): p. 213-20.
IRB #: STU00072695 Approved by NU IRB for use on or after 9/24/2018 through 9/23/2019.

Study Number:  NU 12H09
Initial Version  March 15, 2016
57
Amendment 9: December 12, 2017
25.
Tschopp, L., et al., The value of frozen section analysis of the sentinel lymph node in clinically N0 
squamous cell carcinoma of the oral cavity and oropharynx. Otolaryngol Head Neck Surg, 2005. 
132(1): p. 99-102.
26.
Sjoberg, J., et al., Expression of the signal transduction molecule zeta in peripheral and tumour-
associated lymphocytes in Hodgkin's disease in relation to the Epstein-Barr virus status of the 
tumour cells. Br J Haematol, 2002. 116(4): p. 765-73.
27.
Macak, J., B. Habanec, and P. Fabian, [Detection of Epstein-Barr virus in Hodgkin's disease]. 
Cesk Patol, 2001. 37(3): p. 124-5.
28.
Deutsch, Y.E., et al., CD30: an important new target in hematologic malignancies. Leuk 
Lymphoma, 2011. 52(9): p. 1641-54.
29.
Navarro, J.T., et al., Influence of highly active anti-retroviral therapy on response to treatment and 
survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma 
treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone. Br J Haematol, 
2001. 112(4): p. 909-15.
30.
Chiarle, R., et al., CD30 in normal and neoplastic cells. Clin Immunol, 1999. 90(2): p. 157-64.
31.
Flavell, K.J., et al., The effect of Epstein-Barr virus status on outcome in age- and sex-defined 
subgroups of patients with advanced Hodgkin's disease. Ann Oncol, 2003. 14(2): p. 282-90.
32.
Siemer, D., et al., EBV transformation overrides gene expression patterns of B cell differentiation 
stages. Mol Immunol, 2008. 45(11): p. 3133-41.
33.
Palandri, F., et al., Front-line treatment of Philadelphia positive chronic myeloid leukemia with 
imatinib and interferon-alpha: 5-year outcome. Haematologica, 2008. 93(5): p. 770-4.
34.
Almasri, N.M. and H.S. Khalidi, Epstein-Barr virus expression in Hodgkin's disease in Jordan. 
Saudi Med J, 2004. 25(6): p. 770-5.
35.
Adcetris Package Insert. Seattle Genetics; Seattle, WA, 2011.
36.
Younes, A., et al., Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl 
J Med, 2010. 363(19): p. 1812-21.
37.
Korbi, S., et al., [Epstein-Barr virus in Hodgkin's disease: the example of central Tunisia]. Ann 
Pathol, 2002. 22(2): p. 96-101.
38.
Jacobson, C.A. and A.S. Freedman, First-line treatment of indolent lymphoma: axing CHOP? 
Lancet, 2013. 381(9873): p. 1163-5.
39.
Bollard, C.M., et al., Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. J 
Exp Med, 2004. 200(12): p. 1623-33.
40.
Piccaluga, P.P., et al., Pathobiology of Epstein-Barr virus-driven peripheral T-cell lymphomas. 
Semin Diagn Pathol, 2011. 28(3): p. 234-44.
41.
Chan, A.T., Nasopharyngeal carcinoma. Ann Oncol, 2010. 21 Suppl 7: p. vii308-12.
42.
Hippocrate, A., L. Oussaief, and I. Joab, Possible role of EBV in breast cancer and other 
unusually EBV-associated cancers. Cancer Lett, 2011. 305(2): p. 144-9.
43.
Smith, C.A., et al., CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand 
defines an emerging family of cytokines with homology to TNF. Cell, 1993. 73(7): p. 1349-60.
44.
Horie, R. and T. Watanabe, CD30: expression and function in health and disease. Semin 
Immunol, 1998. 10(6): p. 457-70.
45.
Pizzolo, G., et al., High serum level of the soluble form of CD30 molecule in the early phase of 
HIV-1 infection as an independent predictor of progression to AIDS. AIDS, 1994. 8(6): p. 741-5.
46.
Zinzani, P.L., et al., Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic 
large-cell lymphoma patients. J Clin Oncol, 1998. 16(4): p. 1532-7.
47.
Nadali, G., et al., Serum levels of soluble CD30 are elevated in the majority of untreated patients 
with Hodgkin's disease and correlate with clinical features and prognosis. J Clin Oncol, 1994. 
12(4): p. 793-7.
48.
this is required if {institution} holds the IND. Otherwise, the affiliate Investigator’s signature on the 
protocol is sufficient to ensure compliance
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Amendment 9: December 12, 2017
APPENDICES
Appendix A: ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
Appendix B: Investigational Drug Request/Shipment Record Form
INVESTIGATIONAL DRUG REQUEST / SHIPMENT RECORD 
PART I – CLINICAL OPERATIONS SHIPPING 
REQUEST
Complete this section and email or fax to Seattle Genetics: 
IST@seagen.com or fax 425-527-2016
PRODUCT NAME:
BRENTUXIMAB VEDOTIN
PROTOCOL NO:
35-IST-
QUANTITY REQUESTED:  
              
Boxes of 10
DATE NEEDED BY:
     
INVESTIGATOR NAME:
SHIPMENT STATUS 
(CHECK ONE):  
  Initial 
Shipment
  Re-
Supply
Ship To: 
(Contact Name) 
     
 (Telephone Number) 
     
(Fax Number) 
     
(Site/Institution Name) 
     
(Site/Institution Address) 
     
(Site/Institution City, State / Province, Zip Code, Country)
     ,      ,      ,      ,      
SATURDAY DELIVERY REQUESTED:    Yes 
  No
  Not Available 
SITE REQUESTOR NAME:   
        
PHONE:       
SIGNATURE:  
   
  DATE:       /     /     
SGN LOT#:  _________     ___________________ ALMAC INVENTORY #:  _________________                                __ ___
RA APPROVAL/PART II        Required
  Not Required
CLINICAL OPERATIONS APPROVAL: _________________________________________ DATE:  _____/_____/_____
PART II- REGULATORY AFFAIRS SHIPPING APPROVAL   
(
Check One) 
   
Initial shipment to first site of country: ___________     
Compassionate Use (Single Patient IND) 
IND accepted? 
