A Phase 2 Study of Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (CHEP-BV) Followed by BV Consolidation in Patients With CD30-Positive Peripheral T-Cell Lymphomas
Phase: PHASE2
Conditions: Adult T-Cell Leukemia/Lymphoma, Anaplastic Large Cell Lymphoma, ALK-Negative, Anaplastic Large Cell Lymphoma, ALK-Positive, Angioimmunoblastic T-Cell Lymphoma, Ann Arbor Stage II Noncutaneous Anaplastic Large Cell Lymphoma, Ann Arbor Stage III Noncutaneous Anaplastic Large Cell Lymphoma, Ann Arbor Stage IV Noncutaneous Anaplastic Large Cell Lymphoma, Enteropathy-Associated T-Cell Lymphoma, Hepatosplenic T-Cell Lymphoma, Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Peripheral T-Cell Lymphoma, Not Otherwise Specified
Sponsor: City of Hope Medical Center

Protocol Number 17058 
 
09/02/2021 
Packet 11 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
 
TITLE:  A Phase 2 Study of Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and 
Prednisone (CHEP-BV) Followed by BV Consolidation in Patients with CD30-Positive Peripheral 
T-cell Lymphomas  
 
CITY OF HOPE PROTOCOL NUMBER: 17058 
 
 
Protocol Date: 09/02/21  
 
              Initial Approval  
                       Protocol dated- 04-25-17 v00 
 
Title Page Version 00 
Amendment 01 
  
     Protocol dated- 05-04-17 v01  
 
Title Page Version 01 
              Amendment 02 
  
     Protocol dated- 08-17-17 v02  
 
Title Page Version 02 
              Amendment 03                                      Protocol dated- 11-29-17 v03                     Title Page Version 03 
              Amendment 04                                      Protocol dated- 07-17-18 v04                     Title Page Version 04 
              Amendment 05                                      Protocol dated- 01-29-19 v05                     Title Page Version 05 
              Amendment 06                                      Protocol dated- 05-10-19 v06                     Title Page Version 06 
              Amendment 07                                      Protocol dated- 08-13-19 v07                     Title Page Version 07 
              Amendment 08                                      Protocol dated- 04-08-20 v08                     Title Page Version 08 
              Amendment 09                                      Protocol dated- 05-11-20 v09                     Title Page Version 09 
              Amendment 10                                      Protocol dated- 06-09-20 v10                     Packet 10 
Amendment 11                                      Protocol dated- 09-02-21 v11                     Packet 11 
 
SPONSOR/IND NUMBER: 
City of Hope/ Pending 
DISEASE SITE: 
Non-Hodgkin Lymphoma 
STAGE (if applicable): 
N/A 
MODALITY: 
Drug-Antibody Conjugate and Chemotherapy 
PHASE/TYPE: 
Phase 2 with Safety Lead-in 
 
PRINCIPAL INVESTIGATOR: 
 
 
Alex Herrera., MD. 
Ph: 626-256-4673 x 62405 
Email: aherrera@coh.org 
CO-INVESTIGATOR(S): 
 
Jasmine Zain, MD 
PARTICIPATING CLINICIANS: 
 
Stephen Forman MD, Matthew Mei MD, Elizabeth Budde, MD., 
Leslie Popplewell, MD., Tanya Siddiqi, MD., Leonardo Farol, MD., 
Firoozeh Sahebi, MD., Ricardo Spielberger, MD., Ji-Lian Cai, 
MD., Thai Cao, MD.,. Eileen Smith MD., Liana Nikolaenko MD., 
Saro Armenian MD., Nicole Karras MD., Karamjeet Sandhu MD, 
William Boswell, MD., Arnold Rotter., MD., Larry Kwak, MD 
 
BIO-STATISTICIAN: 
Lu Chen, PhD 
 
 
PARTICIPATING SITES: 
City of Hope, Duarte, CA 
Kaiser Permanente 
MD Anderson  
Hackensack University 
BC Cancer Agency (Canada) 
 

This document is confidential and for research purposes only. Do not copy, redistribute, 
disclose or use except as authorized. 
 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 2 Study of Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, 
Etoposide, and Prednisone (CHEP-BV) Followed by BV Consolidation in Patients 
with CD30-Positive Peripheral T-cell Lymphomas  
Version Date: September 02 2021 
Protocol Version: 11 
 
City of Hope #: 17058 
Agents: Brentuximab vedotin, 
Cyclophosphamide, Doxorubicin, 
Etoposide, Prednisone 
IND Number: 134902 
Sponsor/ IND Holder: City of Hope 
Funding Support/ Industry Partner: Seattle Genetics 
NCT Number: NCT03113500 
 
Principal Investigator 
Alex F. Herrera, MD 
City of Hope National Medical Center 
Dept. of  Hematology 
T: 626-256-4673 x 62405 
F: 626-301-8256 
Email: aherrera@coh.org  
 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
Email: DCC@coh.org 
 
 
 

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PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD. 
Dept. Information Sciences 
City of Hope National Medical 
Center 
T: 626-256-4673 x 86626 
Email: lchen@coh.org 
Co-Investigator 
Jasmine Zain, MD 
Dept. of Hematology 
City of Hope National Medical 
Center 
T: (626)-256-4673 ext 82405 
Email: jazain@coh.org 
 
 
 
 
 
  
 
Participating non-COH sites  
Site Lead Investigator 
Swaminathan P. Iyer, MD 
The University of Texas 
MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 429 
Houston, TX 77030 
T: 713-792-5242 
F: 713-792-1897 
Email: SPIyer@mdanderson.org 
 
Site Lead Investigator 
Tatyana Feldman, MD 
Hackensack University 
John Theurer Cancer Center 
92 2nd Street 
Hackensack, NJ, 07601 
T: 551-996-4469 
Email:  
Tatyana.Feldman@hackensack
meridian.org 
 
 
Site Lead Investigator 
Kerry Savage, MD 
BC Cancer Agency, 
British Columbia, Canada 
Email: KSavage@bccancer.bc.ca  
 
 
Site Lead Investigator 
Jonathan Brammer, MD 
Ohio State University 
460 W. 10th Avenue 
Columbus, OH 43210 
T: 614-366-6963 
Email: 
Jonathan.Brammer@osumc.edu 
 
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Study of Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone 
(CHEP-BV) Followed by BV Consolidation in Patients with CD30-Positive Peripheral T-cell Lymphomas 
Study Detail 
Population/Indication(s): 
CD30-Positive Peripheral T-cell Lymphomas 
Phase: 
Safety Lead-in/ Phase 2 
Sample Size: 
Safety Lead-in: Evaluable 6-12 
Phase 2: Evaluable 48 (includes evaluable participants from Safety Lead-
in  treated at the RP2D) 
Anticipated Maximum: 53 
Estimated Accrual Duration: 
36 months 
Estimated Study Duration 
~ 8 years 
Participant Duration: 
~ 5 years 
Participating Sites: 
 City of Hope Duarte, CA 
 MD Anderson 
 Hackensack University 
 BC Cancer Agency 
 Ohio State University 
Study Agents: 
Brentuximab vedotin, Cyclophosphamide, Doxorubicin, Etoposide, 
Prednisone 
Sponsor: 
City of Hope 
Industry Partner:  Seattle Genetics  
Industry Partner Protocol ID: 
35-IST-039 
Rationale for this Study 
Peripheral T-cell lymphomas (PTCL) are an uncommon group of disorders, accounting for about 10% of all non-
Hodgkin lymphomas (NHL). EBV-associated extranodal NK/T-cell lymphoma (NKTCL) is more common in parts 
of Asia and South America, while angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, 
not otherwise specified (PTCL NOS) are more common in Western countries. PTCLs are generally associated 
with poor outcomes after standard therapy, with variation in prognosis according to disease subtype. With 
high relapse rates after standard therapy including ASCT and inadequate second line treatment options, novel 
strategies for decreasing relapse rates in patients with PTCL are urgently needed. 
CD30 is a cell surface antigen expressed on several malignancies including Hodgkin lymphoma (HL), anaplastic 
large cell lymphoma (ALCL) and other peripheral T-cell lymphomas (PTCL). Brentuximab vedotin (BV), 
previously known as SGN-35, is an antibody drug conjugate (ADC) directed against the CD30 antigen that is 
being developed to treat patients with CD30-positive hematologic malignancies. 
Brentuximab vedotin is an effective treatment for patients with PTCL. Brentuximab vedotin is FDA-approved 
for relapsed CD30 expressing systemic anaplastic large cell lymphoma [39]. In a single-arm Phase 2 study, 58 
patients were treated with brentuximab vedotin 1.8mg/kg intravenously every 3 weeks, resulting in a 86% 
ORR, including 33 patients (57%) complete remissions, and 17 (29%) partial remissions. The median durations 
of overall response and CR were 12.6 and 13.2 months, respectively. More recently, in a Phase 2 study of 
brentuximab vedotin in 34 patients with relapsed or refractory PTCLs other than ALCL, brentuximab vedotin 
treatment resulted in an ORR of 41%, with a 54% ORR in patients with AITL. The median duration of response 
was 7.6 months, and the median follow-up time was 2.7 months. The overall disease control rate was 59%, 
with a 77% disease control rate in patients with AITL [1]. 

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The ECHELON-2 trial is a randomized trial that is currently comparing the addition of brentuximab vedotin to 
cyclophosphamide, doxorubicin, and prednisone (CHP) with standard-of-care cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) in the initial treatment of patients with CD30-positive PTCL. However, 
based on evidence that the addition to etoposide to standard CHOP (CHOEP) is beneficial, CHOEP is often 
administered as initial treatment of patients with PTCL. Therefore, while ECHELON-2 will address whether 
brentuximab vedotin added to CHP is superior to CHOP therapy, there are no data regarding the safety and 
efficacy of brentuximab vedotin added to etoposide-containing induction chemotherapy (cyclophosphamide, 
doxorubicin, etoposide, and prednisone - CHEP). Since November 16, 2018 and based on the ECHELON-2 trial, 
brentuximab vedotin is FDA-approved in combination with CHP chemotherapy for previously untreated, 
systemic ALCL or other CD30-expressing PTCL. We propose a Phase 2 study to assess the anti-lymphoma 
activity brentuximab vedotin when combined with CHEP (CHEP-BV) in patients with newly-diagnosed CD30-
positive PTCL. 
Objectives 
Primary Objectives 
Safety Lead-in 
 Assess the safety and tolerability of CHEP-BV, as induction therapy in patients with CD30-positive 
peripheral T-cell lymphoma (PTCL)  
Phase 2 
 Assess the anti-lymphoma activity of CHEP-BV as induction treatment in patients with CD30-positive PTCL. 
Secondary Objectives 
 Describe outcomes of CD30-positive PTCL patients who go on to receive BV consolidation therapy post 
CHEP-BV induction with/without autologous hematopoietic cell transplantation/radiation. 
Exploratory Objective 
 Explore the rate of minimal residual disease (MRD) negativity (as assessed by next-generation sequencing) 
and MRD kinetics after CHEP-BV and BV consolidation therapy in CD30-positive PTCL. 
 Explore the possible association between outcome after study treatment and CD30 expression, gene 
expression profiles (GEP), and genetic mutations as measured in PTCL tumor samples. 
Study Design 
This is an open-label multi-site Phase 2 study with a Safety Lead-in to test the safety and efficacy of CHEP-BV as 
Induction therapy followed by single-agent brentuximab vedotin consolidation therapy for the treatment of 
CD30-positive PTCL.  
The safety lead-in segment with 2 dose levels (starting dose level and 1 de-escalation level) will follow 
standard 3+3 dose escalation/de escalation/expansion rules based on observed toxicity during Induction Cycle 
1. The study will accrue 48 response evaluable patients for the Phase 2 response evaluation. 
Newly diagnosed CD30-postitive PTCL patients will be treated with up to 6 cycles of CHEP-BV followed by up to 
10 cycles of single-agent brentuximab vedotin for responding patients. Treatment cycles will be 21-days.  
Following CHEP-BV Induction, responding patients in this trial may receive consolidation ASCT/ radiation prior 
to initiating Consolidation brentuximab vedotin.  
Participants will continue with treatment until disease progression, unacceptable toxicity or completion of 
protocol therapy (induction and consolidation, ~ 12 months), whichever comes first. Participants who 
discontinue brentuximab vedotin during Induction may continue to receive CHEP therapy per standard of care. 

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Evaluation Criteria and Endpoints 
Safety 
 Toxicity will be recorded using the NCI CTCAE v 4.0. The highest grade of any toxicity will be collected for 
each cycle during protocol treatment and for the period of safety follow-up after end of treatment. For 
Cycle 1 only, all Grade ≥2 AEs (highest grade or not) will also be collected. 
Unacceptable toxicity  
Unacceptable toxicity will be defined as one of the following AEs that is at least possibly related to study 
treatment during Cycle 1 of Induction 
Hematologic 
 Delay in planned initiation of Cycle 2 Day 1 by more than 14 days due to Grade 4 neutropenia that does not 
resolve to Grade ≤ 2 or baseline despite growth factor support  
 Grade 4 thrombocytopenia lasting ≥ 7 days  
 Platelet nadir < 10,000/ mm3 
 Delay in planned initiation of Cycle 2 Day 1 by more than 7 days due to Failure to recover platelets to ≥ 
50,000/ mm3 and/or ANC to ≥ 1000/ mm3  
 Any Grade 5 AE 
Non-hematologic 
 Any clinically relevant ≥ Grade 3 AE that does not resolve to Grade ≤ 2 within 7 days with the exception of: 
− 
Grade 3 asymptomatic laboratory abnormalities, including lipase or amylase, that are not 
clinically relevant, not requiring hospitalization or delay of treatment 
− 
Grade 3 nausea, vomiting, or fatigue controlled with supportive measures 
− 
Grade 3 inflammatory response attributed to local antitumor response 
− 
Vitiligo 
 Delay in planned initiation of Cycle 2 Day 1 by more than 7 days due to Grade ≥2 peripheral motor 
neuropathy 
 Any Grade 5 AE 
Response 
  Lymphoma response/progression will be evaluated using 2014 Lugano Classification. 
Clinical Outcome Endpoints 
Endpoint 
Definition 
Progression-Free Survival 
(PFS)* 
Defined as the time from enrollment to the first observation of disease 
relapse/progression or death from any cause, whichever occurs first.  
For patients who are alive and have not had disease relapse/progression at 
the last follow-up, it is censored at the time of last follow-up.  If a patient 
recieves non-protocol anti-lymphoma treatment prior to disease 
progression, it is censored at the time of non-protocol anti-lymphoma 
treatment. 
Overall Survival (OS) 
Defined as the time from enrollment to death from any cause.   
For patients alive at the last follow-up, it is censored at the time of last 
follow-up. 
Overall response (ORR) rate  
Proportion of patients achieving CR or PR 
Complete response (CR) rate  
Proportion of patients achieving CR 

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Statistical Considerations 
Safety Lead-in 
The safety lead-in segment will follow standard 3+3 dose escalation/de-escalation/expansion rules based on 
observed toxicity during Induction Cycle 1. The starting dose level for brentuximib ventodin in CHEP-BV will be 
1.8mg/kg (dose level 1). If ≥2/3 (after the initial 3) or ≥2/6 (after the total 6 in 2 cohorts) patients experience 
unacceptable toxicities during Cycle 1, 1.8 mg/kg will be considered not tolerable, and the study will then 
evaluate the safety and tolerability of the lower dose level of brentuximab vedotin at 1.2 mg/kg (dose level -1).  
If ≥2/3 (after the initial 3) or ≥2/6 (after the total 6 in 2 cohorts) patients experience unacceptable toxicities 
during Cycle 1, 1.2 mg/kg will be considered not tolerable, and the study accrual will be suspended. 
Phase 2 
The primary endpoint is CR rate after CHEP-BV induction. The Phase 2 sample size of 48 is based on the desire 
to discriminate a promising CR rate of 71% from a disappointing CR rate of 56%, using a type I error rate of 
0.10 and power of 80% based on an exact binomial test. The design will require 32 or more CR among the 48 
patients to consider the outcome encouraging. Patients enrolled during the Safety Lead-in segment who are 
treated at the final dose deemed tolerable will be included in the Phase 2 response evaluation provided that 
they are also evaluable for response. 
CR rate after CHEP-BV induction therapy will be estimated by the proportion of evaluable patients achieving 
CR after CHEP-BV induction therapy, along with the 95% exact binomial confidence interval. ORR after CHEP-
BV induction therapy and CR rate after BV consolidation will be similarly estimated.  PFS and OS will be 
estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of 
standard error. Observed toxicities of CHEP-BV induction therapy, those of BV consolidation after CHEP-BV 
induction and ASCT, and those of BV consolidation after CHEP-BV induction without ASCT will be summarized 
by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE 
v4.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution. 
Eligibility Criteria 
Inclusion Criteria 
 Documented informed consent of participant and/or Legally Authorized Representative. 
 Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions 
may be granted with Study PI approval. 
 Age: ≥ 18 years  
 ECOG status ≤ 2 
 Histologically confirmed mature peripheral T-cell or NK-cell lymphoma per WHO classification, including: 
− 
*ALK-positive ALCL with IPI of 2 or higher (must have bulky [defined as mass ≥ 10 cm] Stage II, or 
Stage III-IV disease), *ALK-negative ALCL, *NOTE: per Amendment dated 05-10-19, ALCL will no 
longer be eligible except for Canada. PTCL-NOS, AITL, ATLL, EATL, Hepatosplenic T-cell lymphoma 
 CD30-positivity (e.g. at least 1%) by immunohistochemistry confirmed by hematopathology review at the 
participating institution. 
 Measurable disease of at least 1.5cm on CT or PET-CT scan 
 ANC ≥ 1,000/mm3 (unless bone marrow involvement by lymphoma) 
 Platelets ≥ 50,000/mm3 (unless bone marrow involvement by lymphoma) 
 Total serum bilirubin ≤ 1.5X upper limit of normal (ULN) (or ≤ 3X ULN for Gilbert’s disease or documented 
hepatic involvement by lymphoma) 
 AST and ALT ≤  2 x ULN OR If hepatic involvement by lymphoma: AST and ALT ≤  5 x ULN 

