A Phase II Study of Single Agent Brentuximab Vedotin in Relapsed/Refractory CD30 Low (<10%) Mature T Cell Lymphoma (TCL)
Phase: PHASE2
Conditions: T-cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Hepato-splenic T-cell Lymphoma, Adult T-cell Leukemia/Lymphoma, Enteropathy Associated T-cell Lymphoma, NK T-cell Lymphoma
Sponsor: Deepa Jagadeesh



 
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Ryan Wilcox, MD 
University of Michigan 
Internal Medicine ‐ Hematology/Oncology | North Ingalls 
Building 
300 N. Ingalls St. | Suite 2C40 
Ann Arbor, MI 48109-5413 
 
 
 
Cleveland Clinic Sub-Investigators: 
Brad Pohlman, MD 
Rob Dean, MD 
Brian Hill, MD 
Christopher D'Andrea, PA-C 
Allison Winter, MD 
Rabi Hanna, MD 
Kathy Bielek, CNP 
Seth Rotz, MD 
Omer Koc, MD 
Genevieve Crane, MD 
  
Statistician:                   
Lisa A Rybicki, MS 
 
 
 
           Cleveland Clinic 
 
SPONSOR-Investigator:  Deepa Jagadeesh, MD, MPH  
 
 
 
  
Drug Supplier/Supporter:  Seattle Genetics 
 
 
 
 
 
Supplied Agent:   
Brentuximab Vedotin 
 
IND #: 
 
 
126990 

 
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SCHEMA 
 
Title: A Phase II Study of Single Agent Brentuximab Vedotin in 
Relapsed/Refractory CD30 Low (<10%) Mature T Cell Lymphoma (TCL) 
 
Objectives:  
Primary Objective: 
 
 To determine overall response rate (ORR) of Brentuximab Vedotin in CD30 low 
(<10%) relapsed or refractory mature T cell lymphoma (TCL) 
 
Secondary Objectives:   
 Complete remission (CR) rate 
 Duration of response (DOR) 
 Progression free survival (PFS) 
 Overall survival (OS) 
 Time to treatment failure (TTF) 
 
Lab Correlatives: 
 To assess and compare the sensitivity of immunohistochemistry (IHC) with 
imaging analysis and RT PCR methods to detect CD30  
 
Patient Population: 
 CD30 low (<10%) relapsed or refractory mature T cell lymphoma (TCL) patients 
who have received at least one prior therapy. 
Study Design: 
Phase II study of Brentuximab Vedotin in CD30 low (<10%) mature TCL as 
determined by current standard IHC.  
 
Inclusion Criteria: 
 
 Histologically confirmed relapsed/refractory CD30 low (<10%) TCL - including 
peripheral TCL not otherwise specified (PTCL NOS), angioimmunoblastic T cell 
lymphoma (AITL), hepato-splenic T cell lymphoma (HTCL), adult T cell 
leukemia/lymphoma (ATLL), enteropathy associated T cell lymphoma (EATL), 
and NK T cell lymphoma (NK/TCL)  
 CD30 level to be determined by IHC using the anti-CD30 BerH2 antibody 
 At least 1 prior chemotherapy regimen 
 Measurable disease ≥1.5 cm seen on CT scan and/or FDG avid disease on PET 
scan. Splenomegaly measuring >12 cm, if attributed to TCL and/or positive bone 
marrow involvement with T cell lymphoma are also eligible 
 ECOG performance status (PS) of 0-2. ECOG 3 is permitted if the decreased PS 
is secondary to lymphoma 

 
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 Age 18 years and above 
 Able to give informed consent 
 Adequate organ function 
 - Bilirubin ≤1.5X upper limit of normal (ULN), alanine aminotransferase (ALT) 
and aspartate aminotransferase (AST) ≤3X ULN even in patients with 
documented hepatic involvement with lymphoma  
- Serum creatinine clearance ≥30 ml/min 
- Absolute neutrophil count (ANC) ≥1000/μL (unless documented bone 
marrow involvement with lymphoma)  
- Platelet count ≥50,000/μL (unless documented bone marrow involvement 
with lymphoma) 
 At least 6 weeks from autologous stem cell transplantation 
 At least 3 months from allogeneic stem cell transplantation and off 
immunosuppression and no evidence of graft versus host disease (GVHD) 
 Previous treatment with Brentuximab Vedotin (BV) will be allowed if it was done 6 
months prior to enrollment and pt was not refractory or had progressive disease 
(PD) while on BV 
 Females of childbearing potential must have a negative serum or urine 
pregnancy test result within 7 days prior to the first dose of study treatment. 
Women of child-bearing age must agree to use an effective contraception 
method during the study and for at least 6 months following the last dose of study 
drug. Females of non-childbearing potential are those who are postmenopausal 
greater 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. 
Exclusion Criteria: 
 Anaplastic large cell lymphoma (ALCL) both alk positive and negative 
 Cutaneous T cell lymphomas including transformed MF  
 Prior treatment with Brentuximab in the last 6 months or previously refractory to 
BV or had PD while on BV  
 Pregnancy or breast feeding women 
 Prior malignancy within the past 3 years except non melanoma skin cancer or 
other localized cancer treated with curative intent 
 Presence of grade >2 peripheral neuropathy or patients with the demyelinating 
form of Charcot-Marie-Tooth syndrome.  
 Presence of central nervous system (CNS) involvement requiring active 
treatment 
 History of progressive multifocal leukoencephalopathy (PML)  
 Myocardial infarction within the past 6 months 
 Patients with the following medical conditions that could affect their participation 
in the study: 
- 
any active acute or chronic or uncontrolled infection 
- 
liver disease including history of viral hepatitis B or C, evidence of cirrhosis, 
chronic active or persistent hepatitis 
- 
a known history of HIV 

 
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- 
symptomatic cardiac disease, including congestive heart failure, coronary 
artery disease, and arrhythmias 
 Prior hypersensitivity to any component in the ADC formulation 
 Treatment  with chemotherapy or investigational agents within 2 weeks of start of 
study treatment 
Sample Size 
We plan to enroll approximately 31 patients to obtain 28 evaluable for overall 
response rate. 
 
Safety Assessments 
Safety assessments will consist of monitoring of adverse events (AEs), physical 
examinations and laboratory tests. The severity of the toxicities will be graded 
according to the NCI CTC version 4.0.  
End Points 
The primary objective is to evaluate overall response rate. Secondary end points 
analyzed are CR, PFS, OS, DOR, and TTF. Response will be assessed using 
CT/PET scans according to the revised Cheson criteria [1]. The distribution of PFS 
and OS will be estimated using the Kaplan-Meier method. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
SCHEMA 
 
1.0  
INTRODUCTION  
 
1.1 
T Cell Lymphoma (TCL) 
1.2  
Brentuximab Vedotin in T Cell Lymphoma 
1.3 
Clinical Data 
1.4 
CD30 Detection 
1.5 
Rationale for Brentuximab Vedotin in CD30 low T Cell Lymphoma 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
2.3  
Lab Correlatives 
 
3.0 
STUDY DESIGN 
3.1 
Number of Subjects 
3.2 
Study discontinuation 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
 
5.0 
REGISTRATION  
 
6.0  
TREATMENT PLAN 
6.1 
Brentuximab Vedotin Administration  
6.2  
Doses and Administration 
6.3 
Required Premedication and Post Medication 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Management of Infusion Reactions 
6.6 
Management of Suspected PML 
6.7 
Expected Duration of Subject Participation 
 
6.7.1 Duration of Therapy 
 
6.7.2 Duration of Follow Up 
 
7.0 
RECOMMENDED DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
8.1 
Adverse Events and Potential Risk List  
 
8.1.1 Brentuximab Vedotin 
8.2 
Definitions 
 
8.2.1 Adverse Events 
 
8.2.2 Serious Adverse Events 

 
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8.2.3 Adverse Event / Serious Adverse Event Data Collection   
 
8.2.4 Adverse Event / Serious Adverse Event Evaluation and Documentation    
         
 
8.2.5 Significance of an Adverse Event 
           8.2.6 Expectedness 
           8.2.7 Attribution 
           8.2.8 Report Form 
8. 3 
Serious Adverse Event Reporting Procedures 
 
8.3.1 Reporting Serious Adverse Events to Seattle Genetics 
 
8.3.2 FDA Reporting 
8.4      SAEs and OnCore™ 
8.5 
Data Safety Toxicity Committee  
  
8.6 
Pregnancy 
 
 
 
9.0      PHARMACEUTICAL INFORMATION  
 
9.1      Brentuximab Vedotin 
 
 
 
9.1.1 Study Drug Description  
 
 
 
9.1.2 Description of Drug Substance 
 
 
 
 
9.1.3 Pharmaceutical Properties   
 
 
 
9.1.4 Chemical and Structural Formula   
 
9.1.5 Formulation 
9.2 
Method of Procurement 
9.3 
Side Effects 
 
9.3.1 Other Important Side Effects 
9.4 
Pregnancy and Breastfeeding 
 
   
9.5      Storage and Handling 
 
9.6     Packaging and Labeling 
 
9.7      Preparation 
 
9.8      Drug Accountability 
 
9.9      Drug Destruction    
  
 
 
 10.0 
CORRELATIVE STUDIES  
 10.1  
Imaging 
 10.2 
T-qPCR Assay for CD30 
 
10.2.1 Regents 
 
10.2.2 Equipment 
 
10.2.3 Cell lines, FFPE Blocks 
 
10.2.4 Experimental Design 
 
10.2.5 Possible Issue 
 10.3 
Tissue Procurement  
 10.4 
Retaining Samples for Future Research 
  
 11.0 
STUDY PARAMETERS AND CALENDAR 
 11.1 
Study Parameters 
  
 
11.1.1 Screening Evaluation (Day -28 to 1) 
 
11.1.2 Screening Visit (Day -28 to 1) 
11.1.3 Baseline Visit (Day -7 to Day 1) 
11.1.4 Treatment Period (21-day cycles) 

 
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11.1.5 Every Cycle: Day 1 
11.1.6 Cycle #4 and #10 day 15-20 
11.2 
End of Study Visit   
11.3 Duration of Follow Up 
11.4 Calendar 
 12.0 
MEASUREMENT OF EFFECT 
 12.1 
Antitumor Effect – Hematologic Tumors 
 12.2 
Definitions 
  
12.2.1 Primary Endpoint 
  
 
12.2.1.1 Overall Response Rate 
  
12.2.2 Secondary Endpoints 
  
 
12.2.2.1 Complete Response 
  
 
12.2.2.2 Progression Free Survival 
  
 
12.2.2.3 Overall Survival 
  
 
12.2.2.4 Duration of Response 
  
 
12.2.2.5 Time to Treatment Failure 
 12.3 
Response Review 
 
 13.0 
DATA REPORTING/REGULATORY CONSIDERATIONS 
 13.1 
Data Reporting 
 13.2 
Regulatory Considerations  
  
13.2.1 Written Informed consent 
  
13.2.2 Subject Data Protection 
  
13.2.3 Accessing Electronic Medical Records for Cleveland Clinic Foundation 
  
13.2.4 Accessing Electronic Medical Records for University Hospitals 
  
13.2.5 Retention of records 
  
13.2.6 Audits and Inspections 
  
13.2.7 Data Safety and Monitoring Plan 
 
 
 14.0 
STATISTICAL CONSIDERATIONS 
 
 15.0 
SAMPLE SIZE 
 
 16.0 
STUDY SITES 
 
REFERENCES 
 
APPENDICES        
 
 
 
APPENDIX 1 
ECOG Performance Status 
 
APPENDIX 2 
IMWG Criteria 
 
APPENDIX 3 
International Prognostic Score (IPI) 