   Yes
  No  
Process released?
   Yes
  No
Protocol filed to IND? 
   Yes
  No  
Process ID (Lot prefix):  
RA APPROVAL:
_________________________________________
DATE: __/_____/_____
PART III – PACKAGING AND SHIPPING              
US:  
Email to palogistics.clinicalservices@almacgroup.com
                                                                    Canada/Europe:  
Email to uklogistics.clinicalservices@almacgroup.com 
Shipping details can be located on the Almac Packing List.
Part IV – STUDY SITE RECEIPT ACKNOWLEDGEMENT    
Complete this section and fax to +1-425-527-4309
                                                                     
                                File original in study files
Shipment Receipt Conditions 
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Amendment 9: December 12, 2017
Package intact?    
 Yes   
 No* 
Correct product per Section I?
 Yes   
 No* 
Correct lot # per Section I?
 Yes   
 No*
Correct quantity per Section I?       Yes      No* 
Alarm triggered?    
    Yes    
 No
* Provide explanation in Comments section below
    Complete IP Quality Complaints & Temperature 
Excursions Form (FM.224)
Comments:  
RECIPIENT NAME: _____________  SIGNATURE: ______________________ DATE REC’D:  ____/_____/_____
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Amendment 9: December 12, 2017
Appendix C
Protocol History of Changes by Amendment
Original Version Approved by the Northwestern University IRB – October 23, 2012
Updated Version Approved by the Northwestern University IRB – November 8, 2012
Amendment 1 – July 25, 2013***
Approved by Scientific Review Committee – August 7, 2013
***NOTE: This was originally approved by SRC on June 13, 2013 – the amendment was then updated based on the 
memo from Seattle Genetics (dated July 9, 2013) and additional changes requested July 25, 2013***
Section(s) 
Affected
Prior Version
Amendment 1 Changes
Rationale
Cover-page
IND listed as pending.
Updates IND# to 117197.
Administrative
Cover-page
Dr. Andrew Evens listed 
as the local PI for 
UMass.
Removes UMass as a 
participating site and adds 
Dr. Evens as the local PI for 
Tufts University. 
Administrative – Dr. 
Evens is now at Tufts 
and UMass will no longer 
be participating on this 
trial.
Sections 1.1 
(Disease 
Background) & 1.3 
(Rationale)
n/a
Adds background on 
indolent lymphomas in 
patients with autoimmune 
disorders and the lack of 
data to support R-CHOP as 
frontline therapy for these 
individuals. 
Provides background 
and rationale for their 
inclusion in the study 
population on a case-by-
case basis.
Section 1.2.1.1 
(Brentuximab 
vedotin – Toxicity 
Summary)
n/a
Adds updated background 
information regarding 
pancreatitis and 
brentuximab vedotin.
Added based on recent 
observations in other 
clinical trials and memo 
from Seattle Genetics 
summarizing a recent 
internal review.
Section 3.1 
(Inclusion Criteria)
No mention of whether 
or not non-PTLD cases 
of immunosuppression 
are eligible.
Adds the following:
NOTE: Patients who are 
immunosuppressed for 
reasons other than PTLD 
may be eligible if, in the 
opinion of the treating 
investigator, the risk of 
immediate treatment with 
R-CHOP outweighs the 
benefit for these patients.
Added based on 
feedback from 
participating 
sites/investigators.
Section 3.1 
(Inclusion Criteria)
No exceptions 
mentioned for patients 
with abnormal renal 
function.
Adds an exception to allow 
patients with abnormal 
renal function in cases 
where the abnormal 
function is due to allograft 
dysfunction resulting from 
diagnosis of PTLD, or from 
reduction/cessation of 
immunosuppression aimed 
at treatment of PTLD.
Added to avoid excluding 
patients who might 
otherwise be eligible and 
good candidates for the 
study.
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
Section 3.2 
(Exclusion Criteria)
n/a
Adds that patients 
diagnosed with DLBCL who 
do not have a defined 
history of 
immunosuppression or 
EBV-related DLBCL of the 
elderly should not be 
enrolled in this study.
Exclusion added based 
on feedback from 
participating 
sites/investigators..
Section 3.2 
(Exclusion Criteria)
n/a
Adds exclusion for patients 
with prior documented 
pancreatitis.
Added for safety 
reasons.
Section 4.1.3 
(Phase II 
treatment)
Simply stated that 
treatment would be at 
the MTD according to 
the same schedule used 
in phase I.
Expands treatment 
schedule details for 
induction, consolidation, 
and maintenance therapy 
for phase II patients. Gives 
specific instructions for 
patients achieving CR, PR, 
SD, or PD after induction 
therapy.
Clarifications necessary 
as trial prepares to enter 
phase II.
Section 4.1.6 
(Administration 
details)
Does not specify 
whether rapid infusion of 
rituximab is allowable.
Clarifies that rapid infusion 
of rituximab is allowable 
after the first dose at the 
discretion of the treating 
investigator.  
