Conditions: CD30 Positive Primary Mediastinal Large B-cell Lymphoma CD30-Positive Diffuse Large B-Cell Lymphoma CD30-Positive Gray Zone Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This is a Phase I/II multicenter single arm non-randomized open label study of the investigational drug, brentuximab vedotin, given in combination with routine chemotherapy (rituximab, cyclophosphamide, doxorubicin and prednisone) every 3 weeks for a total of 6 cycles.

Detailed description:

Arms:
arm 1: Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion).

Cycle 1:

Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin)

Cycles 2-6:

Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg

Interventions: intervention 1: brentuximab vedotin
Intervention descriptions: intervention 1: Trade name: Adcetris

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania. 
Do not disclose or use except as authorized in writing by the study sponsor 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
A PHASE I/II STUDY OF BRENTUXIMAB VEDOTIN IN 
COMBINATION WITH MULTI-AGENT CHEMOTHERAPY AS FRONT-
LINE TREATMENT IN PATIENTS WITH CD30 POSITIVE PRIMARY 
MEDIASTINAL LARGE B-CELL, DIFFUSE LARGE B-CELL, AND 
GREY ZONE LYMPHOMAS 
 
Principal Investigator/ 
Regulatory Sponsor: 
Jakub Svoboda, MD 
Department of Medicine, Division Hematology-Oncology 
Hospital of the University of Pennsylvania 
3400 Civic Center Blvd. 
Philadelphia, PA 19104 
Tel: 215-614-1846 
 
Sub-Investigators: 
Stephen Schuster, MD (UPenn) 
Sunita Nasta, MD (UPenn) 
Daniel Landsburg, MD (UPenn) 
Joanne Filicko-O’Hara, MD (TJUH) 
Stefan K. Barta, MD (FCCC) 
Megan S. Lim, MD, PhD (UPenn) 
Marco Ruella, MD (UPenn) 
 
Funding Sponsor: 
 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 
Participating Sites: 
Hospital of the University of Pennsylvania 
Thomas Jefferson University 
Fox Chase Cancer Center 
 
Study Product: 
Brentuximab vedotin (Adcetris) 
 
Protocol Number: 
818280 / UPCC 17413 
 
IND Number: 
118739 
 
Medical Monitor: 
Naomi Haas, MD 
 
Initial version:  08.13.2013 
Amended: 
 06.02.2014 
Amended: 
 03.09.2015 
Amended: 
 06.22.2015 
Amended: 
 10.25.2017 
Amended: 
 01.12.2018 
Amended: 
 01.31.2018 
Amended: 
 06.21.2018 
 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
 
CONFIDENTIAL 
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page i 
INVESTIGATOR AGREEMENT 
 
 
Study Title: A Phase I/II Study of Brentuximab Vedotin in Combination with Multi-agent 
Chemotherapy as Front-Line Treatment in Patients with CD30-Positive Primary 
Mediastinal Large B-Cell, Diffuse Large B-cell, and Grey Zone Lymphomas (UPCC 17413) 
 
I agree to conduct this clinical trial according to the principles and methods set forth in this 
protocol and in accordance with GCP, and applicable regulatory requirements. 
 
 
 
 
 
 
__________________________________________________________________ 
Investigator’s Signature 
 
 
 
 
__________________________________________________________________ 
Investigator’s Printed Name 
 
 
 
__________________________________________________________________ 
Institution 
 
 
 
_________________________________ 
Date 
 
 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
 
 
CONFIDENTIAL 
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Do not disclose or use except as authorized in writing by the study sponsor 
page ii 
 
Table of Contents 
 
STUDY SUMMARY ....................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................... 3 
1.1 BACKGROUND ..................................................................................................................... 3 
1.2 INVESTIGATIONAL AGENT ...................................................................................................... 5 
1.3 PRECLINICAL DATA .............................................................................................................. 5 
1.4 CLINICAL DATA TO DATE ...................................................................................................... 6 
1.5 STUDY RATIONALE AND RISK/BENEFITS ................................................................................ 7 
1.5.1 Correlative Study Rationale ........................................................................................... 8 
2 
STUDY OBJECTIVES ........................................................................................................... 9 
3 
STUDY DESIGN .................................................................................................................. 10 
3.1 GENERAL DESIGN .............................................................................................................. 10 
3.2 PRIMARY STUDY ENDPOINTS .............................................................................................. 10 
3.3 SECONDARY STUDY ENDPOINTS ......................................................................................... 11 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................... 11 
4.1 INCLUSION CRITERIA FOR PHASE I AND PHASE II ................................................................... 11 
4.2 EXCLUSION CRITERIA FOR PHASE I AND PHASE II .................................................................. 12 
4.3 INCLUSION CRITERIA FOR CORRELATIVE STUDY .................................................................... 13 
4.4 EXCLUSION CRITERIA FOR CORRELATIVE STUDY ................................................................... 13 
4.5 SUBJECT RECRUITMENT AND SCREENING ............................................................................ 13 
4.6 EARLY WITHDRAWAL OF SUBJECTS ..................................................................................... 13 
4.6.1 When and How to Withdraw Subjects ....................................................................... 13 
4.6.2 Data Collection and Follow-up for Withdrawn Subjects ............................................. 14 
5 
STUDY DRUG ..................................................................................................................... 14 
5.1 DESCRIPTION .................................................................................................................... 14 
5.2 TREATMENT REGIMEN ........................................................................................................ 14 
5.2.1 Dose Limiting Toxicities ............................................................................................ 15 
5.2.2 Dose Modifications ................................................................................................... 17 
5.3 PREPARATION AND ADMINISTRATION OF STUDY DRUG .......................................................... 19 
5.4 SUBJECT COMPLIANCE MONITORING ................................................................................... 19 
5.5 PREMEDICATION AND CONCOMITANT THERAPY .................................................................... 19 
5.5.1 Premedication .......................................................................................................... 19 
5.5.2 Concomitant Therapy .................................................................................................. 20 
5.6 PACKAGING ....................................................................................................................... 21 
5.7 RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................ 21 
5.7.1 Receipt of Drug Supplies .......................................................................................... 21 
5.7.2 Storage ..................................................................................................................... 21 
5.7.3 Return or Destruction of Study Drug ......................................................................... 21 
 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
 
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6 
STUDY PROCEDURES ....................................................................................................... 21 
6.1 SCHEDULE OF EVENTS ....................................................................................................... 21 
6.2 SCREENING/BASELINE: WITHIN 28 DAYS OF CYCLE 1/DAY 1 .................................................. 22 
6.3 TREATMENT PERIOD (CYCLES 1-6) ...................................................................................... 22 
6.4 END OF TREATMENT (30 ± 7 DAYS AFTER LAST DOSE OF BRENTUXIMAB VEDOTIN AND R-CHP) ..... 24 
6.5 LONG TERM FOLLOW-UP .................................................................................................... 24 
6.6 STUDY ASSESSMENTS ........................................................................................................ 25 
6.7  CORRELATIVE STUDY PROCEDURES .................................................................................... 26 
7 
STATISTICAL PLAN ........................................................................................................... 26 
7.1 SAMPLE SIZE DETERMINATION ............................................................................................ 26 
7.2 STATISTICAL METHODS ...................................................................................................... 27 
7.3 SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................. 28 
7.4 STUDY ENDPOINT DEFINITIONS ........................................................................................... 28 
8 
SAFETY AND ADVERSE EVENTS ..................................................................................... 29 
8.1 DEFINITIONS ...................................................................................................................... 29 
8.2 RECORDING OF ADVERSE EVENTS ...................................................................................... 31 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ........................ 31 
8.4 STOPPING RULES .............................................................................................................. 36 
8.5 MEDICAL MONITORING ....................................................................................................... 36 
9 
DATA HANDLING AND RECORD KEEPING ...................................................................... 36 
9.1 CONFIDENTIALITY ............................................................................................................... 36 
9.2 SOURCE DOCUMENTS ........................................................................................................ 37 
9.3 CASE REPORT FORMS ....................................................................................................... 37 
9.4 RECORDS RETENTION ........................................................................................................ 37 
10 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................... 37 
10.1 
STUDY MONITORING PLAN .............................................................................................. 37 
10.2 
AUDITING AND INSPECTING ............................................................................................. 38 
11 ETHICAL CONSIDERATIONS ............................................................................................. 38 
12 STUDY FINANCES .............................................................................................................. 39 
12.1 
FUNDING SOURCE .......................................................................................................... 39 
12.2 
CONFLICT OF INTEREST .................................................................................................. 39 
12.3 
SUBJECT STIPENDS OR PAYMENTS.................................................................................. 39 
13 PUBLICATION PLAN .......................................................................................................... 39 
14 REFERENCES .................................................................................................................... 39 
15 APPENDIX A SCHEDULE OF ASSESSMENTS ................................................................. 43 
 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
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page iv 
 
List of Abbreviations 
 
ABVD adriamycin-bleomycin-vinblastine-dacarbazine 
ACC Abramson Cancer Center 
ADC antibody-drug conjugate 
AE adverse event 
ALCL anaplastic large cell lymphoma 
ALT alanine transaminase 
ASCT autologous stem cell transplant 
AST aspartate transaminase 
AVD adriamycin, vinblastine, dacarbazine 
CD cluster of differentiation 
cHL classical Hodgkin lymphoma 
CHP cyclophosphamide-doxorubicin -prednisone 
CHOP cyclophosphamide-doxorubicin -vincristine-prednisone 
CIITA class II transactivator 
CNS central nervous system 
CR complete remission 
CRF case report form 
CT computerized tomography 
CTCAE Common Terminology Criteria for Adverse Events 
CTMS clinical trials management system 
CTSRMC Clinical Trials Scientific Review and Monitoring Committee 
DLBCL diffuse large B-cell lymphoma 
DLT dose limiting toxicity 
DOCM Department of Compliance and Monitoring 
DSMC Data Safety Monitoring Committee 
EBV Epstein-Barr virus 
EFS event free survival 
EOT end of treatment 
FCCC Fox Chase Cancer Center 
FDA Food and Drug Administration 
FFPE formalin-fixed, paraffin-embedded 
G-CSF granulocyte colony-stimulating factor 
GEP gene expression profiling 
GFR glomerular filtration rate 
GM-CSF granulocyte macrophage colony-stimulating factor 
GZL grey zone lymphoma 
HB hepatitis B 
HBcAb hepatitis B core antibody 
HBsAb hepatitis B surface antibody 
HBsAg hepatitis B surface antigen 
HIPPA Health Insurance Portability and Accountability Act 
HIV human immunodeficiency virus 
IND investigational new drug 
IRB Institutional Review Board 
MACOP methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, bleomycin 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
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MMAE monomethyl auristatin E 
MTD maximum tolerated dose 
NCCN National Comprehensive Cancer Network 
NHL non-Hodgkin lymphoma 
N/A not applicable 
N/D not done 
ORR objective response rate 
OS overall survival 
PCR polymerase chain reaction 
PD progressive disease 
PD-L programmed death ligand 
PET positron emission tomography 
PFS progression-free survival 
PHI protected health information 
PI principal investigator 
PMBL primary mediastinal (thymic) large B-cell lymphoma 
PML progressive multifocal leukoencephalopathy 
PR partial remission 
R rituximab 
R-CHOP rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone 
R-CHP rituximab-cyclophosphamide-doxorubicin-prednisone 
RT radiation therapy 
SAE serious adverse event 
SD stable disease 
SMC Safety Monitoring Committee 
TJUH Thomas Jefferson University Hospital 
ULN upper limit of normal 
UPCC University of Pennsylvania Cancer Center 
UPENN University of Pennsylvania 
WHO World Health Organization 
 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
 
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Do not disclose or use except as authorized in writing by the study sponsor 
page 1 
 
 
Study Summary 
 
Title 
A phase I/II study of brentuximab vedotin in combination with 
multi-agent chemotherapy as front-line treatment in patients with 
CD30 positive primary mediastinal large B-cell, diffuse large B-cell, 
and grey zone lymphomas 
Short Title 
Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Protocol Number 
818280 / UPCC 17413 
Phase 
Phase I/II 
Methodology 
Open-label, non-randomized 
Study Duration 
3-5 years 
Study Center(s) 
Multicenter: Hospital of the University of Pennsylvania, Thomas 
Jefferson University, Fox Chase Cancer Center 
Objectives 
Primary Objective for Phase I component of study: 
- Safety and maximum tolerated dose of brentuximab vedotin when 
delivered in combination with rituximab, cyclophosphamide, 
doxorubicin, and prednisone in untreated CD30-positive primary 
mediastinal large B-cell, diffuse large B-cell, and grey zone 
lymphomas 
Secondary Objectives for Phase I component of study: 
- Overall response rate 
- Complete remission rate 
- Progression-free survival at year 1 and 2 
- Overall survival at year 1 and 2 
- Progression-free and overall survival 
- Correlation between CD30 expression and clinical outcome 
- Correlation between B-cell lymphoma subtype and clinical outcome 
Primary Objective for Phase II component of study: 
- Overall response rate of the combination of brentuximab vedotin, 
rituximab, cyclophosphamide, doxorubicin and prednisone in 
untreated CD30-positive primary mediastinal large B-cell, diffuse 
large B-cell, and grey zone lymphomas 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
 
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Secondary Objectives for Phase II component of study: 
- Complete remission rate 
- Progression-free survival at year 1 and 2 
- Overall survival at year 1 and 2 
- Progression-free and overall survival 
- Safety and toxicity of the combination of brentuximab vedotin, 
rituximab, cyclophosphamide, doxorubicin and prednisone in 
untreated CD30-positive primary mediastinal large B-cell, diffuse 
large B-cell and grey zone lymphomas 
- Correlation between CD30 expression and clinical outcome 
- Correlation between B-cell lymphoma subtype and clinical outcome 
Correlative objective: 
- Conduct multiplexed gene expression profiling of primary tumor 
samples to characterize differential gene expression patterns in 
PMBL and DLBCL 
Number of Subjects 
32 
Diagnosis and 
Main Inclusion 
Criteria 
Patients 18 years and above with histologically confirmed, previously 
untreated CD30 positive primary mediastinal large B-cell lymphoma, 
CD30 positive diffuse large B-cell lymphoma or CD30 positive grey 
zone lymphoma 
Study Product, 
Dose, Route, 
Regimen 
Brentuximab vedotin (1.8 mg/kg or 1.2 mg/kg), intravenous injection 
as part of combination regimen including rituximab, 
cyclophosphamide, doxorubicin, and prednisone 
Duration of 
administration 
To be administered approximately once every 3 weeks for total of 
6 cycles 
Statistical 
Methodology 
Phase I study to identify maximum tolerated dose, followed by 
Phase II study using the Simon optimal two-stage design. 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
 
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1 Introduction 
This document is a protocol for a human research study using brentuximab vedotin combined with 
multi-agent chemotherapy in patients with new diagnosis of primary CD30 positive primary 
mediastinal (thymic) large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL) or 
grey zone lymphoma (GZL). This study is to be conducted according to US and international 
standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and institutional research policies 
and procedures. 
 