 
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APPENDIX 4 
Prognostic Index for PTCL (PIT) 
 
APPENDIX 5 
Summary of Protocol Changes 
 
LIST OF ABBREVIATIONS 
 
ADC      
antibody drug conjugate 
AE              adverse event 
AITL             angioimmunoblastic T-cell lymphoma 
ALK          
anaplastic lymphoma kinase 
ALT            
alanine aminotransferase 
ANC       
absolute neutrophil count 
AST        
aspartate aminotransferase 
ATA        
antitherapeutic antibodies 
ATLL        
adult T-cell leukemia/lymphoma 
AUC   
area under the concentration-time curve 
β-hCG   
beta human chorionic gonadotrophin 
CBC     
complete blood count 
Ceoi     
concentration at the end of infusion 
CFR       
Code of Federal Regulations 
CHOP      
cyclophosphamide, doxorubicin, vincristine, and prednisone 
Cmax       
maximum concentration 
CNS         
central nervous system 
CR         
complete remission 
CRF     
case report form 
CT       
computed tomography 
Ctrough   
trough concentration 
EATL        
enteropathy-associated T-cell lymphoma 
ECG       
electrocardiogram 
ECOG   
Eastern Cooperative Oncology Group 
EFS             event-free survival 
EOT          
end of treatment 
FDA         
Food and Drug Administration 
FDG         
fluorodeoxyglucose 
GCP         
Good Clinical Practice 
HEENT 
head, eyes, ears, nose, and throat 
HIPAA      
Health Information Portability and Accountability Act 
HIV             human immunodeficiency virus 
HR               hazard ratio 
HRA              Health Regulatory Authority 
HTLV-1         human T-cell leukemia virus-1 
ICH              International Conference on Harmonisation 
IV                 intravenous 
IDMC            Independent Data Monitoring Committee 
IPI              
International Prognostic Index 

 
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IEC            
Independent Ethics Committee 
IND               investigational new drug 
INN            
International Nonproprietary Name 
IRB              Institutional Review Board 
JCV         
John Cunningham virus 
LDH           
lactate dehydrogenase 
MedDRA     Medical Dictionary for Regulatory Activities 
MF       
mycosis fungoides 
MMAE    
monomethyl auristatin E 
MRI        
magnetic resonance imaging 
MRU     
medical resource utilization 
MTD       
maximum tolerated dose 
MUGA      
multi-gated acquisition 
NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NHL     
non-Hodgkin lymphoma 
NK       
natural killer 
ORR    
objective response rate 
OS         
overall survival 
PCP     
Pneumocystis jiroveci pneumonia 
PCR       
polymerase chain reaction 
PD        
pharmacodynamics 
PD         
progressive disease 
PET        
positron emission tomography 
PFS      
progression-free survival 
PK          
pharmacokinetics 
PML         
progressive multifocal leukoencephalopathy 
PR           
partial remission 
PRO       
patient-reported outcome 
PTCL         
peripheral T-cell lymphoma 
SAE  
serious adverse event 
sALCL       
systemic anaplastic large cell lymphoma 
SAP      
statistical analysis plan 
SCT       
stem cell transplant 
Tmax      
time at which the maximum concentration occurs 
ULN        
upper limit of normal 
USAN     
United States adopted name 
USP    
United States Pharmacopeia 
WHO    
World Health Organization 
 
 
 
 
 
 
 
 
 

 
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1.0 
INTRODUCTION 
 
1.1 T Cell Lymphoma (TCL) 
 
T cell lymphomas (TCL) are a heterogeneous group of malignancies that are derived 
from post-thymic T cells. TCL are less frequent and compromises about 10-15% of 
all NHL and they are more aggressive with inferior survival compared with B cell 
non-Hodgkin lymphoma (NHL). Peripheral T cell lymphoma (PTCL) consists of 
several common subtypes such as PTCL not otherwise specified (PTCL-NOS), 
anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T cell lymphoma 
(AITL). Less common subtypes include enteropathy associated T cell lymphoma 
(EATL), hepato-splenic T cell lymphoma (HTCL), NK T cell lymphoma (NKTCL), and 
adult T cell leukemia/lymphoma (ATLL) associated with HTLV-1. Due to the low 
overall incidence of these subtypes, they are all commonly grouped together for the 
purpose of clinical trials.  
 
Due to paucity of data and rarity of the disease, there is no well-established standard 
of care for PTCL. The 5-year overall survival (OS) rate with current treatment 
modalities is 30-35% in most PTCL series except for ALK+ ALCL [2], where OS 
rates in some series approach 70%. Outcomes in relapsed and/or refractory PTCL 
are worse with no standard salvage regimen. Failure to demonstrate improved 
outcome with aggressive chemotherapy regimens necessitates exploration of 
therapy with biologically targeted novel agents. Even though incremental benefit has 
been observed in the outcome with the advent of the newer agents, it still remains 
suboptimal. Currently approved agents like romidepsin and pralatrexate have less 
than desirable response rate (RR) with overall RR (ORR) ranging from 25-29% with 
only 11-15% achieving a complete response (CR)  [3, 4]. Identifying the key targets 
and agents directed against these targets is crucial to improve results in PTCL.  
 
 
1.2 Brentuximab Vedotin in TCL 
CD30 is a member of the tumor necrosis factor receptor (TNFR) super family 
commonly expressed on activated T and B cells. The pleiotropic nature of CD30 
signaling can result in either cell proliferation and survival or apoptosis and cell 
death. Interaction of cytoplasmic domain of CD30 with TNFR associated factor 
(TRAF) family like TRAF1, TRAF2 and TRAF5 leads to the activation of NF B, 
which promotes cell proliferation, survival, and inhibits apoptosis [5-8].  CD30 is 
highly expressed in ALCL and Hodgkin lymphoma and to varying degree in other 
subtypes of PTCL, CTCL and B cell lymphoma, making it an attractive target for 
antibody-based therapy.   
 
Brentuximab Vedotin (SGN-35) is an antibody drug conjugate (ADC) consisting of 
the chimeric anti-CD30 monoclonal antibody, Brentuximab Vedotin, chemically 
conjugated to the anti-microtubule agent monomethyl auristatin E (MMAE) [9, 10].  
After binding to CD30, the ADC is internalized into lysosomes where cleavage of the 
ADC linker by the lysosomal proteases releases MMAE. The MMAE causes G2/M 
phase growth arrest resulting in cell death. Considerable response to this agent has 

 
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led to its rapid approval for treatment of the relapsed CD30+ diseases, ALCL and 
Hodgkin lymphoma.  
 
1.3 Clinical Data  
The approval of Brentuximab Vedotin in ALCL was based on the phase II study of 
Brentuximab Vedotin  in 58 relapsed or refractory ALCL patients that demonstrated 
an ORR of 86%, with 57% CR. Median duration of response (DOR) was 13 months, 
median progression free survival (PFS) 13 months, and median OS was not reached 
[11]. Fanale et al presented results for the phase I study combining brentuximab with 
either CHOP (cyclophosphamide, adriamycin vincristine and prednisone) or CHP 
(CHOP without vincristine) in ALCL, CD30 positive mature T cell and NK cell 
lymphomas [12]. Objective RR was 100% with 88% attaining a CR. Interim subset 
analysis of phase II study of brentuximab in CD30 positive NHL was presented at 
2013 International Conference of Malignant Lymphoma (ICML) [13]. This analysis 
illustrated an ORR of 36% with 27% CR in mature T/NK cell lymphoma. Better 
outcome was observed in AITL patients with an ORR 50% (5/10) compared to 25% 
(3/12) in PTCL NOS patients.  
 
1.4 CD30 Detection: 
At present, a commonly utilized method to detect CD30 is IHC using the anti-CD30 
BerH2 antibody. Other methods include flow cytometry and reverse transcriptase 
(RT) polymerase chain reaction (PCR). The sensitivity for these methods vary. The 
basis for the activity of brentuximab in low CD30 positive TCL remains unexplained. 
It is possible that the current available methods used to detect CD30 are not 
capturing all the cells that are positive thus providing a less than actual expression 
rate. Newer methods or antibodies for IHC stain may enhance the detection of CD30 
expression.  
 
1.5 Rationale for Brentuximab Vedotin in CD30 low T Cell Lymphoma 
Recent data suggest that brentuximab is efficacious in cutaneous TCL (CTCL) and 
PTCL with varying degree of CD30 expression. Data presented at ICML 
demonstrated clinical efficacy with brentuximab in patients with either undetectable 
or up to 15% expression of CD30 [13]. Krathen et al presented data showing 
significant clinical activity with brentuximab in relapsed/refractory mycosis fungoides 
regardless of CD30 expression [14]. In this study, CD30 was estimated with 
immunohistochemistry (IHC) using the BerH2 antibody. The ORR was 68%; 
moreover, response did not correlate with the CD30 expression. Of the 31 biopsies 
samples taken from 16/19 patients, 12 were negative for CD30 by IHC staining.  
 
Collectively emerging evidence of clinical activity of brentuximab in CD30 negative 
TCL is intriguing. If significant activity could be demonstrated in CD30 low (≤10%) 
PTCL, brentuximab will be a valuable addition to the armamentarium to treat 
patients with relapsed/refractory disease, which otherwise carries a grim prognosis.  
Based on these emerging data, we propose a phase II study of Brentuximab Vedotin 
in CD30 low (≤10%) TCL as determined by current standard IHC.  
 
 
 

 
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2.0 OBJECTIVES 
 
2.1 Primary Objective  
 To determine overall response rate (CR+PR) of Brentuximab Vedotin in CD30 
low (<10%) relapsed or refractory T cell lymphoma (TCL) 
 
2.2 Secondary Objective(s) 
 Complete remission (CR) rate 
 Duration of response (DOR) 
 Progression free survival (PFS) 
 Overall survival (OS) 
 Time to treatment failure (TTF) 
 
2.3 Lab Correlatives: 
 To assess and compare the sensitivity of immunohistochemistry (IHC) with 
imaging analysis and reverse transcription polymerase chain reaction (RT-PCR) 
methods to detect CD30  
 
3.0  STUDY DESIGN 
This is a non-randomized phase II study of single agent Brentuximab Vedotin in 
CD30 low, <10%, relapsed/refractory T cell lymphoma subjects. All subjects who 
meet the eligibility criteria described below will be enrolled to participate in the study. 
Eligibility criteria may not be waived by the investigator. 
3.1  Number of Subjects 
We plan to enroll up to 31 patients to obtain 28 evaluable subjects to assess ORR. 
 
3.2 Study Discontinuation 
Patients may discontinue the study drug for the following reasons: 
 Treatment completion 
 Disease progression 
 Adverse events (AE) 
 Subject consent withdrawal 
 Investigator decision 
All patient discontinuations should be reported to the primary site, Cleveland Clinic 
study staff.   
 
4.0 PATIENT SELECTION 
Patients who meet all the inclusion criteria and have none of the exclusion criteria 
can be considered eligible for this study.   
 
4.1 Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
4.1.1  Patients must have histologically or cytologically confirmed relapsed/refractory 

 
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CD30 low (<10%) TCL: 
o peripheral TCL not otherwise specified (PTCL NOS) 
o angioimmunoblastic T cell lymphoma (AITL) 
o hepato-splenic T cell lymphoma (HTCL) 
o adult T cell leukemia/lymphoma (ATLL) 
o enteropathy associated T cell lymphoma (EATL) 
o NK T cell lymphoma (NK/TCL) 
 
4.1.2  At least 1 prior chemotherapy regimen.    
 
4.1.3  Age >18 years.   
 
4.1.4  ECOG Performance status 0-2. ECOG PS 3 will be permitted if the decreased  
 
 
PS is attributed to the lymphoma [See Appendix A].   
 