Clarification
Section 4.3 [Dose-
Limiting Toxicity 
(DLT) and 
Maximally 
Tolerated Dose 
(MTD)]
n/a
Adds the following as an 
exclusion to the definition of 
DLT for future patients:
Cases involving 
hyperbilirubinemia that is 
primarily indirect, and 
considered not reflective of 
underlying liver disease (ie, 
resulting from transfusion of 
red blood cells), will not be 
considered a DLT.
Clarification
Section 4.3 – Table 
2 (Hematological 
Toxicity Dose 
Reductions for 
Brentuximab 
vedotin)
For the first occurrence 
of ANC 500-999/L, 
Table 2 stated to hold 
the current dose.
Changes this to state that 
the treating investigator 
should be notified, and it 
will be at his or her 
discretion whether to hold 
the dose.
Changed based on the 
PI’s recommendation to 
allow for investigator’s 
assessment.
Section 4.3 
(Toxicity and Dose 
Delays/Dose 
Modifications)
n/a
Adds separate instructions 
regarding the management 
of hyperamylaseemia and 
pancreatitis.
Added for safety reasons 
and to increase 
monitoring of these 
events.
Section 4.3 – Table 
3 (Non-
Hematological 
Toxicity Dose 
Reductions for 
Brentuximab 
vedotin & 
Rituximab)
n/a
Adds the following 
clarification regarding 
elevated bilirubin:
In cases involving 
hyperbilirubinemia that is 
primarily indirect, and 
considered not reflective of 
Clarification.
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
underlying liver disease (ie, 
resulting from transfusion of 
red blood cells), treating 
investigators may consider 
avoiding protocol-specified 
dose reductions, after 
consultation with principal 
investigator.  
Section 5.0 Study 
Procedures)
n/a
Adds serum amylase to be 
drawn up to 72 hours prior 
to brentuximab vedotin 
dosing, with instructions to 
also test lipase if amylase is 
elevated and modify dose 
as needed based on 
guidelines added to Section 
4.3.
Added for safety reasons 
and to increase 
monitoring of these 
events.
Sections 1.4 
(Correlative 
Studies), 2.5 
(Exploratory 
Objectives), 5.1 
(Screening and/or 
Baseline 
Procedures), 5.2 
(Procedures During 
Treatment), 5.4 
(Time and Events 
Table), 9.1 
(Objectives of 
correlative studies), 
9.2.5 (Objective 5), 
& 9.3 (Specimen 
Collection 
Guidelines)
Did not include specific 
information on peripheral 
blood to be drawn for 
correlative testing. 
Specifies that one red top 
and one green top tube will 
be collected for banking of 
samples for future, 
unspecified use. Clarifies 
that this will be done for 
phase II patients only. 
Gives details for procuring 
and storing the samples. 
Includes timeframes for 
these collections (baseline, 
Day 1 of induction, and Day 
1 of the first 3 maintenance 
therapy cycles).
The protocol allowed for 
peripheral blood to be 
drawn for correlatives in 
section 9.0, but the 
details were not 
specified.
Appendices
n/a
Adds Appendix D – 
Protocol History of Changes 
by Amendment
Administrative
Amendment 2 – October 15, 2013
Approved by Scientific Review Committee – October 16, 2013
Section(s) 
Affected
Prior Version
Amendment 2 Changes
Rationale
Schema, 4.0 
(Treatment Plan), 
5.4 (Table 4 – Time 
& Events Table), 
Cycle length unclear 
from one phase of 
treatment to the next.
Clarifies cycle length for 
induction and consolidation 
as 4 weeks and for 
maintenance as 3 weeks. 
Removes references to 
specific study weeks as the 
time between re-staging 
and the start of the next 
phase of therapy is meant 
to be flexible to allow 
patients to proceed when 
Clarification
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
they are ready per treating 
investigators’ discretion.
3.1 (Inclusion 
Criteria)
n/a
Adds a statement regarding 
the requirement for 
measureable disease that 
patients are eligible after 
resection of disease (and 
will be evaluable for all 
endpoints besides 
response).
Added to enhance 
eligibility parameters.
3.1 (Inclusion 
Criteria)
n/a
Adds that patients may 
have received up to 1 prior 
dose of rituximab before 
registration.
Added to enhance 
eligibility parameters.
4.3 (Toxicities and 
Dosing 
Delays/Dose 
Modifications)
No mention of restarting 
or increasing doses of 
brentuximab after 
interruption/decrease 
due to toxicity.
Revised to permit restarting 
and/or increasing the dose 
of an individual patient’s 
brentuximab vedotin in the 
event that toxicity 
completely resolves (for 
cases where it was stopped 
or decreased for toxicity in 
that same patient).
Changed by PI to avoid 
under-treating patients.
4.3 (Table 3 – Non-
hematologic dose 
reductions)
Rituximab also required 
to be held in the event of 
all grade 3-4 non-
hematologic toxicities.
Changed to permit 
continuation of rituximab for 
grade 3-4 non-hematologic 
toxicities that are clinically 
attributed to brentuximab 
vedotin.
Changed by PI to avoid 
under-treating patients.
4.3 (Table 2 –
Hematologic dose 
reductions)
Dose modifications listed 
in one table for both 
ANC and platelet 
toxicities.
Splits Table 2 in to Table 2a 
and 2b to distinguish 
between ANC and platelet 
events (they should be 
handled separately and not 
as either/or in terms of 
when to hold or reduce 
brentuximab vedotin.