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 Creatinine clearance of ≥ 60 mL/min 
 Left ventricular ejection fraction (LVEF) ≥ 45% 
 Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. 
 Agreement by women of childbearing potential and males of childbearing potential to use an effective 
method of birth control or abstain from heterosexual activity for the course of the study through at least 6 
months after the last dose of protocol therapy. 
Exclusion Criteria 
 Prior treatment of PTCL with systemic anti-lymphoma therapies, investigational agents, radiation 
− 
Exception: May have received 1 cycle of CHOP-like therapy (e.g. CHOP, CHOEP, EPOCH) or 1 cycle 
of CHP-BV; these participants must initiate Day 1 Cycle 1 of study therapy (CHEP-BV) no less than 
19 days from prior CHOP-like or CHP-BV therapy. Patients who received 1 cycle of CHOP-like or 1 
cycle of CHP-BV therapy prior to initiating induction with CHEP-BV are allowed to receive only 5 
cycles of CHEP-BV instead of 6 cycles, per investigator’s discretion. 
 History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has 
not been in remission for at least 3 years. Exceptions: Non-melanoma skin cancer and in situ cervical cancer. 
 Symptomatic cardiac disease (including symptomatic ventricular dysfunction, symptomatic coronary artery 
disease, and symptomatic arrhythmias), cerebrovascular event/stroke or myocardial infarction within the 
past 6 months. 
 Central nervous system involvement by lymphoma, including leptomeningeal involvement. 
 History of progressive multifocal leukoencephalopathy (PML).  
 Active  ≥ Grade 3 viral, bacterial, or fungal infection within 2 weeks prior to Day 1 of protocol therapy 
 Any known human immunodeficiency virus (HIV) infection, hepatitis B surface antigen-positive status, or 
known or suspected active hepatitis C infection 
 Baseline peripheral neuropathy ≥ Grade 2 or patients with the demyelinating form of Charcot-Marie-Tooth 
syndrome. 
 Known severe hypersensitivity to any study related agent excipient(s)  
 Females only: pregnant or breastfeeding 
 Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in 
the clinical study due to safety concerns with clinical study procedures. 
 Prospective participants who, in the opinion of the investigator, may not be able to comply with all study 
procedures (including compliance issues related to feasibility/logistics). 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Investigational Product Dosage and Administration 
 
 
Agent 
Dose 
Route 
Schedule 
(Days 
within 
each 21-
day cycle) 
Maximum # Cycles 
 
Induction  
CHEP-BV^ 
Consolidation** 
BV 
CHEP 
Cyclophosphamide 
750 mg/m2 
IV 
Day 1  
6 
N/A 
Doxorubicin 
50 mg/m2 
IV 
Day 1  
6 
Etoposide*** 
100 mg/m2 
IV 
Days 1-3  
6 
Prednisone 
100 mg daily 
Orally 
Days 1-5  
6 
 
Brentuximab 
Vedotin (BV) 
Safety Lead-in 
 Dose Level 1*: 1.8 mg/kg 
 Dose Level -1: 1.2 mg/kg 
 
*Starting dose 
IV over 
30 
minutes 
(+10 
minutes) 
Day 1  
6 
10 
Phase 2:  
RP2D from Safety Lead-in  
 
^ G-CSF prophylaxis should be administered with each CHEP-BV Induction cycle. The schedule and 
G-CSF formulation are per investigator discretion. 
**For participants with objective response (CR or PR)  
*** Alternatively, etoposide may be given orally. In such case, the daily dose of oral etoposide will 
be 200 mg/m2 [56] and the dose should be rounded to the nearest 50 mg.  
Note: Patients who received 1 cycle of CHOP-like or 1 cycle of CHP-BV therapy prior to initiating induction with 
CHEP-BV are allowed to receive only 5 cycles of CHEP-BV instead of 6 cycles, per investigator’s discretion. 
 
Clinical Observations and Tests to be Performed 
 Medical history and physical exam 
 Safety assessments (CBCs with differential, comprehensive chemistry panel, ECHO/MUGA) 
 CT/ PET-CT scans 
 Bone marrow biopsies  
 Correlative tumor tissue and blood samples. 

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TABLE OF CONTENTS 
SECTION 
 
 
 
 
 
 
 
 
 
          PAGE 
Protocol Team ................................................................................................................................................ 2 
Experimental Design Schema ......................................................................................................................... 3 
Protocol Synopsis............................................................................................................................................ 4 
Table of Contents ......................................................................................................................................... 10 
List of Tables and Figures .............................................................................................................................. 12 
Abbreviations ................................................................................................................................................ 13 
1.0 
Objectives ....................................................................................................................................... 14 
1.1 
Primary Objectives .................................................................................................................... 14 
1.2 
Secondary Objectives ............................................................................................................... 14 
1.3 
Exploratory Objective ............................................................................................................... 14 
2.0 
Background..................................................................................................................................... 14 
2.1 
Introduction/Rationale for Development ................................................................................. 14 
2.2 
Study Rationale ......................................................................................................................... 17 
2.3 
Rationale for Brentuximab vedotin Maintenance in PTCL ........................................................ 18 
2.4 
Rationale for Correlative Studies .............................................................................................. 19 
2.5 
Overview of Study..................................................................................................................... 20 
3.0 
Eligibility Criteria ............................................................................................................................ 22 
3.1 
Inclusion Criteria ....................................................................................................................... 22 
3.2 
Exclusion Criteria ...................................................................................................................... 23 
4.0 
Participant Enrollment ................................................................................................................... 25 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ................................................. 25 
4.2 
Participant Enrollment .............................................................................................................. 25 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment .................. 26 
4.4 
Dose Level Assignment ............................................................................................................. 26 
5.0 
Treatment Program ........................................................................................................................ 27 
5.1 
Treatment Program Overview .................................................................................................. 27 
5.2 
Induction and Consolidation Treatment Cycle Definition ........................................................ 27 
5.3 
Treatment Plan ......................................................................................................................... 28 
5.4 
Safety Lead-In Cohort ............................................................................................................... 28 
5.5 
Phase 2 Cohort .......................................................................................................................... 28 
5.6 
Induction (CHEP-BV) ................................................................................................................. 29 
5.7 
Consolidation (Brentuximab Vedotin Single-Agent) ................................................................. 29 
5.8 
Agent Administration ................................................................................................................ 31 
5.9 
Assessments and Special Monitoring ....................................................................................... 32 
5.10 
Duration of Therapy and Criteria for Removal from Protocol Therapy .................................... 32 
5.11 
Follow-Up.................................................................................................................................. 32 
5.12 
Duration of Study Participation ................................................................................................ 33 
5.13 
Supportive Care, Prohibited Medications and Concomitant Therapy ...................................... 33 
6.0 
Anticipated Toxicities & Dose Modification/ Delay ........................................................................ 35 
6.1 
Anticipated Toxicities ................................................................................................................ 35 
6.2 
Dose Delay/ Modification Guidelines ....................................................................................... 37 
7.0 
Reporting of Adverse Events, Unanticipated Problems & other events of interest ....................... 41 
7.1 
Assessment of Adverse Events ................................................................................................. 41 

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7.2 
Secondary Malignancy .............................................................................................................. 41 
7.3 
Pregnancies ............................................................................................................................... 42 
7.4 
Routine AE Collection and Reporting Guidelines ...................................................................... 42 
7.5 
Expedited Reporting ................................................................................................................. 42 
7.6 
Reporting to the FDA ................................................................................................................ 44 
7.7 
Reporting to Industry Partner ................................................................................................... 44 
8.0 
Agent Information .......................................................................................................................... 46 
8.1 
Brentuximab Vedotin ................................................................................................................ 46 
8.2 
Cyclophosphamide ................................................................................................................... 50 
8.3 
Doxorubicin ............................................................................................................................... 51 
8.4 
Etoposide .................................................................................................................................. 52 
8.5 
Prednisone ................................................................................................................................ 53 
9.0 
Correlative/ Special Studies............................................................................................................ 55 
9.1 
Correlative Study Plan .............................................................................................................. 55 
9.2 
Tumor Tissue Studies ................................................................................................................ 55 
9.3 
Blood samples ........................................................................................................................... 57 
10.0 
Study Calendar ............................................................................................................................... 60 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 63 
11.1 
Safety ........................................................................................................................................ 63 
11.2 
Unacceptable Toxicity ............................................................................................................... 63 
11.3 
Response and Clinical Endpoints .............................................................................................. 63 
12.0 
Statistical Considerations ............................................................................................................... 65 
12.1 
Study Design ............................................................................................................................. 65 
12.2 
Evaluable Participants and Participant Replacement ............................................................... 66 
12.3 
Sample Size Accrual Rate .......................................................................................................... 67 
12.4 
Statistical Analysis Plan ............................................................................................................. 67 
12.5 
Toxicity Monitoring after Safety Lead-in .................................................................................. 68 
13.0 
Data Handling, Data Management, Record Keeping ...................................................................... 69 
13.1 
Source Documents .................................................................................................................... 69 
13.2 
Data Capture Methods and Management ................................................................................ 69 
13.3 
Case Report Forms/Data Submission Schedule ........................................................................ 69 
13.4 
Regulatory Records ................................................................................................................... 70 
14.0 
Adherence to the Protocol ............................................................................................................. 70 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring ............................................. 70 
15.1 
All Investigator Responsibilities ................................................................................................ 70 
15.2 
Study Principal Investigator Responsibilities ............................................................................ 70 
15.3 
Protocol Management Team (PMT) ......................................................................................... 71 
15.4 
Quality Assurance ..................................................................................................................... 71 
15.5 
Risk Determination ................................................................................................................... 71 
15.6 
City of Hope Data and Safety Monitoring Committee .............................................................. 71 
16.0 
Ethical and Regulatory Considerations ........................................................................................... 71 
16.1 
Ethical Standard ........................................................................................................................ 71 
16.2 
Regulatory Compliance ............................................................................................................. 71 
16.3 
Institutional Review Board ....................................................................................................... 72 
16.4 
Informed Consent ..................................................................................................................... 72 
16.5 
Participant Withdrawal ............................................................................................................. 73 
16.6 
Special and Vulnerable Populations ......................................................................................... 73 
16.7 
Participant Confidentiality ........................................................................................................ 74 
16.8 
Use of  Unused (Leftover) Specimens Collected for this Trial................................................... 75 

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16.9 
Conflict of Interest .................................................................................................................... 75 
16.10 
Financial Obligations, Compensation, and Reimbursement of Participants ............................ 75 
16.11 
Publication/ Data Sharing ......................................................................................................... 76 
17.0 
References ...................................................................................................................................... 77 
Appendix A: Performance Status .................................................................................................................. 81 
Appendix B: 2014 Lugano Response Criteria ................................................................................................ 82 
Appendix C: NYHA Cardiac Grading Criteria ................................................................................................. 86 
Appendix D-1: Correlative Tissue Form (for all sites) ................................................................................... 87 
Appendix D-2: Tissue Shipping Guidelines for External Non-COH Sites ....................................................... 88 
Appendix D-3: Correlative Blood Collection Form (Non-COH Sites) ............................................................. 89 
Appendix D-4: Blood Shipping Guidelines For External Non-COH Sites ....................................................... 90 
Appendix E: DCC Registration Coversheet .................................................................................................... 91 
 
LIST OF TABLES AND FIGURES 
Table 5.3 Treatment Regimen and Schedule .......................................................................................... 28 
Table 6.2.1 Dose Modifications for Brentuximab Vedotin ...................................................................... 38 
Table 7.5 Expedited Reporting Guidelines .............................................................................................. 43 
Table 8.1.10 Examples of Dose Preparation Calculations ....................................................................... 48 
Table 9.1 Correlative Study Plan ............................................................................................................. 55 
Table 9.3 Overview of correlative blood studies .................................................................................... 57 
Table 10.0 Study Activity Calendar ......................................................................................................... 60 
Table 13.3 Data Submission Schedule .................................................................................................... 69 
 

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ABBREVIATIONS 
Abbrevation 
 
 
Meaning 
ASCT 
AE 
ALT 
ANC 
AST 
BV 
C 
CFR 
CHEP 
COH 
CR 
CRA 
CRF 
CTCAE 
CTEP 
CTMS 
DSMC 
ECOG 
EOT 
FDA 
GCP 
G-CSF 
NHL 
IB 
ICD 
IND 
IRB 
IV 
PD 
PFS 
PI 
PMT 
PR 
PTCL 
SAE 
SD 
WHO 
Autologous Stem Cell Transplant 
Adverse Event 
Alanine Aminotransferase 
Absolute Neutrophil Count 
Aspartate Aminotransferase 
Brentuximab vedotin 
Cycle 
Code of Federal Regulations 
Cyclophosphamide-Doxorubicin-Etoposide-Prednisone 
City of Hope 
Complete Response 
Clinical Research Associate 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Cancer Therapy Evaluation Program 
Clinical Trial Management System 
Data Safety Monitoring Committee 
Eastern Cooperative Oncology Group 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Granulocyte-colony stimulating factor 
Non-Hodgkin Lymphoma 
Investigator Brochure 
Informed Consent Document 
Investigational New Drug  
Institutional Review Board 
Intravenous 
Progressive Disease 
Progression-Free Survival 
Principal Investigator 
Protocol Monitoring Team 
Partial Response 
Peripheral T-cell Lymphoma 
Serious Adverse Event 
Stable Disease 
World Health Organization 
 
 

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1.0 
OBJECTIVES 
1.1 
Primary Objectives  
Safety Lead-in 
o Assess the safety and tolerability of CHEP-BV, as induction therapy in patients with CD30-
positive peripheral T-cell lymphoma (PTCL)  
Phase 2 
o Assess the anti-lymphoma activity of CHEP-BV as induction treatment in patients with CD30-
positive PTCL. 
1.2 
Secondary Objectives 
o Describe outcomes of CD30-positive PTCL patients who go on to receive BV consolidation 
therapy post CHEP-BV induction with/without autologous hematopoietic cell 
transplantation/radiation. 
1.3 
Exploratory Objective 
o Explore the rate of minimal residual disease (MRD) negativity (as assessed by next-generation 
sequencing) and MRD kinetics after CHEP-BV and BV consolidation therapy in CD30-positive 
PTCL. 
o Explore the possible association between outcome after study treatment and CD30 expression, 
gene expression profiles (GEP), and genetic mutations as measured in PTCL tumor samples. 
2.0 
BACKGROUND 
2.1 
Introduction/Rationale for Development 
CD30 is a cell surface antigen expressed on several malignancies including Hodgkin lymphoma (HL), 
anaplastic large cell lymphoma (ALCL) and other peripheral T-cell lymphomas (PTCL), Kaposi’s sarcoma 
(KS), cutaneous T-cell lymphomas (CTCL), a fraction of diffuse large B-cell lymphomas (DLBCL), some 
follicular lymphomas, and other lymphoproliferative diseases.[2-6] Brentuximab vedotin (BV), previously 
known as SGN-35, is an antibody drug conjugate (ADC) directed against the CD30 antigen that is being 
developed to treat patients with CD30-positive hematologic malignancies. Hodgkin lymphoma and ALCL 
are among the most common CD30-positive malignancies. BV is currently approved for the treatment of 
relapsed or refractory Hodgkin lymphoma and ALCL. 
2.1.1 
Peripheral T-cell Lymphoma 
Peripheral T-cell lymphomas (PTCL) are an uncommon group of disorders, accounting for about 10% of 
all non-Hodgkin lymphomas (NHL). EBV-associated extranodal NK/T-cell lymphoma (NKTCL) is more 
common in parts of Asia and South America, while angioimmunoblastic T-cell lymphoma (AITL) and 
peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) are more common in Western 
countries[7]. PTCLs are generally associated with poor outcomes after standard therapy, with variation 
in prognosis according to disease subtype [7]. ALK-expressing anaplastic large cell lymphomas (ALCL) 
have a favorable prognosis with 5-year survival exceeding 80%, though some studies suggest outcomes 
in ALCL are dependent on age rather than ALK status [7-9]. Anthracycline-based induction combination 

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chemotherapy is standard upfront treatment for patients with TCL; however, with the exception of ALK-
positive ALCL, relapse rates are high [10-12]. The addition of etoposide to standard CHOP induction 
therapy (CHOEP) has been evaluated in patients with PTCL. In an analysis of multiple prospective clinical 
trials by the German High Grade Lymphoma Study Group, CHOEP, as compared to CHOP, resulted in 
improved 3-year event-free survival (75.4% [95% CI 62.1%-88.7%] vs 51.0% [95% CI 35.7%-66.3%], P = 
.003) However, the benefit of etoposide was only observed in patients < 60 years old. In a separate 
study, the addition of etoposide to CHOP was associated with improved PFS compared to CHOP alone in 
patients 60 years old or younger [13]. Based on the findings from these and other studies, CHOEP is a 
recommended regimen in the NCCN guidelines,[14] and is a commonly-used induction regimen for PTCL, 
particularly in younger patients. 
Autologous hematopoietic stem cell transplantation (ASCT) is widely used as consolidation for PTCL 
patients in first remission to reduce the risk of relapse. Single-arm prospective and retrospective studies 
of consolidative ASCT for PTCL in 1st remission report improvements in survival compared to historical 
controls, but progression-free survival (PFS) remains low, ranging from 44-58% at 3-5 years [15-19]. 
Outcomes are poorer in patients who undergo ASCT with relapsed PTCL, with 3-5 year PFS ranging from 
32-41% [19, 20]. 
Current approved therapies available for relapsed or refractory PTCLs include histone deacetylase 
inhibitors (romidepsin and belinostat), pralatrexate, and brentuximab vedotin (for ALCL). With the 
exception of brentuximab vedotin for ALCL, these agents are associated with poor single-agent response 
rates and short median progression free survival [21-23].  
In the pivotal PROPEL trial, 115 heavily pre-treated PTCL patients (median 3 prior systemic therapies) 
received pralatrexate as a single agent. The overall response rate (ORR) in 109 evaluable patients was 
29%, including 12 (11%) complete responses (CR) and 20 (18%) partial responses (PR), with a median 
remission duration of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The 
most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia 
(22%), and anemia (18%) [23].  
Romidepsin is a histone deacetylase (HDAC) inhibitor that has been approved for the treatment of PTCL 
and cutaneous TCL (CTCL). Of the 131 patients enrolled in the pivotal phase II trial, 130 had histologically 
confirmed PTCL by central review. The objective response rate was 25% (33 of 130), including 15% (19 of 
130) with CR/CRu. The median duration of response was 17 months, with the longest response ongoing 
at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease 
progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were 
thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%) [21]. 
Belinostat is a potent hydroxamic acid-derived pan-HDAC inhibitor. It was evaluated in an open-label 
phase II study. A total of 129 relapsed/refractory PTCL patients received 1000 mg/m2 belinostat infusion 
on days 1–5 of every 3-week cycle. Among 120 evaluable patients, the ORR was 26%, including 10% CR, 
and median response duration was 8.3 months. The most common Grade 3–4 AEs were 
thrombocytopenia (13%), neutropenia (13%), and anemia (10%) [24].  
With high relapse rates after standard therapy including ASCT and inadequate second line treatment 
options, novel strategies for decreasing relapse rates in patients with PTCL are urgently needed. 
2.1.2 
Autologous Stem Cell Transplantation for Peripheral T-cell Lymphoma 
High dose therapy and ASCT is commonly used to treat patients with PTCL, both in the relapsed setting 
and as first-line consolidation. ASCT is widely used as consolidation for PTCL patients in first remission to 