The study started enrolling patients in January 2013 and as of December 2014, the Phase I 
portion concluded.  Six patients were treated per the Phase I protocol without evidence of DLT.  
Phase I data established a maximum tolerated dose of 1.8 mg/kg brentuximab vedotin. 
 
1.1 Background 
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma worldwide accounting 
for about 25-30% of all non-Hodgkin lymphomas (NHL). In recent years, it has been 
increasingly recognized that DLBCL is not just a single entity. It represents a group of 
aggressive lymphomas that have heterogeneous clinical, immunohistochemical and genetic 
characteristics. 
 
Cluster of differentiation (CD) 30 is a cell membrane protein of the tumor necrosis factor receptor 
family and can serve as a tumor marker (Schneider and Hubinger 2002, 1355-1366). It is a 
positive regulator of apoptosis, and also has been shown to limit the proliferative potential of 
auto-reactive CD8 effector T cells. CD30 is expressed on malignant cells in classical Hodgkin 
lymphoma (cHL), anaplastic large cell lymphoma (ALCL), and also on some forms of DLBCL 
(Campuzano-Zuluaga et al. 2012, 1592; Slack et al. 2012, 1558). 
 
The usage of an anti-CD30 antibody drug conjugate presents an intriguing option for CD30 
positive B-cell lymphomas since CD30 expression was shown to be a promising target in 
other CD30-positive tumors, such as cHL and ALCL. Using standard immunohistochemistry, 
CD30 is expressed in about 20-25% of DLBCLs, but the number is up to 70-80% in a DLBCL 
subtype called primary mediastinal large B-cell lymphomas (PMBL). The significance of CD30 
expression in B-cell lymphomas is actively being investigated. 
 
The most common form of CD30 positive DLBCL is PMBL. It is considered a unique clinic-
pathologic entity by World Health Organization classification of lymphomas (Swerdlow 2008, 439). 
It arises in the mediastinum, presumably from B-cells of thymic origin and represents less than 5% 
of DLBCL (A Clinical Evaluation of the International Lymphoma Study Group Classification of 
Non-Hodgkin’s Lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. 1997, 3909-
3918). CD30 positivity in the majority of PMBL cases makes distinction from cHL difficult at times; 
especially since clinical presentation with bulky mediastinal mass in younger patients is similar for 
both of these entities. CD30 expression in PMBL is usually heterogeneous when compared to 
cHL and may range from strong membrane staining of majority of the neoplastic cells to positivity 
of rare individual cells (Pileri et al. 2003, S21-6; Higgins and Warnke 1999, 241-247). Similarities 
in genetic and epigenetic signatures between PMBL and cHL have been also reported (Eberle et 
al. 2011, 558-566; Rosenwald et al. 2003, 851-862). In some cases, pathologists may not be able 
to distinguish between PMBL and cHL due to overlapping characteristics. In 2008, WHO added an 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
 
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official category of aggressive lymphomas which are described as B-cell lymphomas, 
unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical 
Hodgkin lymphoma (Swerdlow 2008, 439). These are usually referred to as grey zone 
lymphomas (GZL) and nearly 100% of these express CD30. 
 
There is limited amount of data on the clinical outcomes of patients with PMBL, CD30 positive 
DLBCL, and GZL. For PMBL, some of the earlier studies suggested poor results with CHOP 
chemotherapy alone. Based on non-randomized comparisons, it appeared that more intense 
multi-agent regimens had better outcomes when compared to standard CHOP (Todeschini et 
al. 2004, 372-376; Zinzani et al. 2009, 381-385). However, the addition of anti-CD20 
monoclonal antibody rituximab to CHOP chemotherapy improved the inferior outcome of 
PMBL treated with CHOP (Rieger et al. 2011, 664-670; Tai et al. 2011, 604-612). On a 
subgroup analysis of the phase III Mabthera trial, addition of rituximab to chemotherapy in 
PMBL revealed improved event-free survival (EFS) compared to chemotherapy alone (78% 
vs. 52%) (Rieger et al. 2011, 664-670). 
 
While the optimal front-line treatment of PMBL remains controversial, rituximab-cyclophosphamide-
doxorubicin-vincristine-prednisone (R-CHOP) is widely used in NCCN institutions (Zelenetz et al. 
2010, 288-334). Since residual mass after completing systemic therapy is not uncommon in PMBL 
patients, some clinicians recommend consolidation with radiation therapy (RT), but this remains 
controversial. 
 
PET/CT imaging is used by some oncologists to determine the need of additional RT (Savage et al. 
2012, 303). The clinical outcome of PMBL patients treated with R-CHOP with or without consolidative 
radiation remains inferior to those with the biologically related cHL treated with ABVD. 
 
Recently, Dunleavy et al published results of phase II NCI trial using dose adjusted etoposide-
prednisone-vincristine-doxorubicin-rituximab (EPOCH-R) regimen in PMBL with excellent result 
showing EFS of 97% in a group of 51 patients (Dunleavy et al. 2013, 1408-1416). Majority of 
patients did not require consolidative radiation. However, these results have not been confirmed 
in a larger cooperative study and there are no randomized trials comparing this regimen to R-
CHOP in PMBL. Some concerns such as long term toxicity, need for inpatient administration, 
and fertility issues with EPOCH-R have been raised. 
 
Outcomes of patients with GZL are not well described in the literature, but anecdotally they 
appear worse when compared to cHL or to PMBL patients. Patients with CD30-positive DLBCL 
(excluding PMBL and GZL) as a group may have better prognosis over CD30 negative cases, 
but that remains controversial (Hu et al. 2013, 2715-2724). The CD30 positive DLBCL cases are 
more likely to be of non-germinal center origin (Campuzano-Zuluaga et al. 2012, 1592; Slack et 
al. 2012, 1558). It has been shown that non-germinal center origin subtype of DLBCL is less 
responsive to chemotherapy, but addition of monoclonal antibody rituximab improved outcomes 
to some extent (Lenz et al. 2008, 2313-2323). 
 
Patients with DLBCL of the elderly (defined as a histologically malignant polymorphic or 
monomorphic EBV-positive B-cell lymphoproliferation in patients who are generally older than 
50 years without any known immunodeficiency, transplantation, or prior lymphoma) frequently 
have CD30 expressed on the malignant lymphocytes and have a poor prognosis in small 
series (Shimoyama et al. 2009, 835-843). 
 


UPCC 17413: Brentuximab plus R-CHP in CD30 positive B-cell lymphomas 
Version date: 06.21.2018 
  
 
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There are no clear guidelines for front line treatment for patients with GZL, but most are treated 
either with R-CHOP or ABVD regimens with or without consolidative RT. Patients with CD30 
positive DLBCL (excluding PMBL and GZL) are usually treated with R-CHOP. Some patients 
with aggressive lymphomas including DLBCL with concerning features on presentation (bone 
marrow involvement, sinus disease, testicular disease) may be considered for central nervous 
system (CNS) prophylaxis using intrathecal chemotherapy, but guidelines are not based on 
randomized trials (Zelenetz et al. 2010, 288-334). 
 
Since the FDA approval of rituximab for NHL 15 years ago, there has been only slow progress in 
developing new targeted therapies for front-line regimens in B-cell lymphomas. While R-CHOP 
works well for a significant portion of patients with PMBL and DLBCL, there is a great need to 
develop less toxic and more effective treatment strategies. 
 
1.2 Investigational Agent 
Brentuximab vedotin is an antibody-drug conjugate (ADC) consisting of three components: 
1) antibody cAC10, specific for human CD30 
2) highly potent antimicrotubule agent monomethyl auristatin E (MMAE) 
3) protease-cleavable linker that covalently attaches MMAE to cAC10 
 
Brentuximab vedotin is proposed to have a multistep mechanism of action that is initiated by 
binding to CD30 on the cell surface and internalization of the ADC. Upon trafficking to 
lysosomes, MMAE is released from the conjugate through proteolytic degradation of the drug 
linker (Sutherland et al. 2006). Binding of released MMAE to tubulin disrupts the microtubule 
network, leading to G2/M phase cell cycle arrest and apoptosis (Francisco et al. 2003). 
 
In August 2011, the FDA granted accelerated approval to this novel agent for the treatment of 
patients with cHL after failure of autologous stem cell transplant (ASCT) or after failure of at least 
two prior multiple chemotherapy regimens in patients not eligible for ASCT. This marks the first 
new drug available for cHL in more than 30 years. Currently this agent is under investigation in 
various clinical settings, including front-line combination therapy with AVD chemotherapy in cHL, 
as well as in combination with multi-agent chemotherapy for front-line treatment of CD30-positive 
mature T-cell and NK-cell neoplasms (Fanale et al. 2012, 60; Younes et al. 2011, 955). 
Brentuximab vedotin was also used in patients with CD30 positive B-cell non-Hodgkin 
lymphomas as part of a phase II study in patients with refractory or relapsed setting with overall 
response rate 35% (Jacobsen et al. 2012, 2746). It appears to be well tolerated as a 
monotherapy or in combination with cytotoxic chemotherapy with the main side effects being 
peripheral neuropathy, fatigue, pyrexia, nausea and neutropenia. 
 
1.3 Preclinical Data 
Preclinical studies of brentuximab vedotin demonstrated antitumor activity in both in vitro and in 
vivo models. The toxicity of multiple doses of brentuximab vedotin has been assessed in rats 
and monkeys.  In both species, hypocellularity of the bone marrow and lymphoid depletion of the 
thymus were observed. Histopathologic lesions were also observed in the spleen in monkeys 
and in the liver and testes in rats. 
 
 
 


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In addition, decreases in peripheral blood counts were observed in both species, and elevations 
in liver enzymes were seen in rats only. The most significant clinical toxicity was neutropenia, 
observed in monkeys, which resulted in secondary bacterial infections leading to early deaths at 
the 6 mg/kg dose. Toxicity was dose-dependent, with a no-observable-adverse-effect level of 0.5 
mg/kg in rats and 1 mg/kg in monkeys. 
 
1.4 Clinical Data to Date 
The clinical safety data observed in the phase I dose-escalation study (SG035-0001) of 
brentuximab vedotin administered once every 3 weeks support the 1.8 mg/kg dose level as the 
maximum tolerated dose (MTD) and this dose and schedule has been selected for phase II 
studies as monotherapy. In this Phase I study, the most frequent adverse events (AEs) were 
peripheral neuropathy, constitutional (fatigue and pyrexia), gastrointestinal (diarrhea, nausea), 
and hematologic (neutropenia) (Younes et al. 2010, 1812-1821). 
 
Recently published results of a multinational, open-label, phase II study established the efficacy 
and safety of brentuximab vedotin in 102 patients with relapsed or refractory cHL after ASCT 
(Younes et al. 2012, 2183-2189). In the absence of disease progression or prohibitive toxicity, 
patients received a maximum of 16 cycles. The ORR was 75% with CR in 34% of patients. The 
median PFS time for all patients was 5.6 months, and the median duration of response for those 
in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients 
were alive and free of documented progressive disease. The most common treatment-related 
adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. 
 
The clinical safety and activity of brentuximab vedotin in non-Hodgkin lymphomas (NHL) were 
further evaluated in a phase II study of patients with relapsed or refractory systemic ALCL 
(SG035-0004) (Pro et al. 2012, 2190-2196). In this study, interim results showed all patients 
had previously received at least one prior regimen of multi-agent systemic chemotherapy with 
curative intent. Relative to the most recent therapy, 50% of patients were refractory. 
Additionally, approximately 60% of patients had primary refractory disease, defined as failure to 
achieve a complete remission (CR) with front-line therapy or progression within 3 months of 
completing front-line therapy, and 24% of patients had never achieved a response with any 
previous therapy. In this study of highly refractory patients, the objective response (CR + PR) 
rate was approximately 86%, with 57% of patients achieving a CR. Brentuximab vedotin was 
generally well tolerated, with manageable side effects. 
 
Interim results of a phase II study using brentuximab vedotin in relapsed and refractory CD30 
positive non-Hodgkin lymphomas other than ALCL was recently presented at ASH 2012 
(Jacobsen et al. 2012, 2746). Among 53 patients enrolled, 35 patients had B-cell neoplasms 
including 22 patients with DLBCL. The responses to single agent brentuximab vedotin at 1.8 
mg/kg administered every 3 weeks (continued until disease progression or unacceptable 
toxicity) were encouraging with 47% overall response rate in DLBCL (3 with complete 
remission, 4 with partial remission) (Jacobsen et al. 2012, 2746). 
 
Brentuximab vedotin has also been used in combination with CHOP like therapy (CHOP minus 
vincristine=CHP) in a phase I trial as front-line treatment for patients with ALCL (Fanale et al. 
2012, 60). Arm 1 of this study used sequential administration of brentuximab vedotin at 1.8 
mg/kg x 2 cycles followed by 6 cycles of CHP therapy and then followed by brentuximab vedotin 
at 1.8 mg/kg x 8 cycles. 


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In Arm 2 of this study, the brentuximab vedotin was given concurrently with CHP chemotherapy x 
6 cycles followed by brentuximab vedotin at 1.8 mg/kg x 10 cycles. Only 1 of 6 patients in Arm 2 
had a dose limiting toxicity (DLT) (Grade 3 rash), but the MTD was not exceeded. Then, Arm 3 
was expanded at this dose to 14 more patients who overall tolerated the combination well 
(serious adverse events related to brentuximab vedotin were rash and febrile neutropenia). At 
the time of interim analysis, all 26 patients had been assessed for clinical response at the end of 
6 cycles of combination therapy or at the latest assessment for 3 patients who had discontinued 
treatment prior to Cycle 6. All patients (100%) achieved an objective response, with 23 patients 
(88%) achieving a CR (Fanale et al. 2012, 60). The recommended dose for the front-line therapy 
for patients with CD30-positive mature T-cell lymphomas was 1.8 mg/kg brentuximab vedotin in 
combination with CHP. 
 