4.1.5  Patients must have adequate hematologic, hepatic, and renal function as defined 
below: 
 
4.1.5.1 Absolute neutrophil count > 1,000/mcL (unless documented bone marrow 
involvement with lymphoma)  
4.1.5.2 Platelet count > 50,000/uL (unless documented bone marrow involvement 
with lymphoma) 
4.1.5.3 Total bilirubin ≤1.5X upper limit of normal (ULN), 
 
 
 
4.1.5.4 AST (SGOT≤3X ULN even in patients with documented hepatic 
involvement with lymphoma  
 
4.1.5.5 ALT (SGPT) ≤3X ULN even in patients with documented hepatic 
involvement with lymphoma 
4.1.5.6 Serum Creatinine clearance ≥30ml/min 
  
4.1.6 At least 6 weeks from autologous stem cell transplantation 
 
4.1.7  At least 3 months from allogeneic stem cell transplantation and off 
immunosuppression and no evidence of graft versus host disease (GVHD) 
 
4.1.8  Previous treatment with Brentuximab Vedotin will be allowed if it was done  
  
6 months to prior to enrollment and was not refractory to or had PD on BV 
4.1.9 Measurable disease ≥1.5 cm seen on CT scan and/or FDG avid disease on PET 
scan. Splenomegaly measuring >12 cm, if attributed to TCL and/or positive bone 
marrow involvement with lymphoma are also eligible 
 

 
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4.1.10 Females of childbearing potential must have a negative serum or urine 
pregnancy test result within 7 days prior to the first dose of study treatment. 
 
The effects of Brentuximab Vedotin on the developing human fetus are unknown.  
For this reason, women of childbearing potential and men must agree to use 
adequate contraception (double barrier method of birth control or abstinence) for 
the duration of study participation and for 6 months after completing treatment.  
 
Should a woman become pregnant or suspect that she is pregnant while she or 
her partner is participating in this study, she should inform the treating physician 
immediately. 
 
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.  
4.1.11 Subjects must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
4.2 Exclusion Criteria 
The presence of any of the following will exclude a patient from study enrollment. 
 
4.2.1 Myocardial infarction within the past 6 months 
 
4.2.2 Patients who are receiving any other chemotherapy or investigational agents.  
Radiation treatment will not be permitted during study treatment. Patients can 
receive XRT 2 weeks prior to study drug administration or 4 weeks post study 
completion or discontinuation. Steroids equivalent to prednisone 60 mg daily are 
permitted prior to study drug administration, but needs to be discontinued 1 day 
prior to BV administration. Patients receiving steroids for lymphoma symptoms 
should have measurable disease as mentioned above on baseline scans.  
 
4.2.3  Presence of central nervous system (CNS) involvement requiring active 
treatment 
 
4.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to Brentuximab Vedotin 
   
4.2.5 Cutaneous T cell lymphomas including transformed MF  
 
4.2.6.  Prior treatment with brentuximab in the last 6 months or had refractory or  
  
progressive disease to prior BV treatment 
 
4.2.7 Patients with uncontrolled intercurrent illness including, but not limited to ongoing 
or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements.  
 

 
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4.2.8  History of progressive multifocal leukoencephalopathy (PML)  
 
4.2.9. Pregnancy or breast-feeding women are excluded from this study because 
Brentuximab Vedotin may have the potential for teratogenic or abortifacient 
effects. Because there is an unknown, but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with Brentuximab Vedotin, 
breastfeeding should be discontinued if the mother is treated with Brentuximab 
Vedotin   
 
4.2.10 A known history of HIV 
HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with Brentuximab Vedotin.  In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated.  
 
4.2.11 Presence of grade >2 peripheral neuropathy or patients with the demyelinating 
form of Charcot-Marie-Tooth syndrome 
 
4.2.12 Prior malignancy within the past 3 years except non-melanoma skin cancer or 
other localized cancer treated with curative intent 
 
4.2.13 Patients with the following medical conditions that could affect their participation 
in the study: 
 any active acute or chronic or uncontrolled infection 
 liver disease including history of viral hepatitis B or C, evidence of cirrhosis, 
chronic active or persistent hepatitis  
 symptomatic cardiac disease, including congestive heart failure, coronary artery 
disease, and arrhythmias 
 
5.0 REGISTRATION 
All subjects who have been consented are to be registered in the OnCore™ Database. 
For those subjects who are consented, but not enrolled, the reason for exclusion must 
be recorded. 
 
All subjects will be registered through Cleveland Clinic and will be provided a study 
number by contacting the study coordinator.   
 
6.0 TREATMENT PLAN 
 
6.1 Brentuximab Vedotin Administration 
Subjects will receive Brentuximab Vedotin 1.8 mg/kg intravenously (IV) once every 3 
weeks. 
 
The treatment will be continued until disease progression, unacceptable toxicity, 
stem cell transplantation or at physician discretion. If a patient has completed 17 
cycles, the treating physician can determine if to continue or discontinue treatment in 
event there is no disease progression or unacceptable toxicity.  

 
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Appropriate dose modifications for Brentuximab Vedotin are described in Section 7.0.   
 
For reported adverse events see section 8.0 and potential risks of Brentuximab Vedotin 
are described in Section 9.0.  
 
No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient's malignancy. 
 
Table 1  
 
Treatment Regimen 
 
 
Agent 
 
 
Pre-
medicate / 
Precautions 
 
Dose 
 
Route 
 
Schedule 
 
Cycle 
Length 
 
 
Brentuximab 
Vedotin  
None 
(please see 
below) 
 
1.8 mg/kg 
 
IV over 
30 
minutes 
 
 
Day 1 of 
each 
cycle 
 
 
21 days 
 
All scheduled treatment visits will have a ±3-day window due to unanticipated or 
unavoidable scheduling conflicts except for cycle 1, day 1.   
 
6.2 Dose and Administration 
The investigational agent will be administered IV infusion given over approximately 
30 minutes. 
In the absence of infusion-related reactions, the infusion rate for all patients should 
be calculated in order to achieve a 30-minute infusion period. Investigational agent 
must not be administered as an IV push or bolus. Investigational agent should not be 
mixed with other medications. 
Dosing is based on patient weight according to the institutional standard; however, 
doses will be adjusted for patients who experience a ≥10% change in weight from 
baseline. An exception to weight-based dosing is made for patients weighing greater 
than 100 kg; doses will be based on 100 kg for these individuals. Rounding is 
permissible within 5% of the nominal dose. 
 
6.3 Required Premedication and Post Medication 
Routine premedication should not be administered for the prevention of infusion-related 
reactions prior to the first dose of study treatment. However, patients who experience an 
infusion-related reaction may receive subsequent infusions of study treatment with 
premedication as described in (section 6.5). Patients who experience a Grade 3 or 
Grade 4 infusion-related reaction may potentially continue to receive treatment at the 
discretion of the investigator after discussion with the primary investigator. 

 
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Patients should be individually evaluated to assess the need for tumor lysis 
prophylaxis prior to the first dose of investigational agent. Patients should receive 
prophylaxis as appropriate per the institutional standards 
6.4 General Concomitant Medications and Supportive Care Guidelines 
There are no required concomitant therapies. 
Routine premedication for infusion reactions should not be administered prior to the 
first dose of Brentuximab Vedotin. However, patients who experience an infusion-
related reaction may receive subsequent treatment with premedication as described 
in Section 6.5. 
The use of transfusions, platelet and/or colony-stimulating factors per institutional 
practice is permitted. Intrathecal prophylactic treatment for cerebral/meningeal 
disease is permitted at the discretion of the investigator. 
All concomitant medications, blood products, and radiotherapy administered will be 
collected from Day 1 (predose) through the safety-reporting period. Any concomitant 
medication given for a study protocol-related adverse event should be recorded from 
the time of informed consent. 
Patients may not receive other investigational drugs, immunosuppressive 
medications, radiotherapy, or systemic anti-neoplastic therapy from Day 1 through 
end of treatment. In addition, other prohibited concomitant therapies should be 
excluded in accordance with the approved prescribing information.  
6.5 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of study treatment. The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis 
should it occur. All supportive measures consistent with optimal patient care should be 
given throughout the study according to institutional standards. Supportive measures 
may include extending the infusion time and/or administering medications for infusion-
related reactions. 
 
Patients who have experienced an infusion-related reaction should be pre-
medicated for subsequent infusions. Premedication may include acetaminophen, an 
antihistamine, and a corticosteroid administered 30–60 minutes prior to each 
infusion or according to institutional standards. 
If anaphylaxis occurs, study treatment administration should be immediately and 
permanently discontinued. 
6.6 Management of Suspected PML 
Signs and symptoms of progressive multifocal leukoencephalopathy (PML) may include 
altered mental status, motor deficits such as hemiparesis or ataxia, visual disturbances, 
or higher cortical dysfunction such as dysphasia or agnosia. See the Investigator’s 
Brochure for further details. 
If PML is suspected, hold further dosing and undertake a diagnostic work-up 
including (but not limited to): 

 
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 Neurologic examinations, as warranted  
 Brain radiologic features by magnetic resonance imaging (MRI)  
 PCR analysis: John Cunningham virus (JCV) DNA detectable in cerebrospinal 
fluid  
If PML is confirmed, Brentuximab Vedotin should be permanently discontinued.  
6.7 Expected Duration of Subject Participation 
6.7.1 Duration of Therapy 
The treatment will be continued until disease progression, unacceptable toxicity, 
stem cell transplantation, or at physician discretion. If a patient has completed 17 
cycles, the treating physician can determine if to continue or discontinue treatment in 
event there is no disease progression or unacceptable toxicity.  
 
6.7.2 Duration of Follow Up 
After completion of the study the subjects will be followed for a total of 3 years. The 
follow up visits will be done at 6, 12, 24 and 36 months after the last cycle of 
therapy. If the patient is unable to follow up with the local site in person, virtual visits 
may be used to capture applicable procedures during long-term follow up only. 
The follow up visits should include the following: 
 Physical Examination 
 Vital signs 
 Height and weight 
 CBC with differential  
 Serum chemistry panel as outlined in section 11.1.2 
 ECOG performance status 
 Adverse event evaluation (only the adverse events attributed to the study 
drug) 
 Diagnostic CT neck, chest, abdomen and pelvis scan with IV and PO contrast 
will be done at 6, 12 and 24 months if no disease progression. Neck CT can 
be omitted if no involvement at baseline 
 
If a virtual visit is completed in follow up every attempt should be made to complete 
the required assessments listed above, though if they are not completed it will not be 
considered a protocol deviation. 
 
Patients who have progressive disease or start a new treatment are not required to 
come in for clinical follow up. These patients can be contacted over the phone by the 
study personnel to obtain the following information 
 
 Disease status 
 Adverse event evaluation only if patients have residual persistent symptoms 
related to BV treatment 
 Current lymphoma treatment 
  

 
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Patients will be followed for toxicity for 30 days after treatment has been 
discontinued or until death, whichever occurs first.  The clinical course of each event 
will be followed until resolution, stabilization, or until has been determined that the 
study treatment or participation is not the cause.  
 
Serious adverse events (SAE) that are still ongoing at the end of the study period 
will necessitate follow-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 will be recorded and reported immediately. 
 