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reduce the risk of relapse. The National Comprehensive Cancer Center Guidelines (NCCN) for NHL 
recommend consideration of ASCT for patients with T-cell NHL who achieve a CR or PR after primary 
therapy and are eligible based on age and co-morbidity [14]. Exceptions to this approach include ALK+ 
ALCL, CTCL, and very aggressive T-cell lymphomas (leukemic presentation). Over the past 20 years there 
have been several studies with more than 1400 T-NHL patients, assessing the role of ASCT for treatment 
at various disease stages. Most studies are heterogeneous in terms of patient populations, upfront 
treatment regimens, and conditioning regimens. Almost all studies exclude patients with leukemic 
variants of T-NHL and are limited to otherwise healthy patients with a median age under 60.  
Single-arm prospective and retrospective studies of consolidative ASCT for PTCLs in 1st remission report 
improvements in survival compared to historical controls, but progression-free survival (PFS) remains 
low, ranging from 44-58% at 3-5 years.[15-19] Outcomes are poorer in patients who undergo ASCT with 
relapsed PTCL, with 3-5 year PFS ranging from 32-41%.[19, 20] Chemosensitive disease and ALCL 
histology seem to confer better outcomes in several studies. Other than transplantation in CR1, there is 
no consensus on prognostic factors that impact outcomes after ASCT in PTCL. 
Prospective intent-to-transplant studies by various groups have shown that 41-73% of T-NHL patients 
enrolled on these trials are able to maintain eligibility for, and receive, ASCT [10, 25-29]. The remaining 
patients have progressive or unresponsive disease, are unable to mobilize sufficient stem cells, or have 
co-morbidities that prohibit ASCT. In the largest study by the Nordic Lymphoma Study Group [29], 160 
patients were enrolled with a median follow-up of 60 months. Transplant-related mortality (TRM) was 
4%, and 5-year OS and PFS were 51% and 44%, respectively. Outcomes were analyzed by histology: ALK- 
ALCL, 5-year OS of 70% and PFS of 61%; AITL, OS 52%, PFS 49%; PTCL-NOS, OS 47%, PFS 38%; EATL, OS 
48%, DFS 38%. Female sex and ALCL histology conferred a favorable prognosis, and International 
Prognosis Index (IPI) had predictive value for OS in AITL, and for PFS in AITL and PTCL-NOS. Bone marrow 
involvement and increasing age were negative prognostic factors. 
Most reports of ASCT for PTCL have reported the use of chemotherapy-based conditioning regimens, the 
most common being BEAM (BCNU/etoposide/ara-C/melphalan), BEAC (BCNU/etoposide/ara-
C/cyclophosphamide), CBV (cyclophosphamide/BCNU/etoposide), and busulfan (Bu)/cyclophosphamide 
(Cy). Many patients have also received total body irradiation (TBI)-based regimens, usually in 
combination with cyclophosphamide or etoposide or both. City of Hope compared outcomes of 41 
patients treated with TBI-based regimens to 26 patients with non-radiation-based regimens and 
reported no differences [30]. Conditioning regimen appears to be determined by physician choice and 
currently there are no specific recommendations regarding conditioning regimens for PTCL ASCT. 
2.1.3 
CD30 Expression in Peripheral T-cell Lymphoma 
CD30 expression is universal in ALCL, but CD30 expression has also been demonstrated in other PTCL 
subtypes. In addition to 100% of ALCLs, some degree of CD30 expression has also been demonstrated in 
about 50% of patients with selected other PTCL subtypes, including: peripheral T-cell lymphoma, not 
otherwise specified (PTCL NOS): 32-58%[31-33]; angioimmunoblastic T-cell lymphoma (AITL): 43-
63%[31, 33]; enteropathy-associated T-cell lymphoma (EATL): 38–100% (Type I)[31, 33, 34]; extranodal 
NK/T-cell lymphoma (NKTCL): 31-80%[31, 33, 35, 36]; and adult T-cell lymphoma/leukemia (ATLL): 50-
56%[31, 37] The prognostic impact of CD30 expression in PTCLs has been evaluated in retrospective 
studies of heterogeneously treated patients, with the impact of CD30 expression varying by PTCL 
subtype. CD30 expression was associated with poorer survival in PTCL NOS, favorable outcome in 
NKTCL, a trend towards longer survival in ATLL, whereas it did not appear to impact prognosis in AITL or 
EATL. 

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2.1.4 
Brentuximab Vedotin 
Brentuximab vedotin, previously known as SGN-35, is an ADC consisting of the chimeric antibody SGN-
30 (cAC10) chemically conjugated to a synthetic analog (monomethylauristatin E [MMAE]) of the 
naturally occurring anti-tubulin agent, dolastatin10. Brentuximab vedotin is proposed to have a multi-
step mechanism of action that is initiated by binding to CD30 on the cell surface and internalization of 
the ADC. Upon trafficking to lysosomes, MMAE is released from the conjugate through proteolytic 
degradation of the drug linker.[38] Binding of released MMAE to tubulin disrupts the microtubule 
network, leading to G2/M phase cell cycle arrest and apoptosis.[39] 
Preclinical studies of brentuximab vedotin demonstrated antitumor activity in both in vitro and in vivo 
models. The toxicity of multiple doses of brentuximab vedotin has been assessed in rats and monkeys. In 
both species, hypocellularity of the bone marrow and lymphoid depletion of the thymus were observed. 
Histopathologic lesions were also observed in the spleen in monkeys and in the liver and testes in rats. 
In addition, decreases in peripheral blood counts were observed in both species, and elevations in liver 
enzymes were seen in rats only. The most significant clinical toxicity was neutropenia, observed in 
monkeys, which resulted in secondary bacterial infections leading to early deaths at the 6 mg/kg dose. 
Toxicity was dose-dependent, with a no-observable-adverse-effect level of 0.5 mg/kg in rats and 1 
mg/kg in monkeys. See the brentuximab vedotin SGN-35 Investigator’s Brochure for details of the 
nonclinical data. 
2.2 
Study Rationale 
Brentuximab vedotin is an effective treatment for patients with PTCL. Brentuximab vedotin is FDA-
approved for relapsed CD30 expressing systemic anaplastic large cell lymphoma [40]. In a single-arm 
Phase 2 study, 58 patients were treated with brentuximab vedotin 1.8mg/kg intravenously every 3 
weeks, resulting in a 86% ORR, including 33 patients (57%) complete remissions, and 17 (29%) partial 
remissions. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. 
Grade 3 or 4 adverse events in 10% of patients were neutropenia (21%), thrombocytopenia (14%), and 
peripheral sensory neuropathy (12%). More recently, in a Phase 2 study of brentuximab vedotin in 34 
patients with relapsed or refractory PTCLs other than ALCL, brentuximab vedotin treatment resulted in 
an ORR of 41%, with a 54% ORR in patients with AITL. The median duration of response was 7.6 months, 
and the median follow-up time was 2.7 months. The overall disease control rate was 59%, with a 77% 
disease control rate in patients with AITL [1]. Response was not associated with the presence or degree 
of CD30 expression. 
In addition, the clinical safety and activity of brentuximab vedotin administered sequentially and 
concurrently with multi-agent chemotherapy were evaluated in a phase 1 study in patients with newly 
diagnosed CD30-positive mature T- and NK-cell neoplasms, including sALCL (Study SGN35-011; 
NCT01309789). This Phase 1 study was implemented to determine the safety and activity of sequential 
and combination frontline treatment approaches of brentuximab vedotin with CHOP or CHP 
chemotherapy. In order to avoid excessive, overlapping toxicity from dual microtubule inhibition, 
vincristine was omitted from CHOP when BV was administered concurrently, so that BV-CHP were 
administered concurrently and CHOP and BV were administered sequentially. The maximum tolerated 
dose of brentuximab vedotin was 1.8 mg/kg given concomitantly with CHP. At an interim analysis in this 
study (data presented at the T-Cell Lymphoma Forum 2012), 20 patients in this study had been treated 
with brentuximab vedotin 1.2 or 1.8 mg/kg given concomitantly with CHP for 6 cycles, followed by 
continued brentuximab vedotin every 3 weeks for up to 10 additional cycles for responding patients. 
The most common adverse events were nausea, fatigue, and peripheral sensory neuropathy. Of the 

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patients who had a response assessment after 6 cycles of brentuximab vedotin plus CHP, 5 of 5 patients 
achieved a CR. In the final report of the study results, published in 2014 by Fanale et al., the ORR to 
sequential CHOP and brentuximab vedotin therapy was 85% with a CR rate of 62%, whereas the ORR to 
CHP-BV therapy was 100% with a CR rate of 88%. The most common Grade 3/4 AEs were febrile 
neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%). Based on the 
safety and efficacy observed in this Phase 1 study, a randomized Phase 3 study of CHP-BV compared to 
CHOP as upfront therapy is being conducted in patients with CD30+ PTCL. 
The ECHELON-2 trial is a randomized trial that is currently comparing the addition of brentuximab 
vedotin 
to 
cyclophosphamide, 
doxorubicin, 
and 
prednisone 
(CHP) 
with 
standard-of-care 
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the initial treatment of patients 
with CD30-positive PTCL. However, based on evidence that the addition to etoposide to standard CHOP 
(CHOEP) is beneficial, CHOEP is often administered as initial treatment of patients with PTCL. Therefore, 
while ECHELON-2 will address whether brentuximab vedotin added to CHP is superior to CHOP therapy, 
there are no data regarding the safety and efficacy of brentuximab vedotin added to etoposide-
containing induction chemotherapy (cyclophosphamide, doxorubicin, etoposide, and prednisone - 
CHEP). Since November 16, 2018 and based on the ECHELON-2 trial, brentuximab vedotin is FDA-
approved in combination with CHP chemotherapy for previously untreated, systemic ALCL or other 
CD30-expressing PTCL. We propose a Phase 2 study to assess the anti-lymphoma activity brentuximab 
vedotin when combined with CHEP (CHEP-BV) in patients with newly-diagnosed CD30-positive PTCL. 
With the exclusion of patients with favorable risk ALK+ ALCL, long term outcomes of patients with PTCL 
treated with standard anthracycline-based chemotherapy are dismal [10-13, 18], even when 
consolidative autologous stem cell transplantation is performed (progression-free survival of 41-58% at 
3-5 years) [13, 15-19], and even among patients who achieve CR with induction therapy and/or 
consolidative transplantation are considered  (4-year event-free survival 59% [10]). Improvement of 
upfront treatment of PTCL that can provide not only responses, but durable responses (the reason we 
are also evaluating BV consolidation with this study) is an urgent unmet need, and since evaluation of 
the safety of CHEP-BV induction is not feasible in patients with relapsed or refractory PTCL, the 
enrollment of newly diagnosed CD30+ PTCL patients in the safety lead-in is appropriate. In this study, 
enrollment will be limited to high risk subtypes of PTCL, whereas patients with early stage and low-risk 
ALK+ ALCL have been excluded to ensure that the use of an investigational induction regimen in newly 
diagnosed patients is appropriate. Furthermore, since BV has been combined with CHP previously and 
has been found to be safe [41], it is anticipated that the addition of etoposide will be safe and tolerable. 
An increased frequency of hematologic toxicity with the addition of etoposide is not anticipated, but is 
possible. Therefore, this study will mandate the use of G-CSF during induction CHEP-BV therapy. To 
ensure that we are adequately assessing the safety of the regimen, we have designed the safety lead-in 
similar to a Phase 1 study, with a starting dose-level and unacceptable toxicity (essentially DLT) criteria 
and a dose de-escalation level if a sufficiently high rate of unacceptable toxicity is observed. Since we 
are performing a Phase 2 study with a new regimen, stopping rules are also included to ensure that we 
are continuing to evaluate the safety of the regimen during the entire study. 
2.3 
Rationale for Brentuximab vedotin Maintenance in PTCL 
Many patients with PTCL are treated with autologous hematopoietic stem cell transplantation (ASCT) in 
1st remission to reduce the risk of relapse after upfront therapy. Single-arm prospective and 
retrospective studies of consolidative ASCT for PTCLs in 1st remission report improvements in survival 
compared to historical controls, but progression-free survival (PFS) remains low, ranging from 44-58% at 

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3-5 years [18, 19]. Based on these data, ASCT in 1st remission is supported by the NCCN guidelines for 
PTCL. 
The AETHERA trial demonstrated that brentuximab vedotin consolidation treatment following ASCT 
prolongs PFS in patients with relapsed or refractory classical Hodgkin lymphoma compared to placebo 
[42]. In this randomized Phase 3 study, 329 patients received either placebo or brentuximab vedotin 
1.8mg/kg IV every 3 weeks for 16 cycles starting 30-45 days after ASCT. Median PFS was 42.9 months for 
patients receiving brentuximab vedotin versus 24.1 months in patients receiving placebo (p=0.0013). A 
similar approach, using brentuximab vedotin consolidation therapy after ASCT, is an attractive strategy 
for PTCL. Outcomes after ASCT for patients with PTCL who undergo ASCT in CR1 are poor. With the 
encouraging response and disease control rates seen across PTCL subtypes, brentuximab vedotin 
treatment after ASCT could deepen and consolidate a patient’s response to pre-ASCT therapy and 
provide continued disease control after ASCT. 
Even if the paradigm of PTCL therapy shifts with the ongoing ECHELON-2 trial, which is currently 
evaluating the addition of brentuximab vedotin to upfront induction chemotherapy for CD30-positive 
PTCL, brentuximab vedotin consolidation after ASCT in patients with PTCL who relapse and require ASCT 
may be beneficial. The role of ASCT is not being evaluated in the ECHELON-2 trial, so patients with PTCL 
in 1st remission after brentuximab vedotin-containing induction therapy may still proceed to ASCT. Even 
in the setting of brentuximab vedotin-containing induction therapy, brentuximab vedotin consolidation 
after upfront ASCT may provide enhanced disease control in a disease with a high rate of relapse after 
initial response.  
In the Phase 1 study of CHP-BV or CHOP followed by brentuximab vedotin, patients in response at the 
end of induction therapy were eligible to receive single-agent brentuximab vedotin consolidation for an 
additional 10 cycles. The 1-year PFS (71%) and OS (88%) rates observed to CHP-BV on this study was 
excellent, with a median PFS not reached in the CHP-BV group. Of note, all patients who were in CR after 
CHP-BV were in continued CR after 16 cycles of brentuximab vedotin therapy and one patient with a PR 
to CHP-BV converted to CR with maintenance therapy. These findings suggest that additional 
brentuximab vedotin treatment after induction therapy may prolong the remissions observed after 
brentuximab vedotin-containing induction therapy for CD30-positive PTCLs. In patients who are not 
treated with ASCT after induction therapy, brentuximab vedotin maintenance therapy could potentially 
deepen and consolidate responses to induction therapy and provide prolonged disease control similar to 
ASCT. 
There is currently no standard of care treatment to prevent relapse after upfront treatment or ASCT for 
CD30-positive TCLs. An agent that could improve outcomes in this population would be a major 
contribution to the field, and is likely to be practice changing.  Therefore, in addition to studying the 
anti-lymphoma activity of CHEP-BV as induction therapy, in patients who respond to induction CHEP-BV 
therapy, as a secondary objective we propose to add brentuximab vedotin consolidation after ASCT in 
patients treated with ASCT and to add brentuximab vedotin consolidation after CHEP-BV in patients who 
are not treated with upfront ASCT. 
2.4 
Rationale for Correlative Studies 
Genomic signatures define distinct subsets of PTCL and are associated with outcome after standard 
therapy [43-45]. Molecularly distinct subgroups exist even within PTCL histologic subtypes that are 
biomarkers of outcome and enhance prognostication over simple morphologic classification. We will 
evaluate whether these genomic signatures as determined by mutational and gene expression profiles 
in pre-treatment tumor samples are associated with response and outcome after CHEP-BV therapy. 