1.5 Study Rationale and Risk/Benefits 
Targeted, monoclonal antibody based therapies have an increasing role in management of 
lymphoma patients. Addition of monoclonal anti-CD20 antibody rituximab to cytotoxic 
chemotherapy has been shown to improve B-cell lymphoma outcomes in several settings, 
including first line treatment of DLBCL (Coiffier et al. 2002, 235-242). Adding a novel antibody 
based therapy to chemoimmunotherapy regimen may enhance efficacy and limit toxicity (both 
acute and long term toxicity). PMBL and GZL in particular affect young adults, who may have 30-
50 year life expectancy once cure is achieved. Therefore, avoiding long-term chemotherapy-
related toxicities from dose intense regimens such as EPOCH-R or MACOP including secondary 
myelodysplasia or infertility are pivotal. Also, the convenience of outpatient administration over 
infusional regimens requiring several days of inpatient hospitalization is of importance to patients. 
The optimal front-line therapy for PMBL and GZL remains controversial and the management of 
CD30 positive DLBCL continues to evolve. 
 
We hypothesize that substituting brentuximab vedotin in place of vincristine in R-CHOP as front-
line multi-agent chemotherapy for PMBL, CD30 positive DLBCL and GZL may be well tolerated 
and improve outcomes in these patients. We propose a phase I/II, multi-center, single-arm, non-
randomized study in which CD30 positive, previously untreated PMBL, DLBCL and GZL patients 
will receive a combination of brentuximab vedotin, rituximab, cyclophosphamide, doxorubicin and 
prednisone for a total of 6 cycles. 
 
The phase I component will evaluate safety and toxicity of the regimen, since the combination of 
brentuximab vedotin and R-CHP has not previously been studied. The phase II portion will 
further investigate safety and toxicity. Overall response rate (ORR) at the conclusion of systemic 
therapy will be the primary end point of the phase II portion of the study, with secondary 
endpoints of complete remission rate, progression-free survival (PFS) and overall survival (OS). 
We will also correlate CD30 expression and lymphoma subtype with clinical outcome. 
 
Due to the neurotoxicity profile of vincristine (vinca alkaloid) which is a part of R-CHOP 
regimen, there is a potential concern for additive neurotoxicity in combination with brentuximab 
vedotin. Vincristine has only moderate contribution to activity in R-CHOP. Substitution of 
brentuximab vedotin for vincristine in this multi-agent combination is likely to enhance efficacy 
of R-CHP while avoiding potential increases in neurotoxicity. This is a safer approach than 
attempting to administer the two agents concurrently, where doses of one or both agents may 
be limited by resultant neurotoxicity. 
 


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In the future, lymphoma management will involve combinations of targeted therapies specifically 
designed for an individual patient as based on various markers including immunohistochemistry. It 
is also clear that early assessment of response during the course of therapy may become an 
important tool to tailor treatment strategy (e.g. escalation or de-escalation of therapy). The 
expression level of CD30 (by immunohistochemistry) on the surface of lymphoma cells did not 
correlate with the clinical response to brentuximab vedotin in cutaneous T-cell lymphoma/mycosis 
fungoides (Krathen et al. 2012, 797), but could be an important correlate to investigate in B-cell 
lymphomas. Interim PET/CT imaging after two cycles of ABVD chemotherapy is an early predictor 
of outcome in Hodgkin lymphoma patients (Hutchings et al. 2006, 52-59) and is being 
incorporated into the design of current trials in this disease. PET/CT does not appear to be as 
strong of a predictor in DLBCL treated with R-CHOP (Pregno et al. 2012, 2066-2073). 
 
The concurrent combination of brentuximab vedotin at 1.8 mg/kg and standard doses of CHP has 
been studied, reported, and safely administered as part of phase I trial for ALCL (Fanale et al. 
2012, 60).  However, the combination of brentuximab vedotin with CHP and another monoclonal 
antibody (rituximab) may result in some unexpected toxicities including higher risk of infections 
and myelotoxicity. Rituximab administration alone may increase risks of developing progressive 
multifocal leukoencephalopathy (PML) in some patients, although the absolute risk of developing 
PML is probably very low (Carson et al. 2009, 4834-4840). PML was also described in a few 
patients undergoing therapy with brentuximab vedotin. 
 
Therefore, subjects receiving the combination of rituximab and brentuximab vedotin will be 
closely monitored for signs and symptoms of PML. The one DLT in the 6 ALCL patients treated 
on the combination of brentuximab vedotin with CHP phase I trial was rash. Rituximab label 
describes that only 1% of patients experience grade 3 or 4 skin rashes with rituximab therapy 
and so combining of brentuximab vedotin with R-CHP is unlikely to have severe dermatologic 
side effects. Other treatment-related adverse events with incidence >30% seen on the 
combination of brentuximab vedotin with CHP trial included nausea (58%), fatigue (50%), 
diarrhea (50%), peripheral sensory neuropathy (38%), and alopecia (38%) which are not 
expected to be greatly enhanced by addition of rituximab. 
 
The Phase I portion of our study has completed and no DLT was found with the combination of 
standard R-CHP doses and brentuximab at 1.8 mg/kg, but patients continue to be closely 
monitored for long term side effects or rare effects that might have been missed in the small 
number of patients in the Phase I portion. 
 
 
1.5.1 Correlative Study Rationale 
DLBCL is increasingly recognized as a very heterogeneous group of diseases in respect to 
morphologic, immunophenotypic, genetic and clinical features.  PMBL is a unique clinic-pathologic 
large B-cell lymphoma subtype that presents most frequently with large mediastinal mass and 
affects young adults (with female predominance).  There are also some characteristic 
immunophenotypic features of PMBL such as positivity for CD30, MUM1, and CD23.  However, it 
remains challenging to distinguish between PMBL and DLBCL with mediastinal involvement based 
on clinical and pathology findings alone. 
Interestingly, gene expression profiling (GEP) suggests a relationship between PMBL and 
classical Hodgkin lymphoma and this is further supported by shared genetic abnormalities. 


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Translocations involving the MHC class II transactivator (CIITA), as well as gains/amplification of 
chromosome 9p24.1 including the gene loci of JAK2 and programmed cell death protein 1 ligands 
(PDL1 and PDL2), have been detected frequently in cases of PMBL.  Several groups have 
described genetic signatures that can distinguish between PMBL vs DLBCL.  At this time, testing 
for these specific signatures is not part of routine pathology testing. 
Gene expression profiling of subject tumor samples to distinguish PMBL and non-PMBL subtypes 
would significantly strengthen pending outcomes and survival analysis of the primary study (UPCC 
17413).  This data may also further illuminate PMBL biology, including potential new therapeutic 
targets.  We aim to conduct a correlative study using Nanostring PanCancer multiplexed GEP 
technology to characterize gene expression patterns in the PMBL and DLBCL among our study 
participants. 
For those who participate in this correlative study, there exists a theoretical risk of tissue 
depletion.  This risk is variable for each patient and is dependent primarily upon the size of the 
archival sample.  For those patients with a large archival specimen, the risk of depletion is low, 
whereas those with a small amount of archived tissue have a higher risk of depletion. It is 
important to clarify that for the majority of patients in the study, the clinical utility of existing 
archived tissue is limited. If a participating patient develops recurrent disease, the standard of care 
would be to obtain tissue from the site of recurrence to guide further treatment decisions (instead 
of performing additional testing on the existing tissue). 
 
 
2 Study Objectives 
 
Primary objective for Phase I: 
 
Safety and MTD of brentuximab vedotin when delivered in combination with rituximab, 
cyclophosphamide, doxorubicin, and prednisone in untreated CD30-positive PMBL, 
DLBCL, and GZL 
 
Secondary objective for Phase I: 
 
ORR rate of the combination of brentuximab vedotin, rituximab, cyclophosphamide, 
doxorubicin, and prednisone in untreated CD30-positive PMBL, DLBCL, and GZL 
 
Complete remission rate 
 
PFS at years 1 and 2 
 
OS at years 1 and 2 
 
PFS and OS 
 
Correlation between CD30 expression and clinical outcome 
 
Correlation between B-cell lymphoma subtype and clinical outcome 
 
Primary objective for Phase II: 
 
Overall response rate of the combination of brentuximab vedotin, rituximab, 
cyclophosphamide, doxorubicin, and prednisone in untreated CD30-positive PMBL, 
DLBCL, and GZL 
 
 


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Secondary objective for Phase II: 
 
Complete remission rate 
 
PFS at years 1 and 2 
 
OS at years 1 and 2 
 
PFS and OS 
 
Safety and toxicity profile of the combination of brentuximab vedotin, rituximab, 
cyclophosphamide, doxorubicin, and prednisone in untreated CD30-positive PMBL, 
DLBCL, and GZL. 
 
Correlation between CD30 expression and clinical outcome Correlation between B-cell 
lymphoma subtype and clinical outcome 
 
Correlative objective: 
 
Conduct multiplexed gene expression profiling of primary tumor samples to characterize 
differential gene expression patterns in PMBL and DLBCL 
 
3 Study Design 
3.1 General Design 
This is a Phase I/II, multicenter, single-arm, non-randomized, open label study. All patients will 
receive combination of brentuximab vedotin, rituximab, cyclophosphamide, doxorubicin, and 
prednisone approximately every 3 weeks for a total of 6 cycles. The Phase I portion of the 
study will determine the safety and MTD of brentuximab vedotin when delivered in combination 
with R-CHP chemotherapy. The Phase II portion of the study will further evaluate the activity of 
brentuximab vedotin when administered in combination with multi-agent chemotherapy in 
patients with CD30 positive PMBL, DLBCL, and GZL. Safety assessments will include 
surveillance and recording of AEs, physical examination findings, and laboratory tests. Disease 
response will be assessed by the Investigator using the Revised Response Criteria for 
Malignant Lymphoma (Cheson et al. 2007, 579-586). 
 
NOTE: As above, Phase I accrual concluded in December 2014; no DLT was observed in 
Phase I patients and Phase II enrollment concluded in June 2017. 
 
3.2 Primary Study Endpoints 
For Phase I: 
 
Type, incidence, severity, relatedness, and seriousness of AEs 
 
Type, incidence, and severity of laboratory abnormalities 
 
Dose-limiting toxicity (DLT) 
 
For Phase II: 
 
Investigator assessment of ORR as determined by the International Working Group 
Response Criteria for non-Hodgkin Lymphoma (Cheson et al. 2007, 579-586) 
 
 


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3.3 Secondary Study Endpoints 
For Phase I: 
 
Investigator assessment of ORR and CR as determined by the International Working 
Group Response Criteria for non-Hodgkin Lymphoma (Cheson et al. 2007, 579-586) 
 
PFS and OS at years 1 and 2 
 
PFS and OS 
For Phase II: 
 
Type, incidence, severity, relatedness, and seriousness of AEs 
 
Type, incidence, and severity of laboratory abnormalities 
 
Investigator assessment of CR as determined by the Revised Response Criteria for 
Malignant Lymphoma (Cheson et al. 2007, 579-586) 
 
PFS and OS at years 1 and 2 
 
PFS and OS 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria for Phase I and Phase II 
 
Age 18 and above. 
 
Histologically confirmed CD30-positive, CD20-positive untreated primary mediastinal B-
cell lymphoma, diffuse large B-cell lymphoma, or grey zone lymphoma. Patients with 
heterogeneous, weak or equivocal CD30 staining will also be included (no specific cut 
off percentage for CD30 stain is required).  Patients with any Ann Arbor stage are 
eligible. 
 
Measurable disease, defined by the Revised Response Criteria for Malignant 
Lymphoma (Cheson et al. 2007, 579-586). 
 
Absolute neutrophil count ≥1,000/mm3 and platelet count ≥ 75,000/µL (unless 
documented bone marrow involvement with lymphoma). 
 
Normal left ventricular ejection fraction of ≥ 50% estimated by MUGA scan or 
echocardiogram. 
 
Estimated creatinine clearance (using Cockcroft-Gault equation) must be > 50 mL/min. 
 
Serum bilirubin ≤ 1.5 x upper limit of normal (ULN). Bilirubin ≤ 3 x ULN is permitted in 
individuals with documented liver involvement by lymphoma or if due to known Gilbert 
syndrome. 
 
Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3 × ULN. 
 
Performance status of ECOG 0-2; patients with ECOG of 3 may be allowed to enroll 
after discussion with the Regulatory-Sponsor/Principal Investigator and medical 
monitor, and if the performance status is believed to be secondary to lymphoma related 
symptoms and performance status is expected to improve once chemotherapy 
commences. 
 
Capable of understanding the investigational nature, potential risks and benefits of the 
study, and able to provide valid informed consent. In patients who are not able to 
consent to the trial due to medical circumstances, the next of kin or power of attorney 
may consent for the study. 


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 
Females of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first 
dose of brentuximab vedotin and must agree to use an effective contraception method 
during the study and for 6 months following the last dose of study drug; females of non-
childbearing potential are those who are post-menopausal for more than 1 year or who 
have had a bilateral tubal ligation or hysterectomy. 
 
Males who have partners of childbearing potential must agree to use an effective 
contraceptive method during the study and for 6 months following the last dose of study 
drug. 
 
Must be able to comply with the study and follow-up requirements. 
4.2 Exclusion Criteria for Phase I and Phase II 
 
Previous use of investigational agents, chemotherapy or immunotherapy for lymphoma 
any time prior to enrollment (i.e. must have untreated disease). Prior allogeneic or 
autologous transplants are also not allowed. 
 
Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as 
specified in the protocol. Consolidative radiation therapy (RT) after completion of 
planned course and/or concurrent intrathecal chemotherapy for CNS disease 
prophylaxis is permissible. 
 
Treatment with systemic steroids for > 4 weeks prior to Cycle 1 Day 1 of study therapy. 
Prior radiation therapy, with the exception of an abbreviated course (not more than 3 
days) if used for SVC syndrome. 
 
History of serious organ dysfunction or disease involving the heart (left ventricular 
ejection fraction < 50%; unstable angina, acute myocardial infarction within 6 months 
prior to randomization, congestive heart failure NYHA III-IV, and arrhythmia unless 
controlled by therapy, with the exception of extra systoles or minor conduction 
abnormalities.),the kidney (creatinine clearance ≤ 50 mL/min), the liver (chronic 
hepatitis B as defined below or elevated AST, ALT, or alkaline phosphatase > 3 ULN; 
serum bilirubin > 1.5 x ULN; bilirubin up to 3 x ULN is permitted in individuals with 
documented liver involvement by lymphoma or if due to known Gilbert syndrome) or 
other organ system that may place the patient at undue risk to undergo treatment. 
 
Uncontrolled systemic fungal, bacterial, viral, or other serious infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment). May be enrolled if controlled on 
treatment. 
 