7.0 RECOMMENDED DOSE MODIFICATIONS 
 
Table 2 describes the recommended dose modifications for study treatment-
associated neuropathy. 
Doses reduced for treatment-related neuropathy should not be re-escalated without 
discussion with the primary site, CCF study team. 
Table 2 
 
Grade of 
Neuropathy 
Recommended Dose Modification 
Sensory Neuropathy 
Motor Neuropathy 
1 
Continue at same dose 
Continue at same dose 
2 
Continue at same dose 
Reduce dose to 1.2 mg/kg 
3 
Reduce dose to 1.2 mg/kg 
Discontinue treatment 
4 
Discontinue treatment 
Discontinue treatment 
 
Brentuximab Vedotin should be held for grade >2 hematological (anemia, neutropenia, 
and thrombocytopenia only) and non-hematological (except neuropathy) toxicities that 
are deemed possibly related to BV. Patients with bone marrow involvement at baseline 
may continue study treatment through cycle 4 despite having grade 3-4 neutropenia or 
thrombocytopenia. If those counts have not recovered to grade ≤2 prior to beginning 
cycle 5 and are considered at least possibly related to BV, then you must get approval 
from the sponsor-investigator (Dr. Jagadeesh) prior to starting cycle 5. 
 
For grade >2 hematological toxicity, the study drug can be restarted at the same dose 
once the toxicity has resolved to grade ≤2 or has returned to baseline. If study drug was 
held for neutropenia, growth factor support to be considered for the treatment or 
prophylaxis with subsequent cycles. Consider discontinuing or dose reducing 
Brentuximab Vedotin to 1.2 mg/kg in patients with recurring grade 4 neutropenia even 
with use of growth factors. In patients with grade 3 non-hematological toxicity the study 
drug can be restarted at the same dose once the toxicity has resolved to grade ≤2 or 

 
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has returned to baseline. In patients with grade 4 non-hematological toxicity the study 
drug can be restarted once the toxicity has resolved to grade ≤2 or has returned to 
baseline at a reduced dose of 1.2 mg/kg. The study drug can be discontinued at 
investigator’s discretion in patients who developed grade 4 non-hematological toxicity. 
No further dose reductions of Brentuximab Vedotin other than mentioned above are 
permitted. If further reduction is required, the study drug should be discontinued. The 
study drug can be held for 3 weeks for toxicity. Delays >3 weeks are not permitted 
without approval from the primary study team at CCF.  
 
8.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
The following is a list of AEs (Section 8.2) and the reporting requirements associated 
with observed AEs and SAEs (Sections 8.3 and 8.4).  
 
The clinical course of each event will 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 will 
necessitate follow-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 will be recorded and reported immediately. 
 
8.1 Adverse Events and Potential Risks  
 
8.1.1 Brentuximab Vedotin 
Brentuximab Vedotin (SGN-35) is an antibody drug conjugate (ADC) consisting of 
the chimeric anti-CD30 monoclonal antibody, SGN-30, chemically conjugated to the 
anti-microtubule agent monomethyl auristatin E (MMAE)  
Detailed information describing the side effects, preparation, administration, 
packaging and storage of Brentuximab Vedotin is located in the Pharmaceutical 
Information (section 9). 
8.2 Definitions  
 
8.2.1 Adverse Events   
An adverse event (AE) is any unfavorable or unintended event, physical or 
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research study. The 
event can include abnormal laboratory findings, symptoms, or disease associated with 
the research study. The event does not necessarily have to have a causal relationship 
with the research, any risk associated with the research, the research intervention, or 
the research assessments. 
 External adverse events are adverse events experienced by subjects 
enrolled in multicenter clinical trials at sites other than the site(s) over which 
the Institutional Review Board has jurisdiction.  

 
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 Internal adverse events are adverse events experienced by subjects 
enrolled at the site(s) under the IRB’s jurisdiction for either multicenter or 
single-center research projects.  
 
8.2.2 Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose 
that results in any of the following outcomes:  
 Results in death.  
 Is life-threatening adverse experience.  The term life threatening in the 
definition of serious refers to an adverse event in which the subject was at 
risk of death at the time of the event.  It does not refer to an adverse event, 
which hypothetically might have caused death if it were more severe.  
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization 
will be considered as Serious, UNLESS at least one of the following 
expectations is met: 
o The admission results in a hospital stay of less than 12 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However, it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable 
as a serious adverse event dependent on clinical judgment.  In addition, 
where local regulatory authorities specifically require a more stringent 
definition, the local regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood disease or 
disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
8.2.3 Adverse Event / Serious Adverse Event Data Collection   
All AEs (regardless of relationship to study drug) will be captured from the time the 
subject signs the ICF through the end of the safety-reporting period. 
 
All active symptoms and current / historical medical conditions present at the time of 
the baseline assessment will be collected; these will be considered baseline 

 
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symptoms / prior medical history.  
Any medical condition that was present at the baseline visit (prior to study treatment) 
and that remains unchanged, or improved, should not be recorded as an AE. If there is 
a worsening of a medical condition that was present at the baseline visit, then this 
should be considered a new AE and recorded appropriately. 
If a sign or symptom is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page of the CRF. 
The following information should be considered when determining whether or not to 
record a test result, medical condition, or other incident on the Adverse Events and 
Pre-existing Conditions case report form (CRF): 
 Complications that occur in association with any procedure (e.g., biopsy) 
should be recorded as AEs whether or not the procedure was protocol 
mandated. Changes in medical conditions and adverse events, including 
changes in severity, frequency, or character, during the safety-reporting 
period should be recorded.  
 In general, an abnormal laboratory value should not be recorded as an 
adverse event unless it is associated with clinical signs or symptoms, requires 
an intervention, results in a serious adverse event, or results in study 
termination or interruption/discontinuation of study treatment. When recording 
an adverse event resulting from a laboratory abnormality, the resulting 
medical condition rather than the abnormality itself should be recorded (e.g., 
record “anemia” rather than “low hemoglobin”). 
8.2.4 Adverse Event / Serious Adverse Event Evaluation and Documentation 
The investigator or designee is responsible for ensuring that all adverse events (both 
serious and non-serious) observed by the clinical team or reported by the subject 
are fully recorded in the subject’s medical records. Source documentation must be 
available to support all adverse events.  
 
The investigator or sub-investigator will provide the following for all adverse 
events (both serious and non-serious): 
 Event term (as per CTCAE) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity  
 Attribution of relatedness to the investigational agent- (this must be assigned by 
an investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, 
dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received conmed or other intervention, etc. 
 Outcome of event 
 
All participating investigators will assess the occurrence of AEs from the time the 
subject signs the ICF through the end of the safety-reporting period.  Subjects will be 

 
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followed for toxicity for 30 days after treatment has been discontinued or until death, 
whichever occurs first (safety-reporting period).  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause.   
 
8.2.5 Significance of an Adverse Event  
The significance of an adverse event is used to describe the patient/event outcome 
or action criteria associated with events that pose a threat to a patient’s life or 
functioning (i.e., moderate, severe or life threatening).  Based on the National 
Cancer Institute Guidelines for the Cancer Therapy Evaluation Program, severity 
can be defined by the following grades of events: 
 
 
 Grade 1 is mild adverse event. (e.g., minor event requiring no specific 
medical intervention; asymptomatic laboratory findings only; marginal clinical 
relevance) 
 Grade 2 is moderate adverse event (e.g., minimal intervention; local 
intervention; non-invasive intervention; transfusion; elective interventional 
radiological procedure; therapeutic endoscopy or operation). 
 Grade 3 is severe and undesirable adverse event (e.g., significant symptoms 
requiring hospitalization or invasive intervention; transfusion; elective 
interventional radiological procedure; therapeutic endoscopy or operation). 
 Grade 4 is life threatening or disabling adverse events (e.g., complicated by 
acute, life-threatening metabolic or cardiovascular complications such as 
circulatory 
failure, 
hemorrhage, 
sepsis; 
life–threatening 
physiologic 
consequences; need for intensive care or emergent invasive procedure; 
emergent interventional radiological procedure, therapeutic endoscopy or 
operation). 
 Grade 5 is fatal adverse event resulting in death. 
 
In this study, descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 available at 
http://ctep.cancer.gov will be utilized for AE reporting. 
 
 
8.2.6 Expectedness 
Adverse Events can be Expected or Unexpected. 
 
 An expected adverse event is an event previously known or anticipated to 
result from participation in the research study or any underlying disease, 
disorder, or condition of the subject. The event is usually listed in the Investigator 
Brochure, consent form or research protocol.  
 An unexpected adverse event is an adverse event not previously known or 
anticipated to result from the research study or any underlying disease, disorder, 
or condition of the subject.  
 
 
 

 
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8.2.7 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and 
the study drug.  Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
 
8.2.8 Report Form 
SAEs and Life Threatening Adverse Events will be recorded on the FDA Form 
3500A (MedWatch) but should only be reported as instructed above.  The electronic 
FDA SAE reporting forms should not be used.  The form can be downloaded at: 
 
         http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
8.3  Serious Adverse Event Reporting Procedures 
Serious adverse events that occur beginning with the signing of the informed 
consent form, during treatment, or within 30 days of the last dose of treatment must 
be reported to the Sponsor-Investigator (Cleveland Clinic Principal Investigator) 
within 24 hours of observation or learning of the SAE, regardless of the relationship 
of the event to the study treatment regimen. 
Investigative sites will report serious adverse events to their respective IRB according to 
the local IRB’s policies and procedures.  
 
For initial SAE reports, available case details are to be recorded on an SAE form. At 
a minimum, the following should be included: 
 Patient number  
 Date of event onset  
 Description of the event  
 Study treatment 
 Attribution  
Participating investigators (all sites) must report all serious adverse events to the 
Sponsor-Investigator (Cleveland Clinic Principal Investigator) within 24 hours of 
discovery or notification of the event. The participating investigator must also provide 
follow-up information on the SAE until final resolution. The completed SAE form and 
SAE Cover Sheet are to be scanned within 24 hours to: 
 
 
 
 
 
 
Contact Name: Hillary Sedlacek  
Email: 
 
Please cc: cancersaeinbox@ccf.org  
Telephone: 
 

 
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 The Sponsor-Investigator (Cleveland Clinic Principal Investigator) will review the 
SAE and report the event to the FDA, external collaborator(s), and IRB as 
applicable. 
 It is the Sponsor-Investigator’s responsibility (Cleveland Clinic Principal 
Investigator) to ensure that ALL serious adverse events that occur on the study 
are reported to all participating sites 
 It is the responsibility of each investigator to report the SAEs to their respected 
institutional review boards  
 
8. 3. 1 Reporting Serious Adverse Events to Seattle Genetics 
It is the responsibility of the Sponsor-Investigator (Cleveland Clinic Principal 
Investigator) to report safety data to the drug supplier (Seattle Genetics) as follows:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.2 FDA Reporting 
 It is the responsibility of the Sponsor- Investigator (Cleveland Clinic Principal 
Investigator) to communicate with the FDA in accordance with 21 CFR 312.32.   
 It is the responsibility of the Sponsor- Investigator (Cleveland Clinic Principal 
Investigator) to report all events that are suspected to be caused by the 
investigational product serious and unexpected to the FDA as soon as possible 
but no later than the time frames in the table below: 
 
The Sponsor- Investigator (Cleveland Clinic Principal Investigator) will report any 
Additional information related to previously submitted IND safety report as soon as 
the information is available to the FDA as a Follow-up IND Safety Report.  
Furthermore, the Sponsor-Investigator will maintain records of its efforts to obtain 
additional information. 
Individual expedited SAE reports 
required by competent health 
authority (i.e. FDA, Health 
Canada) 
At time of submission to 
competent authority: 
 
Seattle Genetics Drug Safety by: 
Facsimile (425) 527-4308 or 
(866) 333-6627 (USA only toll 
free) 
Email: drug.safety@seagen.com  
 
Aggregate listing of all SAEs  
Monthly: 
 
IST@seagen.com or portal 
 
Within 15 days 
Serious, unexpected, suspected 
adverse reactions 
Within 7 days 
Fatal or life-threatening, unexpected* 
suspected adverse reactions 

 
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8.4 SAEs and OnCore™  
 All SAEs will be entered into OnCore™  
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded 
into OnCore™ 
8.5 Data Safety Toxicity Committee 
 It is the responsibility of the PIs (including the CCF PI) to ensure that ALL 
SAEs occurring at their respective sites (internal or external) are reported to 
the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee (DSTC). SAEs are automatically reported to the DSTC via 
OnCore (once an event is entered into OnCore the DSTC is notified of the 
event).  
 The sponsor-investigator is responsible for submitting an annual report to the 
DSTC as per CCCC Data and Safety Monitoring Plan. 
  