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In addition, next-generation sequencing (NGS)-based minimal residual disease (MRD) detection using 
the immunoglobulin or T-cell receptor genes can identify circulating tumor DNA (ctDNA) in the 
peripheral blood mononuclear cells (PBMC) and plasma (cell-free) of patients with lymphoid 
malignancies.  NGS-based ctDNA detection is at least as sensitive as existing MRD detection methods, 
and can detect MRD not identified by multi-parameter flow cytometry or allele-specific oligonucleotide 
polymerase chain reaction testing [46-48]. The NGS-based MRD detection method can identify ctDNA at 
diagnosis in a range of lymphomas, including classical Hodgkin lymphoma (HL) and diffuse large B-cell 
lymphoma (DLBCL), subtypes in which MRD detection has previously been challenging [49-52]. In 
addition, ctDNA levels track with treatment response in DLBCL, and the persistence or recurrence of 
ctDNA during and after upfront therapy is associated with subsequent DLBCL relapse [51, 52]. We have 
previously shown that ctDNA assessment is feasible and that ctDNA can be detected in patients with 
PTCL [53]. In this study, we aim to further validate ctDNA detection in patients with PTCL, assess ctDNA 
kinetics in the setting of induction and consolidation therapy, and determine the rate of ctDNA-
negativity after CHEP-BV induction and brentuximab vedotin consolidation. 
2.5 
Overview of Study  
This is an open-label multi-site Phase 2 study with a Safety Lead-in to test the safety and efficacy of 
CHEP-BV as Induction therapy followed by single-agent brentuximab vedotin consolidation therapy for 
the treatment of CD30-positive PTCL. 
Eligibility 
Eligible patients will be adults with histologically confirmed CD30-positive PTCL or NK-cell lymphoma 
defined per WHO 2008 criteria [54]. NOTE: per Amendment dated 05-10-19, ALCL will no longer be 
eligible except for Canada. Eligible patients must be treatment naïve but may have received 1 cycle of 
CHOP-like therapy (e.g. CHOP, CHOEP, EPOCH) or 1 cycle of CHP-BV prior to initiating Induction with 
CHEP-BV. PTCL is an aggressive malignancy and patients are often started on therapy urgently, and BV is 
now FDA-approved in combination with CHP chemotherapy for previously untreated, systemic ALCL or 
other CD30-expressing PTCL. Allowing a prior cycle of chemotherapy or one cycle of CHP-BV before 
study entry will allow us to enroll a more representative population of PTCL patients with aggressive and 
non-aggressive disease and will facilitate accrual. Patients who received 1 cycle of CHOP-like or 1 cycle 
of CHP-BV therapy prior to initiating induction with CHEP-BV are allowed to receive only 5 cycles of 
CHEP-BV instead of 6 cycles, per investigator’s discretion. 
Treatment program 
Newly diagnosed CD30-positive PTCL patients will be treated with up to 6 cycles of CHEP-BV followed by 
up to 10 cycles of single-agent brentuximab vedotin (IV once every 21-days) for responding patients. 
CHEP will be administered per institutional standards, and IV or oral etoposide is acceptable (see Section 
5.3). 
Since ASCT and/or radiation in 1st response is standard of care for some patients with PTCL, following 
CHEP-BV Induction, responding patients in this trial may receive consolidation ASCT/radiation prior to 
initiating Consolidation brentuximab vedotin.  
Participants will continue with treatment until disease progression, unacceptable toxicity or completion 
of protocol therapy (induction and consolidation, ~ 12 months), whichever comes first. Participants who 
discontinue brentuximab vedotin during Induction may continue to receive CHEP therapy per standard 
of care. 

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Safety Lead-in 
During the Safety Lead-in, up to 6-12 evaluable participants will be enrolled using a 3+3 design. The 
starting dose for brentuximab vedotin will be 1.8 mg/kg (Dose level 1) in combination with CHEP based 
on prior experience from study SGN35-011 (NCT01309789). Unacceptable toxicities will be evaluated 
during the first cycle of Induction therapy. 
In the event the initial starting brentuximab vedotin dose is not tolerable (2+ patients with unacceptable 
toxicity in  ≤6 evaluable participants), a brentuximab vedotin dose of 1.2 mg/kg (Dose level -1) will be 
explored in combination with CHEP in an additional 6 evaluable participants .  
Phase 2 
The Recommended Phase 2 Dose (RP2D) of brentuximab vedotin established during the Safety Lead-in 
will be used for the Phase 2 portion to test the Induction regimen. Per Amendment dated 05-10-19: 
Given the ECHELON-2 data results, the statistical design is being revised to consider a baseline rate of 
56% instead of 40%, and to increase the total study accrual to 48 evaluable patients. 
Response  
Response assessments will occur during Induction (end of Cycles 3 and 6) and during Consolidation 
every 3-4 cycles. End of Cycle 6 response assessment will determine which participants may continue 
onto receive Consolidation therapy. Lymphoma response and progression will be assessed by 
investigators based on PET-CT/CT scans according to the 2014 Lugano Classification. [55] Patients who 
are receiving only 5 cycles of CHEP-BV per investigator’s discretion (because they received 1 cycle of 
CHOP-like or 1 cycle of CHP-BV therapy prior to start of protocol therapy) will have their response 
assessment during Induction at end of Cycles 3 and 5. 
Correlative studies 
The correlative analyses that will be performed as part of this clinical trial are exploratory and intended 
to generate hypotheses that can be validated in larger studies. The list of correlative studies below is not 
meant to be exhaustive, as it is anticipated that the exact nature and type of correlative studies may 
change as new scientific data emerges during the course of the study. 
Planned correlative studies include: 
o Gene expression and mutational profiling of PTCL tumor specimens to determine whether there 
are expression profiles and/or mutations associated with outcome after study therapy. 
o Next-generation sequencing-based minimal residual disease (MRD) assessment. We will assess 
MRD at baseline, and at all pre-specified imaging time points. These sequential samples will 
allow us the track the temporal dynamics of MRD after CHEP plus BV, and to determine whether 
maintenance therapy can eradicate MRD in patients who are MRD+ after induction therapy. 
 

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3.0 
ELIGIBILITY CRITERIA 
Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution 
Participants must meet all of the following criteria on screening examination to be eligible to participate 
in the study:  
3.1 
Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent of participant and/or Legally Authorized Representative. 
__2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies will be retrieved and 
submitted post-enrollment (See Section 9.2 for details) 
 If unavailable, exceptions may be granted with Study PI approval. 
Age Criteria and Performance Status 
__3. Age: ≥ 18 years  
__4. ECOG status ≤ 2 
Nature of Illness and Transplant Related Criteria 
__5. Histologically confirmed mature peripheral T-cell or NK-cell lymphoma per WHO classification, 
including: 
 
*ALK-positive ALCL with IPI of 2 or higher (must have bulky [defined as mass ≥ 10 cm] 
Stage II, or Stage III-IV disease) 
 
*ALK-negative ALCL 
*NOTE: per Amendment dated 05-10-19, ALCL will no longer be eligible except for Canada. 
 
PTCL-NOS 
 
AITL 
 
ATLL 
 
EATL 
 
Hepatosplenic T-cell lymphoma 
__6. CD30-positivity (e.g. at least 1%) by immunohistochemistry confirmed by hematopathology review 
at the participating institution. 
__7. Measurable disease of at least 1.5cm on CT or PET-CT scan 
Clinical Laboratory and Organ Function Criteria  
__8. ANC ≥ 1,000/mm3  
Exception: Unless documented bone marrow involvement by lymphoma. 
ANC: 
Date: 
__9. Platelets ≥ 50,000/mm3  
Exception: Unless documented bone marrow involvement by lymphoma. 
Plts: 
 
Date: 
__10. Total serum bilirubin ≤ 1.5X upper limit of normal (ULN) OR 
 If hepatic involvement by lymphoma: ≤ 3X ULN for Gilbert’s disease or 
documented hepatic involvement by lymphoma 
ULN: 
Bil: 
Date: 
__11. AST ≤ 2 x ULN OR 
If hepatic involvement by lymphoma: AST ≤ 5 x ULN  
ULN: 
AST: 
Date: 

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Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution 
 
__12. ALT ≤ 2 x ULN OR 
If hepatic involvement by lymphoma: ALT ≤ 5 x ULN 
ULN: 
ALT: 
Date: 
__13. Creatinine clearance of ≥ 60 mL/min per the Cockcroft-Gault formula 
 
Serum Cr: 
 
Cr Cl: 
Date: 
__14. Left ventricular ejection fraction (LVEF) ≥ 45% 
LVEF: 
Date: 
__15. Women of childbearing potential (WOCBP): negative urine or serum 
pregnancy test  
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required 
Urine: 
Serum: 
Date: 
 
 
 
 
 
 
 
Contraception 
__16. Agreement by WOCBP and males of childbearing potential* to use an effective method of birth 
control or abstain from heterosexual activity for the course of the study through at least 6 months after 
the last dose of protocol therapy.  
 
Childbearing potential defined as not being surgically sterilized (men and women) or have 
not been free from menses for > 1 year (women only). 
3.2 
Exclusion Criteria 
Prior therapies 
__1.  Prior treatment of PTCL with systemic anti-lymphoma therapies, investigational agents, 
radiation  
 
Exception: May have received 1 cycle of CHOP-like therapy (e.g. CHOP, CHOEP, EPOCH) or 
1 cycle of CHP-BV; these participants must initiate Day 1 Cycle 1 of study therapy (CHEP-
BV) no less than 19 days from prior CHOP-like or CHP-BV therapy. Patients who received 1 
cycle of CHOP-like or 1 cycle of CHP-BV therapy prior to initiating induction with CHEP-BV 
are allowed to receive only 5 cycles of CHEP-BV instead of 6 cycles, per investigator’s 
discretion. 
Other illnesses or conditions 
__2.  History of another primary invasive cancer, hematologic malignancy, or myelodysplastic 
syndrome that has not been in remission for at least 3 years.  
 
Exceptions: Non-melanoma skin cancer and in situ cervical cancer. 

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Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Institution 
 
__3.  Symptomatic cardiac disease (including symptomatic ventricular dysfunction, 
symptomatic coronary artery disease, and symptomatic arrhythmias), cerebrovascular 
event/stroke or myocardial infarction within the past 6 months. See Appendix C. 
__4.  Central nervous system involvement by lymphoma, including leptomeningeal 
involvement. 
__5.  History of progressive multifocal leukoencephalopathy (PML). 
__6.  Active  ≥ Grade 3 viral, bacterial, or fungal infection within 2 weeks prior to Day 1 of 
protocol therapy 
__7.  Any known human immunodeficiency virus (HIV) infection, hepatitis B surface antigen-
positive status, or known or suspected active hepatitis C infection.  
__8.  Baseline peripheral neuropathy ≥ Grade 2 or patients with the demyelinating form of 
Charcot-Marie-Tooth syndrome. 
__9.  Known severe hypersensitivity to any study related agent excipient(s)  
__10.  Females only: pregnant or breastfeeding 
__11.  Any other condition that would, in the Investigator’s judgment, contraindicate the 
patient’s participation in the clinical study due to safety concerns with clinical study 
procedures. 
Noncompliance 
__12.  Prospective participants who, in the opinion of the investigator, may not be able to 
comply with all study procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* 
by (Choose as 
applicable): 
Print Name 
Signature 
Date 
 Site Lead Investigator 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 

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4.0 
PARTICIPANT ENROLLMENT  
NOTE: Sites must meet activation requirements prior to enrolling participants. 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. 
The informed consent process is to be fully documented (see Section 16.4), and the prospective 
participant must receive a copy of the signed informed consent document.  Screening procedures are 
listed in Section 10.0. 
4.2 
Participant Enrollment 
4.2.1 
COH DCC Availability and Contact Information 
Eligible participants will be registered on the study centrally by the DCC at City of Hope. 
DCC staff are available between the hours of 8:00 a.m. and 5:00 p.m. PST, Monday through Friday 
(except holidays).   DCC contact information is as follows: 
o E-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
Designated study staff should email the DCC to verify current slot availability, and to reserve a slot for a 
specific prospective subject (provide DCC with subject initials), including a tentative treatment date.  
Slots can only be held for a limited time, at the discretion of the study PI.   
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible. 
4.2.3 
Registration Process 
Allow up to 24 hours for the DCC to review. To register a participant, the subsequent procedure must be 
followed: 
1. The study team should contact the DCC via email to provide notification regarding the pending 
registration and communicate desired timeline of the registration, especially if it must be completed 
promptly to meet the registration window. 
2. The study team should then e-mail a Complete Registration Packet to the DCC, which consists of a 
copy of the following documents:  
 Registration Cover Sheet (Appendix E) 
 Completed Eligibility Checklist (printed from Section 3.0 of the protocol) with required 
signature(s) 
 Signed informed consent 
 Signed HIPAA authorization form (if separate from the informed consent) 
 Signed subject’s Bill of Rights (California only)  

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3. In some cases, the DCC may request additional documentation prior to registration. Please refer to 
the Work Instruction – Reviewing Packets and Registering Subjects for more information. A copy of 
this work instruction can be provided by the DCC, upon request. 
4. When all documents are received, the DCC will review and work with the study team to resolve any 
missing elements. Any missing documents may delay registration. A participant failing to meet all 
requirements will not be registered and the study team will be immediately notified.  
5. The DCC will send a Confirmation of Registration Form, including the Subject Study Number and 
cohort assignement:  
 The study team: Site Lead Investigator, treating physician/ sub investigator, protocol nurse, 
CRC and pharmacy (as needed) 
 The COH Study PI and COH study team designees (including but not limited to study 
monitor(s) and statistician(s). 
6. Upon receipt of the Confirmation of Registration Form, COH study team will register the patient in 
OnCore.  The DCC will register non-COH patients in OnCore. 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC immediately if the participant screen fails after registration or if the participant does not 
start treatment. 
For non-COH sites, the reason for screen failure will be documented in the registration coversheet 
(Appendix E) and submitted to the DCC. 
Issues that would cause treatment delays should be discussed with the Study PI. 
4.4 
Dose Level Assignment 
During the Safety Lead-in stage, eligible participants will be assigned a dose level (Section 5.3). Once the 
recommended phase 2 dose (RP2D) is defined, participants will enroll at the RP2D dose (Section 5.4). 

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5.0 
TREATMENT PROGRAM 
5.1 
Treatment Program Overview 
This is a multi-center, open-label, Phase 2  clinical trial of brentuximab vedotin (BV) plus 
cyclophosphamide, doxorubicin, etoposide, and prednisone (CHEP-BV) followed by brentuximab vedotin 
consolidation for CD30-positive PTCL patients (Section 5.3).  
The trial consists of a: 
o Safety Lead-in stage to evaluate safety/tolerability of brentuximab vedotin with CHEP (Section 
5.4) and  
o Phase 2 stage to evaluate anti-tumor activity of the regimen in the study population (Section 
5.5).  
Each cycle will be 21 days (Section 5.2). Up to 16 cycles of protocol therapy is planned in the absence of 
unacceptable toxicity or disease progression (Section 5.10). If one agent is discontinued due to toxicity 
during CHEP-BV induction, then the participant may continue to receive the other protocol therapy 
agents. 
Participants with objective response following Induction may undergo consolidative autologous stem 
cell therapy (ASCT)/ receive radiation prior to continuing with Consolidation brentuximab vedotin. See 
Section 5.7 for details. 
Participants who end protocol therapy will undergo follow-up (Section 5.11).  Windows for all 
assessments and treatments are detailed in Section 10.0. 
5.2 
Induction and Consolidation Treatment Cycle Definition 
In the absence of a delay due to toxicity, each treatment cycle lasts 21 days with a ± 3 day window 
during Induction and Consolidation. 
o Induction CHEP-BV (Section 5.6):  
 Day 1 of each cycle will be defined as the first day of administration of chemotherapy.  
 If chemotherapy is permanently discontinued and brentuximab vedotin is being continued, 
then Day 1 of each cycle will be defined as the day of administration of brentuximab vedotin.  
o Consolidation brentuximab vedotin (Section 5.7): Day 1 of each treatment cycle is defined by 
the day of administration of brentuximab vedotin. 

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5.3 
Treatment Plan 
The treatment plan for the Safety Lead-in and Phase 2 cohorts is as follows (Table 5.3). 
Table 5.3 Treatment Regimen and Schedule 
 
Agent 
Dose 
Route 
Schedule 
(Days within 
each 21-day 
cycle) 
Maximum # Cycles 
 
Induction^  
CHEP-BV 
(Section 5.6) 
Consolidation-
BV** 
(Section 5.7) 
CHEP 
Cyclophosphamide 
750 mg/m2 
IV 
Day 1  
6 
N/A 
Doxorubicin 
50 mg/m2 
IV 
Day 1  
6 
Etoposide*** 
100 mg/m2 
IV 
Days 1-3  
6 
Prednisone 
100 mg daily 
Orally 
Days 1-5  
6 
 
Brentuximab 
Vedotin (BV) 
Safety Lead-in (Section 5.4)  
 
Dose Level 1*: 1.8 mg/kg 
 
Dose Level -1: 1.2 mg/kg 
 
*Starting dose 
IV over 
30 
minutes 
(+10 
minutes) 
Day 1  
6 
10 
Phase 2:  
RP2D from Safety Lead-in (Section 5.5) 
 
^ G-CSF prophylaxis should be administered with each CHEP-BV Induction cycle. The schedule and G-CSF 
formulation are per investigator discretion. 
**For participants with objective response (CR or PR)  
*** Alternatively, etoposide may be given orally. In such case, the daily dose of oral etoposide will be 200 
mg/m2 [56] and the dose should be rounded to the nearest 50 mg. 
Note: Patients who received 1 cycle of CHOP-like or 1 cycle of CHP-BV therapy prior to initiating 
induction with CHEP-BV are allowed to receive only 5 cycles of CHEP-BV instead of 6 cycles, per 
investigator’s discretion. 
5.4 
Safety Lead-In Cohort 
During the Safety Lead-in, up to 6-12 evaluable participants will be enrolled using a 3+3 design. The 
starting dose for brentuximab vedotin will be 1.8 mg/kg in combination with CHEP (Table 5.3). 
Unacceptable toxicities (defined in Section 11.2) will be evaluated during Cycle 1 of CHEP-BV Induction 
therapy. 
In the event the initial starting brentuximab vedotin dose is not tolerable (2+ patients with unacceptable 
toxicity in  ≤6 evaluable participants), a brentuximab vedotin dose of 1.2 mg/kg will be explored in an 
additional 6 evaluable participants.  
5.5 
Phase 2 Cohort 
The Recommended Phase 2 Dose (RP2D) of brentuximab vedotin established during the Safety Lead-in 
will be used for the Phase 2 portion (Table 5.3). Participants treated at the tolerable dose during the 
Safety Lead-in participants will be included in the Phase 2 portion of the study if they are evaluable for 

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response. Per Amendment dated 05-10-19: Given the ECHELON-2 data results, the statistical design is 
being revised and the total study accrual is being increased to 48 evaluable patients. 
See Section 12.0 for details. 
5.6 
Induction (CHEP-BV)   
o See Section 5.13.2 regarding pegfilgrastim administration as supportive care. 
o Up to 6 cycles of CHEP-BV 
o If one agent is discontinued due to toxicity, then the participant may continue to receive the 
other protocol therapy agents.  
o Participants with PR or CR on restaging prior to cycle 4 will continue to receive Cycles 4-6 
o Participants with stable disease on restaging prior to cycle 4 may continue to Cycles 4-6 per 
investigator discretion  
Timing and windows for imaging are detailed in Section 10.0. 
5.7 
Consolidation (Brentuximab Vedotin Single-Agent)   
NOTE: Participants must meet criteria in Section 5.7.1 to initiate Consolidation.  
o Maximum 10 cycles of brentuximab vedotin 
o Initiate after 
 Post-consolidative autologous stem cell transplantation (ASCT); OR 
 Post-consolidative radiation therapy (with/without ASCT); OR  
 Post-Induction 
o If NOT receiving consolidation ASCT 
 Initiate Consolidation within 8 weeks post-Induction. 
o If receiving consolidation ASCT 
 Stem cell mobilization and collection and ASCT will be performed per institutional standards. 
 Initiate Consolidation between Day + 30 and Day + 60 post-ASCT. A delay of up to Day + 75 is 
permitted following consultation with the Study PI for certain criteria (see Section 5.7.1 
below). 
 Screening may initiate 21 days after ASCT. 
5.7.1 
Criteria to Receive Consolidation Brentuximab Vedotin  
Participants must meet the below criteria to receive Consolidation therapy with single-agent 
brentuximab vedotin after completing 6 cycles of CHEP-BV. 
Note: Patients who qualify for receiving 5 cycles of CHEP-BV instead of 6 cycles can start consolidation 
therapy after completing Cycle 5 of CHEP-BV. 