Significant concurrent disease, illness, or psychiatric disorder that would compromise 
patient safety or compliance, interfere with consent, study participation, follow-up, or 
interpretation of study results. 
 
Subjects who have current active hepatic or biliary disease (with exception of patients 
with Gilbert's syndrome, asymptomatic gallstones, liver involved with lymphoma or 
stable chronic liver disease per investigator’s assessment). 
 
History of significant cerebrovascular disease in the past 6 months or ongoing event 
with active symptoms or sequelae. 
 
 
 


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 
Other malignancy, unless the patient has been disease-free for at least 3 years 
following the completion of curative intent therapy, with the following exceptions: 
o 
Treated non-melanoma skin cancer, any in situ carcinoma, or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible for 
this study if definitive treatment for the condition has been completed. 
o 
Organ-confined prostate cancer with no evidence of recurrent or progressive 
disease based on prostate-specific antigen (PSA) values are also eligible for this 
study if hormonal therapy has been initiated, or radical prostatectomy or 
definitive prostate irradiation has been performed. 
 
Positive test for the Human Immunodeficiency Virus (HIV) unless undetectable viral load 
within 3 months of enrolment (HIV RNA less than 48 copies/mL) and on HAART therapy. 
 
Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface 
antigen or hepatitis B core antibody. 
 
Active involvement of the central nervous system (CNS) by lymphoma. Work-up for CNS 
involvement at diagnosis will be directed as per the treating physician and will depend on 
specific clinical circumstances (no brain imaging or lumbar puncture is required by this 
protocol). 
 
Pregnant or lactating women. 
Exceptions to eligibility may not be accepted. 
 
4.3 Inclusion criteria for correlative study 
 
Patient participated in Phase I or Phase II of the UPCC 17413 and received at least one 
cycle of therapy 
 
Patient consent to participating in this correlative study 
 
4.4 Exclusion criteria for correlative study 
 
No tissue available for multiplexed gene expression profiling 
 
4.5 Subject Recruitment and Screening 
Subjects will be recruited from the clinical oncology practices at participating sites (Hospital 
of the University of Pennsylvania, Thomas Jefferson University Hospital, and Fox Chase 
Cancer Center). No advertising or recruitment materials will be utilized. Subjects will not be 
reimbursed for participation. 
 
4.6 Early Withdrawal of Subjects 
4.6.1 When and How to Withdraw Subjects 
A patient may be discontinued from treatment regimen using brentuximab vedotin in combination 
with R-CHP prior the expected completion for disease progression, failure to adhere to protocol 
requirements, or if the investigator or patient deems it in the patient’s best interest to 
discontinue. The reason justifying study treatment discontinuation should be documented in 
the case report form (CRF). Patients who discontinue the study regimen prior to completion will 
remain on study for follow-up, unless they withdraw consent. All patients who receive at least 1 
dose of study drug will be followed for toxicity, response and survival. 
 


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A patient may be withdrawn from the study (during treatment or follow-up) for reasons 
including death, patient withdrawal of consent for further follow-up, if the patient is lost to follow-
up, or at study termination by a participating site, study sponsor or by Seattle Genetics (drug 
manufacturer/funding sponsor). 
 
If the Sponsor and/or the Investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted. 
4.6.2 Data Collection and Follow-up for Withdrawn Subjects 
The University of Pennsylvania must be notified in writing if a patient is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the patient’s 
medical records and CRF. The investigators will make every reasonable effort to keep each 
patient on the study until all planned treatments and assessments have been performed. If a 
subject withdraws from study treatment, every attempt should be made to follow the patient until 
death or administrative study closure. If a subject withdraws consent to participate in the study, 
attempts should be made to obtain permission to record at least survival data up to the protocol-
described end of subject follow-up period. Final treatment assessments will be performed before 
any other therapeutic intervention if possible. Additionally, any planned alternative treatments 
should be documented on the patient’s medical records and CRF. Adequate attempts will be 
made to reach out to subjects to collect required follow-up. All attempts to reach subjects will be 
documented appropriately. Subjects will be considered lost to follow-up if phone calls to the 
subject or to next of kin are not successful. 
5 Study Drug 
5.1 Description 
Brentuximab vedotin is an ADC consisting of the chimeric antibody SGN-30 (cAC10) chemically 
conjugated to a synthetic analog (monomethyl auristatin E [MMAE]) of the naturally occurring 
antitubulin agent, dolastatin10. Brentuximab vedotin is proposed to have a multistep mechanism 
of action that is initiated by binding to CD30 on the cell surface and internalization of the ADC. 
Upon trafficking to lysosomes, MMAE is released from the conjugate through proteolytic 
degradation of the drug linker (Sutherland et al. 2006, 10540-10547). Binding of released 
MMAE to tubulin disrupts the microtubule network, leading to G2/M phase cell cycle arrest and 
apoptosis (Francisco et al. 2003, 1458-1465). 
 
5.2 Treatment Regimen 
The treatment regimen consists of standard R-CHOP chemotherapy, but without vincristine (“R-
CHP”) and with the addition of brentuximab vedotin. Therapy will be administered in 21-day 
cycles for a total of 6 cycles, as summarized in Table 1. 
 
During cycle 1, rituximab dosing will be divided between Days 1 and 2 to prevent severe infusion 
reactions in rituximab naïve patients. This may also allow us to distinguish between infusional 
reaction from rituximab which occurs usually during the first exposure vs. the less likely infusional 
reaction from brentuximab. During Cycle 1, the brentuximab vedotin and the cytotoxic 
chemotherapy will be administered on Day 2. During Cycles 2 through 6, brentuximab vedotin and 
R-CHP will be administered on Day 1. Prednisone (oral or intravenous steroid equivalent) will be 
administered on Days 1-5 of each cycle. Patients will receive rituximab first, then 
cyclophosphamide and doxorubicin, followed by brentuximab. Prednisone (oral or intravenous 
steroid equivalent) should be taken prior to rituximab infusion. 


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TABLE 1: Summary of the combination regimen using brentuximab vedotin in combination with 
rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). 
 
Agent 
Dose 
Route 
Cycle 1 
Cycle 2-6 
Prednisone  
(or equivalent) 
100 mg 
PO or IV 
equivalent 
Days 1-5 
Day 1-5 
Rituximab 
375 mg/m2 
IV 
Day 1 and 2 (split dose 
of 100 mg/m2 and 275 
mg/m2, respectively) 
Day 1 
Cyclophosphamide 750 mg/m2 
IV 
Day 2 
Day 1 
Doxorubicin 
50 mg/m² 
IV 
Day 2 
Day 1 
Brentuximab 
vedotin* 
1.8 mg/kg or 
1.2 mg/kg 
IV 
Day 2 
Day 1 
 
*1.8 mg/kg brentuximab vedotin has been established as MTD per Phase I enrollment 
 
For R-CHP administration, dosing should be based on the patient’s baseline (pre-dose, Cycle 1 
Day 1) height and weight, or per institutional standards at the site. Doses will be adjusted for 
patients who experience a change in weight ≥10% from baseline during the study. 
 
For brentuximab vedotin, actual weight at baseline (pre-dose, Cycle 1 Day 1) will be used except 
for patients weighing greater than 100 kg. For patients > 100 kg, the brentuximab vedotin dose 
will be calculated based on a weight of 100 kg. Brentuximab vedotin dose should be rounded to 
the nearest whole number of milligrams. Doses will be adjusted for patients who experience a 
change in weight ≥10% from baseline during the study. 
 
5.2.1 Dose Limiting Toxicities 
 
The initial planned dose of brentuximab vedotin for the Phase I cohort is 1.8 mg/kg. The 
Phase I 1.8 mg/kg cohort will enroll 6 patients who will be evaluated for DLT in the first cycle of 
treatment. Dose de-escalation to 1.2 mg/kg will not occur unless ≥2 of 6 patients at the 1.8 
mg/kg dose level experience a DLT, defined as any grade 3 or 4 new non-hematologic toxicity 
occurring during Cycle 1 requiring a dose delay of >14 days from the planned Day 1 of Cycle 2 
(21 days from Day 1 of Cycle 1). 
 
Hematologic toxicities which are expected from multi-agent chemotherapy will not be considered 
for DLT unless the hematologic toxicity will not return to baseline or ≤ grade 2 by 21 days from 
the planned Day 1 of Cycle 2. The hematologic toxicities will be managed according to the 
institutional guidelines. Prophylactic use of G-CSF or GM-CSF and use of transfusions are 
allowed and should be administered according to institutional guidelines. It is permissible to 
use G-CSF (filgrastim or pegfilgrastim) or GM-CSF empirically during the first cycle in patients 
who are felt to be in risk of leukopenia. 


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The DLT evaluation period consists of the time between Day 2 of Cycle 1 (following 
administration of brentuximab vedotin) up through the start of the Cycle 2. Therefore, only 
delays that occur during this period will be considered for decisions regarding brentuximab 
vedotin dose de-escalation. Additional safety experiences in Cycles 2-6 of the Phase I cohort 
will be monitored and closely recorded. These will be considered when declaring MTD for 
Phase II of the trial. 
 
In Cycles 2-6, the brentuximab vedotin dose may be withheld or modified according to the 
guidelines in Table 2. Rituximab dose modifications should not occur. Dose modifications to 
cyclophosphamide, doxorubicin chemotherapy and prednisone due to toxicity are discouraged, 
but allowed after the DLT evaluation period (after Cycle 2 Day 1) at the discretion of the 
Investigator. These may include adjustment of prednisone dose due to severe intolerance (e.g. 
psychiatric issues or severe hyperglycemia). Some elderly patients who develop severe (but 
expected) toxicities attributed to cytotoxic chemotherapy (e.g. recurrent neutropenic fevers 
despite G-CSF) may be considered for modification of the chemotherapy dose by the treating 
physician as per institutional guidelines. Practically, it is not possible to define exact 
modifications of the standard cytotoxic chemotherapy component of the regimen, but we 
expect that only a very small minority of patients would need any modifications. Therefore, the 
impact on the quality of toxicity and efficacy data should be minimal if any. 
 
Initiation of the next cycle (Cycle 3 through 6) may be delayed for up to 3 weeks if additional 
time is required for the patient to recover from study treatment-associated toxicity experienced 
during the current cycle. Delays of greater than 3 weeks are prohibited and will result in 
discontinuation of study participation, unless an exception is granted by the Principal 
Investigator, Sponsor and the Medical Monitor. Patients who may develop some of the well 
described (but rare) toxicities of R-CHOP regimen including new onset of cardiomyopathy or 
hemorrhagic cystitis will also be discontinued from the study and best efforts will be made to 
attribute the toxicities accurately. 
 
If ≥2 of the initial 6 patients in the 1.8 mg/kg cohort experience a DLT, the MTD for brentuximab 
vedotin in combination with R-CHP will be considered to have been exceeded. Six patients will 
then be enrolled and treated at 1.2 mg/kg and monitored for DLT during the first cycle of therapy. 
 
If ≤1 DLT occurs in the 6 patients in the 1.8 mg/kg cohort during the evaluation period, 
enrollment in Phase II will commence using 1.8 mg/kg.  If the dose was de-escalated to 1.2 
mg/kg and ≤1 DLT occurs in the 6 patients in the 1.2 mg/kg cohort, then the Phase II will 
commence using 1.2 mg/kg. If ≥ 2 of 6 patients at the 1.2 mg/kg dose level experience a DLT, 
then the study will be terminated. 
 
At least 6 patients must be enrolled and complete one cycle of dosing at the determined MTD 
prior to beginning patient enrollment in Phase II. If any patient enrolled in a cohort does not 
complete at least 1 Cycle of treatment through Cycle 2 Day 1, that patient will be replaced 
unless discontinuation is due to a DLT. 
 
NOTE: Six patients were enrolled and treated per Phase I without evidence of DLT.  Phase I data 
established a MTD of 1.8 mg/kg brentuximab vedotin. 
 


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5.2.2 Dose Modifications 
 
The Phase II part of this study will use the determined MTD of brentuximab vedotin. Dose 
modifications for treatment-associated toxicity with brentuximab vedotin and R-CHP (after the 
MDT was determined) are summarized in Table 2. As described in detail in Section 7.1, we will 
raise a red flag if the Bayesian probability that the serious toxicity rate exceeds 20% is greater 
than 90% in Phase II cohort. If the study raises a red flag, we will review data and consider 
modification or termination of the trial for lack of safety. 
 
TABLE 2: Recommended dose modifications for treatment-associated toxicity with brentuximab vedotin 
and R-CHP (during the period after the MTD was determined)a. Toxicities should be graded 
using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  NOTE: 
Toxicities reported after March 29, 2018 should be graded using CTCAE version 5.0. 
Toxicity 
Therapeutic 
Agent 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
Neuropathy: 
Sensory 
Brentuximab 
Vedotin 
Continue 
at same 
dose level 
Continue at same 
dose level 
For patients receiving 
1.8 mg/kg, reduce 
dose to 1.2 mg/kg. 
For patients on 1.2 
mg/kg hold until 
toxicity resolves to       
≤ Grade 1 or has 
returned to baseline. 
Treatment may be 
resumed at the same 
dose level at the 
discretion of the 
Treating Investigator 
after discussion with 
the Sponsor-
Investigator. 
Discontinue 
treatment with 
brentuximab 
vedotin. 
Peripheral 
Neuropathy: 
Motor 
Brentuximab 
Vedotin 
Continue 
at same 
dose level 
For patients 
receiving 1.8 mg/kg, 
reduce dose to 1.2 
mg/kg. 
For patients on 1.2 
mg/kg hold until 
toxicity resolves to   
≤ Grade 1 or has 
returned to baseline. 
Treatment may be 
resumed at the 
same dose level at 
the discretion of the 
Treating Investigator 
after discussion with 
the Sponsor-
Investigator. 
Withhold until toxicity 
resolves to ≤ Grade 
1 or has returned to 
baseline; resume 
treatment at the 
discretion of the 
Treating Investigator 
after discussion with 
the Sponsor-
Investigator. 
Discontinue 
treatment with 
brentuximab 
vedotin. 