8.6 Pregnancy  
Notification to Drug Safety: Based on the estimated date of conception, complete a 
Pregnancy Report Form for all pregnancies that occur from the time of informed consent 
to the end of the protocol-defined contraception period, including any pregnancies that 
occur in the partner of a male study patient. Fax the form to primary study team at CCF 
and sponsor’s Drug Safety Department within 48 hours of becoming aware of the 
pregnancy. All pregnancies that occur during this time period will be monitored for the 
full duration; all perinatal and neonatal outcomes should be reported. Infants should be 
followed for a minimum of 8 weeks.  
 
If a woman becomes pregnant or suspects that she is pregnant while participating in 
the study, she must inform the investigator immediately and must permanently 
discontinue study drug. 
 
Collection of data: Based on the estimated date of conception, all pregnancies that 
occur from time of informed consent to within 30 days of last study drug dose, including 
any pregnancies that occur in the partner of a male study patient, will also be recorded 
on the Adverse Events and Pre-Existing Conditions CRF. Abortion, whether accidental, 
therapeutic, or spontaneous, should be reported as an SAE. Congenital anomalies or 
birth defects, as defined by the ‘serious’ criterion above (see definitions 8.0) should be 
reported as SAEs. 
 
 
 
 
9.0 PHARMACEUTICAL INFORMATION    
 
9.1 Brentuximab Vedotin 
 
9.1.1 Study Drug Description 
Brentuximab Vedotin (SGN-35) is a CD30-directed antibody-drug conjugate (ADC) 
consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for 
human CD30; 2) the microtubule-disrupting agent monomethyl auristatin E (MMAE); 
and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10. The 
anticancer activity of Brentuximab Vedotin is due to the binding of the ADC to CD30-

 
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expressing cells, followed by internalization of the ADC-CD30 complex, and the 
release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the 
microtubule network within the cell, subsequently inducing cell cycle arrest and 
apoptotic death of the cell.  
 
9.1.2 Description of Drug Substance 
Brentuximab Vedotin is an ADC composed of a CD30 targeted chimeric monoclonal 
antibody (cAC10) covalently linked, via an enzyme-cleavable linker, to the anti-tubulin 
agent MMAE (Figure 1). cAC10 has a typical structure of the human IgG1 subclass. 
Brentuximab Vedotin is produced by the chemical conjugation of MMAE to cAC10. Each 
antibody molecule has, on average, two of its interchain disulfides reduced and the 
resulting cysteine residues alkylated with SGD-1006 Intermediate (enzyme-cleavable 
linker + MMAE), leading to a molar ratio of four drugs per antibody. 
 
Brentuximab Vedotin is a heterogeneous mixture of a range of drug-load variants and 
isoforms. The overall average drug-to-antibody mole ratio (MRD) is approximately 4. 
The calculated molecular mass for the nominal form of Brentuximab Vedotin is 
approximately 153 kDa. 
 
9.1.3 Pharmaceutical Properties 
Brentuximab Vedotin is a sterile, preservative-free, white to off-white lyophilized cake or 
powder, supplied in single-use vials. Brentuximab Vedotin drug product is reconstituted 
with water for injection (WFI), USP, or equivalent. The reconstituted Brentuximab 
Vedotin drug product is a clear to slightly opalescent, colorless solution with no visible 
particulate matter. The reconstituted solution is subsequently diluted in sterile 0.9% 
Sodium Chloride for Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection for 
intravenous (IV) administration. The diluents should be USP grade or equivalent. 
 
Brentuximab Vedotin is the United States Adopted Name (USAN) and the International 
Nonproprietary Name (INN) assigned to SGN-35. Drug product vials may be labeled as 
SGN-35 or as Brentuximab Vedotin; the 2 names can be used interchangeably. 
9.1.4 Chemical and Structural Formula 
A representative structure of Brentuximab Vedotin (MRD=4) is shown in Figure 1. 

 
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9.1.5 Formulation 
Each vial contains 55 mg SGN-35 for Injection (Brentuximab Vedotin), trehalose, 
sodiumcitrate, and polysorbate 80. The 5 mg overfill in each vial is to ensure that the 
labeled quantity of 50 mg SGN-35 may be withdrawn. The drug product vial is 
reconstituted with the appropriate amount of Sterile Water for Injection. The pH of 
reconstituted product is approximately 6.6. 
9.2 Method of Procurement 
Brentuximab Vedotin will be provided by Seattle Genetics. 
9.3 Side Effects 
The bulleted list of side effects corresponds to adverse events, which have occurred in 
patients in pivotal phase 2 studies and are considered to have a possible association 
with Brentuximab Vedotin by the Sponsor.   
Side Effect (Incidence) 
MedDRA Term  
Abnormal nerve function in arms or legs 
Peripheral Neuropathy 

 
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(56%) 
Alopecia (hair loss) (13%) 
Alopecia 
Back pain (12%) 
Back pain  
Chills (13%) 
Chills  
Constipation (18%) 
Constipation 
Cough (19%) 
Cough  
Diarrhea (34%) 
Diarrhoea  
Dizziness (13%) 
Dizziness  
Fever (31%) 
Pyrexia  
High blood sugar (6%) 
Hyperglycaemia 
Itching (17%) 
Pruritus 
 
 
Low platelets (10%) 
Thrombocytopenia  
Low red blood cells (9%) 
Anaemia 
Low white blood cells (21%) 
Neutropenia  
Joint pain (15%) 
Arthralgia  
Muscle pain (16%) 
Myalgia  
Nausea (41%) 
Nausea  
Rash (18%) 
Rash  
Shortness of breath (15%) 
Dyspnea  
Tiredness (43%) 
Fatigue  
Upper respiratory tract infection (31%) 
Upper and lower respiratory tract 
infection  
Vomiting (20%) 
Vomiting 
 
 
Some additional context for notable expected side effects is presented by topic in the 
paragraphs that follow the bulleted list.   
 
Side Effect (Incidence) 
Infusion-related reactions (11%) 
Peripheral neuropathy (see above) 
Low blood cell counts (see above for 
thrombocytopenia, anemia, and neutropenia) 
Infection risk (61%) 
 
9.3.1 Other Important Side Effects 
This section presents additional serious or potentially life-threatening events that could 
have possible association to Brentuximab Vedotin.  Events in this section have occurred 
infrequently in patients treated with Brentuximab Vedotin in clinical trials or in the 
commercial setting.   

 
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Side Effect (Incidencea) 
Stevens-Johnson syndrome and toxic epidermal 
necrolysis (≤0.1%) 
Tumor lysis syndrome (≤0.1%)  
Progressive multifocal leukoencephalopathy 
(≤0.1%)  
Acute pancreatitis (≤0.5%) 
Hepatotoxicity (1%) 
Pneumonitis (1%) 
 
a 
Incidence is derived from the Brentuximab Vedotin global safety database, which 
includes all spontaneous reports and clinical trial SAEs. 
 
9.4 Pregnancy and Breastfeeding 
Brentuximab Vedotin causes miscarriages and birth defects in animals. Brentuximab 
Vedotin also affects the testes (sperm-producing organs) in animals.  Men being treated 
with Brentuximab Vedotin should not get their partner pregnant. 
 
Recommended contraception duration for men and women receiving Brentuximab 
Vedotin monotherapy is 6 months from the last dose.    
 
It is not known whether Brentuximab Vedotin or its breakdown products end up in breast 
milk.  If it does end up in breast milk, it could hurt a nursing baby. 
 
9.5 Storage and Handling 
 
The guidelines for the storage should be followed per the Pharmacy Manual. 
 
Refrigeration should be set at 2–8°C for storage of vials and solutions containing 
Brentuximab Vedotin. The controlled location must be accessible only to the pharmacist 
or a duly designated person. Brentuximab Vedotin does not contain preservatives; 
therefore, opened and reconstituted vials should be used immediately. If not used 
immediately, reconstituted vials and solutions must be stored no longer than 24 hours 
from vial reconstitution under refrigeration at 2–8°C. It is recommended that vials and 
solutions be protected from direct sunlight until the time of use. Reconstituted vials and 
solutions must not be shaken. 
 
Drug accountability instructions are provided in the Pharmacy Manual. 
 
9.6 Packaging and Labeling 
Drug product vials may be labeled as Brentuximab Vedotin, the United States adopted 
name (USAN) and the International Nonproprietary Name (INN), or as SGN-35, the 
compound code; the 2 names can be used interchangeably. 
 
9.7 Preparation 
Brentuximab Vedotin vials are provided via single-use containers. Any partially used 
vials or diluted dosing solutions should be discarded using appropriate institutional drug 

 
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disposal procedures. 
 
Brentuximab Vedotin should be reconstituted with the appropriate amount of Sterile 
Water for Injection, United States Pharmacopeia (USP), or equivalent standard. The vial 
should be gently swirled until the contents are completely dissolved. The vial must not 
be shaken. The reconstituted drug product should be inspected visually for any 
particulate matter and discoloration. 
 
The required volume of reconstituted drug product should be diluted into an infusion 
bag. The bag should be gently inverted to mix the solution. The bag must not be 
shaken. Prior to administration, the reconstituted and diluted drug product should be 
inspected visually for any particulate matter and discoloration. 
 
9.8 Drug Accountability  
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of the study drug.  All study drugs must be accounted for, including 
study drug accidentally or deliberately destroyed.  Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the 
protocol.  If appropriate, drug storage, drug dispensing, and drug accountability may be 
delegated to the pharmacy section of the investigative site.   
 
9.9 Drug Destruction 
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. 
 
10.0 CORRELATIVE STUDIES  
The current standard IHC method using the anti-CD30 BerH2 antibody will be 
utilized to define CD30 positivity. The other lab correlatives used to detect CD30 are 
imaging analysis and RT-PCR using RNA isolated from formalin fixed paraffin 
embedded (FFPE) tissue. We propose to correlate the IHC CD30 positivity using the 
following methods 
 Aperio Image Scanner Analysis and ImageScope Software for IHC 
quantitation 
 Quantification of  CD30 mRNA expression levels by RT-PCR on FFPE tissue 
10.1 Aperio Image Analysis 
   CD30 stained slides will be scanned using the Aperio Image Scanners in the 
ePathology Department of Pathology and Laboratory Medicine. Analysis will then 
be completed by the staff pathologist using ImageScope software for quantification 
of the CD30 positivity. Results will be correlated with clinical endpoints and with the 
T-qPCR assay results.            
 
 
 

 
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10.2. T-qPCR Assay for CD30 
This will be conducted in the Pathology Research Core in the Robert J. Tomsich 
Pathology and Laboratory Medicine Institute (RT-PLMI) at Cleveland Clinic 
Foundation. 
 
CD30 (Ki-1, TNFRSF8) is expressed by anaplastic large cell lymphoma, Hodgkin lymphoma, 
peripheral T-cell lymphoma NOS. CD30 is also found in activated T and B cells. Long isoform 
of CD30 is located in cell membrane, while short isoform is in cytoplasm. 
 