Clarification
7.0 (Adverse 
Events), 11.0 
(Study 
Management), 
Appendix C (Data 
Collection and 
Submission for 
Phase I Patients), 
Appendix E (Data 
Collection and 
Submission for 
Phase II Patients), 
Appendix F (Slot 
Reservation 
Procedure), 
Contained outdated 
and/or generic language 
pertaining to AE 
reporting, registration 
procedures, data 
submission guidelines 
and requirements, and 
study monitoring.
Updates language and 
introduces new, study-
specific procedures, 
requirements, guidelines, 
and forms.
Administrative update
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
Appendix G (Data 
Safety Monitoring 
Plan), Appendix H 
(NU CRO SAE 
Form)
Amendment 3 – March 24, 2014
Approved by Scientific Review Committee: May 2, 2014
Section(s) 
Affected
Prior Version
Amendment 3 Changes
Rationale
4.3 (Toxicities and 
Dosing 
Delays/Dose 
Modifications)
Dose modifications 
given for asymptomatic 
hyperamylasemia 
referenced “normalizing” 
of lipase and amylase 
levels prior to restarting 
brentuximab vedotin.
Revises guidelines for 
asymptomatic elevated 
amylase and lipase to 
reflect instructions by grade 
(1-2 no change, 3-4 hold 
dose until ≤ grade 2 and 
then resume as described).
Changed based on 
experience with current 
patients & the advice of 
Seattle Genetics.
4.1.3 (Phase II 
Treatment)
Stated that all patients 
with PR or CR after 
initial re-staging would 
proceed to 
Consolidation.
Changes this to state that 
patients may receive 
Consolidation but in some 
cases, those with CR after 
Induction may proceed 
directly to Maintenance 
therapy at the discretion of 
the treating investigator.
This was changed to 
avoid excessive toxicity 
and allow for more 
flexibility in the treatment 
plan for each patient.
Amendment 4 – March 18, 2015
Approved by Scientific Review Committee: March 18, 2015
Section(s) 
Affected
Prior Version
Amendment 4 Changes
Rationale
1.2.1.1 
(Brentuximab 
vedotin Toxicity 
Summary) & 
8.1.10 (Side 
effects)
n/a
Clarified that safety
data are based on oncology 
studies and that 1.8 mg/kg is 
the recommended dose for 
the approved indications. 
Added
toxic epidermal necrolysis 
and pulmonary toxicity with 
monotherapy as notable 
adverse events. Added 
results of studies in patients 
with hepatic or renal 
impairment.. Updated side 
effects.
Updated Version 12 of 
Brentuximab vedotin 
IB released.
3.2.12 (Exclusion 
Criteria)
n/a
Added exclusion 
“Patients with severe 
renal impairment (CrCL 
<30 mL/min). A 
calculated CrCl is 
acceptable.”
Added due to Updated 
Version 12 of 
Brentuximab vedotin 
IB.
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Study Number:  NU 12H09
Initial Version  March 15, 2016
66
Amendment 9: December 12, 2017
8.1.12 (Nursing 
/patient 
implications)
n/a
Revised to add: 
Avoid use in patients 
with severe renal 
impairment
Avoid use in patients 
with moderate or severe 
hepatic impairment 
(Child-Pugh B or C).
Updated prescribing 
information released
Amendment 5 – November 16, 2015
Approved by Scientific Review Committee: December 17, 2015
Section(s) 
Affected
Prior Version
Amendment 5 Changes
Rationale
Cover-Page
Adam Petrich listed as 
Principal Investigator 
and IND Holder
Adam Petrich has been 
removed as PI and Jason 
Kaplan has been added; 
contact information and IND 
Holder Name have been 
updated appropriately
Administrative: Adam 
Petrich has left the 
institution and will no 
longer serve as the study 
PI; Jason Kaplan will 
take over role of PI
Cover-Page, 1.4.1 
(Correlative 
Studies) & 9.3 
(Sample Collection 
Guidelines)
Amy Chadburn listed as 
Sub-Investigator & 
hematopathologist
Amy Chadburn has been 
removed and replaced by 
Amir Behdad as Sub-
Investigator and 
hematopathologist involved 
in TMA analysis
Administrative: Amy 
Chadburn has left the 
institution and Amir 
Behdad has taken over 
her role on this study
Signature Page
Signature Page included
Signature Page removed
Administrative: NU 
protocol template no 
longer includes a 
signature page
4.3 (Toxicities and 
Dosing Delays/ 
Dose 
Modifications)
Language allowed for 
holding study treatment 
due to toxicity
Language has been added 
to clarify that study 
treatment should be 
skipped rather than held. 