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Criteria to be met in order to initiate Consolidation 
brentuximab vedotin 
Action if criterion to the LEFT is NOT met 
1. Achieved objective response per 2014 Lugano 
Classification on Cycle 6 Day 15 Induction assessment 
(or on Cycle 5 Day 15 for patients who qualify for 
receiving 5 cycles of CHEP-BV instead of 6 cycles) 
Discontinue protocol therapy.   
2. No ≥ Grade 3 peripheral motor neuropathy or Grade 4 
peripheral sensory neuropathy  
Follow dose modification guidelines in Section 
6.2 if the participant is experiencing peripheral 
neuropathy. 
3. Absence of unrelated toxicity not present at baseline 
that might adversely affect participation/ administration 
of brentuxiumab vedotin  
Discontinue protocol therapy.   
Additionally, participants who also received ASCT MUST meet below criteria 
Note: Screening can initiate 21 days post-ASCT 
1. Recovered from ASCT toxicities 
Including: outpatient status, able to drink and eat 
normally, and do not need intravenous hydration prior 
to Cycle 1 Day 1 of Consolidation therapy 
Following consultation with Study PI delay 
initiation of Consolidation up to Day +75 post-
ASCT may be permitted. 
 
 
2. Will initiate treatment between Day +30 and Day +60 
post-ASCT 
3. ECOG ≤ 2  within the screening period  
4. ANC ≥ 1,000/mm3 within 14 days prior to Day 1 of 
Consolidation 
Exception: Unless documented bone marrow 
involvement by lymphoma 
5. Platelets ≥ 50,000/mm3 within 14 days prior to Day 1 of 
Consolidation 
Exception: Unless documented bone marrow 
involvement by lymphoma. 
6. Total serum bilirubin ≤ 1.5X upper limit of normal (ULN) 
OR if hepatic involvement by lymphoma ≤ 3X ULN for 
Gilbert’s disease or documented hepatic involvement by 
lymphoma within 14 days prior to Day 1 of 
Consolidation 
7. AST ≤ 2 x ULN OR if hepatic involvement by lymphoma 
AST  ≤  5 x ULN within 14 days prior to Day 1 of 
Consolidation 
8. ALT ≤ 2 x ULN OR If hepatic involvement by lymphoma 
ALT ≤ 5 x ULN within 14 days prior to Day 1 of 
Consolidation 
9. Creatinine clearance of ≥ 60 mL/min within 14 days prior 
to Day 1 of Consolidation 

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Criteria to be met in order to initiate Consolidation 
brentuximab vedotin 
Action if criterion to the LEFT is NOT met 
10. No active  ≥ Grade 3 infection within 14 days prior to Day 
1 of Consolidation 
11. No other primary invasive cancer, hematologic 
malignancy, or myelodysplastic syndrome since last 
response assessment 
Except: Non-melanoma skin cancer and in situ cervical 
cancer  
Discontinue protocol therapy.   
12. No symptomatic cardiac disease (including symptomatic 
ventricular dysfunction, symptomatic coronary artery 
disease, and symptomatic arrhythmias), cerebrovascular 
event/stroke or myocardial infarction within the last 6 
months 
Discontinue protocol therapy.   
13. History of or current central nervous system involvement 
by lymphoma, including leptomeningeal involvement  
Discontinue protocol therapy.   
14. History of or current progressive multifocal 
leukoencephalopathy (PML)  
Discontinue protocol therapy.   
5.8 
Agent Administration 
NOTE: Infusion of study agents should occur at a site properly equipped and staffed to manage 
anaphylaxis should it occur.  
5.8.1 
Cyclophosphamide, doxorubicin, etoposide, and prednisone (CHEP) 
Administer CHEP per institutional standards during Induction (Section 5.6) prior to brentuximab vedotin. 
Dosing should be based on the patient’s pre-dose Cycle 1 baseline height and weight or per institutional 
standards. 
IV or oral etoposide is acceptable (see Section 5.3). If etoposide is administered orally, the dose should 
be rounded to the nearest 50 mg. 
There are no protocol-required pre- or post-medications for CHEP. See Section 5.13 for supportive care. 
Dose modification guidelines for CHEP are described in Section 6.2. 
5.8.2 
Brentuximab vedotin  
Brentuximab vedotin will be administered as an IV infusion over 30 minutes (+10 minutes) on Day 1 
during Induction (Section 5.6) and Consolidation (Section 5.7). Refer to Section 8.1 for reconstitution, 
preparation and additional administration details. 
Brentuximab vedotin will be administered within 1 hour of completing treatment with other agents 
during Induction.  
Dosing is based on participant actual body weight. It is not necessary to re-calculate subsequent doses if 
the participant weight is within 10% of the weight from baseline. Other dose adjustments for changes in 
body weight are permitted per institutional standard. An exception to weight-based dosing is made for 
participants weighing > 100 kg; doses will be based on 100 kg for these individuals. Rounding is 
permissible within 5% of the nominal dose. 

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There are no premedications recommended for the first dose of brentuximab vedotin. Consider 
observing the participant for 60 minutes following the first infusion with brentuximab vedotin. See 
Section 5.13 for supportive care. 
Management and dose reductions associated with brentuximab vedotin AEs are outlined in Section 6.2. 
5.9 
Assessments and Special Monitoring 
Refer to Section 10.0 summarizes the trial procedures to be performed. Note: Protocol therapy should 
be administered on Day 1 of each cycle after all procedures/safety assessments have been completed. 
It may be necessary to perform study procedures at unscheduled time points if deemed clinically 
necessary by the investigator. 
5.9.1 
Infusion-related reactions 
o Infusion or hypersensitivity reactions may occur to brentuximab vedotin or CHEP.  
o If such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
o Refer to Section 5.13.2 for infusion-related reaction/hypersensitivity guidelines. 
5.10 Duration of Therapy and Criteria for Removal from Protocol Therapy 
Participants will receive protocol therapy (Induction with CHEP-BV and Consolidation with brentuximab 
vedotin) until one of the below criteria are met: 
o Confirmed disease progression per 2014 Lugano Classification 
o Participant unable to proceed with Consolidation (Section 5.7.1) 
o Completed protocol therapy (induction and consolidation) (~12 months)  
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose 
modification/ delay  
 
Note: If one agent is discontinued due to toxicity, then the participant may continue to 
receive the other study agents  
o General or specific changes in the patient's condition which render the patient unacceptable for 
further treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy (See Section 16.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to Follow-up assessments. 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC and the Study PI should be promptly notified 
of the change in participant status. 
5.11 Follow-Up 
All participants who end protocol therapy will enter follow-up. Patients will be followed for 5 years (time 
from start of treatment). NOTE: Assessments may be combined if the windows for the two visits 
overlap. 
Follow-up is comprised of: 

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o Safety Follow-up- 30 days post-last dose of protocol therapy. 
 Note the period for safety follow-up will be extended until stabilization or resolution for all 
reportable AEs (per the agreement of the Study PI) and accompanying follow-up safety 
report. 
o Active Follow-up- for those who have yet to have disease progression. 
o Survival Follow-up- for all participants who have progressed OR completed Active Response 
Follow-Up. This follow-up will be performed typically via medical record review. It will entail (a) 
Disease status (for those who have yet to progress) (b) Vital status (all participants). 
Assessment time points and windows are detailed in Section 10.0. 
5.12 Duration of Study Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities (treatment and follow-up after protocol treatment) 
o Withdrawal of consent (See Section 16.5) 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative 
reasons 
Documentation of the reason for discontinuing study participation and the date effective should be 
made in the medical record and appropriate eCRF. The COH DCC should be promptly notified of the 
change in participant status. 
5.13 Supportive Care, Prohibited Medications and Concomitant Therapy  
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. 
If concomitant therapy must be added or changed, including over-the-counter medications or 
alternative therapies, the reason and name of the agent/therapy should be recorded in the eCRF and 
the medical record. 
Participants should be cautioned against excessive consumption of grapefruit, grapefruit juice or Seville 
orange juice while receiving Induction therapy. For a comprehensive list of CYP3A4 inhibitors and 
inducers refer to the Indiana University P450 Drug Interaction Table. 
5.13.1 Prohibited medications/ therapies 
o Prohibited from Day 1 of protocol therapy until end of Induction: 
 Strong CYP3A4 inhibitors/inducers: If there are no reasonable alternatives and these drugs 
are clinically necessary then participants must discontinue protocol therapy 
 
o Prohibited from Day 1 of protocol therapy until end of protocol therapy (last day of study agent 
or decision to end study agent(s) whichever occurs later). 
 Herbal and natural remedies 
 Other investigational therapy  

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 Other concurrent systemic anti-cancer therapy: chemotherapy, biological response 
modifiers, hormone therapy, surgery, palliative radiation therapy, or immunotherapy. 
− Exceptions post-Induction but prior to Consolidation with brentuximab vedotin: 
(a) consolidation ASCT (b) consolidation radiation after ASCT, or (c) consolidation 
radiation without ASCT. 
5.13.2 Supportive Care 
With the exception of prohibited therapies (see Section 5.13.1), participants should receive prophylactic 
or supportive care as clinically indicated per institutional policies.  
Routine anti-emetic prophylaxis should be administered per institution standard with induction 
chemotherapy. 
Patients should be individually evaluated to assess the need for tumor lysis prophylaxis prior to the first 
dose of CHEP-BV. Patients should receive prophylaxis as appropriate per the institutional standards. 
Blood products and growth factors 
 Platelet and/or red blood cell supportive growth factors or transfusions 
− 
Permitted when applicable 
 Colony stimulating factors (CSFs) 
− 
Induction: - All patients should receive G-CSF with each CHEP-BV cycle. The schedule 
and G-CSF formulation are per investigator discretion. 
− 
Consolidation: Per investigator discretion and institutional practice use G-CSF for 
neutropenia. 
Strong CYP3A4/5 inhibitors during Consolidation  
 Closely monitor for AEs. 
Routine infectious prophylaxis for Pneumocystis jiroveci pneumonia (PCP)  
 Consider for all patients 
Intrathecal prophylactic treatment for cerebral/meningeal disease  
 Permitted at the discretion of the investigator 
Infusion related reactions 
 Supportive measures include: 
− 
infusion time extension and/or  
− 
premedication 
 Premedicate if participant experienced infusion related reaction 
− 
Consider acetaminophen and a corticosteroid per institutional standards  
− 
For Grade 1 or Grade 2 infusion-related reaction to brentuximab vedotin 
premedicate 30–60 minutes prior to each brentuximab vedotin infusion. 
− 
The routine use of steroids as premedication is discouraged. 
 If anaphylaxis occurs 
− 
Immediately stop infusion of study agent 
− 
Per investigator discretion permanently discontinue study agent/regimen 

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6.0 
ANTICIPATED TOXICITIES & DOSE MODIFICATION/ DELAY  
6.1 
Anticipated Toxicities 
6.1.1 
Brentuximab vedotin 
Per the IB V16 (Oct 2018) the expected toxicities for brentuximab vedotin are as follows: 
System Organ Class 
Adverse Reactions 
Infections and infestations  
 
Very common 
Infectiona, upper respiratory tract infection 
 
Common 
Herpes zoster, pneumonia, herpes simplex, oral candidiasis 
 
Uncommon 
Pneumocystis jiroveci pneumonia, staphylococcal bacteremia, 
cytomegalovirus infection or reactivation, sepsis/septic shock 
 
Frequency not known 
Progressive multifocal leukoencephalopathy 
Blood and lymphatic system disorders 
 
Very common 
Neutropenia 
 
Common 
Anamia, thrombocytopenia 
 
Uncommon 
Febrile neutropenia 
Immune system disorders 
 
Uncommon 
Anaphylactic reaction 
Metabolism and nutrition disorders 
 
Common 
Hyperglycemia 
 
Uncommon 
Tumor lysis syndrome 
Nervous system disorders 
 
Very common 
Peripheral sensory neuropathy, peripheral motor neuropathy 
 
Common 
Dizziness 
 
Uncommon 
Demyelinating polyneuropathy 
Respiratory, thoracic and mediastinal disorders 
 
Very common 
Cough, dyspnea 
Gastro-intestinal disorders 
 
Very common 
Nausea, diarrhea, vomiting, constipation, abdominal pain 
 
Uncommon 
Pancreatitis acute 
Hepatobiliary disorders 
 
Common 
Alanine aminotransferase/aspartate aminotransferase 
increased 
Skin and subcutaneous tissue disorders 
 
Very common 
Rasha, pruritus 
 
Common 
Alopecia 
 
Uncommon 
Stevens-Johnson syndrome/toxic epidermal necrolysis 
Musculoskeletal and connective tissue disorders 
 
Very common 
Arthralgia, myalgia 
 
Common 
Back pain 

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System Organ Class 
Adverse Reactions 
General disorders and administration site conditions 
 
Very common 
Fatigue, pyrexia, infusion-related reactionsa 
 
Common 
Chills 
Investigations 
 
Very common 
Weight decreased 
a Represents pooling of preferred terms 
Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 
to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data). 
6.1.2 
Cyclophosphamide 
Per the package insert the expected toxicities for cyclophosphamide are as follows (no asterisk 
signifies>10%; * signifies 1-10%; †signifies < 1%): 
Blood and Lymphatic System 
Neutropenia, febrile neutropenia, myelosuppression* 
Cardiac 
Pericardial effusion†, arrythmias†, congestive heart failure† 
Gastrointestinal  
Nausea, vomiting, diarrhea 
General Disorders and Administration 
Site 
Pyrexia 
Hepatobiliary 
Veno-occlusive Liver Disease† 
Infections and infestations 
Infections* 
Neoplasms benign, malignant and 
unspecified (including cysts and 
polyps) 
Secondary malignancy† 
Renal and urinary  
Hematuria 
Respiratory, Thoracic and Mediastinal 
Pneumonitis†, pulmonary fibrosis†,respiratory failure† 
Skin and Subcutaneous Tissue  
Alopecia 
6.1.3 
Doxorubicin 
Per the package insert the expected toxicities for doxorubicin are as follows (no asterisk signifies ≥ 10%; 
* signifies 1-10%, and † signifies < 1%): 
Blood and lymphatic (including 
hematological labs) 
Myelosuppression, leucopenia, haemorrhage, thrombocytopenia*, 
anaemia*, febrile neutropenia* 
Cardiac 
Cardiotoxicity, pericardial effusions* 
Eye 
Conjunctivitis*, lacrimation* 
Gastrointestinal  
Nausea, vomiting, mucositis, diarrhea, abdominal pain, ulceration* 
General Disorders and 
Administration Site 
Dehydration, facial flushing, chills and fever* 
Immune system 
Anaphylaxis* 
Investigations (excluding 
hematological labs) 
Transaminase changes* 
Metabolism and Nutrition 
Anorexia* 
Nervous system 
Drowsiness*  
Renal and urinary  
Renal damage*, hyperuricaemia* 

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Skin and Subcutaneous Tissue  
Alopecia, rash*, palmar plantar erythrodysaesthesia* 
Vascular 
Thromboembolism* 
6.1.4 
Etoposide 
Per the package insert the expected toxicities for etoposide are as follows (no asterisk signifies ≥ 10%; * 
signifies 2-10%, and † signifies < 2%): 
Blood and lymphatic (including 
hematological labs) 
Neutropenia, thrombocytopenia, anemia 
Gastrointestinal  
Nausea, vomiting, diarrhea*, stomatitis†, abdominal pain† 
General Disorders and 
Administration Site 
Fever* 
Hepatobiliary 
Hepatic toxicity† 
Immune system 
Hypersensitivity† 
Metabolism and Nutrition 
Anorexia 
Nervous system 
Peripheral neuropathy† 
Skin and Subcutaneous Tissue  
Alopecia 
Vascular 
Hypotension† 
6.1.5 
Prednisone 
Per the package insert the expected toxicities for prednisone are as follows (no asterisk signifies ≥ 10%; 
* signifies 1-10%, and † signifies < 1%): 
Cardiac 
Bradycardia†, cardiac arrest†, cardiac arrhythmias†, congestive heart 
failure†, tachycardia† 
Endocrine 
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome 
Eye 
Cataracts*, glaucoma* 
Gastrointestinal  
Gastrointestinal perforation* 
General Disorders and 
Administration Site 
Edema* 
Immune system 
Anaphylaxis†, angioedema† 
Infections and infestations 
Infections* 
Investigations (excluding 
hematological labs) 
Weight gain 
Metabolism and Nutrition 
Hyperglycemia, increased appetite, increased eletrolytes*, hypocalcemia*, 
hypokalemia*,  
Musculoskeletal and Connective 
Tissue  
Decreased bone density*, actue myopathy* 
Psychiatric 
Mood changes 
Respiratory, Thoracic and 
Mediastinal 
Pulmonary edema† 
Vascular 
Hypertension, thromboembolism†, thrombophlebitis†, vasculitis† 
6.2 
Dose Delay/ Modification Guidelines 
o Toxicities will be graded using the NCI CTCAE v 4.0. 
o Baseline values are from the last values obtained prior to treatment. 