For extraction of RNA from FFPE tissue, 10 sections of 10 microm paraffin tissues will 
be deparaffinized and total RNA will be isolated using the FFPE RNA extraction kit 
(Qiagen, Valencia, CA) according to manufacturer’s protocol.  The resulting RNA will be 
converted to cDNA using the Hi Quality RNA to cDNA kit (Applied Biosystems, Foster 
City, CA).  50ng of cDNA will be used as the starting template for the qPCR with 
following primers: CD30 Forward (5’- CACATCAGCCACCAACTCC-3’), CD30 Reverse 
(5’-TGTCCTTCTCAGCCATATCCT -3’), GAPDH Forward (5’- 
TCTTTTGCGTCGCCAGCCGAG-3’) and GAPDH Reverse (5’-
GCGCCCAATACGACCAAATCCGTT-3’) for resulting amplicons of 95 bp and 87 bp 
respectively. SYBR Green master mix (BioRad, Hercules, CA) will be used to mix the 
cDNA and primers.  Calculation of the expression level will be determined using the 
delta-Ct method using GAPDH as the control. CD30 positive cell line Karpas299 and 
CD30 negative cell line DHL16 will be used as the calibrator cDNA.  
 
10.2.1 Regents  
1) Primers 
CD30F: CAC ATC AGC CAC CAA CTC C 
CD30R: TGT CCT TCT CAG CCA TAT CCT   (NM-000417) 
 
CD30 amplicon size: 95bp 
 
GAPDH-F: TCT TTT GCG TCG CCA GCC GAG 
GAPDH-R: GCG CCC AAT ACG ACC AAA TCC GTT (NM-002046.3) 
 
GAPDH amplicon size: 87 bp 
 
2) FFPE RNA extraction kit (Qiagen, Valencia CA) 
3) High quality RNA to cDNA kit (Applied Biosysyems, Foster City, CA) 
4) SYBR Green master mix (BioRad, Hercules, CA) 
 
10.2.2 Equipment  
Applied Biosystems 7500 Real-Time PCR system (MMP Lab.) 
 
10.2.3 Cell lines, FFPE Blocks 
1) CD30 positive (Karpas 299) and negative cell line (B lymphoma cell line) control  
 
2) FFPE blocks or five 10 micron sections (unbaked on charged slides) of CD30 
positive/negative (IHC) tissues. 
 

 
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10.2.4 Experimental Design 
1) Set up RT-qPCR with CD30 positive and negative control cell lines at first.  
2) Calibration curve of RT-qPCR with series diluted RNA isolated from CD30 positive and 
negative control cell lines. 
3) RT-qPCR for CD30 positive/negative (IHC) tissues 
4) Testing with RNA isolated from selected FFPE lymphoma cases and data interpretation. 
 
10.2.5 Possible Issue 
Poor RNA quality of some FFPE tissues (Consulting for multiple gene-specific RT protocol 
using RNA from PPFE sections [16].  
 
10.3 Tissue Procurement 
Subjects should have histologically confirmed relapse/refractory disease to participate in the 
study.  
 
We will collect unstained biopsy slides from the most recent biopsy that confirms the 
relapse/refractory disease to perform CD30 IHC staining using the Aperio Image Scanner and 
ImageScope software, and the RT PCR for CD30. The slides should be done after the patient 
has signed the consent form to participate in the study and within 4 weeks of receiving the 
study drug.  
 
Please submit the following materials: 
1. Fifteen 4 micron unstained sections on charged (plus) slides (for diagnosis confirmation 
and CD30 IHC) AND 
2. Four 10 micron sections (if an incisional or excisional biopsy) or eight 10 micron 
sections (if needle biopsy) on slides or in a tube (preferred). 
 
Please ship the tissue to the Cleveland Clinic Biorepository at the address provided 
below: 
 
Robert J. Tomsich Pathology and Laboratory Medicine Institute (RT-PLMI) 
ATTN: Dr. Genevieve Crane 
2119 East 93 Street, L25 
Cleveland, Ohio 44106 
 
Please refer to the Manual of Operating Procedures (MOP) for more specific 
instructions on shipment of the slides.  
 
10.4 Retaining Samples for Future Research 
All unused biospecimen samples will be archived at the Cleveland Clinic Central 
Biorepository for 10 years for future research with the consent from the participating 
subjects. The retained samples can be used for any research that pertains to T cell 
lymphoma including, exploring the molecular biology, development of novel therapies, 
the biology of sensitivity and resistance mechanisms for drugs, and to identify predictive 
pharmacodynamic biomarkers for TCL. 
 
  
 

 
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11.0 STUDY PARAMETERS AND CALENDAR  
 
11.1 Study Parameters 
 
11.1.1 Screening Evaluation (Day -28 to 1) Screening studies and evaluations will 
be used to determine the eligibility of each subject for study inclusion. All evaluations 
must be completed < 28 days prior to administration of protocol therapy.  
The labs and clinic visit with the treating physician can be done within 3 days of D1 
of cycle 2-17 if needed for scheduling purposes 
 
11.1.2 Screening Visit/Baseline Visit (Day -28 to 1) 
 Informed consent 
 Study eligibility per inclusion/exclusion criteria 
 Medical history 
 CD30 IHC stain and histological confirmation to be done at site enrolling the 
patient  
 Send tumor biopsy slides to CCF for correlative studies. Biopsy slides should 
be sent within 4 weeks of start of the study drug. Please see section 10 for 
detailed information 
 Human T-cell leukemia virus-1 (HTLV-1) status  
 IPI score  
 PIT score (prognostic index for PTCL) 
 Diagnostic CT of neck, chest, abdomen, pelvis with IV and oral contrast and 
PET scan (CT neck can be omitted at the discretion of the study investigator if 
the suspicion for involvement is low/absent. If unable to obtain both CT and 
PET scan due to insurance restrictions, either CT or PET are acceptable, but 
PET scan is preferred 
 Bone marrow (BM) aspiration and biopsy if patient had previous history of 
bone marrow involvement or any suspicion of BM involvement with this 
relapse - may be obtained within 30 days of the first dose of study treatment. 
BM biopsy is not needed if there was no evidence of involvement previously 
and if there is no suspicion of involvement at the time of current relapse 
 Concomitant medication documentation including over the counter medication 
and supplements 
 Vital signs, height, and weight 
 Electrocardiogram (ECG) 
 Echocardiogram (ECHO)    
 Pregnancy test for females of childbearing potential  
 ECOG performance status  
 Serum chemistry panel: sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, calcium, glucose, total protein, albumin, alkaline phosphatase, 
total bilirubin, SGOT [AST], SGPT [ALT] 
 Lactate dehydrogenase (LDH) level, uric acid, phosphorous. 
 CBC with differential  
 Physical examination 

 
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11.1.4 Treatment Period (21-day cycles) 
11.1.5 Every Cycle: Day 1 ±3 days (except Cycle1) 
Day 1 pre-dose assessment do not need to be repeated if being done same day as 
screening. If the same assessments are being used for both screening and day 1, 
the data should be entered at screening in the database. 
 ECOG performance status  
 Serum chemistry as detailed above (11.1.2) 
 LDH, uric acid and phosphorous only for cycle 1 
 CBC with differential  
 Physical examination 
 Vital signs and weight 
 Concomitant medication documentation including over the counter medication 
and supplements 
 Adverse event documentation starting with cycle 2 
 
11.1.6 Cycle #4 and #10 day 15 +5 days 
 CT neck, chest, abdomen and pelvis with IV and oral contrast.  Neck CT can 
be omitted at the discretion of the investigator if there was no involvement 
seen at baseline.  
11.1.7 The treatment will be continued until disease progression, unacceptable 
toxicity, stem cell transplantation or at physician discretion. If a patient has 
completed 17 cycles, the treating physician can determine if to continue or 
discontinue treatment in event there is no disease progression or unacceptable 
toxicity. Patients who have completed 17 cycles of treatment can continue on the 
protocol at the discretion of the treating physician until disease progression or 
unacceptable toxicity. For patients continuing beyond 17 cycles, CT neck, chest, 
abdomen and pelvis with IV and oral contrast will be done every 6 months ±2 weeks 
as long as they are receiving study treatment. Neck CT can be omitted at the 
discretion of the investigator if there was no involvement seen at baseline. For 
treatment schedule please refer to section 11.1.5. 
 
11.2 End of Study Treatment Visit   
End of study visit will be conducted within 30-45 days of last cycle of therapy 
 Physical Examination 
 Vital signs 
 Height and weight 
 Concomitant medication documentation, including over the counter 
medication and supplements 
 CBC with differential  
 Serum chemistry panel as mentioned above 
 LDH 
 Pregnancy test for females of childbearing potential  
 ECOG performance status (not required if patient has disease 
progression) 
 Adverse event evaluation 

 
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 Diagnostic CT of neck, chest, abdomen, pelvis with IV and oral contrast and 
PET scan to be done between 30-45 days after the last cycle of therapy. 
Neck CT can be omitted at the discretion of the investigator if there was no 
involvement at baseline. If unable to obtain both CT and PET scan due to 
insurance restrictions, either CT or PET are acceptable, but PET scan is 
preferred 
 For patients coming off treatment due to disease progression, scans are 
only required, if the last scan within 60 days did not show disease 
progression. If the patient had a scan within the last 60 days that 
document progression, no further scans are needed.  
 BM biopsy to be repeated between 30-45 days after the last cycle of 
therapy if it was positive prior to start of the study drug. 
 BM biopsy may be omitted for patients who are coming off treatment 
due to disease progression. 
 
11.3 Duration of Follow Up 
As stated in section 6.7.2 after completion of the study the subjects will be followed 
for a total of 3 years. The follow up visits will be done at 6, 12, 24 and 36 months 
after the last cycle of therapy and will include: 
 
 Physical Examination 
 Vital signs, height, and weight 
 CBC with differential  
 Serum chemistry panel as mentioned above 
 LDH 
 ECOG performance status 
 Adverse events evaluation (only the adverse events attributed to the study 
drug) 
 CT scans - neck, chest, abdomen and pelvis with IV and oral contrast to 
be done at 6, 12, and 24 months after the last cycle of therapy if no 
progressive disease. Neck CT can be omitted at the discretion of the 
investigator if there was no involvement at baseline 
 
If the patient is unable to follow up with the local site in person, virtual visits may be 
used to capture applicable procedures during long-term follow up only. If a virtual visit 
is completed in follow up every attempt should be made to complete the required 
assessments listed above, though if they are not completed it will not be considered a 
protocol deviation. 
 
Patients who have progressive disease or start a new treatment are not required 
come in for clinical follow ups. These patients can be contacted over the phone by 
the study personnel to obtain the following information 
 
 Disease status  
 Adverse event evaluation only if patients have residual persistent 
symptoms related to BV treatment 
 Current lymphoma treatment  

 
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11.4 Calendar 
Screening procedures including scans are to be conducted within 28 days to 
administration of protocol therapy unless otherwise noted.  
 