Table 2a & 2b reflect 
changes by replacing the 
word “Hold” with “Withhold” 
or “Skip treatment” in each 
line
Clarification 
5.4 (Table 4: Time 
and Events Table) 
& 9.3 (Sample 
Collection 
Guidelines)
The footnote (#) for 
peripheral blood banking 
and instructions in 9.3 
called for samples at 
baseline, day 1 of 
induction, and day 1 of 
the first 3 maintenance 
cycles
The footnote (#) and 
instructions in 9.3 now state 
that samples should be 
collected at baseline OR 
day 1 of induction. The 
word “products” has been 
added to clarify that “blood 
products” rather than 
“blood” will be frozen and 
stored for future, 
unspecified use
Clarification 
5.4 (Table 4: Time 
The footnote (@) for 
serum amylase states 
This has been changed to 
state that the test may be 
Clarification
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Study Number:  NU 12H09
Initial Version  March 15, 2016
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Amendment 9: December 12, 2017
and Events Table
that the test may be 
drawn 72 hours prior to 
dosing
drawn up to 72 hours prior 
to dosing
9.3 (Sample 
Collection 
Guidelines)
Pathology Core Facility 
is listed as the center for 
picking up correlative 
samples
Clinical Trials Pathology 
Office will pick up and store 
correlative samples
Administrative: 
Pathology Core Facility 
has changed their name 
to Clinical Trials 
Pathology Office; they 
will also be responsible 
for storing samples 
9.3.1 (Blood 
Processing and 
Shipping)
n/a
Details have been provided 
for processing and shipping 
of correlative samples (Red 
Top Tube and Green Top 
Tube drawn at Baseline and 
day 1 of the first 3 
maintenance cycles)
Updated with new 
information for 
correlative sample 
analysis
Amendment 6 – March 15, 2016
Approved by Scientific Review Committee: March 15, 2016
Section(s) 
Affected
Prior Version
Amendment 6 Changes
Rationale
Study Schema, 
2.3.3 (Primary 
Endpoints),
There were many 
discrepancies in the 
protocol about when 
patient scans and the 
Phase II primary 
objective assessment 
would take place
Scans will be performed 
after induction, after 
consolidation (if applicable), 
and every 12 weeks (4 
cycles) thereafter during 
maintenance
Clarification for many 
discrepancies in the 
protocol which have 
caused deviations; new 
study PI decided on a 
straightforward scanning 
schedule of q12weeks
3.0 (Patient 
Eligibility)
Inclusion and exclusion 
criteria listed as 
incomplete phrases
Lists inclusion and 
exclusion criteria as 
complete sentences
Grammatical clarification
4.1.1 (Phase I 
Dosage), 4.1.2 
(Phase II Dosage)
Listed maintenance 
treatment continuing for 
one year or until PD
Lists maintenance 
treatment continuing for one 
year from starting induction 
or until PD
Clarification – previous 
language may be 
interpreted as 
maintenance continuing 
for one year, when total 
treatment (including 
induction and 
consolidation) should be 
one year
4.1.1 (Phase I 
Dosage)
“Those patients failing to 
achieve CR after the 
Induction course may 
receive an additional 
treatment of the same 
(termed Consolidation)”
“Those patients who 
achieve response (PR or 
CR) after the induction 
course may receive an 
additional treatment…”
Clarification
Schema; 4.1.2 
(Phase I treatment 
plan); 4.2 (DLT & 
MTD)
DLT period is first 21 
days of treatment /  first 
cycle (cycle = 21 days)
DLT period is the first 21 
days of induction
Clarification – prior 
language was unclear 
whether DLT period is 
during induction or 
maintenance therapy
4.2 (DLT & MTD),
CTCAE v4
CTCAE v4.03
Administrative update
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Study Number:  NU 12H09
Initial Version  March 15, 2016
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Amendment 9: December 12, 2017
6.1.2 (Safety/ 
tolerability)
7.2.2. (Severity of 
AE’s)
5.4 (Table 4: Time 
and Events Table
Table did not include 
complete information 
about study procedures 
and treatment
Table has been reformatted 
completely. Changes 
include:
-Separate columns for 
Induction, Consolidation, 
and Maintenance, including 
study visit time points and 
cycle lengths
-Includes a row for 
Brentuximab vedotin and 
Rituximab administration
-Replaces “Tumor 
Assessment” and 
“Response Assessment” 
with simply “Scans”; timing 
of scans has also been 
clarified as being q12weeks 
in Maintenance
-Includes screening window 
and study visit windows
-Replaces footnote symbols 
with numbers
Major clarifications
9.3.1 (Blood 
Processing & 
Shipping)
Listed Clinical Trials 
Pathology office (CTPO) 
for sample processing
Changes sample 
processing center for 
Pathcore Facility Clinical 
Trials Unit (PCF-CTU)
Administrative name 
change
7.1 (Adverse Event 
Monitoring), 11.5 
(Data Management 
and Monitoring/ 
Auditing), 
Appendices
Study monitoring plan 
and data submission 
guidelines were included 
as Appendix C, E, and G
Removes Appendix C, E, 
and G and any references 
in the protocol; instead 
references NOTIS for such 
guidelines
Administrative – aligns 
with current 
departmental policies
Appendices
Included the NU SAE 
Form as Appendix H
Removes Appendix
Administrative – the most 
recent version of the 
SAE form can be found 
elsewhere
Amendment 7 – November 14, 2016
Approved by Scientific Review Committee: December 16, 2016
Section(s) 
Affected
Prior Version
Amendment 7 Changes
Rationale
Title Page; Study 
Summary
Title: “A Phase I-II Trial 
of Brentuximab Vedotin 
Plus Rituximab as Front-
Line Therapy for 
Patients with CD30+ 
and/or EBV+ 
Lymphomas”
Title: “A Phase I-II Trial of 
Brentuximab Vedotin Plus 
Rituximab as Front-Line 
Therapy for Patients with 
Lymphomas Associated 
with Immunosuppression”
It is no longer a 
requirement for patients 
to be CD30+, as long as 
the lymphoma is 
associated with a state of 
immunosuppression as 
listed in 3.1.1. CD30 and 
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
EBV status will still be 
investigated in all 
patients.
Title Page
n/a
Adds Reem Karmali as sub-
Investigator
Administrative – new 
faculty
Study Schema; 
Study Summary; 
2.1 (Primary 
Objectives); 3.1.1 
(Inclusion Criteria)
Patients were required 
to have CD30+ and/or 
EBV+ lymphoma
Patients are not required to 
specifically have CD30+ or 
EBV+ lymphoma, but rather 
a lymphoma that is 
associated with 
immunosuppression (e.g. 
PTLD, DLBCL of the elderly 
etc. as listed in 3.1.1). This 
may include patients with 
CD30+ or EBV+ lymphoma. 