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o If one agent is held due to toxicity for a given cycle, administration of the delayed agent should 
resume once the toxicity is resolved on the same schedule with the next cycle of combination 
therapy.   
o If one agent is permanently discontinued, then the participant may continue with other agent(s).  
o If all agents are held together due to toxicity and the toxicity lasts > 6 weeks, then protocol 
therapy will be discontinued.  
o Brentuximab vedotin  
 Dose modification/ delay brentuximab vedotin-related toxicity are described in Table 6.2.1.  
 If toxicity does not resolve within 6 weeks, permanently discontinue brentuximab vedotin. 
 Doses reduced for brentuximab vedotin-related toxicity should not be re-escalated without 
discussion with the Study PI.  
 Dose reductions below 1.2 mg/kg are not permitted, and toxicities should be managed with 
dose delays or brentuximab vedotin should be permanently discontinued. 
o CHEP 
 Dose modifications/ discontinuation of cyclophosphamide, doxorubicin, etoposide, or 
prednisone due to toxicity are permitted per investigator discretion/ institutional standards. 
Table 6.2.1 Dose Modifications for Brentuximab Vedotin  
Toxicity 
Brentixumab Vedotin Dose Management Guidelines 
Peripheral Sensory Neuropathy 
Grade 1 
Asymptomatic; loss of deep tendon reflexes or 
paresthesia 
Continue at same dose level 
Grade 2  
Moderate symptoms; limiting instrumental ADL 
Reduce dose to 1.2 mg/kg and resume treatment 
Grade 3 
Severe symptoms; limiting self care ADL 
Withhold until toxicity resolves to ≤ Grade 2 or baseline, then 
resume treatment at 1.2 mg/kg  
See above for guidance if the participant dose is already 1.2 
mg/kg. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Discontinue brentuximab vedotin 
Peripheral Motor Neuropathy 
Grade 1 
Asymptomatic; clinical or diagnostic observations 
only; intervention not indicated 
Continue at same dose level 
Grade 2 
Moderate symptoms; limiting instrumental ADL 
Withhold until toxicity resolves to ≤ Grade 1 or baseline, then 
resume treatment at 1.2 mg/kg  
See above for guidance if the participant dose is already 1.2 
mg/kg. 
Grade 3/4 
G3: Severe symptoms; limiting self care ADL; 
Discontinue brentuximab vedotin 

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Toxicity 
Brentixumab Vedotin Dose Management Guidelines 
assistive device indicated 
 
G4: Life-threatening consequences; urgent 
intervention indicated 
Infusion Related Reaction 
Grade 1/2 
G1: Mild transient reaction; infusion interruption 
not indicated; intervention not indicated 
G2: Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for <=24 hrs 
 
During subsequent cycles 
− 
Prophylactic premedication is recommended (Section 
5.13.2) 
− 
Maintain same dose level 
Grade 3 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae 
 
Stop infusion for that visit 
 
Once toxicity resolves ≤ Grade 2 or baseline 
− 
Consult Study PI to continue to administer brentuximab 
vedotin during subsequent cycle(s) at the same dose level 
with prophylaxis premedication (Section 5.13.2) 
− 
Otherwise, permanently discontinue brentuximab 
vedotin. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
 
Discontinue brentuximab vedotin. 
 
See Section 5.13.2 for supportive care. 
Other unspecified non-hematologic  
Grade 1/2 
Continue at same dose level 
Grade 3  
Withhold dose until toxicity is ≤ Grade 2 or has returned to 
baseline, then resume treatment at the same dose level.  
− 
Note: Patients who develop Grade 3 or 4 electrolyte 
laboratory abnormalities may continue study treatment 
without interruption. 
Grade 4 
Withhold dose until toxicity is ≤ Grade 2 or has returned to 
baseline, then reduce dose to 1.2 mg/kg and resume treatment, or 
discontinue at the discretion of the investigator a,b 
a. 
See above for guidance if the participant dose is already 1.2 
mg/kg. 
b. 
Patients who develop Grade 3 or 4 electrolyte laboratory 
abnormalities may continue study treatment without 
interruption. 
Hematologic 
Grades 1-2 
Continue at same dose level 
Grade 3-4 
 Withhold until toxicity resolves to ≤ Grade 2 or baseline 
− 
 NOTE: Patients who develop Grade 3 or 4 lymphopenia 
may continue study treatment without interruption 
 Growth factor support (G-CSF or GMCSF) for neutropenia 
should be considered for subsequent cycles. 
 First occurrence resume at same dose level 
 Second occurrence 

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Toxicity 
Brentixumab Vedotin Dose Management Guidelines 
- 
For any toxicity (including neutropenia despite the use of 
G-CSF), dose reduction to 1.2mg/kg should be considered  
- 
If the participant is already receiving 1.2 mg/kg, dose 
discontinuation should be considered. 
 

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7.0 
REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF INTEREST  
The research team is responsible for classifying adverse events (AEs) and unanticipated problems (UPs) 
as defined in the relevant regulations and reporting to all applicable parties, including but not limited to 
the COH IRB, DSMC, Food and Drug Administration (FDA), National Institutes of Health (NIH) and other 
collaborators, e.g., pharmaceutical companies. The research team is responsible for the continued 
monitoring and tracking of all AEs in order to ensure non-reportable events are reviewed and monitored 
and do not rise to a reporting level. 
7.1 
Assessment of Adverse Events 
The site investigator will be responsible for determining the event name, and assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope Clinical 
Research Adverse Event and Unanticipated Problem policy (available from the DCC). 
Adverse events will be characterized using the descriptions and grading scales found in NCI CTCAE 
version 4.0. A copy of the scale can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
• 
Unrelated – The event is clearly NOT related to study treatment, and is clearly related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
• 
Unlikely – The event is unlikely related to the study treatment, and is most likely related to 
other factors such as the participant’s clinical state, other therapeutic interventions, or 
concomitant drugs. 
• 
Possible – The event may be related to study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration, but could have been produced by other factors 
such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.  
• 
Probable – The event is most likely related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is unlikely related to the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
• 
Definite – The event is clearly related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is not reasonably explained by other factors such as the participant’s condition, 
therapeutic interventions, or concomitant drugs. 
7.2 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm. 

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7.3 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female participant occurring while the participant receives the first dose of protocol therapy 
up to 6 months post-last dose of brentuximab vedotin are considered immediately reportable events.  
Protocol therapy is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to the Study PI/ DCC immediately within 24 hours of awareness (see 
Section 7.7.2); the Study PI or designee will subsequently inform Seattle Genetics using the Seattle 
Genetics Pregnancy Report Form (Section 7.6). The female subject may be referred to an obstetrician-
gynecologist (preferably one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies, and should notify the Study PI/ DCC.  
Abnormal pregnancy outcomes and neonatal deaths that occur within 28 days of birth should be 
reported as an SAE per expedited reporting guidelines (see Section 7.6). 
Any infant death after 28 days that the Investigator suspects is related to the in utero exposure to 
protocol therapy should also be reported as an SAE per expedited reporting guidelines (see Section 7.6); 
the Study PI or designee will subsequently inform Seattle Genetics using the Pregnancy Report Form 
(Section 7.6). 
7.3.1 
Male participants 
If a female partner of a male participant becomes pregnant within 90 days post-last dose, the male 
participant should notify the Investigator, and the pregnant female partner should be advised to call 
their healthcare provider immediately.  
The Investigator should make every effort to follow the outcome of the pregnancy per institutional 
policies, and should notify the Study PI/ DCC.  
7.4 
Routine AE Collection and Reporting Guidelines 
Routine recording of adverse events (AEs) will occur via data entry into the study eCRF.   
AEs reported through expedited processes (e.g., reported to the IRB, DSMC, FDA, etc.) must also be 
reported in routine study data submissions. 
AEs will be collected from the signing of informed consent until ending study participation.  
AEs will be monitored by the Protocol Management Team (PMT). 
The highest grade of any toxicity will be collected for each cycle during protocol treatment and for the 
period of safety follow-up after end of treatment. For Cycle 1 only, all Grade ≥2 AEs (highest grade or 
not) will also be collected. 
7.5 
Expedited Reporting  
Table 7.5 indicates what events must be reported expeditiously. 
  

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Table 7.5 Expedited Reporting Guidelines 
Time point 
What to report expeditiously 
From the signing of the consent to 
study completion 
All unanticipated problems 
 
From Screening until Day 1 of protocol 
therapy 
All SAEs related to protocol procedures 
 
From first dose of protocol therapy up 
to 30 days after the last dose of 
protocol therapy  
 
 
All SAEs regardless of relationship to protocol therapy, study 
procedure, underlying disease or concomitant treatment. 
 
AEs that meet the definition of an unanticipated problem 
 
AEs associated with pregnancies (Section 7.3) 
 
Discontinuation of protocol therapy due to unusual or unusually 
severe AE considered related to brentuximab vedotin. 
After 30 days post-last dose of 
brentuximab vedotin (follow-up)  
 
All SAEs that are considered possibly, probably, or definitely related 
to therapy. 
 
Pregnancy and lactation (up to at least 6 months post-last dose) 
NOTE: All events reported expeditiously require follow-up reporting until the event is resolved, stabilized, or 
determined to be irreversible by the investigator.  
The DCC should be consulted prior to ending the follow-up of events that have stabilized. 
 
7.5.1 
Expedited reporting guidelines (COH only) 
7.5.1.1 To the COH DSMC/IRB 
Serious Adverse Events that require expedited reporting and unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated Problem 
policy. This includes all SAEs and UPs that meet COH DSMC/IRB expedited reporting criteria that 
occurred at COH and non-COH sites. For non-COH sites, the DCC will be responsible for reporting (see 
Section 7.5.2). 
7.5.1.2 To Participating Investigators 
o Report all expedited reportable AEs to participating investigators as an IND Safety Report 
occurring within 30 calendar days of receipt of sponsor (lead site) notification, and indicate 
whether or not a protocol and/or consent form change is required. A cover letter will indicate 
the protocol title, the IND#, whether the FDA was informed (if applicable), and, for non-COH 
sites, a statement that the report should be submitted to their local IRB for review if applicable 
per local IRB policy. 
o Forward to participating sites all IND safety reports received from Seattle Genetics, indicating 
whether a consent form or protocol change is required within 30 days of notification to Study PI. 
7.5.2 
Expedited reporting guidelines (Non COH Sites only) 
7.5.2.1 To the DCC/Study PI 
All events that meet the criteria specified in Table 7.5 will be reported to the DCC and Study PI within 
24 hours of notification that the event met the expedited reporting criteria. 
1. Sites are to report to their local IRB per their site’s specific institutional and IRB guidelines. As soon 
as possible, non-COH sites will provide to the COH DCC copies of the IRB submission and 
corresponding IRB response. 

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2. Document/describe the AE/UP on each of the following: 
a. MedWatch 3500A or local IRB submission document* 
MedWatch 3500A is downloadable form at http://www.fda.gov/medwatch/getforms.htm 
*The local IRB submission document may be used if the document template is approved 
by the DCC 
b. Expedited Reporting Coversheet. A modifiable Microsoft Word document is available from 
the DCC. An electronic signature on the document will be accepted. 
3. Scan and email above documents to the Study PI (aherrera@coh.org) and DCC@coh.org with the 
subject title as “Herrera CHEP-BV 17058 SAE”.  
a. If available, sites may include the local IRB submission for this event in the submission.  
If an email receipt from DCC personnel is not received within one working day, please email 
DCC@coh.org. 
7.6 
Reporting to the FDA  
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, regardless of the site of occurrence, will be reported 
as an IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
- Any unexpected fatal or life threatening adverse experience associated with use of the drug 
must be reported to the FDA no later than 7 calendar days after initial receipt of the information 
[21 CFR 312.32(c)(2)] 
- Any adverse experience associated with use of the drug that is both serious and unexpected 
must be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
- Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
The study PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA will 
assist the PI with the preparation of the report and submit the report to the FDA in accordance with the 
approved City of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
In addition, on behalf of the study PI, OIDRA will submit annually within 60 days of the anniversary of 
the date the IND went into effect, an annual report to the FDA which is to include a narrative summary 
and analysis of the information of all FDA reports within the reporting interval, a summary report of 
adverse drug experiences, and history of actions taken since the last report because of adverse drug 
experiences. 
7.7 
Reporting to Industry Partner 
a. Promptly forward to Seattle Genetics copies of all written IND safety reports submitted 
to the FDA. 
Email: drug.safety@seagen.com 
b. Report to Seattle Genetics aggregate SAEs monthly via email: IST@seagen.com 

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or portal. 
c. Assist Seattle Genetics in investigating any SAE and will provide any follow-up 
information reasonably requested by Seattle Genetics.  
d. Submit to Seattle Genetics all pregnancy related events within 48 hours of being aware 
of the event on the Seattle Genetics Pregnancy Report Form.  
Email: drug.safety@seagen.com 
e. Forward to Seattle Genetics (via COH OIDRA) copies of initial/annual/final FDA IND 
submissions.  
Email: IST@seagen.com 
 

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8.0 
AGENT INFORMATION 
8.1 
Brentuximab Vedotin 
Brentuximab vedotin has been FDA approved for the treatment of patients with classical HL after failure 
of autologous hematopoietic stem cell transplantation (auto-HSCT), after failure of at least 2 prior multi-
agent chemotherapy regimens in patients who are not auto-HSCT candidates, and treatment of patients 
with classical HL at high risk of relapse or progression as post-auto-HSCT consolidation. Brentuximab 
vedotin is FDA-approved for relapsed CD30 expressing systemic anaplastic large cell lymphoma [40]. 
Brentuximab vedotin is FDA-approved in combination with CHP chemotherapy for previously untreated, 
systemic ALCL or other CD30-expressing PTCL.  
Please refer to the investigator brochure for a detailed description. 
8.1.1 
Other Names 
ADCETRIS®, SGN-35 
8.1.2 
Description  
Structural Formula: 
Empirical Formula: 
C6476H9930N1690O2030S40 (C68H105N11O15)3–5 
Type: 
Antibody-drug conjugate (ADC).  
The chimeric monoclonal IgG1 antibody cAC10 is covalently linked to the 
monomethyl auristatin E (MMAE) via a protease-cleavable linker.  
About 4 molecules of MMAE are attached to each antibody molecule. 
Source: 
Mouse-human chimera 
Target: 
CD30 
Molecular weight:  153 kDa 
8.1.3 
Mechanism of Action 
Brentuximab vedotin targets the cell surface receptor CD30 which is expressed in Hodgkin’s lymphoma 
(HL). Nonclinical data suggest that the binding of the ADC to CD30-expressing cells leads to the 
internalization of the ADC-CD30 complex. Proteolytic cleavage of ADC within the cell results in the 
release of the MMAE. Free MMAE binds to the microtubule network and subsequently leads to cell cycle 
arrest and apoptosis. 
8.1.4 
Pharmacokinetics 
MMAE Tmax: 
1 to 3 days 
MMAE Steady-State  21 days with every 3-week dosing  
ADC Vd: 
6 to 10 L 
MMAE protein binding: 
68-82% 
MMAE Metabolism: 
Metabolized via CYP3A4/5; inhibits CYP3A4/5 
MMAE Excretion: 
renal excretion up to 24% and in feces 72% 

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ADC Elimination half-life: 
4-6 days 
8.1.5 
Human Toxicity 
See Section 6.1.1. 
8.1.6 
Formulation 
Each vial contains 55 mg SGN-35 for Injection (brentuximab vedotin), trehalose, sodium citrate, 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. 
8.1.7 
Storage 
Refrigeration should be set at 2–8°C for storage of vials and solutions containing brentuximab vedotin. 
Chemical and physical stability of the reconstituted brentuximab vedotin drug product has been 
demonstrated for 24 hours at 2–8°C and 25°C. However, brentuximab vedotin does not contain 
preservatives; therefore, from a microbiological standpoint, opened and reconstituted vials should be 
used immediately. If not used immediately, the in-use storage should not be longer than 24 hours. It is 
recommended that brentuximab vedotin vials and solutions be protected from direct sunlight until the 
time of use. 
8.1.8 
Handling and Dispensing 
The investigator should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as per product information and the Investigator Brochure 
and per local regulations. It is the responsibility of the investigator to ensure that investigational product 
is only dispensed to study subjects.  
The investigational product must be dispensed only from official study sites by authorized personnel 
according to local regulations.  
If concerns regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact Seattle Genetics immediately using the investigational product complaint form. 
The DCC should be notified of any potential irregularities. 
8.1.9 
Reconstitution 
1. Reconstitute lyophilized brentuximab vedotin by adding 10.5 mL Sterile Water for Injection, 
USP, or equivalent to the 50 mg vial, directing the stream to the side of the vial. The 
concentration of reconstituted brentuximab vedotin is 5 mg/mL with a total volume of 11 mL. 
2. Gently swirl the vial until contents are completely dissolved. The vial must not be shaken. Slight 
“bubbling” of the solution upon reconstitution may be observed. 
3. Allow the reconstituted vial to settle for a minute to allow bubbles to dissipate. The 
reconstituted product should be a colorless, clear to slightly opalescent solution with no visible 
particulates. 