 
 
 
 
 

 
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Study Calendar 
  
 
 
 
 
Tasks 
Baseline/screening 
Day -28 to 1 
Cycle 1  day 1 
Cycle 2 -17 Day 1±3days 
Cycle 4 and 10 Day 15+5days 
Cycle 18 and beyond; Day  1 ±3days 
EOT Day 30-45 post last cycle 
Long term follow upm 
6 months 
12 months 
24 months 
36 months 
Informed 
consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
Physical exam 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
CD30 statuse 
x 
 
 
 
 
 
 
 
 
 
HTLV-1 status 
x 
 
 
 
 
 
 
 
 
 
IPI score 
x 
 
 
 
 
 
 
 
 
 
PIT score 
x 
 
 
 
 
 
 
 
 
 
ECHO 
x 
 
 
 
 
 
 
 
 
 
EKG 
x 
 
 
 
 
 
 
 
 
 
Vital signs, Height 
& weight 
xl 
x 
x 
 
x 
x 
x 
x 
x 
x 
CBC with 
differential 
x 
xk 
x 
 
x 
x 
x 
x 
x 
x 
Serum chemistry 
x 
xk 
x 
 
x 
x 
x 
x 
x 
x 
LDH 
x 
xk 
 
 
 
x 
x 
x 
x 
x 
Uric, Phosphorous 
x 
xk 
 
 
 
 
 
 
 
 
Pregnancy test 
 
xc 
 
 
 
x 
 
 
 
 
ECOG 
performance 
status 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Conmeds 
x 
x 
x 
 
x 
x 
 
 
 
 
AE assessment 
 
 
x 
 
x 
x 
Xi 
Xi 
Xi 
Xi 
Tumor tissuef 
x 
 
 
 
 
 
 
 
 
 
CT 
neck/chest/abdom
en/ 
Pelvisa, h  
Xj 
 
 
x 
 
x 
xd 
xd 
xd 
 
BM aspiration and 
biopsy 
Xg 
 
 
 
 
xb 
 
 
 
 
PET scan 
x 
 
 
 
 
x 
 
 
 
 
Brentuximab 
Vedotin 
 
x 
x 
 
x 
 
 
 
 
 
 
a. 
Neck CT can be omitted at the discretion of the investigator if there was no involvement at baseline. A +5-day 
window for scans during Cycle 4 and Cycle 10 is acceptable.  
b. 
Bone marrow biopsy only if positive prior to start of the study drug 
c. 
Pregnancy test to be done within 72 hours of starting the study drug 

 
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d. 
Restaging CT scans not required if disease has progressed 
e. 
CD30 status to be assessed by the site enrolling the patient  
f. 
Tumor biopsy slides should be sent to CCF for correlative studies within 4 weeks of the start of the treatment 
g. 
Bone marrow biopsy only if evidence of involvement previously, and/or suspicion of involvement at the time of 
current relapse. 
h. 
For Cycles 18 and beyond, scans are to be done every six months +/- two weeks.  
i. 
 Only adverse events attributed to the study drug 
j. 
CT neck can be omitted at baseline if the investigator feels there is no or low suspicion for involvement 
k. 
These labs do not need repeated on C1D1 if they were performed at baseline within 72 hours of start of study 
treatment 
l. 
Height is only required at screening. 
m. 
Long term follow up visits may be completed via virtual visit if necessary. Every attempt should be made to complete 
the assessments although if they are not completed this is not considered a protocol deviation. 
 
12.0  MEASUREMENT OF EFFECT   
 
12.1 Antitumor Effect  
Response will be assessed using CT scans according to the revised Cheson Criteria  
[1]. Please see section 11.4 for the schedule of the imaging studies. Patients will 
have pre-treatment and end of treatment FDG-PET and/or CT to monitor their 
response to treatment. Interim response will be assessed after cycle 4 and 10 using 
CT scans. During follow up patients will have CT scans done at 6, 12, and 24 
months after the last cycle of therapy. 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Brentuximab Vedotin  
 
The following guidelines are to be used for establishing tumor measurements at 
baseline and for subsequent comparison:  
 The six largest dominant nodes or extranodal masses must be identified at 
baseline.  
 If there are 6 or fewer nodes and extranodal masses, all must be listed as 
dominant.  
If there are more than 6 involved nodes or extranodal masses, the 6 largest 
dominant nodes or extranodal masses should be selected according to the 
following features: 
 nodes should be clearly measurable in at least two perpendicular 
measurements  
 nodes should be from as disparate regions of the body as possible  
 nodes should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved.  
 Measurements for all dominant nodes and extranodal masses will be reported at 
baseline. Measurements on non-dominant nodes are not required. The lymph 
nodes or extranodal masses selected for measurement should be measured in 
two perpendicular diameters, one of which is the longest perpendicular diameter. 
The lymph nodes should be measured in centimeters to the nearest one tenth of 
a centimeter (e.g. 2.0 cm, 2.1cm, 2.2 cm, etc.)  
 The two measured diameters of each lymph node site or extranodal mass should 
be multiplied giving a product for each nodal site or extranodal mass. The 

 
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product of each nodal site should be added, yielding the sum of products of the 
diameters (SPD). The SPD will be used in determining the definition of response 
for those who have less than a complete response.  
 
12.2   Definitions 
 
12.2.1 Primary Endpoint 
 
12.2.1.1 Overall Response Rate 
The primary objective is to evaluate overall response rate (ORR). Overall response 
rate will be estimated by the total number of patients who achieve a CR and PR 
divided by the total number of evaluable patients. Response will be assessed using 
CT scans according to the revised Cheson criteria [1].  
 CR is defined as complete resolution of all clinically detectable disease and 
disease related symptoms that were present prior to therapy 
 PR is defined as at least 50% decrease in sum of the product of the diameters 
(SPD) of up to six of the largest dominant nodes or nodal masses 
Patients should have completed at least 1 cycle of treatment to be evaluable for ORR.  
12.2.2 Secondary Endpoints 
 
12.2.2.1 Complete Response 
CR is defined as complete resolution of all clinically detectable disease and disease 
related symptoms that were present prior to therapy.  A post-treatment residual 
mass of any size is permitted as long as it is PET negative. CR rate will be 
calculated by dividing the total number of patients who have achieved a complete 
response by the total number of evaluable patients.   
 
12.2.2.2 Progression Free Survival 
Progression-free survival (PFS) is defined as the time from enrollment into the study 
to disease progression or death due to any cause. The distribution of PFS will be 
estimated using the Kaplan-Meier method. Disease progression may be defined as 
the date of documentation of a new lesion or enlargement of a previous lesion, or 
the date of the scheduled clinic visit immediately after radiologic assessment has 
been completed. For a patient who is alive without progression at the end of study 
follow-up, observation of PFS is censored on the date of last contact. 
 
12.2.2.3 Overall Survival 
The OS is defined as the time from enrollment to the time of death due to any cause. 
For a patient who is alive at the end of study follow-up, observation of OS is 
censored on the date of last contact. The distribution of OS will be estimated using 
the Kaplan-Meier method.  
12.2.2.4 Duration of Response 
Duration of response (DOR) is defined as the time from first documentation of 
objective tumor response (CR or PR) to the time to tumor progression or death due 

 
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to any cause. 
 
12.2.2.5 Time to Treatment Failure 
Time to treatment failure (TTF) is defined as the time from enrollment to 
discontinuation of treatment for any reason, including disease progression, treatment 
toxicity, and death.  
 
12.3 Response Review  
Responses will be reviewed by the investigator (PI or co-investigator) who is treating 
the patient at each participating site. 
 
13.0 RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS  
Adverse event lists, guidelines, and instructions for AE reporting can be found in 
Section 8.0 (Adverse Events: List and Reporting Requirements). 
  
13.1 Data Reporting  
 
The Advarra EDC™ and OnCore™ databases will be utilized, as required by the 
Case Comprehensive Cancer Center and Cleveland Clinic, to provide data collection 
for both accrual entry and trial data management. Advarra EDC and OnCore™ are 
Clinical Trials Management Systems housed on secure servers. Access to data 
through Advarra EDC and OnCore™ is restricted by user accounts and assigned 
roles. Once logged into the Advarra EDC or OnCore™ system with a user ID and 
password, Advarra EDC™ and OnCore™ define roles for each user which limits 
access to appropriate data. Applications for user accounts can be obtained by 
contacting the OnCore™ Administrator at OnCore-registration@case.edu for 
OnCore™ access, and taussigoncore@ccf.org for Advarra EDC™ access. 
Advarra EDC™ is designed with the capability for study setup, activation, tracking, 
reporting, data monitoring and review, and eligibility verification. When properly 
utilized, Advarra EDC™ is 21 CFR 11 compliant. This study will utilize electronic 
Case Report Form completion in the Advarra EDC™ database. A calendar of events 
and required forms are available in Advarra EDC™. 
 
13.2 Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all 
applicable federal (including 21 CFR parts 56 & 50), state or local laws.  
 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures.  The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the 
information provided.  
 

 
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The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of the 
signed written Informed Consent Form must be given to the subject. 
 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history. 
 
In order to insure patient safety, investigators and study personnel must have up-to-
the-minute health information for subjects enrolled to this study.  Therefore, 
electronic medical records must be utilized to obtain medical information in a timely 
manner.   
 
13.2.3 Accessing Electronic Medical Records for Cleveland Clinic Foundation 
(CCF) 
For Cleveland Clinic, the electronic systems utilized will be EPIC, COPATH to locate 
archived pathology records; and AGFA and/or EasyViz to access radiology imaging 
results  
 
Access to these systems is required for the life of this research study. Information 
obtained from electronic systems will be copied into the Taussig Cancer Institute 
research chart and/or printed (lab results, physician notes, etc.) and stored in the 
research chart. Research charts are kept secure and destroyed according to CCF 
policy.  
 
Study data will be obtained by the PI, co-investigators, study coordinator, and/or 
data manager for this study via password-protected login. All study personnel 
involved in this research will adhere to the CCF policies regarding confidentiality and 
PHI. 
 
13.2.4 Accessing Electronic Medical Records for University Hospitals (UH) 
The following electronic systems will be used: SORIAN to access scheduling 
information; UH Physician Portal or UHCARE to access lab results, physician notes 
and to locate archived medical and pathology records; PACS to access radiological 
imaging results.   
   
 
Access to these systems is required for the life of this research study.  Information 
obtained from electronic systems will be copied into the Seidman Cancer Center 
Clinical Trials Unit research chart and/or printed (lab results, physician notes, etc.) 
and stored in the research chart.  Research charts are kept secure and destroyed 
according to UH policy.   
 
Study data will be obtained by the PI, co-investigators, study coordinator, and/or 
data manager for this study via password-protected login. All study personnel 

 
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involved in this research will adhere to the UH policies regarding confidentiality and 
Protected Health Information.   
 
13.2.5 Retention of records 
The Principal Investigator of the Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, case report forms, source documents, 
records of study drug receipt and dispensation, and all IRB correspondence for as long 
as needed to comply with national and international regulations and the institution in 
which the study will be conducted, or for the period specified by the sponsor, whichever 
is longer. No records will be destroyed until the Principal Investigator confirms 
destruction is permitted.  
 
13.2.6 Audits and Inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform 
audits or inspections, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities 
and documents to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and 
any applicable regulatory requirements.   
 
13.2.7 Data Safety and Monitoring Plan 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center 
Data and Safety Monitoring Plan in accordance with NCI regulations.  
 
14.0 STATISTICAL CONSIDERATIONS 
Please refer section 12.2 for endpoint definitions. The primary objective is to 
evaluate overall response rate.  For this patient population, response of 15% or less 
is unacceptable and 35% or more is promising.  Twenty-eight evaluable patients will 
be accrued; if 8 or more patients respond, then the regimen will be considered 
promising.  The significance level of this one-sided test is 5%, and the power is 
82%.   
 
Other end points analyzed are CR, PFS, OS, DOR, and TTF. ORR and CR will be 
estimated using exact 95% confidence intervals.  PFS and OS will be estimated 
using the Kaplan-Meier method.  DOR and TTF will be estimated using standard 
descriptive statistics such as median and range, or mean and standard deviation.   
 
McNemar’s test will be used to compare incidence of CD30 positivity via IHC with 
multi- spectral imaging and RT-PCR to see if different methods result in different 
findings. 
 
15.0 Sample Size 
We plan to enroll 31 patients, allowing for 10% ineligibility, to obtain 28 patients 
evaluable for primary end point, overall response rate. 
 