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TABLE 2: Recommended dose modifications for treatment-associated toxicity with brentuximab vedotin 
and R-CHP (during the period after the MTD was determined)a. Toxicities should be graded 
using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  NOTE: 
Toxicities reported after March 29, 2018 should be graded using CTCAE version 5.0. 
Toxicity 
Therapeutic 
Agent 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-
Hematologic 
Brentuximab 
Vedotin 
Continue 
at same 
dose level 
Continue at same 
dose level 
Withhold dose until 
toxicity is ≤ Grade 2 
or baseline, then 
resume treatment at 
the same dose levelb 
Withhold dose until 
toxicity is ≤ Grade 2 
or has returned to 
baseline; then for 
patients receiving 
1.8 mg/kg, reduce 
dose to 1.2 mg/kg. 
For patients on      
1.2 mg/kg, hold until 
toxicity resolves to   
< Grade 1 or has 
returned to baseline. 
Treatment may be 
resumed at the 
same dose level at 
the discretion of the 
Treating Investigator 
after discussion with 
the Sponsor 
Investigator.b 
Hematologic c Brentuximab 
Vedotin 
Continue 
at same 
dose level 
Continue at same 
dose level 
Withhold dose until toxicity is ≤ Grade 2, or 
has returned to baseline, then resume 
treatment at the same dose level. Will be 
managed as per institutional guidelinesc,d 
 
a The next cycle may be delayed up to 3 weeks if additional time is required for the patient to recover 
from study treatment-associated toxicity. 
b Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption. 
c The use of colony-stimulating factors and transfusions are permissible during Cycle 1 and subsequent 
cycles as per institutional preferences. 
d Patients who develop Grade 3 or Grade 4 lymphopenia may continue study treatment without interruption. 
Patients with any signs and symptoms of PML will have the brentuximab vedotin and 
rituximab held. They will undergo a diagnostic work-up and if PML confirmed, patients will 
permanently discontinue brentuximab vedotin and rituximab. Patients will be removed from the 
study if PML develops. 
 
The decision to use consolidative radiation therapy to any residual mass after completion of 
systemic treatment will be at the discretion of the treating physician. However, radiation will 
not be started until after the final response assessment after cycle 6 (days 21-28). The use 
of prophylactic intrathecal therapy (with intrathecal methotrexate or cytarabine) in patients with 
high risk for CNS relapse during or after completion of systemic therapy is allowed and will be 
determined by the treating physician. 


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Subjects will be followed at routine study visits for 2 years after the last dose of the study drug.  
Follow-up will be performed every 3 months (+/- 30 days) for the first year and every 3 – 6 
months (+/- 30 days) during the second year.   Follow-up information about the initiation of 
alternative therapy and survival status may be obtained from the medical record or via telephone 
or email correspondence for up to 5 years after the end of treatment. 
 
5.3 Preparation and Administration of Study Drug 
Brentuximab vedotin is a sterile, preservative-free, white to off-white lyophilized cake for 
reconstitution for IV administration. Brentuximab vedotin is supplied by Seattle Genetics in 
single-use, Type 1 borosilicate glass vials with FluroTec®-coated butyl rubber stoppers and 
aluminum seals. Each vial of the product contains brentuximab vedotin (SGN-35), trehalose, 
sodium citrate, and polysorbate 80. 
 
For combination treatment with R-CHP, administration of brentuximab vedotin will begin 
within approximately one hour (up to 1.5 hours) after the completion of R-CHP infusion on 
Day 1 (± 1 day) of each 21-day cycle for cycles 2-6 and on Day 2 of Cycle 1. Planned dose 
level is 1.8 mg/kg. Brentuximab vedotin is administered by IV infusion given over 
approximately 30 minutes. In the absence of infusion toxicities, the infusion rate for all 
patients should be calculated in order to achieve a 30-minute infusion period. Brentuximab 
vedotin must not be administered as an IV push or bolus.  Brentuximab vedotin may be 
administered through the same IV line used for R-CHP. 
 
In each case of brentuximab vedotin administration, dosing may be based on the patient’s 
baseline (pre-dose, Cycle 1 Day 1) weight or per institutional standards at the site; doses will be 
adjusted for patients who experience a ≥10% change in weight during the study. Actual weight 
will be used except for patients weighing greater than 100 kg; then the brentuximab vedotin dose 
will be calculated based on 100 kg for these individuals. Brentuximab vedotin dose should be 
rounded to the nearest whole number of milligrams. 
 
The individual components of R-CHP chemotherapy should be prepared and administered per 
institutional guidelines with standard doses (Table 1). 
 
5.4 Subject Compliance Monitoring 
Treatment administration will be performed by site staff and documented in source documents 
and the CRF. Patient administration of the prednisone component of R-CHP chemotherapy will 
be documented in the CRF (as self-reported and recorded in a diary) and reviewed to ensure 
compliance with the treatment regimen. 
 
5.5 Premedication and Concomitant Therapy 
5.5.1 Premedication 
Routine premedication will be administered prior to rituximab administration for R-CHP regimen 
on Day 1 of Cycles 2-6 consisting of acetaminophen (650 mg orally) and diphenhydramine (25–
50 mg orally or 10– 25 mg IV) or as per institutional guidelines. For Cycle 1 (split dose rituximab 
on Day 1 and Day 2) the same premedication before rituximab will be given on Day 1 and Day 2. 
Of note, the 100 mg of prednisone (or equivalent) for Day 1 and Day 2 (on Cycle 1) or on Day 1 
(Cycles 2-6) should be administered with premedications prior rituximab infusion. 


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Routine premedication should not be re-administered for the prevention of brentuximab vedotin 
infusion-related reactions prior to the first dose of brentuximab vedotin (after R-CHP administration 
is completed). Infusion-related reactions may occur during the infusion of brentuximab vedotin. 
The infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis, should it occur. The patient should be observed for 60 minutes following the first 
infusion of brentuximab vedotin. During this observation period, the IV line should remain open for 
at least one hour to allow administration of IV drugs, if necessary. All supportive measures 
consistent with optimal patient care will be given throughout the study according to institution 
standards. Medications for infusion related reactions, such as epinephrine, antihistamines, and 
corticosteroids, should be available for immediate use. 
 
Patients who experience a Grade 1 or Grade 2 infusion-related reaction with brentuximab vedotin 
may receive subsequent brentuximab vedotin infusions with premedication consisting of 
acetaminophen (650 mg orally) and diphenhydramine (25–50 mg orally or 10–25 mg IV) or 
according to institutional standards, administered 30–60 minutes prior to each 30-minute 
brentuximab vedotin infusion. 
 
Patients who experience a Grade 3 or Grade 4 infusion-related reaction may potentially receive 
additional treatment with brentuximab vedotin at the discretion of the Investigator after discussion 
with the Sponsor-Investigator. Those patients who will develop anaphylaxis-like reaction to 
brentuximab vedotin will permanently discontinue the drug, but may continue on the study for the 
reminder of the treatment. 
 
Patients should be individually evaluated to assess the need for tumor lysis syndrome prophylaxis 
prior to the first dose of treatment (brentuximab vedotin or any component of R-CHP 
chemotherapy). Patients should receive prophylaxis (e.g. allopurinol) as appropriate per 
institution standards. 
 
5.5.2 Concomitant Therapy 
The use of blood and platelet transfusions, and/or colony-stimulating factors per institutional 
practice is permitted during therapy. Empiric use of colony-stimulating factors is allowed as per 
institutional guidelines. Patients who develop documented neutropenia with an ANC ≤500/μL 
during Cycle 1 (CBC will be obtained around day 8 of Cycle 1) will use G-CSF or GM-CSF 
support at that time and in subsequent cycles. Those who develop any grade 3 or 4 cytopenias 
or symptomatic cytopenias should be transfused per institutional practice. 
 
Radiotherapy (RT) may be given at the investigator’s discretion no sooner than 4 weeks after the 
last dose of brentuximab vedotin and after completion of final response assessment. 
 
Patients with high risk of developing CNS relapse may be treated with prophylactic intrathecal 
chemotherapy (methotrexate or cytarabine) at the discretion of the treating physician and as per 
institutional standards during or after completion of systemic therapy. 
 
Patients may not receive other investigational drugs, immunosuppressive medications, or anti-
neoplastic therapy during the study. 
 
 


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5.6 Packaging 
Vialed drug product may be labeled as brentuximab vedotin, the United States adopted name 
(Adcetris), or as SGN-35, the compound code; these names can be used interchangeably. The 
individual components of R-CHP chemotherapy are commercially available. 
 
5.7 Receiving, Storage, Dispensing and Return 
5.7.1 
Receipt of Drug Supplies 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment. It is important that the 
designated study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. The investigator must notify study sponsor of 
any damaged or unusable study treatments that were supplied to the investigator’s site. 
 
5.7.2 
Storage 
Vials containing brentuximab vedotin must be refrigerated at 2–8°C in a controlled location 
accessible only to the pharmacist, the investigator, or a duly designated person. Brentuximab 
vedotin (SGN-35) for injection does not contain preservatives; therefore, opened and 
reconstituted vials of brentuximab vedotin must be used within the same day when stored under 
refrigeration at 2–8°C. It is recommended that brentuximab vedotin vials and solutions be stored 
protected from direct sunlight until the time of use. 
 
Reconstituted vials must not be shaken. Drug accountability records will be kept according to the 
local standards of each institution. 
 
5.7.3 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation 
form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
6 Study Procedures 
6.1 Schedule of Events 
Concomitant medications information will be collected from the time of informed consent until the 
End of Treatment (EOT) visit or 30 days after the last dose, whichever is later. Adverse events will 
be collected from the time of first drug administration (Cycle 1/Day 1) until the End of Treatment 
(EOT) visit or 30 days after the last dose, whichever is later. Other study activities are listed by visit 
in this section and descriptions of study assessments are presented in Section 6.6. A schedule of 
events is provided in Appendix A.  Note: assessment schedule may be adjusted as needed to 
account for treatment delays.  The calendar may also be adjusted as needed in order to account for 
additional unscheduled visits (for example, if a subject has an unscheduled visit at 6 weeks 
following the end of treatment, the calendar may be adjusted to schedule the next assessment at 3 
months from the unscheduled visit timepoint). 
 


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6.2 Screening/Baseline: within 28 days of Cycle 1/Day 1 
 
Informed consent 
 
Study eligibility per inclusion/exclusion criteria (see Section 4.1 and 4.2) 
 
Medical history 
 
Staging PET/CT or CT scan of neck (if indicated), chest, abdomen and pelvis 
with contrast, to be performed within 60 days of first dose of study therapy 
Note:  Use of non-contrast CT imaging is permitted where IV contrast is 
contraindicated (i.e. documented, reported, or suspected contrast dye allergy).  
If non-contrast CT scans are used in disease staging, this same modality should 
be used in subsequent radiographic evaluation 
 
MUGA scan or ECHO to assess ejection fraction 
 
Bone marrow aspirate and biopsy is elective and under the discretion of treating 
physician in patients who underwent PET/CT scan as part of staging 
 
B symptom assessment 
 
Physical examination including vital signs and baseline neurological exam (see 
Section 6.6.3) 
 
Height/weight 
 
Serum chemistry panel (see Section 6.6.2) 
 
Complete blood count (CBC) with differential (see Section 6.6.2) 
 
Viral (HIV and hepatitis B) studies (see Section 6.6.2) 
 
Pregnancy test (Day -7 to Day 1) for females of childbearing potential 
 
ECOG performance status 
 
6.3 Treatment Period (Cycles 1-6) 
6.3.1 Cycle 1, Day 1 
 
Serum chemistry panel (if not previously performed within 7 days of dosing) 
 
CBC with differential (if not previously performed within 7 days of dosing) 
 
LDH, uric acid 
 
Vital signs 
 
Weight 
 
Physical examination (if not previously performed within 7 days of C1D1) 
 
ECOG performance status (if not previously performed within 7 days of C1D1) 
 
B symptom assessment (if not previously performed within 7 days of C1D1) 
 
Administration of prednisone (PO or IV steroid equivalent) and premedications 
 
Administration of rituximab, 100 mg/m2 
 
 
 


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6.3.2 Cycle 1, Day 2 
 
Administration of prednisone (dosing to continue for days 3-5) and premedications 
 
Administration of rituximab, 275 mg/m2 
 
Administration of cyclophosphamide 
 
Administration of doxorubicin 
 
Administration of brentuximab vedotin (after completion of rituximab and chemotherapy) 
 
Observation for one hour after completion of brentuximab vedotin infusion completion 
6.3.3 Day 8 (± 3 days) of Cycle 1 only 
 
Serum chemistry panel 
 
CBC with differential 
6.3.4 Day 1 of Cycle 2-6 (+/- 3 days) 
 
Administration of brentuximab vedotin in combination with R-CHP 
 
CBC with differential 
 
Serum Chemistry 
 
LDH, Uric Acid 
 
Physical Exam, including neurological exam (mental status, strength, sensation) 
 
Vital signs, including weight 
 
ECOG PS 
 
Adverse event and concomitant medication assessment 
 
B Symptom assessment 
Responses will be assessed as follows: 
 
CT scan with contrast after Cycles 2 and 4 and with PET/CT after cycle 6 (3-5 
weeks after completion of the last cycle) as well as whenever disease progression 
is suspected.  Non-contrast CT may be used if IV contrast is contraindicated. 
 
Radiographic imaging should then be performed at least every 8 months (+/- 30 
days) for the first two years of follow-up. More frequent imaging may be performed 
as clinically indicated. 
 
Bone marrow biopsy should be completed to confirm a complete remission to 
therapy in patients with bone marrow involvement at baseline 
Management of Suspected PML 
Patients with any signs and symptoms of PML which may include altered mental status, motor 
deficits such as hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such 
as dysphagia or agnosia, will have the dose of brentuximab vedotin held and will undertake a 
diagnostic work-up including (but not limited to): 
 
Neurologic examination, as warranted 
 
Brain radiologic features by magnetic resonance imaging (MRI) 
 
PCR analysis: JC virus DNA detectable in cerebrospinal fluid 
If PML is confirmed, patients will permanently discontinue treatment with brentuximab vedotin 
and rituximab. They will be permanently removed from the study. 


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6.4 End of Treatment (30 ± 7 days after last dose of brentuximab vedotin 
and R-CHP) 
Note: EOT evaluations should be obtained prior to initiation of non-protocol therapy, including RT. If 
the EOT evaluations are completed within 30 days of the last day of treatment, the site will conduct 
a phone screen 30-37 days following the patient’s last treatment to ensure that the adverse event 
profile has not changed. 
 