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4. Refrigeration should be set at 2–8°C for storage of the reconstituted vials. The reconstituted 
vials must be administered within 24 hours of vial reconstitution. Protect infusion bag from 
direct sunlight until time of use. 
8.1.10 Preparation  
1. Transfer the required volume of reconstituted product to a 100 mL to 250 mL infusion bag. (A 
glass, sterile bottle may be used instead of an infusion bag.)  
a. The infusion bag size should allow enough diluent to achieve a concentration of 0.4–1.8 
mg/mL.  
b. The following bag types are compatible with brentuximab vedotin: polyvinylchloride 
(PVC), ethylene vinyl acetate (EVA), polyolefin, polypropylene, or polyethylene.  
c. Discard any remaining reconstituted product. 
2. Dilute reconstituted product in either 0.9% Sodium Chloride Injection, Lactated Ringer’s 
solution, or dextrose 5% in water (D5W). The diluents should be USP grade or equivalent. The 
final concentration of brentuximab vedotin in infusion bag should be in the range of 0.4–1.8 
mg/mL. See example calculations in Table 8.1.10 below. 
 Total dose = patient weight x dose level. Note that for patients weighing more than 100 kg, 
total dose will be calculated using 100 kg. 
 Volume of reconstituted product required = total dose/5 mg per mL 
 Final concentration = total dose/total volume of infusion 
Table 8.1.10 Examples of Dose Preparation Calculations 
 
3. Gently invert the infusion bag. DO NOT SHAKE or expose the prepared dosing solution to excess 
vibration at any time when transferring or transporting the reconstituted product. Pneumatic 
tube systems are not recommended. 
4. Prior to administration, inspect the prepared dosing solution (in infusion bag) for any particulate 
matter or discoloration. 

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5. Do not prepare a single dose of brentuximab vedotin using vials from different lots or kits. Use 
vials from the same lot or kit number for a given dose. 
6. Refrigeration should be set at 2–8°C for storage of the prepared dosing solution. The solution 
must be used within 24 hours of vial reconstitution. Protect infusion bag from direct sunlight 
until time of use. 
8.1.11 Dose and Administration 
Administer brentuximab vedotin as an intravenous infusion only, over 30 minutes (+10 minutes). 
Do not mix brentuximab vedotin with, or administer as an infusion with, other medicinal products.  
See Section 5.8.2 for dosing and additional administration guidelines. 
8.1.12 Supplier 
• US sites: 
- 
For the induction phase: brentuximab vedotin will be supplied free of charge by Seattle Genetics 
until February 8, 2019 (included). Starting February 9, 2019 (BV is FDA-approved for previously 
untreated CD30-expressing PTCL in the US as of November 16, 2018), BV will be commercial 
supply. For patients who started the induction phase before February 8, 2019, Seattle Genetics 
will keep supplying BV free of charge for the remainder of the induction phase. 
- 
For the maintenance/consolidation phase: Seattle Genetics will supply BV free of charge. 
• Non-US site: 
Seattle Genetics will supply BV free of charge for all parts (induction and maintenance/consolidation) of 
the study. 
8.1.13 Ordering 
Sites will place orders for brentuximab vedotin via the Seattle Genetics Investigational Drug Request 
Form; the Seattle Genetics Protocol ID 35-IST-039 must also be stated in the form. The timing for initial 
shipment will be about 3 weeks and resupply will be about 1 week.  
Sites should place orders a week in advance of the shipment. 
8.1.14 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using a drug accountability 
log. 
8.1.15 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from Seattle 
Genetics or designee, the amount dispensed to participants, and the amount remaining at the 
conclusion of the trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed 
according to applicable federal, state, local and institutional guidelines and procedures.  
Destruction will be documented in a drug accountability log. 

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8.2 
Cyclophosphamide 
Cyclophosphamide is FDA approved for the treatment of a) malignant diseases, including Hodgkin’s 
disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma, 
multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, 
retinoblastoma, breast carcinoma and b) biopsy proven minimal change nephrotic syndrome in pediatric 
patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.  
Please refer to the package insert for a detailed description. 
8.2.1 
Other Names 
Cytoxan®, Neosar® 
8.2.2 
Description 
Structural formula: 
Empirical formula: 
C7H15Cl2N2O2P • H2O 
Molecular weight:  279.1 g/mol 
Chemical name: 
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide 
monohydrate 
8.2.3 
Mechanism of Action 
Cyclophosphamide is an alkylating agent that inhibits cell proliferation. 
8.2.4 
Pharmacokinetics 
Elimination half-life: 
3 to 12 hours 
Total body clearance: 
4 to 5.6 L/h 
Distribution: 
20% is protein bound. Some metabolites are protein bound to an extent greater than 
60%. 
Volume of 
distribution: 
~ total body water 30 to 50 L 
Metabolism: 
~75% is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 
3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6. Cyclophosphamide appears to induce its 
own metabolism. 
Auto-induction results in an increase in the total clearance, increased formation of 4-
hydroxyl metabolites and shortened t values following repeated administration at 12- 
to 24-hour interval 
Elimination: 
10-20% via urine, 4 % via bile 
8.2.5 
Human Toxicity 
See Section 6.1.2 for details. 
8.2.6 
Formulation 
Formulation for infusion will be used for this study. 

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8.2.7 
Storage, Handling, Preparation 
Follow package insert instructions. 
8.2.8 
Dose and Administration 
See Section 5.8.1 for dosing and additional administration guidelines. 
8.2.9 
Supplier 
Cyclophosphamide is available commercially. 
8.3 
Doxorubicin 
Indications:  
o Breast Cancer: adjuvant therapy in women with evidence of axillary lymph node involvement 
following resection of primary breast cancer. 
o Metastatic cancers or disseminated neoplastic conditions: acute lymphoblastic leukemia, acute 
myeloid leukemia, Wilms tumor, neuroblastoma, soft tissue and bone sarcomas, breast cancer, 
ovarian cancer, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, 
Hodgkin lymphoma, non-Hodgkin lymphoma, and bronchogenic carcinoma in which the small 
cell histologic type is the most responsive compared with other cell types. 
Please refer to the package insert for a detailed description. 
 
8.3.1 
Other Names 
ADRIAMYCIN®, doxorubicin hydrochloride 
8.3.2 
Description 
Structural formula: 
Empirical formula: 
C27H29NO11,HCl 
Molecular weight:  580 g/mol 
Chemical name: 
(8S,10S)-10-[(3-Amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]- 6,8,11-trihydroxy-
8-(hydroxyacetyl)-1-methoxy-7,8,9,10- tetrahydrotetracene-5,12-dione hydrochloride 
8.3.3 
Mechanism of Action 
Doxorubicin hydrochloride is an antineoplastic antibiotic. The precise mechanism of action is not fully 
understood. Cytotoxic effect of the drug may be related to a number of mechanisms including free 
radical formation secondary to metabolic activation of doxorubicin by electron reduction, intercalation 
of the drug into DNA, induction of DNA breaks and chromosomal aberrations, and alterations in cell 
membranes induced by the drug. In vitro studies suggests that apoptosis (programmed cell death) also 
may be involved in the drug's mechanism of action. These and other mechanisms (chelation of metal 
ions to produce drug-metal complexes) also may contribute to the cardiotoxic effects of the drug. 

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8.3.4 
Pharmacokinetics 
Half-life: 
Multi-phasic; initial t½ is  5 minutes suggests rapid tissue uptake of 
doxorubicin. Slow elimination from tissues is reflected by a terminal t½ of 
20-48 hours 
Steady state distribution volume: 
Exceeds 20-30 L/kg 
Distribution: 
75% protein bound  
Metabolism: 
Major matabolite is doxorubinol; metbolized via CYP3A4/ CYP2D6 
Elimination: 
40% of dose in bile in 5 days; 5-12% in urine in same period 
8.3.5 
Human Toxicity 
See Section 6.1.3 for details. 
8.3.6 
Formulation 
Formulation for infusion will be used for this study. 
8.3.7 
Storage, Handling, Preparation 
Follow package insert instructions. 
8.3.8 
Dose and Administration 
See Section 5.8.1 for dosing and additional administration guidelines. 
8.3.9 
Supplier 
Doxorubicin is available commercially. 
8.4 
Etoposide 
Indications:  
o First-line small cell lung cancer  
o Refractory testicular tumors 
Please refer to the package insert for a detailed description. 
8.4.1 
Other Names 
VePesid®, Etopophos®, VP-16 
8.4.2 
Description 
Structural formula: 
Empirical formula: 
C29H32O13 

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Molecular weight:  589 g/mol 
Chemical name: 
(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-
hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-
5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one 
8.4.3 
Mechanism of Action 
Etoposide, a semisynthetic derivative of podophyllotoxin, forms a complex with topoisomerase II and 
DNA resulting in DNA breaks.  
8.4.4 
Pharmacokinetics 
Half-life: 
Initial t½ is 1.5 hours. Mean terminal t½ is 4 to 11 hours 
Distribution: 
7-17 L/m2 
Protein binding: 
94-98% 
Metabolism: 
Hepatic via CYP3A4/5 
Elimination: 
Urine (56%) within 120 hours; feces (44%) within 120 hours 
8.4.5 
Human Toxicity 
See Section 6.1.4 for details. 
8.4.6 
Formulation 
Formulation for infusion or oral formulation will be used for this study. 
8.4.7 
Storage, Handling, Preparation 
Follow package insert instructions. 
8.4.8 
Dose and Administration 
See Section 5.8.1 for dosing and additional administration guidelines. 
8.4.9 
Supplier 
Etoposide is available commercially. 
8.5 
Prednisone 
Indications: 
o Anti-inflammatory or immunosuppressive agent 
o Treatment of certain endocrine disorders 
o Palliation of certain neoplastic conditions 
Please refer to the package insert for a detailed description. 
8.5.1 
Other Names 
Orasone®, Pediapred®, Sterapred®, Deltasone, RAYOS 

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8.5.2 
Description 
Structural formula: 
Empirical formula: 
C21H26O5 
Molecular weight:  358.43 g/mol 
Chemical name: 
pregna-1,4-diene-3,11,20-trione monohydrate,17,21-dihydroxy- 
8.5.3 
Mechanism of Action 
Prednisone suppresses the immune system. Anti-tumor effects may be related to inhibition of glucose 
transport, phosphorylating or induction of cell death in immature lymphocytes.  
8.5.4 
Pharmacokinetics 
Elimination half-life: 
2-3 hours 
Protein binding: 
< 50% 
Metabolism: 
Hepatic via CYP3A4 to active metabolite prednisolone 
Elimination: 
Urine 
8.5.5 
Human Toxicity 
See Section 6.1.5 for details. 
8.5.6 
Formulation 
Oral formulation will be used for this study. 
8.5.7 
Storage, Handling, Preparation 
Follow package insert instructions. 
8.5.8 
Dose and Administration 
See Section 5.8.1 for dosing and additional administration guidelines. 
8.5.9 
Supplier 
Prednisone is available commercially. 

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9.0 
CORRELATIVE/ SPECIAL STUDIES 
9.1 
Correlative Study Plan 
The correlative analyses that will be performed as part of this clinical trial are exploratory and intended 
to generate hypotheses that can be validated in larger studies. The list of correlative studies below is not 
meant to be exhaustive, as it is anticipated that the exact nature and type of correlative studies may 
change as new scientific data emerges during the course of the study. 
Table 9.1 Correlative Study Plan 
Tissue type 
Planned correlative analysis 
Tumor tissue 
 
Gene expression and mutational profiling of PTCL tumor specimens to determine 
whether there are expression profiles and/or mutations associated with outcome 
after study therapy. 
Blood 
 
Next-generation sequencing-based minimal residual disease (MRD) assessment. We 
will assess MRD at baseline, and at all pre-specified imaging time points –see Table 
9.3. These sequential samples will allow us to track the temporal dynamics of MRD 
after CHEP plus BV, and to determine whether maintenance therapy can eradicate 
MRD in patients who are MRD+ after induction therapy 
9.2 
Tumor Tissue Studies 
9.2.1 
Timepoints of Collection 
o Baseline tissue: Archival tissue from diagnostic tumor biopsies will be retrieved and submitted 
post-enrollment.  
 NOTE: If unavailable, exceptions may be granted with Study PI approval. 
o From participants who progress/ relapse during study (strongly encouraged, but not mandatory): 
If safe and feasible, submission of a tumor lesion core or excisional biopsy. 
9.2.2 
Guidelines for archival specimens  
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples will be processed 
for correlative studies:  
o If tissue block is available submit: 
 6 paraffin scrolls measuring 10 µm thick placed into a Nunc tube and frozen at -80° C AND 
− 10 x 5 micron unstained slides 
 If tissue block is unavailable submit 20 x 5 µm unstained slides 
9.2.3 
Guidelines for fresh tumor tissue processing (for patients with insufficient remaining tissue in 
diagnostic tissue block) 
9.2.3.1 
Non-COH sites 
Tumor lesion core or excisional biopsies should be flash frozen and kept at -80 oC until batch shipment. 

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9.2.3.2 
COH only 
Three core biopsies OR excisional biopsies should be submitted. If fewer than 3 core biopsies are 
available because of safety, then 1 or 2 cores may be submitted. 
Core biopsies:  
o Three core biopsies will be obtained for diagnostic purposes and 3 similar additional cores will 
be obtained for research.  
1. One core biopsy will snap frozen in OCT fixative, and an additional half of a core will be 
snap frozen without OCT fixative.  
2. Half of a core will be finely minced in a 10cm petri dish and frozen at -80° C in a Nunc tube 
in 1 ml of RPMI-1640 medium containing 20% fetal calf serum and 10% DMSO, then will 
be transferred to liquid nitrogen.  
3. Half of a core will be processed for DNA and RNA extraction according to the 
manufacturer’s recommendation.  
4. The final half of a core biopsy will be processed to dissociate the cells, with the cell 
suspension cryopreserved in liquid nitrogen. 
For excisional biopsies:   
o An approximately 1cm x 1cm tumor sample will be divided into 5 equal portions and processed 
as described for core biopsies. 
The diagnostic portion of the specimen:  
o Process in a routine fashion by hematopathology. Using the formalin-fixed paraffin embedded 
(FFPE) tissue block, 15 x 5 micron unstained slides will be obtained 
9.2.4 
Labeling of samples 
Samples will be labeled with the study number, institution (for non-COH sites), subject ID (issued by 
DCC), date, time point of collection (i.e. baseline or progression) and if applicable patient initials.  
9.2.5 
Sample shipment and receiving lab 
Tissue specimens collected at the above indicated timepoints will either be taken to (COH only) or 
batch-shipped (non-COH sites) to COH Pathology Core. For all sites, please include the Correlative Tissue 
form (Appendix D-1) with your shipment. 
Please note that samples should be batch shipped from non-COH sites on Monday to Wednesday in 
time for receipt Tuesday to Friday. Refer to Appendix D-2 for shipping details.  

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9.3 
Blood samples 
The table below provides an overview of correlative blood studies. Blood samples will be collected from 
an indwelling venous catheter or by venipuncture. 
Table 9.3 Overview of correlative blood studies 
Timepoint of collection 
Total 
volume 
per 
timepoint  
Tube Type 
Processing/ 
Receiving 
Laboratory 
Type of 
Laboratory 
Analysis 
Induction 
 Cycle 1 Day 1 (baseline), 
 Cycle 3 Day 15 
 Cycle 6 Day 15* 
~20 mL 
COH only 
Purple-top (K+EDTA)  
 
 
Non-COH 
Cell-free BCT® DNA 
tubes.  
 
 
COH Analytical 
Pharmacology 
Core Facility 
(APCF) 
Minimal 
residual 
disease (MRD) 
assessment 
using next-
generation 
sequencing 
(NGS)  
Consolidation 
 Cycle 5 Day 1 
 
Safety Follow-up (30-days post-last 
dose) 
 
Note for Canada site: Efforts should be made collect correlative blood at the above stated timepoints. If blood is not 
collected, it will not be considered a protocol deviation. A note should be made to the study regulatory binder and the 
Study PI/ designee should also be notified promptly that blood was not collected for that timepoint.   
 
* Patients who qualify for receiving only 5 cycles of CHEP-BV will have their blood collection done on Cycle 5 Day 15. 

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9.3.1 
Blood sample collection and Labeling 
Notification to COH 
APCF of Pending 
Collection 
Site 
Tube 
Type 
Labeling and Collection Details 
Post-collection 
Instructions 
 Notify at least 
one day in 
advance) 
 Send calendar 
invite via e-mail: 
Leslie Smith-
Powell (LSmith-
Powell@coh.org) 
or Stephanie Lee 
(stlee@coh.org) 
COH  
Purple-
top 
1. 
Label tubes with COH protocol #, subject ID (issued by 
DCC), institution (for non-COH sites), date and timepoint 
of collection (e.g. D1C1 for Day1 of Cycle 1), and if 
applicable patient initials. 
2. 
Timepoints of collection are stated in Table 9.3. 
3. 
Invert tubes eight times after collection.  
4. 
Immediately place the tubes on ice. 
Promptly deliver the 
blood samples on ice to 
the APCF, Shapiro room 
1042 for processing 
within 1-2 hours (± 15 
minutes). 
Non-
COH 
Cell free 
DNA 
BCT® 
tubes 
1. 
Label tubes with COH protocol #, subject ID, institution 
(for non-COH sites), date and timepoint of collection 
(e.g. D1C1 for Day1 of Cycle 1), and if applicable patient 
initials.  
2. 
Timepoints of collection are stated in Table 9.3. 
3. 
Fill in sample collection details in Appendix D-3. 
4. 
If applicable, follow recommendations for order of draw 
outlined in Clinical and Laboratory Standards Institute 
(CLSI) H3-A6. 
a. BCT® tubes may not be drawn immediately 
following a heparin tube; if necessary collect a non-
additive or EDTA tube as “waste tube” prior to 
collection in the BCT® tube. 
5. 
Blood samples will be collected from an indwelling 
venous catheter or by venipuncture.  
6. 
Below guidelines to avoid possible backflow from the 
tube should be followed since BCT® tubes contain a 
formaldehyde-free preservative: 
a. 
Keep patient’s arm in the downward position during 
collection. 
b. 
Hold the tube with the stopper in the uppermost 
position so that the tube contents do not touch the 
stopper or the end of the needle during sample 
collection. 
c. 
Release tourniquet once blood starts to flow in the 
tube, or within 2 minutes of aapplication. 
7. 
Completely fill the tube. 
8. 
Remove tube from adapter and immediately invert the 
tubes 8 to 10 times.  
9. 
DO NOT FREEZE samples. Store samples at 18-25 oC until 
shipment. 
See Appendix D-4  for 
shipment details.  
 