The overall purpose of 
requiring CD30+ or 
EBV+ status was to 
ensure patients had 
lymphoma associated 
with 
immunosuppression. 
Degree of CD30 
positivity doesn’t 
correlate to response to 
BV, and conventional 
methods of assessing 
CD30 have limitations. 
Therefore removing this 
requirement is 
appropriate.
Study Summary
Included “Short Title”
Removes “Short Title”
To align with current 
protocol template and 
avoid deviating from the 
title in CT.gov
3.1.5 (Inclusion 
Criteria)
NOTE: Patients with fully 
resected disease are 
eligible, and will be 
evaluable for all toxicity 
and efficacy endpoints 
except response.
NOTE: Patients with fully 
resected disease are 
eligible, and will be 
evaluable for all toxicity and 
efficacy endpoints except 
objective response.
Clarification to specify 
that the only efficacy 
endpoint affected by 
resected disease is 
objective response. 
4.3 (Toxicities and 
Dosing 
Delays/Dose 
Modifications)
n/a
Adds “pre-dose lab values 
must be assessed prior to 
dosing at each treatment 
visit”.
Clarification requested 
by IRB to avoid 
inappropriate patient 
dosing.
4.8 (Removal of 
Patients from 
Protocol Therapy); 
5.5 (Removal of 
Subjects from 
Treatment and/or 
Study)
Included language in 4.8 
on removing patients 
from treatment, and 
referenced sections 4.6 
and 5.5.
Compiles all language 
about patient 
discontinuation into section 
4.8 (moved from section 
5.5). This incorporates 
removal from both 
treatment and study. 
Information was 
previously redundant; 
language is now 
simplified and aligns with 
current protocol template 
setup. 
5.0 (Study 
Procedures)
Included paragraph 
listing of all study 
procedures prior to the 
study table
n/a
Removes paragraph 
description of study 
procedures
Adds footnote #3 to state 
“CBC and Chemistry 
panels must be resulted 
prior to dosing to assess 
the need for dose delays 
or modifications”. Also 
adds notes to #6 & #7. 
Re-numbers footnotes.
Including both 
descriptions is 
redundant. The table 
aligns with the current 
protocol template. 
Clarification requested 
by IRB to avoid 
inappropriate patient 
dosing.
6.1 (Toxicity 
Definitions); 
Listed limited 
descriptions of 
Includes descriptions of 
evaluability for each study 
Clarification requested 
by internal Quality 
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
6.2 (Efficacy 
Definitions)
evaluability for endpoints 
(just overall “toxicity” and 
objective response)
endpoint (toxicity, safety, 
survival [PFS, OS], and 
each exploratory objective)
Assurance team. 
6.2.1.1 (Evaluable 
for objective 
response)
n/a
Defines measurable 
disease as “at least 1 cm”
Clarification for 
consistency
7.2.2 (Severity of 
AE’s)
CTCAE v4.0
CTCAE v4.03
Administrative update
8.1.4.3 (Special 
Handling)
n/a
“Each study site will be 
responsible for regular 
inventory checks and 
disposing of expired drug in 
a timely manner”
Clarification requested 
by the IRB to ensure 
expired drug is disposed 
of appropriately and to 
avoid the risk of 
dispensing to patients.
11.5 (Data 
Management and 
Monitoring/ 
Auditing
n/a
Adds “All participating sites 
are responsible for entering 
data in the timeframe 
outlined in the data 
submission guidelines.”
Clarification requested 
by the IRB to encourage 
timely data submission.
Amendment 8 – June 14th, 2017
Approved by Scientific Review Committee: 
Section(s) 
Affected
Prior Version
Amendment 8 Changes
Rationale
Cover Page
Jason Kaplan was 
affiliated with 
Northwestern Medicine 
Development 
Therapeutic Institute
Changes affiliation to 
Developmental 
Therapeutics Program of 
Department of Hematology 
Oncology 
Administrative
Study Schema; 
2.3.2 (Primary 
Endpoints)
“Primary objective 
assessment: after week 
4 treatment (Phase I 
only); after cycle 4 and 8 
of maintenance (Phase 
II only)”
“Primary objective 
assessment: toxicity after 
week 4 treatment (Phase I 
only); scans after 
induction treatment 
and/or after consolidation 
treatment (if applicable) 
(Phase II only)”
Clarification to align with 
protocol objectives in 
each phase and 
appropriate timing. The 
intention was to look at 
response after induction 
and/or consolidation, 
when applicable.
Study Summary
Included University of 
Massachusetts as an 
affiliate
Removes University of 
Massachusetts
To fix discrepancy; had 
been previously removed 
everywhere else.
Study Summary
IV frequency listed as 
“weekly” or “every 3 
weeks”
Adds once weekly and 
once every 3 weeks
Clarification
2.2.3 (Secondary 
Objectives); 2.4.3 
(Secondary 
Endpoints)
n/a
Adds an objective and 
endpoint to look at best 
response to therapy, with 
scans after induction and/or 
consolidation, and every 12 
weeks during maintenance 
Added per PI discretion 
to analyze more long-
term response results
2.3.1 (Primary 
Endpoints)
Defined DLT as the 
occurrence of ≥ Grade 3 
toxicity
Removes Grade 3 definition 
and refers to section 4.2, 
which contains a more 
detailed definition
DLT definitions are 
different for non-
hematologic (≥G3) vs 
hematologic (≥G4) 
toxicities 
3.0 (Patient 
Eligibility)
n/a
Adds introductory language 
with the overall population, 
To align with current NU 
protocol template 
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
participating sites, accrual, 
and registration details.