Serum chemistry panel 
 
CBC with differential 
 
Pregnancy test 
 
Weight/Vital signs 
 
Physical exam 
 
ECOG performance status 
 
Response assessment with imaging to be done prior any RT 
 
B symptoms assessment 
 
Bone marrow aspirate and biopsy (only if positive prior starting therapy; if bone marrow 
aspirate and biopsy were done prior during the treatment and found to be negative for 
lymphoma involvement – then this does not have to be performed again) 
6.5 Long Term Follow-up 
Patients who discontinue study treatment for any reason other than disease progression or 
initiation of a non-protocol therapy for treatment of lymphoma (other than RT or CNS prophylaxis 
with intrathecal chemotherapy) will remain on study for follow-up visits until 2 years from EOT or 
until disease progression or relapse or until they withdraw from the study (see Section 4.6).  
Follow-up information about the initiation of alternative therapy and survival status may be 
obtained from the medical record or via telephone or email correspondence for up to 5 years 
after the end of treatment. 
All patients who receive at least 1 dose of study drug will be followed for survival and disease 
status according to the following schedule: 
 
Year 1 following EOT: Physical exam and blood work (CBC, platelet, differential) every 3 
months (± 30 days) 
 
Year 2 following EOT: Physical exam and blood work (CBC, platelet, differential) every 3 - 6 
months (± 30 days) 
 
Years 1 and 2 following EOT: imaging (by dedicated CT scan or PET/CT) will be performed 
at least every 8 months (± 30 days). Of note, patients undergoing consolidative RT may 
delay imaging for response assessment until after 2 months of completing RT 
 
After 2 years from EOT, routine care evaluations should be performed per the practice of the 
treating physician. The frequency of imaging will be at discretion of the treating physician. 
 
The initiation of an alternative form of treatment for lymphoma will also be collected for up to 
5 years from the EOT. 
 
Patients who are no longer seen at the participating institution may be queried by phone or email to 
obtain survivorship data and initiation of alternative therapy for up to 5 years from the EOT. 


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6.6 Study Assessments 
Only patients who meet all inclusion and exclusion criteria specified in Section 4 will be enrolled 
onto this study. 
 
6.6.1 Response Assessments 
Treatment response will be assessed by imaging with PET/CT and/or standard CT scans with IV 
contrast (chest, abdomen, pelvis and if clinically indicated the neck) at protocol-specified time 
points.  Non-contrast CT imaging may be used if IV contrast is contraindicated – a single modality 
should be used throughout the study. The determination of antitumor efficacy will be based on 
objective response assessments made according to the International Working Group Response 
Criteria for non-Hodgkin Lymphoma (Cheson et al. 2007, 579-586) and treatment decisions by the 
investigator will be based on these assessments. Clinical response of progressive disease (PD), 
stable disease (SD), partial remission (PR), or complete remission (CR) will be determined at each 
assessment. Up to 6 of the largest dominant nodes or nodal masses will be followed for response 
assessment. 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. If the bone marrow was 
positive at baseline, a follow-up bone marrow aspirate and biopsy is required and must be negative 
for assessment of a CR. If the follow-up morphology is indeterminate, the biopsy tissue must be 
negative by immunohistochemistry or the patient will be assessed as a PR. 
 
Tumor imaging will be performed at screening, after Cycles 2, 4, and three to five weeks after 
Cycle 6, as well as whenever disease progression is suspected. The post-therapy imaging (3-5 
weeks after completion of Cycle 6) will be performed prior initiation of RT in patients who are 
planned to undergo consolidative RT. 
 
After the patient is withdrawn from study treatment for any reason, an additional response 
assessment will be performed if an assessment has not been performed within the prior 6 weeks. 
Patients may continue on study treatment for a total of 6 cycles in the absence of disease 
progression, unacceptable toxicity or withdrawal of consent. All patients’ clinical data and tumor 
images must be available for CRF source verification. Copies of all imaging studies must be 
made available for review by the Sponsor (or its designee). 
 
6.6.2 Clinical Laboratory Evaluations 
The following laboratory assessments will be performed to evaluate safety at scheduled time 
points (see Appendix A) during the course of the study: 
 
Chemistry panel, including sodium, chloride, potassium, blood urea nitrogen (BUN), serum 
creatinine, calcium, total protein, albumin, glucose, total bilirubin, alkaline phosphatase, ALT, 
AST 
 
The hematology panel includes the following tests: white blood cell count, 
hemoglobin/hematocrit, and platelets and the differential includes: neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils 
 
Initial blood work will also include testing for HIV and Hepatitis B surface antibody, Hepatitis 
B core antibody, Hepatitis B surface antigen 


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6.6.3 Other Study Assessments 
Other study assessments include the following: 
 
Biopsies for CD30 expression: results of CD30 expression (quantitative estimate) from the 
diagnostic biopsy of PMBL, DLBCL or GZL will be obtained from pathology reports or 
from review of the biopsy specimen 
 
Patient medical history, including a thorough review of: 
o 
The patient’s current and previous conditions 
o 
Concomitant medications and prior therapies 
 
Physical examination, including evaluation of skin, HEENT (head, eyes, ears, nose, and 
throat), nodes, spleen, heart, lungs, abdomen, back, and extremities. Neurological exam 
will include gross assessment of mental status, strength, and sensation. Any new 
neurological symptoms concerning for PML will be worked up immediately. 
 
ECOG performance status 
 
B symptom assessment (unexplained fevers greater than 38°C, drenching night sweats 
and/or weight loss greater than 10% of body weight) 
6.7 Correlative Study Procedures 
Patients will be consented in person or by telephone or email correspondence depending on study 
follow-up requirements.  Those consented by telephone will be sent a description of the correlative 
study to patients via the United States Postal Service.  A member of the study team will then call 
patients to describe the study and risks and to provide an opportunity to ask any questions.  The 
study staff will then obtain verbal consent for participation in the correlative study.  If the study 
team is unable to reach patients by telephone, an email will be sent to the address previously 
provided by the patient, requesting the patient to reply via email to indicate willingness to 
participate.  A phone number will be included in order to provide an opportunity to answer any 
questions and to further discuss the correlative study. 
After consent has been obtained, archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue 
will be retrieved and 8-10 rolls (or slices) of fixed tissue will be collected from each specimen as 
available.  RNA will be isolated from each specimen and, in collaboration with the Centre for 
Lymphoid Cancer, gene expression profiling will be performed using a customized Nanostring 
PanCancer Immune Profiling Panel.  This panel has been designed to help distinguish between 
PMBL and CD30+ DLBCL.  Statistical analysis will be conducted by Dr. Marco Ruella and Dr. 
Megan Lim at the University of Pennsylvania in conjunction with statistical support from 
NanoString Technologies, Inc. 
7 Statistical Plan 
7.1 Sample Size Determination 
The number of patients enrolled and evaluable in the Phase I cohort is defined as at least 6 
patients. The operating characteristics of the dose de-escalation scheme are presented here. 
If the true proportion of patients that would experience a DLT is 10%, then the probability of de-
escalating to the lower dose cohort when 2 or more patients experiences a DLT is 9%. If the 
true proportion of patients that would experience a DLT is 50%, then the probability of dose de-
escalation is 83%. 
 


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With this type of study design, the exact number of patients that will be enrolled in Phase I is 
unknown because it depends upon the number of patients required to reach MTD and the 
number of patients enrolled in each cohort. A maximum of 12 safety-evaluable patients will 
participate in Phase I. 
 
Since the Phase I subjects will be recruited, treated and followed in the same way as the Phase II 
subjects, the 6 Phase I subjects accrued at the MTD will be considered as accrued to the Phase II 
study as well. The total number of subjects recruited to Phase II will be affected by the CR rate. 
 
We design this trial with the potential for early termination in the case of a poor overall response rate 
(ORR). We will use the optimal two-stage design of Simon. Choice of design is guided by a desire 
to stop the trial early if the actual ORR is 50% or less. If the ORR is 70% or greater, we would like 
to have a low probability of failing to conclude the combination is effective. We select the type I 
error rate (probability of accepting the drug if the ORR = 50%) to be 10% and the type II error rate 
(probability of rejecting the drug if the ORR = 70%) to be 20%. The table below gives the optimal 
(smallest expected sample size under the null) two-stage design exhibiting these properties. 
 
Patients treated 
Stop/Reject if number of successes < than 
12 
7 
32 
20 
 
Under the null hypothesis of a 50% ORR, this design has an expected sample size of 19.7 and 
a probability of early termination of 0.61. 
 
With n=32 patients, we will have 90% power to detect any unforeseen toxicity that occurs in 
6.9% or more of patients. The standard error of any proportion will be no larger than 8.8%. 
 
We will monitor continuously for toxicity in the phase II portion of the trial. We will raise a red 
flag if the Bayesian probability that the serious toxicity rate exceeds 20% is greater than 90%. 
Assuming a beta (2,6) prior (equivalent to 1 toxicity in 6 prior patients), we will raise a red flag if 
the first 2 subjects experience serious toxicities, if there are 3 serious toxicities occurring by the 
6th patient, 4 by the 9th, 5 by the 13th, 6 by the 17th, 7 by the 21st, 8 by the 25th, 9 by the 29th, 
and 10 by the 32nd. If the study raises a red flag, we will review data and consider modification 
or termination of the trial for lack of safety. 
 
7.2 Statistical Methods 
The ORR and CR rate and its two-sided 95% exact confidence interval will be calculated using the 
Clopper-Pearson method. PFS and OS at year 1 and 2 will be estimated using the Kaplan-Meier 
method. The median PFS and 95% confidence interval will be calculated where possible. We will 
calculate ORR, CR, PFS, and OS for all the subjects as a group and also separately for each 
subtype (PMBL, DLBCL, GZL). 
 
We will assess correlation of baseline CD30 expression level with clinical response by a two-
sample t test comparing mean CD30 level among complete responders to the level among 
those who do not have complete responses. We will assess correlation of baseline CD30 level 
with survival outcomes (PFS, OS) by the Cox proportional hazards regression model, taking 
baseline CD30 level as a continuous predictor. 
 


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For the correlative study with multiplexed gene expression profiling of primary tumor samples, the 
statistics are descriptive.  The data will be analyzed by calculating a single linear predictor score 
for each biopsy sample.  Based on the distributions of linear predictor scores in each cancer group, 
Bayes rule can be used to estimate the probability that a sample belongs to cancer group A (ie 
PMBL) vs cancer group B (DLBCL, non-PMBL). An arbitrary probability cutoff of ≥90% will be used 
to classify a sample into a subgroup and correlation with outcome will be conducted. 
 
7.3 Subject Population(s) for Analysis 
All patients who are enrolled in the study and receive any clinical trial material will be included in the 
intent-to-treat analysis. All safety analyses will be performed on the intent-to treat population. The 
efficacy analysis will include any patient who has received at least one dose of the investigational 
drug brentuximab vedotin and were evaluable for response. We will allow up to 4 additional patients 
to be enrolled in the Phase II part of the study to substitute for the missing data. All estimates of 
rates (e.g., response and toxicity) will be presented with corresponding confidence intervals. 
 
7.4 Study Endpoint Definitions 
 
7.4.1 Objective Response Rate 
 
Objective response rate is defined as the proportion of patients with CR or PR according to the 
International Working Group Response Criteria for non-Hodgkin Lymphoma (Cheson et al. 2007, 
579-586) as of the designated time point for the treatment period under consideration. 
Patients whose disease response cannot be assessed, including those patients who do not 
have CT scans performed, will be scored as non-responders for calculating the ORR. 
 
7.4.2 Complete Remission Rate 
 
Complete remission rate is defined as the proportion of patients with CR according to the 
International Working Group Response Criteria for non-Hodgkin Lymphoma (Cheson et al. 
2007, 579-586) as of the designated time point for the treatment period under consideration. 
 
7.4.3 Progression-Free Survival 
 
Progression-free survival is defined as the time from start of study treatment (brentuximab 
vedotin with R-CHP chemotherapy) to first documentation of objective tumor progression or to 
death due to any cause, whichever comes first. Progression-free survival data will be censored 
on the day following the date of the last lymphoma assessment documenting absence of 
progressive disease for patients who do not have objective tumor progression and are still on 
study at the time of an analysis, are given antitumor treatment other than the study treatment or 
stem cell transplant, or are removed from study prior to documentation of objective tumor 
progression. Patients lacking an evaluation of tumor response after their first dose will have their 
event time censored at day one. 
 
7.4.4 Overall Survival 
 
Overall survival (OS) is defined as the time from start of study treatment to date of death due 
to any cause. In the absence of confirmation of death, survival time will be censored at the last 
date the patient is known to be alive. Patients lacking data beyond the day of first dose will 
have their survival time censored at day one. 
 
 


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8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria: 
 
Unexpected in nature, severity, or frequency (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc.) 
 
Related or possibly related to participation in the research (i.e. possibly related 
means there is a reasonable possibility that the incident experience, or outcome 
may have been caused by the procedures involved in the research) 
 
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
 
results in study withdrawal 
 
is associated with a serious adverse event 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE 
that is: 
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 
 
results in persistent or significant disability or incapacity 
 
a congenital anomaly or birth defect 
 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events. 


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Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the 
period from the initiation of the first study treatment (Cycle 1/Day 1) to the end of the study 
treatment follow-up. For this study, the study treatment follow-up is defined as 30 days 
following the last administration of study treatment. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. 
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study. The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study. The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met: 
 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 
The abnormality suggests a disease and/or organ toxicity 
 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed 
otherwise in this protocol. Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for and adverse event. 
 
 
 


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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition. Surgery should not be reported as an outcome of an adverse event if 
the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). Adverse events will be graded according to the 
CTCAE v4.0. NOTE: Adverse events reported after March 29, 2018 should be graded according 
to the CTCAE v5.0.  All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any 
serious adverse event that occurs after the study period and is considered to be possibly related 
to the study treatment or study participation should be recorded and reported immediately.  Of 
note, disease progression is not considered an AE or SAE. 
 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a 
minimum those events that must be reported are those that are: 
 
related to study participation 
 
unexpected, and 
 
serious or involve risks to subjects or others (see definitions, Section 8.1). 
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the study are NOT to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or later 
than planned). 
 
For both serious and non-serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. If the relationship to the 
study drug cannot be determined at the time of the initial SAE report, the event should be 
considered possibly related until additional information is available to fully evaluate the event. 
 
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE, 
Version 4.0.  NOTE: Adverse events reported after March 29, 2018 should be graded using the 
CTCAE version 5.0. 


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University of Pennsylvania Institutional Review Board: 
Serious adverse events which in the opinion of the principal investigator are both unexpected and 
related to research procedures should be reported to the IRB within 10 working days of 
investigator notification. An event is considered “unexpected” when its specificity and severity are 
not accurately reflected in the protocol-related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, applicable package insert information, and/or 
the current IRB-approved informed consent document. An event is considered “related to the 
research procedures” if the event is deemed probably or definitely related. 
 