16.0 Study Sites 

 
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Primary site: Cleveland Clinic Foundation (CCF) 
Participating sites: 
 Site PI: Paolo Caimi, MD, Case Comprehensive Cancer Center  
 Site PI:, Dipenkumar Modi, MD Karmanos Cancer Institute 
 Site PI: Tatyana Feldman MD, Hackensack Medical Center 
 Site PI: Ryan Wilcox MD, University of Michigan 
REFERENCES 
1. 
Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J 
Clin Oncol, 2007. 25(5): p. 579-86. 
2. 
Vose, J., et al., International peripheral T-cell and natural killer/T-cell 
lymphoma study: pathology findings and clinical outcomes. J Clin Oncol, 
2008. 26(25): p. 4124-30. 
3. 
Coiffier, B., et al., Results from a pivotal, open-label, phase II study of 
romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior 
systemic therapy. J Clin Oncol, 2012. 30(6): p. 631-6. 
4. 
O'Connor, O.A., et al., Pralatrexate in patients with relapsed or refractory 
peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin 
Oncol, 2011. 29(9): p. 1182-9. 
5. 
Wright, C.W., J.M. Rumble, and C.S. Duckett, CD30 Activates Both the 
Canonical and Alternative NF-κB Pathways in Anaplastic Large Cell 
Lymphoma Cells. Journal of Biological Chemistry, 2007. 282(14): p. 10252-
10262. 
6. 
Horie, R., et al., Ligand-independent signaling by overexpressed CD30 drives 
NF-kappaB activation in Hodgkin-Reed-Sternberg cells. Oncogene, 2002. 
21(16): p. 2493-503. 
7. 
Deutsch, Y.E., et al., CD30: an important new target in hematologic 
malignancies. Leuk Lymphoma, 2011. 52(9): p. 1641-54. 
8. 
Muta, H., et al., CD30 signals integrate expression of cytotoxic effector 
molecules, lymphocyte trafficking signals, and signals for proliferation and 
apoptosis. J Immunol, 2000. 165(9): p. 5105-11. 
9. 
Francisco, J.A., et al., cAC10-vcMMAE, an anti-CD30-monomethyl auristatin 
E conjugate with potent and selective antitumor activity. Blood, 2003. 102(4): 
p. 1458-65. 
10. 
Sutherland, M.S., et al., Lysosomal trafficking and cysteine protease 
metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-
auristatin conjugates. J Biol Chem, 2006. 281(15): p. 10540-7. 
11. 
Pro, B., et al., Brentuximab vedotin (SGN-35) in patients with relapsed or 
refractory systemic anaplastic large-cell lymphoma: results of a phase II 
study. J Clin Oncol, 2012. 30(18): p. 2190-6. 
12. 
Fanale, M.A., et al., 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, 2012. 120(21): p. 60-. 
13. 
ORAL PRESENTATIONS. Hematological Oncology, 2013. 31(S1): p. 96-150. 

 
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14. 
Krathen, M., et al., Brentuximab Vedotin Demonstrates Significant Clinical 
Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 
Expression. ASH Annual Meeting Abstracts, 2012. 120(21): p. 797-. 
15. 
Bodo, J., L. Durkin, and E.D. Hsi, Quantitative in situ detection of 
phosphoproteins in fixed tissues using quantum dot technology. J Histochem 
Cytochem, 2009. 57(7): p. 701-8. 
16. 
Agnelli, L., et al., Identification of a 3-gene model as a powerful diagnostic 
tool for the recognition of ALK-negative anaplastic large-cell lymphoma. 
Blood, 2012. 120(6): p. 1274-81. 
17. 
Gallamini, A., et al., Peripheral T-cell lymphoma unspecified (PTCL-U): a new 
prognostic model from a retrospective multicentric clinical study. Blood, 2004. 
103(7): p. 2474-9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 1 
ECOG PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
 
 
0 
 
Normal activity. Fully active, able to carry on all 
pre-disease performance without restriction. 
 
 
 
1 
 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary 
nature (e.g., light housework, office work). 
 
 
 
2 
 
In bed < 50% of the time. Ambulatory and capable 
of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking 
hours. 
 
 
 
3 
 
In bed > 50% of the time. Capable of only limited 
self-care, confined to bed or chair more than 50% 
of waking hours. 
 
 
 
4 
 
100% bedridden. Completely disabled. Cannot 
carry on any self-care. Totally confined to bed or 
chair. 
 
5 
 
 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 2 
IWC RESPONSE CRITERIA (adapted from [1]) 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 3 
International Prognostic Index (IPI) 
 
 
Age > 60 
Serum LDH above normal 
Stage III-IV 
ECOG PS ≥2 
>1 extranodal site involvement 
 
Each characteristic receive 1 point each and the total score ranges from 0-5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 4 
Prognostic Index for PTCL (PIT) Score  
 
Age > 60 
Serum LDH above normal 
ECOG PS ≥2 
Bone marrow involvement 
 
 
Each characteristic receives 1 point each and the total score ranges from 0-4 [17] 

 
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New Protocol Version #/Date: 11/19/2016 
Previous Protocol Version #/Date:  8/20/2016 
 
Rational for Changes:  All Administrative updates  
 
 
 
 
 
Pg. 17  
discontinuation 
defined 
Treatment Plan / 
Pg. 18 
No window added to 
Cycle 1 day 1 
Clarification  
Duration of 
Follow Up / Pg. 
20 
Defined serum 
chemistry Panel and 
added specifics to 
CT’s to adverse 
event follow up.  
Clarification  
Tissue 
Procurement / 
Pg. 34 
Defined Instructions 
for shipping and 
retaining samples 
Clarification  
Screening / Pg. 
36 
Added PIT score, CT 
scan instructions, BM 
Biopsy defined.  
PIT scoring I specific 
to disease. Scans and 
Biopsy are just 
Clarifications.  
Cycles & Study 
Table / Pg. 
Multiple 
Outlined expectation 
for LDH, Uric Acid 
and Phosphorus 
All 3 are ordered 
separately from CMP 
and required at 
specific time points  
Cycles & Study 
Table / Pg. 
Multiple 
Defined Adverse 
event collection 
Clarification  
Study Table / Pg. 
39 
Added PIT, Split 
AE’s/Conmeds, 
Added Uric Acid and 
Phosphorus 
Clarification 
Appendix 
Added Appendix 3 & 
4 
Scoring Systems  
Section #/Page # 
Change 
Rationale 
Title Page / Page 
2 
Added NCT # 
Mandated by 
Scientific Review 
Committee  
SAE’s / Page 26 
Removal of Katie 
Klemencic and 
addition of Ashley 
Ochaba 
Katie has left the 
program and Ashley 
has taken over her 
duties.  

 
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New Protocol Version #/Date: 7/20/2017 
Previous Protocol Version #/Date:  11/19/2016 
 
Rational for Changes:  Administrative updates to protocol and adding risk of 
pneumonitis 
 
 
New Protocol Version #/Date: 9/27/2018 
Previous Protocol Version #/Date:  7/20/2017 
 
Section #/Page # 
Change 
Rationale 
Title Page / Page 
2 
Adding external sites 
(Hacksack and 
University of 
Michigan) 
Sites preparing to 
open study, need 
added to protocol 
11.1.6 / Page 26 
Clarifying CT scans 
to be done at Cycles 
4 and 10 (5 day 
window so scans 
should be done 
between days 15 and 
20) 
Previous verbiage 
(day 15-20) was 
unclear and 
inconsistent   
11.4 / Page 38 
Clarifying window for 
CT scans performed 
at Cycles 4 and 10 
The protocol defined 5 
day window was not 
clear in previous 
version 
13.1 & 13.2.4 / 
Page 41-42 
Updating EMR 
information for 
University Hospitals 
and Overture 
language for data 
collection 
Previous version was 
outdated 
9.3.1 / Page 31 
Adding risk of 
Pneumonitis 
This is important 
information in the 
current IB  
Section #/Page # 
Change 
Rationale 
Schema / Pages 
3&4 
4.1 & 4.2./ Page 
14&15 
Removing  
transformed mycosis 
fungoides as an 
approved indication 
for enrollment in this 
study 
Recent FDA approval 
of the study drug for 
this indication. 
Patients with  
transformed mycosis 
fungoides may no 
longer enroll on this 
study  
Schema / Page 3 
Adding 
splenomegaly as 
indicator of 
Updated for patients 
with splenomegaly 

 
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New Protocol Version #/Date: 2/6/2020 
Previous Protocol Version #/Date:  9/27/2018 
 
 
measurable disease 
Schema / Page 5 
4.2/ Page 15 
Reducing treatment 
washout time from 4 
to 2 weeks before 
start of study drug 
Updated to allow 
patients with rapid 
disease progression 
to enroll without 
delaying treatment 
6.2 / Page 17 
The threshold for 
dose recalculation 
based on change in 
body weight is being 
changed from 5% to 
10% 
This change was 
made to be consistent 
with the pharmacy 
instructions distributed 
by Seattle Genetics  
7.0 / Pages 
20&21 
Adding information 
on when the study 
drug may be held or 
modified 
Previously the 
protocol did not 
provide guidance on 
when the study drug 
could/should be held 
8.3 / Page 25 
Updating CCF SAE 
reporting contact 
information 
Previous contact 
information was 
outdated.  
10.3 / Pages 34 
Updating information 
on shipping slides 
Previous information 
was outdates and 
further detailed 
instructions are stated 
to be located in the 
Manual of Operating 
Procedures 
Section/Page 
Change 
Rationale 
Pages 1 & 2 
Updated Karmanos PI 
and other administrative 
information 
Updated to the most current 
information 
Section 4.1 
Corrected numbering for 
some inclusion criteria 
Fixing incorrect numbering of 
items 
Section 7.0 
Adding information on 
when to hold BV 
More detailed was added on how 
to appropriately hold BV for BV-
related toxicities 
Pages 34-39 
Details were added in the 
schedule of assessments 
Height is only required at 
screening. Clarification that 
screening and C1D1 is allowed on 
the same day. Certain EOT 
procedures are not required for 
patients with disease progression. 

 
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New Protocol Version #/Date: 8/21/2020 
Previous Protocol Version #/Date:  2/6/2020 
 
 
New Protocol Version #/Date: 7/6/21 
Previous Protocol Version #/Date:  8/21/2020 
 
 
Section/Page 
Change 
Rationale 
Section 
6.7.2 & 11.3 
Allowing virtual visits for 
long-term follow up visits 
Increasing flexibility to more 
reliably capture long-term follow 
up data 
Section/Page 
Change 
Rationale 
Title Page / 
Page 
1/Section 16 
Updating Karmanos PI to 
Dipenkumar Modi, MD 
Change in site PI 
Title Page / 
Page 2 
Removing Eric Hsi, MD 
and Xiaoxian Zhao, PhD.,  
Alex Mejia-Garcia, MD 
Adding Genevieve 
Crane, MD 
Personnel updates 
Section 10.2 
Processing for T-qPCR 
Assay for CD30 updated 
from Dr. Hsi to the RT-
PLMI facility  
The RT-PLMI facility will now 
complete sample processing 
Section 10.3 
Change Cleveland Clinic 
Biorepository shipping 
title and ATTN to 
Genevieve Crane, MD 
Title correction and pathologist 
replacement 
 
Schema Page 
3, Section 2.3, 
Section 10.0 
 
References to Nuance 
FX multispectral Imaging 
camera deleted or 
changed to  Asperio 
image analysis 
To align with current PLMI 
processes.  
 
 
 
Section 8.3 
SAE contact info updated 
To reflect personnel updates at 
CCF. 
Section 6.7.2, 
11.3, study 
calendar 
Clarifying that if a virtual 
visit is completed in 
follow up, assessments 
not completed will not be 
considered a protocol 
deviation.  
Patients that start new 
treatment enter survival 
follow up.  
For patient convenience.  
13.1 
Overture changed to 
Advarra 
To be consistent with current EDC 
used.