language
3.1.1 (Inclusion 
Criteria)
“Patients must have a 
histologically confirmed 
CD20+ lymphoid 
malignancy…”
Replaces “lymphoid 
malignancy” with 
lymphoproliferative disease
Clarification – 
lymphoproliferative 
disease is inclusive of 
non-malignant disease, 
as intended
3.1.2 (Inclusion 
Criteria)
“In cases of PTLD 
arising in patients who 
are pharmacologically 
immunosuppressed…”
“NOTE: Patients who 
are immunosuppressed 
for reasons other than 
PTLD may be eligible…”
“In cases of 
lymphoproliferative 
disease arising…”
NOTE: Patients who are 
otherwise 
immunosuppressed (for 
reasons such as immune 
dysregulation related to 
autoimmune conditions, 
in the absence of 
pharmacological 
immunosuppression) may 
be eligible…”
Clarification; any study 
patient may have 
pharmacologic 
immunosuppression, not 
just PTLD patient
3.1.3, 3.1.4 
(Inclusion Criteria); 
3.2.1 (Exclusion 
criteria)
Requirements to have 
no prior treatment or 
surgical intervention 
included as inclusion 
criteria
Removed from inclusion 
and included as exclusion 
criteria 3.2.1 and 3.2.3. 
More appropriate as 
exclusion criteria 
3.2.1 (Exclusion 
Criteria)
Excluded patients with 
no history of 
immunosuppression or 
EBV-related DLBCL
Removes exclusion criteria
Redundant of inclusion 
3.1.1, which states that 
lymphoproliferative 
disease must be 
immunosuppressed
3.2.2, 3.2.1 
(Exclusion 
Criteria); 4.1.1.2.1 
(Pre-Registration 
Rituximab)
n/a
Patients are allowed to 
receive one dose of 
rituximab prior to entering 
the study, and in such 
cases, patients will only 
have 3 doses during 
induction (a total of 4 
doses)
Added for clarification 
and consistency
3.2.4, 3.2.5 
(Exclusion 
Criteria); 4.4.3 
(Concomitant 
medications and 
treatments not 
allowed)
n/a
Clarifies timing of washout 
as 4 weeks or 14 days prior 
to registration for 
unrecovered AE’s, 
chemotherapy, radiotherapy 
or investigational agents, 
respectively
Clarification 
3.2.11 (Exclusion 
Criteria); 
5.0 (Study 
Procedures)
Patients were not 
eligible with clinically 
active Hep A, B, or C
Clarifies that Hep B will be 
tested at screening, and 
Hep A and C will be based 
on known history.
Adds Hepatitis B testing 
within 4 months prior to 
registration.
Hepatitis B testing is 
standard prior to 
rituximab treatment.
4.0 (Treatment 
Plan)
n/a
Adds paragraph and table 
as a treatment summary 
Added for clarity and 
simplification
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
before subsequent details 
of dosage and 
administration (updates all 
subsequent table numbers 
and references)
4.1.1 (Phase I and 
II dosage); 4.1.3 
(Phase II 
Treatment)
Referred to Phase I 
dosing only
Refers to both Phase I and 
II dosing details with a 
statement that RP2D was 
found to be the same as 
Phase I dosing on 
3/12/2014. Refers to 
section 4.1.3 for Phase II 
instructions for treatment 
after SD 
Updated for accuracy 
and simplicity 
4.1.6 
(Administration 
Details, Table 2)
Rituximab treatment for 
the full study was listed 
in a shaded box
Separates rituximab 
treatment by 
induction/consolidation vs 
maintenance, similar to BV
Revised for clarity
4.2 (DLT and MTD)
n/a
Adds “For Phase I…” to 
preface DLT definitions
Clarification 
Referenced section 
1.3.1.1 for risk 
information
Updates to section 1.2.2.1
Revised for accuracy
4.3 (Toxicities and 
Dosing 
Delays/Dose 
Modifications)
Tables listed dose 
reduction instructions for 
hematologic and non-
hematologic toxicities
Adds “Drug-related” prior to 
toxicity descriptions
Added for clarity 
4.4 (Concomitant 
Medications / 
Treatments)
Required Tylenol and 
Benadryl with specific 
doses and timing prior to 
infusions
Adds “or equivalent as per 
standard practice” 
To allow flexibility and 
avoid unnecessary 
deviations
4.7 (Duration of 
Follow Up); 5.0 
(Study Procedures 
#11)
Follow up was to take 
place for up to 3 years 
from start of treatment
Follow up will take place for 
up to 3 years from 
discontinuation of 
treatment
Correction of 
discrepancy and to 
standardize safety follow-
up for all patients  
Listed “Informed consent 
and demographic 
information” 
Removes “Demographic 
information”
Demographic information 
will be collected by 
default during H&P
#2: Scans were to take 
place after week 4 and 
week 8
Changes scans to after 
induction and after 
consolidation
Adds that patients with a 
CR after induction do not 
need to repeat a scan 
after consolidation
Adds that although 
PET/CT is preferred, 
patients may be 
assessed by CT alone at 
any time point
Clarification, allowing 
flexibility in exact 
timing of induction and 
consolidation
To account for 
standard practice and 
the possibility of 
insurance denial  
“” 
5.0 (Study 
Procedures)
#7: n/a
#7: Adds that consolidation 
and maintenance should 
start 7-21 days after the 
fourth induction or 
consolidation dose of 
Adds guidance with 
flexibility  
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Amendment 9: December 12, 2017
rituximab
#9: Performance status 
was to be performed 
every 4 months during 
maintenance
Removes note about PS
PS is standard to collect 
at each visit
n/a
#12: Adds note with criteria 
for patients to receive 
optional consolidation 
Clarification 
Procedures were listed 
by weeks with no 
indication of the actual 
day of procedures 
Adds footnote 13 to clarify 
that procedures will take 
place on Day 1 of each 
week
Clarification
Amendment 9 – December 12, 2017
Section(s) 
Affected
Prior Version
Amendment 9 Changes
Rationale
Cover Page; 
3.0 (Patient 
Eligibility)
Study PI was Dr. Jason 
Kaplan
Updates study PI to Dr. 