Deaths occurring for patients on-study and within 30 days of study drug administration that are 
considered unforeseen and indicates participants or others are at increased risk of harm (i.e. 
unexpected and probably/definitely related), must be reported to the IRB within 24 hours of 
notification. 
 
In addition, if other information becomes available that indicates a change to the risks or potential 
benefits of the research, in terms of severity or frequency, this should be reported within 3 days. 
Examples of this include: 
 
An interim analysis indicates that participants have a lower rate of response to treatment 
than initially expected. 
 
Safety monitoring indicates that a particular side effect is more severe, or more frequent 
than initially expected. 
 
A paper is published from another study that shows that an arm of your research study is 
of no therapeutic value. 
 
Any adverse event that represents a serious, unexpected problem that is rare in absence 
of drug exposure. 
 
Withdrawal from marketing for safety of a drug, device, or biologic used in a research 
protocol. 
 
Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
 
Violation, meaning an accidental or unintentional change to the IRB approved protocol that 
placed one or more participants at increased risk, or has potential to occur again. 
 
Breach of confidentiality. 
The IRB will accept other reports when the investigator is unsure whether the event should be 
reported, and the IRB will review such reports to determine whether the event meets the 
threshold for an unanticipated event presenting risk to the participant. 
Office of Regulatory Affairs, Institutional Review Board 
3800 Spruce Street 
Old Vet Quad Building 
First Floor Room 151 
Philadelphia, PA 19104 
Phone: 215-573-2540 
Fax: 215-573-9438 
 


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Abramson Cancer Center Data Safety Monitoring Committee (DSMC): 
Grade 3 or higher AEs, determined to be related to the study drug regardless of expectedness, 
or that affect subject safety, must be submitted to the Abramson Cancer Center’s DSMC 
within 10 days of notification. Other events should be submitted if clinically significant or if a 
relationship to the study drug cannot be ruled out. AEs that are related to the subjects’ disease 
and/or other co-morbidity, or routine therapy, are not reportable to the ACC DSMC. All 
unexpected deaths or deaths related to the study drug should be reported within 24 hours of 
notification. All other deaths should be reported within 30 days. All AEs occurring within 30 days 
of the last dose of the study drug must be record/reported appropriately. 
 
AEs will be submitted to the DSMC through the Velos Clinical Trial Management System. 
Data and Safety Monitoring Committee 
3400 Spruce Street, 2017 Penn Tower 
Philadelphia, PA 19104-4283 
Website: https://pennctms.pmacs.upenn.edu/velos/jsp/ereslogin_new.jsp 
 
Reportable Events: 
A one-time accidental or unintentional deviation from the approved protocol, identified 
retrospectively, that in the opinion of the investigator or as defined by the protocol, placed one 
or more participants at increased risk, compromises the rights or welfare of subjects, and/or 
disrupts the study design, is considered a reportable event and must be reported to the Study 
Principal Investigator, Study Medical Monitor, IRB, and ACC DSMC within 10 working days of 
notification. Principal Investigator and Medical Monitor approval/ acknowledgement must be 
received first and included in with the IRB/DSMC submission. 
 
Deviations to protect subjects from immediate harm/danger should be reported immediately 
following the event to the entities outlined above. 
Exceptions: 
An exception is defined as a one-time, unintentional action or process that departs from the 
IRB and CTSRMC approved study protocol, intended for one occurrence. AND this action 
disrupts the study progress, such that the study design or outcome (endpoints) may be 
compromised, or the action compromises the safety and welfare of study subjects (i.e. requests 
to enroll and/or treat subjects outside of the current protocol criteria). Exceptions that meet this 
criteria will not be allowed unless reviewed and approved first by the Study Medical Monitor and 
the Study Principal Investigator/Sponsor-Investigator, and then subsequently by the ACC 
DSMC, and UPenn IRB prior to this subject being enrolled/treated. PI/Sponsor-Investigator and 
Medical Monitor approval must be received first and included in with the IRB/DSMC 
submission. All entities should be given sufficient time to evaluate this request. 
 
Examples of Exceptions/Deviations that require submission include: 
 
Dose adjustments/stopping rules that were not completed per protocol 
 
Other dosing errors 
Exceptions to eligibility may not be granted. 
 
Events not deemed reportable as outlined above will require a PI assessment regarding study 
and/or safety impact. This assessment should be documented appropriately. 
 


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Seattle Genetics SAE Reporting: 
All serious adverse events that occur during the onstudy period must be reported to the drug 
manufacturer within 24 hours of awareness of the event. Events occurring more than 30 days 
after discontinuation of the study product that are assessed by the Investigator to be related 
to the study product should also be reported. 
 
A MedWatch 3500A form should be used to report all SAEs. This report must include an 
assessment of the causality of this event to the study product. The investigator will keep a copy 
of this SAE form and fax/email confirmation on file at the study site. Report serious adverse 
events by email or fax to: 
 
Seattle Genetics Drug Safety: 
Email: drug.safety@seagen.com 
Fax: 425-527-4308 
Phone: 866-333-6627 
Follow-up information on this event should be reported when received. 
AE Reporting Requirements - Participating Institutions: 
The Participating Institution should report all on-site SAEs to their local IRB per their guidelines. 
In addition, all on-site SAEs occurring at the Participating Site must be reported to the 
University of Pennsylvania Sponsor-Investigator and Study Team within 24 hours of notification. 
This initial notification to the Sponsor-Investigator and Study Team can take place via email to 
meet the 24 hour deadline, but must be followed by submission of a formal report. SAEs should 
be reported using an FDA MedWatch Form 3500A and should include a full written summary, 
detailing relevant aspects of the adverse event in question. Once received, the University of 
Pennsylvania Study Team/PI will provide a copy of this SAE report to UPenn Medical Monitor, and 
report this event to the FDA (as applicable) and the UPenn IRB (as applicable). 
 
All Grade 3 or higher AEs, determined to be related to the study drug regardless of expectedness, 
or that affect subject safety, must be submitted to the Abramson Cancer Center’s DSMC 
through the Velos CTMS within 10 days of notification. Other events should be submitted if 
clinically significant or if a relationship to the study drug cannot be ruled out. AEs that are 
related to the subjects’ disease and/or other co-morbidity, or routine therapy, are not reportable 
to the ACC DSMC. All unexpected deaths or deaths related to the study drug should be 
reported within 24 hours of notification. All other deaths should be reported within 30 days. All 
AEs occurring within 30 days of the last dose of the study drug must be record/reported 
appropriately. 
 
U.S. Food and Drug Administration: 
In accordance with 21 CFR 312.32, sponsor-investigators of studies conducted under an IND 
must notify the FDA of the following: 
 
Any adverse experience associated with the use of the drug that is both serious and 
unexpected; or 
 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
 


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Each notification shall be made as soon as possible and in no event later than 15 calendar days 
after the sponsor-investigator’s initial receipt of the information. Each written notification may be 
submitted on the FDA Form 3500A which should clearly identify its contents and the Study IND 
Number. 
 
Each written notification to FDA shall be transmitted to the FDA new drug review division in the 
Center for Drug Evaluation and Research or the product review division that has responsibility for 
review of the IND (Division of Medical Imaging and Hematology Products). If FDA determines that 
additional data are needed, the agency may require further data to be submitted. 
 
Telephone and facsimile transmission safety reports: The sponsor-investigator shall also notify 
FDA by telephone or by facsimile transmission of any unexpected fatal or life-threatening 
experience associated with the use of the drug as soon as possible but in no event later than 7 
calendar days after the sponsor-investigator’s initial receipt of the information. Each telephone 
call or facsimile transmission to FDA shall be transmitted to the FDA new drug review division in 
the Center for Drug Evaluation and Research or the product review division that has responsibility 
for review of the IND. 
 
Follow-up information to a safety report shall be submitted as soon as the relevant information is 
available. 
 
The following describes the overall safety reporting requirements by timeline for reporting and 
associated type of event: 
 
 
Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected 
– fatal or life-threatening 
 
Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable) 
Any finding from tests in laboratory animals that: 
– suggests a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity 
 


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8.3.1 Sponsor reporting: Notifying Participating Investigators 
 
It is the responsibility of the study sponsor to notify all participating investigators, in a written IND 
safety report, of any adverse event associated with the use of the drug that is both serious and 
unexpected, as well as any finding from tests in laboratory animals that suggest a significant 
risk for human subjects. Additionally, sponsors are also required to identify in IND safety 
reports all previous reports concerning similar adverse events and to analyze the significance of 
the current event in light of the previous reports. 
 
These reports will be issued to the participating investigators via email by the University of 
Pennsylvania study team upon receipt, for local review and processing. 
8.4 Stopping Rules 
See Section 7.1 for a safety monitoring plan. We will also stop enrollment if 2 or more patients are 
unable to complete 6 cycles of treatment with the combination therapy. 
8.5 Medical Monitoring 
The medical monitor for this study will be Dr. Naomi Haas from the University of Pennsylvania. 
Dr. Haas is an Associated Professor in the Department of Hematology-Oncology at University of 
Pennsylvania, with extensive oncology and research experience. Dr. Haas is not directly 
involved in the trial and is not collaborating with the Sponsor-Investigator on any other trials. 
 
In the role, Dr. Haas will review all AEs including grading, toxicity assignments, all other safety 
data and activity data observed in the ongoing clinical trial. This will include a real-time review of 
safety data in the event of any unexpected and related SAE regardless of grade, and any on-
study deaths. The Medical Monitor will also be consulted in the case of exception requests or the 
evaluation of deviations that may compromise subject safety or disrupt the design of the study. 
This information will be communicated to the Medical Monitor via email and filed in the 
Regulatory Binder/Subject Chart appropriately. As applicable, copies of this correspondence will 
be included in the corresponding IRB/ACC DSMC submission of these events. 
 
The Medical Monitor will also be asked to review study data and comprehensive adverse event 
data at least bi-annually (every 6 months). This meeting will take place in person, and all 
study/safety information will be presented appropriately. This meeting will be clearly 
documented on a Medical Monitor Review Sheet, signed off on by the Medical Monitor. At any 
point during the course of the study, the Medical Monitor may recommend reporting of adverse 
events and relevant safety data not previously reported and may recommend suspension or 
termination of the trial. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this 
study Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI. 


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
9.3 Case Report Forms 
Velos electronic case report forms (eCRFs) are the primary data collection instrument for this 
study. All data requested on the CRF must be recorded according to the guidelines set forth in 
the Multi-Site Manual of Procedures. All missing data must be explained. If a space on the CRF 
is left blank because the procedure was not done or the question was not asked, write “N/D”. If 
the item is not applicable to the individual case, write “N/A”. 
 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period if required by an agreement with the sponsor. In such an instance, 
it is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan. This monitoring will include a regular assessment of the number and 
type of serious adverse events. 
 
It is the responsibility of the Sponsor-Investigator to oversee the safety and conduct of this study at 
all participating sites. Please refer to the Penn MultiSite Manual of Procedures for an overview of 
the Sponsor-Investigator’s role, the expectations for Participating Sites, sponsor monitoring 
requirements, and guidelines for overseeing this research at participating institutions. 
 


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10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance offices. 
 
This investigator-initiated protocol is considered high risk as per the ACC DSMC. As such, high 
risk protocols are audited approximately six months from their first subject accrual and 
approximately every six months thereafter for the duration of the study by the ACC Department of 
Compliance and Monitoring (DOCM). However, this schedule may be changed at the discretion of 
the DSMC. High or quick enrolling studies may be audited more frequently as necessary. 
 
The investigator will be notified in advance of the selection of their protocol for review and 
cases are randomly selected. Three randomly selected subjects or 10% of the total accrual 
(up to 10 subjects), whichever is higher, are audited. A formal report is written to the PI within 
about 5 business days of the audit. The committee may alter the frequency of re-monitoring 
based on the audit findings and degree of deficiencies. 
 
Upon review of inspection findings, the Committee designates the audit outcome as Minor, 
Moderate, or Major deficiencies. The deficiency assigned by the Committee initiates specific 
follow-up actions. 
 
If an audit is unacceptable due to major deficiencies, representatives from the Department of 
Monitoring and Compliance (DOCM) meet with the PI to discuss the findings of the audit and 
review necessary corrective actions mandated by the DSMC. If the deficiencies involve subject 
safety or serious regulatory violations, the Cancer Center Director, DSMC Chair, and DSMC 
Administrative Director will meet to discuss necessary actions concerning study status. 
 
An evaluation of the deficiencies will be re-evaluated upon receiving the PI’s response. At this 
time, if the DSMC Chair and the Administrative Director do not find the response satisfactory, the 
IRB will be alerted of the actions taken by the ACC. The DSMC Director will update the IRB of 
the corrective actions being taken and progress being made. 
 
Team meetings may also be held throughout the course of this study in order to discuss the 
protocol, ongoing patients, toxicity data, and applicable recruitment issues. 
 
11 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct. The decision of the IRB concerning the conduct of the study will be made in writing to 
the investigator and a copy of this decision will be provided to the Sponsor-Investigator before 
commencement of this study. 


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All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
and Clinical Trials Scientific Review and Monitoring Committee (CTSRMC) for the study. The 
formal consent of a subject, using the IRB-approved consent form, must be obtained before that 
subject undergoes any study procedure. The consent form must be signed by the subject or 
legally acceptable surrogate, and the investigator-designated research professional obtaining 
the consent. 
 
12 Study Finances 
12.1 Funding Source 
This study will be supported by funds from Seattle Genetics. 
 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study. All University of Pennsylvania investigators will follow the applicable 
University conflict of interest policies. 
 
12.3 Subject Stipends or Payments 
There are no plans to provide payments or stipends to subjects. 
 
13 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 
 
 
14 References 
 
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Campuzano-Zuluaga, German, Maureen Cioffi-Lavina, Izidore S. Lossos, and Jennifer R. 
Chapman-Fredricks. 2012. "CD30 Expression in Diffuse Large B-Cell Lymphoma and its Relation 
to Important Clinical and Biological Disease Features." ASH Annual Meeting Abstracts 120 (21): 
1592. 
 


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Carson, Kenneth R., Andrew M. Evens, Elizabeth A. Richey, Thomas M. Habermann, Daniele 
Focosi, John F. Seymour, Jacob Laubach, et al. 2009. "Progressive Multifocal 
Leukoencephalopathy After Rituximab Therapy in HIV-Negative Patients: A Report of 57 Cases 
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Cheson, B. D., S. J. Horning, B. Coiffier, M. A. Shipp, R. I. Fisher, J. M. Connors, T. A. Lister, et 
al. 1999. "Report of an International Workshop to Standardize Response Criteria for Non-
Hodgkin's Lymphomas. NCI Sponsored International Working Group." Journal of Clinical 
Oncology : Official Journal of the American Society of Clinical Oncology 17 (4): 1244. 
 
Cheson, B. D., B. Pfistner, M. E. Juweid, R. D. Gascoyne, L. Specht, S. J. Horning, B. Coiffier, et al.  
2007. "Revised Response Criteria for Malignant Lymphoma." Journal of Clinical Oncology : Official 
Journal of the American Society of Clinical Oncology 25 (5): 579-586. 
 
Coiffier, B., E. Lepage, J. Briere, R. Herbrecht, H. Tilly, R. Bouabdallah, P. Morel, et al. 2002. 
"CHOP Chemotherapy Plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse 
Large-B-Cell Lymphoma." The New England Journal of Medicine 346 (4): 235-242. 
 
Dunleavy, K., S. Pittaluga, L. S. Maeda, R. Advani, C. C. Chen, J. Hessler, S. M. Steinberg, et 
al. 2013. "Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell 
Lymphoma." The New England Journal of Medicine 368 (15): 1408-1416. 
 
Eberle, F. C., J. Rodriguez-Canales, L. Wei, J. C. Hanson, J. K. Killian, H. W. Sun, L. G. Adams, 
et al. 2011. "Methylation Profiling of Mediastinal Gray Zone Lymphoma Reveals a Distinctive 
Signature with Elements Shared by Classical Hodgkin's Lymphoma and Primary Mediastinal 
Large B-Cell Lymphoma." Haematologica 96 (4): 558-566. 
 
Fanale, Michelle A., Andrei R. Shustov, Andres Forero-Torres, Nancy L. Bartlett, Ranjana H. 
Advani, Barbara Pro, Robert W. Chen, et al. 2012. "Brentuximab Vedotin Administered 
Concurrently with Multi-Agent Chemotherapy as Frontline Treatment of ALCL and Other CD30-
Positive Mature T-Cell and NK-Cell Lymphomas." ASH Annual Meeting Abstracts 120 (21): 60. 
 
Francisco, J. A., C. G. Cerveny, D. L. Meyer, B. J. Mixan, K. Klussman, D. F. Chace, S. X. Rejniak, 
et al. 2003. "cAC10-vcMMAE, an Anti-CD30-Monomethyl Auristatin E Conjugate with Potent and 
Selective Antitumor Activity." Blood 102 (4): 1458-1465. 
 
Higgins, J. P. and R. A. Warnke. 1999. "CD30 Expression is Common in Mediastinal Large B-Cell 
Lymphoma." American Journal of Clinical Pathology 112 (2): 241-247. 
 
Hu, S., Z. Y. Xu-Monette, A. Balasubramanyam, G. C. Manyam, C. Visco, A. Tzankov, W. M. Liu, 
et al.  2013. "CD30 Expression Defines a Novel Subgroup of Diffuse Large B-Cell Lymphoma with 
Favorable Prognosis and Distinct Gene Expression Signature: A Report from the International 
DLBCL Rituximab-CHOP Consortium Program Study." Blood 121 (14): 2715-2724. 
 
Hutchings, Martin, Annika Loft, Mads Hansen, Lars Møller Pedersen, Thora Buhl, Jesper 
Jurlander, Simon Buus, et al. 2006. "FDG-PET After Two Cycles of Chemotherapy Predicts 
Treatment Failure and Progression-Free Survival in Hodgkin Lymphoma." Blood 107 (1): 52-59. 
 


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page 41 
 
Jacobsen, Eric D., Ranjana H. Advani, Yasuhiro Oki, Jeff Sharman, Steven M. Horwitz, Andres 
Forero-Torres, Owen A. O'Connor, et al. 2012. "A Phase 2 Study of Brentuximab Vedotin in 
Patients with Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results." 
ASH Annual Meeting Abstracts 120 (21): 2746. 
 
Krathen, Michael, Uma Sundram, Sameer Bashey, Katherine Sutherland, Katrin Salva, Gary S. 
Wood, Ranjana H. Advani, et al. 2012. "Brentuximab Vedotin Demonstrates Significant Clinical 
Activity in Relapsed Or Refractory Mycosis Fungoides with Variable CD30 Expression." ASH 
Annual Meeting Abstracts 120 (21): 797. 
 
Lenz, G., G. Wright, S. S. Dave, W. Xiao, J. Powell, H. Zhao, W. Xu, et al. 2008. "Stromal Gene 
Signatures in Large-B-Cell Lymphomas." The New England Journal of Medicine 359 (22): 2313-
2323. 
 
Moskowitz, C. H., H. Schoder, J. Teruya-Feldstein, C. Sima, A. Iasonos, C. S. Portlock, D. Straus, 
et al.  2010. "Risk-Adapted Dose-Dense Immunochemotherapy Determined by Interim FDG-PET 
in Advanced-Stage Diffuse Large B-Cell Lymphoma." Journal of Clinical Oncology : Official 
Journal of the American Society of Clinical Oncology 28 (11): 1896-1903. 
 
Pileri, S. A., P. L. Zinzani, G. Gaidano, B. Falini, P. Gaulard, E. Zucca, E. Sabattini, et al. 2003. 
"Pathobiology of Primary Mediastinal B-Cell Lymphoma." Leukemia & Lymphoma 44 Suppl 3: S21-6. 
 
Pregno, Patrizia, Annalisa Chiappella, Marilena Bellò, Barbara Botto, Simone Ferrero, Silvia 
Franceschetti, Francesca Giunta, et al. 2012. "Interim 18-FDG-PET/CT Failed to Predict the 
Outcome in Diffuse Large B-Cell Lymphoma Patients Treated at the Diagnosis with Rituximab-
CHOP." Blood 119 (9): 2066-2073. 
 
Pro, B., R. Advani, P. Brice, N. L. Bartlett, J. D. Rosenblatt, T. Illidge, J. Matous, et al. 2012. 
"Brentuximab Vedotin (SGN-35) in Patients with Relapsed Or Refractory Systemic Anaplastic 
Large-Cell Lymphoma: Results of a Phase II Study." Journal of Clinical Oncology : Official Journal 
of the American Society of Clinical Oncology 30 (18): 2190-2196. 
 
Rieger, M., A. Osterborg, R. Pettengell, D. White, D. Gill, J. Walewski, E. Kuhnt, et al. 2011. 
"Primary Mediastinal B-Cell Lymphoma Treated with CHOP-Like Chemotherapy with Or without 
Rituximab: Results of the Mabthera International Trial Group Study." Annals of Oncology : 
Official Journal of the European Society for Medical Oncology / ESMO 22 (3): 664-670. 
 
Rosenwald, A., G. Wright, K. Leroy, X. Yu, P. Gaulard, R. D. Gascoyne, W. C. Chan, et al. 
2003. "Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically 
Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma." The 
Journal of Experimental Medicine 198 (6): 851-862. 
 
Savage, Kerry J., Paul R. Yenson, Tamara Shenkier, Richard Klasa, Diego Villa, Ozge Goktepe, 
Christian Steidl, et al. 2012. "The Outcome of Primary Mediastinal Large B-Cell Lymphoma 
(PMBCL) in the R-CHOP Treatment Era." ASH Annual Meeting Abstracts 120 (21): 303. 
 
Schneider, C. and G. Hubinger. 2002. "Pleiotropic Signal Transduction Mediated by Human 
CD30: A Member of the Tumor Necrosis Factor Receptor (TNFR) Family." Leukemia & 
Lymphoma 43 (7): 1355-1366. 


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Shimoyama, Y., N. Asano, M. Kojima, S. Morishima, K. Yamamoto, T. Oyama, T. Kinoshita, and S. 
Nakamura. 2009. "Age-Related EBV-Associated B-Cell Lymphoproliferative Disorders: Diagnostic 
Approach to a Newly Recognized Clinicopathological Entity." Pathology International 59 (12): 835-
843. 
 
Slack, Graham W., Christian Steidl, Laurie H. Sehn, and Randy D. Gascoyne. 2012. "CD30 
Expression in Diffuse Large B-Cell Lymphoma." ASH Annual Meeting Abstracts 120 (21): 1558. 
 
Sutherland, M. S., R. J. Sanderson, K. A. Gordon, J. Andreyka, C. G. Cerveny, C. Yu, T. S. Lewis, 
et al. 2006. "Lysosomal Trafficking and Cysteine Protease Metabolism Confer Target-Specific 
Cytotoxicity by Peptide-Linked Anti-CD30-Auristatin Conjugates." The Journal of Biological 
Chemistry 281 (15): 10540-10547. 
 
Swerdlow, S. H., ed. 2008. WHO Classification of Tumours of Haematopoietic and Lymphoid 
Tissues, Fourth Edition. 
 
Tai, W. M., D. Quah, S. P. Yap, S. H. Tan, T. Tang, K. W. Tay, Y. X. Koo, M. Tao, R. Quek, and S. 
T. Lim. 2011. "Primary Mediastinal Large B-Cell Lymphoma: Optimal Therapy and Prognostic 
Factors in 41 Consecutive Asian Patients." Leukemia & Lymphoma 52 (4): 604-612. 
 
Todeschini, G., S. Secchi, E. Morra, U. Vitolo, E. Orlandi, F. Pasini, E. Gallo, et al. 2004. "Primary 
Mediastinal Large B-Cell Lymphoma (PMLBCL): Long-Term Results from a Retrospective 
Multicentre Italian Experience in 138 Patients Treated with CHOP Or MACOP-B/VACOP-B." 
British Journal of Cancer 90 (2): 372-376. 
 
Younes, A., N. L. Bartlett, J. P. Leonard, D. A. Kennedy, C. M. Lynch, E. L. Sievers, and A. 
Forero-Torres. 2010. "Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas." 
The New England Journal of Medicine 363 (19): 1812-1821. 
 
Younes, A., A. K. Gopal, S. E. Smith, S. M. Ansell, J. D. Rosenblatt, K. J. Savage, R. 
Ramchandren, et al. 2012. "Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients 
with Relapsed Or Refractory Hodgkin's Lymphoma." Journal of Clinical Oncology : Official Journal 
of the American Society of Clinical Oncology 30 (18): 2183-2189. 
 
Younes, Anas, Joseph M. Connors, Steven I. Park, Naomi N. H. Hunder, and Stephen M. 
Ansell. 2011. "Frontline Therapy with Brentuximab Vedotin Combined with ABVD Or AVD in 
Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma." ASH Annual Meeting 
Abstracts 118 (21): 955. 
 
Zelenetz, A. D., J. S. Abramson, R. H. Advani, C. B. Andreadis, J. C. Byrd, M. S. Czuczman, L. 
Fayad, et al. 2010. "NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphomas." 
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Zinzani, P. L., V. Stefoni, E. Finolezzi, E. Brusamolino, M. G. Cabras, A. Chiappella, F. Salvi, A. 
Rossi, A. Broccoli, and M. Martelli. 2009. "Rituximab Combined with MACOP-B Or VACOP-B and 
Radiation Therapy in Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study." 
Clinical Lymphoma & Myeloma 9 (5): 381-385. 
 
 


 
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15 Appendix A 
Schedule of Assessments14 
 
 
Screening1 
C1D12 
C1D23 
C1D83 
C2D13 
C3D13 
C4D13 
C5D13 
C6D13 
EOT visit 30 days 
post-therapy 
completion4 
Q3 month 
FU visit 
year 113 
Q3-6 month
FU visits 
year 213 
Sign Informed Consent 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pathology Review 
X 
Medical History 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram/MUGA 
X 
Hematology Panel6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDH/Uric Acid 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test8 
X 
X 
HIV/Hepatitis B sAg, 
cAb, sAb 
X 
Bone Marrow 
Biopsy/Aspirate9 
X 
X 
Radiographic Disease 
Evaluation10 
X 
X 
X 
X 
X 
X 
IV Brentuximab Vedotin 
X 
X 
X 
X 
X 
X 
IV Rituximab11 
X 
X 
X 
X 
X 
X 
X 
IV Cyclophosphamide 
X 
X 
X 
X 
X 
X 
IV Doxorubicin 
X 
X 
X 
X 
X 
X 
IV or PO Prednisone12 
X 
X 
X 
X 
X 
X 
X 


 
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1. 
All screening procedures should be performed within 28 days of C1D1, with the exception of baseline imaging, which should be obtained 
within 2 months (60 days) of C1D1. 
2. 
Assessments performed within 7 days of starting therapy do not need to be repeated on C1D1. 
3. 
+/- 3 days 
4. 
+/- 7 days 
5. 
Vital signs to include blood pressure, heart rate, oral temperature, and body weight.  Vital signs during infusions should be performed per 
institutional standards of care. 
6. 
Hematology panels should include a complete blood count, platelet count and differential. 
7. 
Chemistry panel to include sodium, potassium, chloride, calcium, glucose, BUN, serum creatinine, total protein, albumin, total bilirubin, 
AST and ALT. 
8. 
Negative serum pregnancy test within 7 days of starting therapy is required for women of childbearing potential. 
9. 
Bone marrow biopsy at screening is elective and at discretion of the treating physician. EOT bone marrow should be done in those patients 
who had positive screening bone marrow biopsy in order to document complete response. 
10. 
PET/CT and/or dedicated CT with contrast of chest, abdomen, pelvis (+/- neck) are the recommended modality of radiographic imaging 
during staging and final response assessment after cycle 6. (unless contrast is contraindicated). Imaging studies should be performed within 
60 days of C1D1 of treatment and three to five weeks after the completion of Cycle 6 (prior to radiation therapy).  Interim imaging (using CT 
scans) will be done after cycle 2 and 4.  Surveillance imaging using PET/CT or dedicated CT C/A/P at least every 8 months (+/- 30 days) 
thereafter for the first 2 years of follow-up.  Imaging can be performed more frequently as clinically indicated. 
11. 
The first dose of rituximab will be administered as a split dose: 100 mg/ m2 will be administered on Cycle 1, Day 1, and 275 mg/ m2 will be 
administered on Cycle 1, Day 2. The full dose of rituximab (375 mg/m2) will be administered on Day 1 of subsequent cycles. 
12. 
Prednisone should be administered on Days 1-5 of each cycle, at a dose of 100 mg po, or the IV equivalent steroid dose. 
13. 
Evaluations to be performed +/- 30 days 
14. 
Follow-up information about the initiation of alternative therapy and survival status may be obtained from the medical record or via 
telephone or email correspondence for up to 5 years after the end of treatment.