Barbara Pro
Administrative faculty 
change due to Dr. 
Kaplan leaving the 
institution 
Cover-page
Dr. Andrew Evens listed 
as the local PI for Tufts.
Removes Dr. Evens and 
lists Dr. Andreas Klein as 
the local PI for Tufts 
University. 
Administrative – Dr. 
Evens is leaving Tufts 
and has identified Dr. 
Klein as the replacement 
sub-I
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
Appendix D:  SLOT RESERVATION PROCEDURE
1.
The Quality Assurance (QA) Department at Northwestern University will coordinate subject and 
cohort assignments.  The QA Department may be contacted by email at 
croqualityassurance@northwestern.edu.
All correspondence regarding subject and cohort assignments should only be directed to and 
received from members of the QA Department.
2.
All sites open to accrual will be notified by the QA Department that the study/cohort is open for 
accrual and the number of slots to be filled in each cohort or part of the study.
3.
Upon identification of a potential protocol patient, the site staff should submit the attached Slot 
Reservation Form.  The Slot Reservation Form will capture proposed dates for:
a)
Proposed date of consent
b)
Start of treatment (C1D1).  
4.
The Slot Reservation Form should then be submitted electronically to the QA Department 
(croqualityassurance@northwestern.edu. Slot Reservation Forms will ONLY be accepted 
electronically. Phone calls and faxes will NOT be accepted. Slots will be assigned on a first come, 
first serve basis.  
5.
Upon receipt of the Slot Reservation Form, a member of the QA Department will send written 
documentation to the site within 24 hours that the Slot Reservation Form has been:
a)
Accepted and a slot has been reserved
b)
Added to the waitlist
6.
If the Slot Reservation Form is accepted, the site has until the date specified on the approved 
reservation form to register the patient. After the specified date the slot reservation will expire. 24 
hours prior to this expiration, if patient has not yet been registered, site will receive written notification 
that the slot will expire in 24 hours. At this point, the site can file a Slot Reservation Extension Form; 
however the Slot Reservation Extension will be granted or denied at the sole discretion of the QA 
Department. Filing a Slot Reservation Extension Form does NOT guarantee that the extension will be 
granted. Site will be notified electronically prior to the original Slot Reservation expiration whether or 
not the Extension has been granted.
7.
After receiving official notification that Slot Reservation Form has been approved, patient consent and 
screening can begin. 
8.
Please Note: ONLY patients with Slot Reservation Approval electronically signed by a member of the 
QA Department of Northwestern University will be registered to the study. If patient initials from the 
approved slot reservation form do not match the initials of the patient site is registering, registration 
WILL be rejected.  
9.
If the patient is not eligible or decides not to participate, the QA Department must be notified ASAP. In 
this case the slot reservation for that patient will be cancelled, and the slot will be returned to the pool 
for re-allocation. 
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
10. The QA Department will communicate with the sites regularly to update the status of any open slots 
within a cohort, as well as any suspensions or re-openings.
Slot reservations are per patient, not per institution, and cannot be transferred or held 
indefinitely.
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Study Number:  NU 12H09
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Amendment 9: December 12, 2017
THE CLINICAL RESEARCH OFFICE OF THE ROBERT H. LURIE COMPREHENSIVE CANCER CENTER OF 
NORTHWESTERN UNIVERSITY
SLOT RESERVATION FORM
Date of Submission: __________________________________
Site Number/Name: __________________________________
Patient Initials: ______________________________________
Planned Date to Obtain Consent:  ____/____/____
Planned Date for Cycle 1 Day 1:  ____/____/____
Comments:
Form Submitted by: _____________________________________________
Contact Information: ____________________________________________
Please email this form to the QA Department at croqualityassurance@northwestern.edu 
QA use Only:
Status:________________________
Date of Expiration (Slot reservation will expire on this day.  The patient will only be 
registered before this date): _____________
QA Signature:__________________________________
Date: _________________________________________
(Printed QA name indicates an electronic signature)
IRB #: STU00072695 Approved by NU IRB for use on or after 9/24/2018 through 9/23/2019.

Study Number:  NU 12H09
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77
Amendment 9: December 12, 2017
THE CLINICAL RESEARCH OFFICE OF THE ROBERT H. LURIE COMPREHENSIVE CANCER CENTER OF 
NORTHWESTERN UNIVERSITY
SLOT RESERVATION EXTENSION FORM
Date of Submission: __________________________________
Site Number/Name: __________________________________
Patient Initials: ______________________________________
Length of Extension Requested: ________________________
Planned Date for Cycle 1 Day 1:  ____/____/____
Reason for Extension Request:
Form Submitted by: _____________________________________________
Contact Information: ____________________________________________
Please email this form to the QA Department at croqualityassurance@northwestern.edu 
QA use Only:
Status:________________________
Length of extension granted: ____________
Date of Expiration (Slot reservation will expire on this day.  The patient will only be 
registered before this date): _____________
QA Signature:__________________________________ Date:__________
(Printed QA name indicates an electronic signature)
IRB #: STU00072695 Approved by NU IRB for use on or after 9/24/2018 through 9/23/2019.