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9.3.2 
Sample Processing by APCF 
 
Tube Type 
and 
Volume 
Processing Details 
Downstream 
assay 
Purple-top 
(~20 mL) 
from COH 
only  
 
Plasma 
1. Centrifuge for 10 minutes at 1800 x g at 4 oC.  
2. Remove the tubes from the centrifuge. Do not disturb the 
cellular layer.  
3. Extract plasma carefully. 
a. Do not disturb the buffy coat while pipetting plasma; leave 
~3-4mm of plasma behind to ensure the buffy coat is 
undisturbed.  
4. Freeze plasma at -80°C in 1-2mL aliquots.  Do not fill tubes 
beyond 70% capacity.  
Sequencing-
cell free 
circulating 
tumor DNA  
PBMC and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
5. 
The remaining content from the tube(s) used to extract the 
plasma will be split into 1/2 and processed as follows: 
a. Process ½ of the content for PDWB; 1-2mL PDWB aliquots 
will be frozen at -80°C 
b. Process ½ of the content for PBMC per COH APCF 
procedures; store per COH APCF procedures until use. 
 
Sequencing 
Cell free 
DNA BCT®  
(~20 mL) 
from Non-
COH sites 
 
Plasma  
1. Centrifuge for 10 minutes at 1600 x g at room temperature. 
2. Remove the upper plasma layer and transfer to a new conical 
tube.  
a. Save the remaining cells for additional processing (see 
below). 
3. Centrifuge the plasma at 16000 x g for 10 minutes.  
4. Collect the plasma. 
5. Freeze plasma at -80°C in 1-2mL aliquots.  Do not fill tubes 
beyond 70% capacity.  
Sequencing-
cell free 
circulating 
tumor DNA  
PBMC and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
6. 
The remaining content from the tube(s) used to extract the 
plasma will be split into 1/2 and processed as follows: 
c. Process ½ of the content for PDWB; 1-2mL PDWB aliquots 
will be frozen at -80°C 
d. Process ½ of the content for PBMC per COH APCF 
procedures; store per COH APCF procedures until use. 
 
Sequencing 
 

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1. 
 
10.0 STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated. 
Table 10.0 Study Activity Calendar  
 
 
Protocol therapy b,c 
Follow-up assessments 
may be combined if the 
windows for the two 
follow-up visits overlap. 
Protocol Activity 
Screening a 
Induction CHEP-BV kk 
End of Cycle 
6 
(If receiving 
ASCT/ RT) g 
Consolidation 
BV 
Follow-up (until ~5 years 
from start of treatment) 
C1 
C2 
C3 
C4-5 
C6 
C1 
C2-10 
Safety 
30-
days 
post i 
Active 
6 months 
& 12 
months j 
Survival k 
D1d,e 
D1e 
D1e 
D15f 
D1e 
D1e 
D15f 
D1h 
D1e  
Informed Consentl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration o 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examp 
&  Vital signs q 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X  
X 
 
 
ECOG Status (Appx. A) 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
Con-med review r  
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
AE Assessment s 
X s 
X t 
X t 
X t 
 
X t 
X t 
 
X t 
X t 
X t  
X t 
 
 
ECHO/MUGA 
X jj 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy u 
X v 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plt  
& Serum chemistry w 
X v 
X 
X 
X 
 
X 
X 
 
X 
X 
X  
X 
 
 
Correlative MRD blood x 
 
X 
 
 
X 
 
 
X kk 
 
 
Cycle 5  
X 
 
 
Correlative tumor tissue  
X y 
---------------------------------------------------------------------- Xz---------------------------------------------------------------------- 
Bone marrow biopsy/ 
aspirate  
X bb 
           ----------------------------------------------------------------------Xaa, cc----------------------------------------------------------------- 
CT  
X dd, jj 
 
 
 
Xff 
 
 
 
 
 
X ee,ff 
X ee 
X ee 
 
PET-CT 
X dd, jj 
 
 
 
 
 
 
X ff, kk  
 
 
X ee, ff 
X ee 
X ee 
 
Response gg 
 
 
 
 
X ff 
 
 
X ff, kk 
 
 
X ff 
X 
X 
 
Cyclophosphamide IV hh 
 
D1 of each cycle 
 
 
 
 
 
Doxorubicin IV hh 
 
D1 of each cycle 
 
 
 
 
 
Etoposide IV hh, ll 
 
D1-3 of each cycle 
 
 
 
 
 
Prednisone-Orally hh 
 
D1-5 of each cycle 
 
 
 
 
 
Brentuximab vedotin IV- 
Inductionhh 
 
D1 of each cycle 
 
 
 
 
 
Criteria to initiate 
Consolidation ii 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Brentuximab vedotin IV 
Consolidation hh, ii 
 
 
 
 
 
 
 
 
 
D1 of each 
cycle 
 
 
 
Survival status k 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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a. Screening activities to occur within 28 days prior to start of protocol therapy except for laboratory assessments and 
bone marrow biopsy. Refer to footnote jj for patients who received one cycle of CHOP-like or one cycle of CHP-BV 
therapy prior to starting study treatment. 
b. Protocol therapy may last up to 16 cycles, until unacceptable toxicity or disease progression (see Section 5.10 for 
more comprehensive list). 
c. 
In the absence of treatment delay, each treatment cycle lasts 21 ± 3 days. 
d. Day 1 of Cycle 1 of Induction is defined as the day of chemotherapy (CHEP) administration.  
e. Activities (except imaging and response assessment- footnote ff) and safety assessment review to be performed 
within 72 hours prior to initiation of the cycle.  
f. 
Day 15 assessments have a ± 7 day window.  
g. End of Cycle 6 safety visit (-7/ + 3 days) for those going on to receive consolidation ASCT/ radiation therapy (RT). Will 
occur at end of Cycle 5 (-7/ + 3 days) for patients who qualified for receiving only 5 cycles of CHEP-BV. 
h. For CR/ PR participants from Induction: Day 1 of Cycle 1 of Consolidation is defined as the day of brentuximab 
vedotin administration. NOTE: Evaluations performed within 14 days prior to start of Consolidation Day 1 may serve 
as Day 1 evaluations. Refer to Section 5.7 for details. 
i. 
The 30 days post-last dose assessments to occur 30 (±7) days post-last dose or, if > 30 days elapsed since last dose, 
within 7 days after decision to end treatment. Expedited reporting will occur during this period (See Section 7.6). 
Safety follow-up may be extended until resolution/ stabilization of reportable AEs. 
j. 
For participants yet to progress, Active Follow-up will occur at 6 months (± 14 days) and 12 months (± 30 days) from 
the day of last response evaluation until progression or the initiation of a new therapy.  
k. 
Participants who end Active Follow-up will enter Survival Follow-up. Survival assessment to occur bi-annually or as 
requested by the Study PI via medical record review, review of social security registry, or telephone call. 
l. 
Informed consent process to be fully documented (see Section 16.4). Informed consent must occur prior to any 
research only (non-SOC) screening procedures. 
m. Medical history to include a review of treatment history, any ongoing medical conditions and medical history 
pertaining to eligibility on study and involvement during study. 
n. Eligibility criteria are detailed in Section 3.0.  
o. Registration into a COH clinical trial management system (CTMS).  
p. Standard physical exam includes weight and skin analysis.  
q. Vital signs: heart rate, blood pressure, respiration rate, and temperature.   
 
r. 
Concurrent medications and reason for administration to be documented from within 28 prior to protocol therapy 
up to 30-days-post last dose visit. See Section 5.13 for concomitant medication restrictions and guidelines.  
s. 
Adverse event (AE) will be assessed using CTCAE v.4.0. SAEs related to study procedures will be recorded and 
reported from time of informed consent until Day 1 of protocol therapy.  
t. 
AE recording and reporting will continue until the completion of Safety Follow-up period or until resolution or 
stabilization of any reportable AE occurring during Safety Follow-up.  
u. Women of child bearing potential: Pregnancy serum or urine test. 
v. 
Screening laboratory assessments to be performed within 14 days prior to start of protocol therapy. 
w. Serum chemistry panel to include: glucose, Blood Urea Nitrogen (BUN), creatinine, uric acid, total protein, albumin, 
magnesium, bicarbonate, calcium, inorganic phosphorous, sodium, potassium, chloride, total bilirubin, alkaline 
phosphatase, ALT, AST, and LDH. 
x. 
Correlative blood will be collected as follows. See Section 9.3 for timepoints and details for notifying APCF, 
processing and non-COH site shipment.  
 
COH only for MRD studies: 20 mL into purple-top tubes per timepoint, and 

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 
Non-COH only for MRD studies: 20 mL into cell free DNA BCT® tubes per timepoint 
y. 
Archival tumor tissue to be submitted post-enrollment. Note: If unavailable, exceptions may be granted by the Study 
PI. Refer to Section 9.2.1. 
z. 
If safe and feasible, submission of left-over tissue from a standard of care tumor biopsy (fresh core or excisional 
biopsy) for participants who progress/relapse during study is encouraged. Refer to Section 9.2.1 
aa. Following initial screening, and unless clinically indicated, bone marrow specimens will be collected only to confirm 
CR, and only on patients who had bone marrow involvement at screening.  
bb. Bone marrow biopsy/aspirate performed within 120 days prior to Day 1 Induction may serve as Screening 
assessment. 
cc. Perform bone marrow biopsies/ aspirate only: (i) to confirm CR, and (ii) as clinically indicated post-CR. 
dd. PET-CT or CT of neck, chest, abdomen and pelvis can be performed at screening. If there is evidence of neck 
involvement by lymphoma, neck CT should be continued at subsequent tumor evaluation.  
ee. Post-Induction: if prior response was CR perform CT for subsequent timepoints; if prior response was PR perform CT 
or PET-CT. NOTE: Conversions from PR to CR should be confirmed with a PET-CT scan. 
ff. Imaging and response assessment to occur: 
 
Induction CHEP-BV: 
Cycle 3 Day 15 (± 7 days) and 
Cycle 6 Day 15 (± 7 days), or Cycle 5 Day 15 (± 7 days) (if patient qualifies for receiving only 5 cycles of CHEP-BV)  
 
Consolidation BV: Cycle 5 Day 1 (-7 days) 
 
30-days post-last dose (± 7 days): Only if last imaging assessment was performed > 8-12 weeks ago. 
 
Active Follow-up: at 6 months (± 14 days) and 12 months (± 30 days) from the day of last response evaluation 
gg. Response per 2014 Lugano Classification: See Section 11.3 and Appendix B-2. 
hh. Refer to Section 5.3 for the treatment plan and Section 5.8 for agent administration details. Refer to Section 6.2 for 
dose modification/ delay guidelines and Section 5.13 for supportive care guidelines. 
ii. 
Criteria to initiate BV Consolidation: Section 5.7.1 criteria must be met. 
jj. Patients who received one cycle of CHOP-like or 1 cycle of CHP-BV therapy prior to starting study treatment do not 
need to repeat echocardiogram/MUGA and pre-treatment (screening) imaging assessment if these tests were 
performed within 60 days of the cycle of CHOP-like or CHP-BV therapy, and providing that the results of these tests 
met the eligibility criteria for the current study. 
kk. Patients who received 1 cycle of CHOP-like or 1 cycle of CHP-BV therapy prior to initiating induction with CHEP-BV 
are allowed to receive only 5 cycles of CHEP-BV instead of 6 cycles, per investigator’s discretion. For these patients 
who qualify for receiving only 5 cycles of CHEP-BV, imaging, response assessment, and correlative blood collection 
scheduled on Cycle 6 will occur on Cycle 5. 
ll. 
Alternatively, etoposide may be given orally (refer to Section 5.3). 
 

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11.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
11.1 Safety 
Toxicity will be recorded using the NCI CTCAE v 4.0. The highest grade of any toxicity will be collected for 
each cycle during protocol treatment and for the period of safety follow-up after end of treatment. For 
Cycle 1 only, all Grade ≥2 AEs (highest grade or not) will also be collected. 
11.2 Unacceptable Toxicity  
Unacceptable toxicity will be defined as one of the following AEs that is at least possibly related to study 
treatment during Cycle 1 of Induction:  
Hematologic 
 Delay in planned initiation of Cycle 2 Day 1 by more than 14 days due to Grade 4 neutropenia 
that does not resolve to Grade ≤ 2 or baseline despite growth factor support 
 Grade 4 thrombocytopenia lasting ≥ 7 days  
 Platelet nadir < 10,000/ mm3 
 Delay in planned initiation of Cycle 2 Day 1 by more than 7 days due to failure to recover 
platelets to ≥ 50,000/ mm3 and/or ANC to ≥ 1000/ mm3  
 Any Grade 5 AE 
Non-hematologic 
 Any clinically relevant  ≥ Grade 3 AE that does not resolve to Grade ≤ 2 within 7 days with the 
exception of: 
− Grade 3 asymptomatic laboratory abnormalities, including lipase or amylase, that 
are not clinically relevant, not requiring hospitalization or delay of treatment 
− Grade 3 nausea, vomiting, or fatigue controlled with supportive measures 
− Grade 3 inflammatory response attributed to local antitumor response 
− Vitiligo 
 Delay in planned initiation of Cycle 2 Day 1 by more than 7 days due to Grade ≥2 peripheral 
motor neuropathy 
 Any Grade 5 AE 
11.3 Response and Clinical Endpoints  
11.3.1 Response/Progression 
Lymphoma response/progression will be evaluated using 2014 Lugano Classification (see Appendix B-2) 
[55, 57].  
Disease parameters and methods for assessing the disease are in Appendix B-1.  Disease assessment will 
be performed either by PET-CT (FDG-avid histologies) or diagnostic quality CT of the neck, chest, 
abdomen and pelvis (N/C/A/P) with IV contrast. Although diagnostic quality CT is acceptable, at baseline 
and end of induction, PET-CT is the preferred assessment method. At the interim assessment on C3D15, 
diagnostic quality CT should be performed. PET and CT may be co-acquired or acquired separately.   
Patients with bone marrow involvement at baseline must have a bone marrow biopsy performed to 

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confirm CR (if applicable). After CR, additional bone marrow biopsy is only required if clinically indicated 
and, after CR, IV contrast-enhanced CT of the chest, abdomen, pelvis (and neck, if involved by 
lymphoma) can be performed rather than PET-CT. For patients not in CR who are receiving 
consolidation, although diagnostic quality CT is acceptable, PET-CT is preferred to assess for possible 
conversion to CR. Additional necessary restaging studies including dedicated CT scans or MRI, are 
permitted at the investigator’s discretion.  PET-CT and CT results will be read by a radiologist at each 
study site and investigator response assessment will be performed. 
For patients with progression of disease on imaging, it is strongly recommended that a confirmatory 
biopsy be obtained whenever possible. Note that an FDG-negative PET scan will only be considered 
complete remission in patients whose tumor was FDG-avid at baseline. In patients who do not have 
FDG-avid disease at screening, diagnostic quality CT scans should be performed for treatment response 
assessment. 
11.3.2 Clinical Outcome Endpoints  
Evaluable patients are defined in Section 12.2. 
Endpoint 
Patients 
Definition 
Progression-Free Survival 
(PFS)* 
Evaluable 
patients 
Defined as the time from enrollment to the first observation of 
disease relapse/progression or death from any cause, whichever 
occurs first.  
For patients who are alive and have not had disease 
relapse/progression at the last follow-up, it is censored at the 
time of last follow-up.  If a patient recieves non-protocol anti-
lymphoma treatment prior to disease progression, it is 
censored at the time of non-protocol anti-lymphoma 
treatment. 
Overall Survival (OS) 
Evaluable 
patients 
Defined as the time from enrollment to death from any cause.   
For patients alive at the last follow-up, it is censored at the 
time of last follow-up. 
Overall response (ORR) 
rate  
Evaluable 
patients  
Proportion of patients achieving CR or PR 
Complete response (CR) 
rate  
Evaluable 
patients 
Proportion of patients achieving CR 

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12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
12.1.1 Study Design Overview 
This will be a multicenter, single-arm Phase 2 study evaluating the addition of brentuximab vedotin to 
cyclophosphamide, doxorubicin, etoposide, and prednisone (CHEP-BV) as induction therapy for CD30-
positive peripheral T-cell lymphomas followed by BV consolidation. Patients will receive up to 6 cycles of 
CHEP-BV in 21-day cycle as induction therapy. Patients with objective response after induction therapy 
will be eligible to undergo consolidation therapy with an additional 10 cycles of single-agent BV, 
administered every 21 days, to be initiated either after a consolidative ASCT/radiation or after the 
completion of induction therapy.  
The primary endpoint is complete response (CR) rate after CHEP-BV induction therapy. Secondary 
endpoints include toxicities of CHEP-BV induction therapy, toxicities of BV consolidation after CHEP-BV 
induction therapy and ASCT/radiation, toxicities of BV consolidation after CHEP-BV induction therapy 
without ASCT/radiation, ORR  after induction therapy, CR rate after BV consolidation therapy, PFS and 
OS. The first 6-12 patients will be monitored as part of the Safety Lead-in segment as described below in 
Section 12.1.2. Patients enrolled during the safety lead-in segment who are treated at the final dose 
deemed tolerable will be included in the Phase 2 response evaluation provided that they are also 
evaluable for response. 
The initial statistical design described below was based on CR rate of 60% vs. 40%. 
The study adopts a Simon Two-Stage Minimax Design, with 16 patients at the first stage and a total of 
28 patients at the second stage. The sample size is based on the desire to discriminate a promising CR 
rate of 60% after CHEP-BV induction from a disappointing CR rate of 40% after CHEP-BV induction, using 
a type I error rate of 0.10 and power of 80%. These rates were chosen based on prospective clinical trial 
data of anthracycline-based induction therapy for PTCL. The CR/CRu rate to CHOEP/CHOP (younger 
patients received CHOEP, patients 60 or older received CHOP) in a Phase 2 study of patients with PTCL is 
52.6% (n=82/156)[18] while the CR/CRu rate to CHOP-based therapy in two prospective clinical trials is 
33% (n=15/45, CHOP) and 49% (20/41, high-dose CHOP plus ESHAP) [10, 11]. Therefore, we would 
consider at least 60% a promising CR rate for this regimen to merit further study and a 40% CR rate 
(similar to CHOP) a discouraging rate. 
In the Simon Two-Stage Minimax design, at the first stage, 16 patients will be entered on the study. If ≤ 6 
complete responses are seen, the study will be terminated. If at least 7 patients achieve a complete 
response, the trial will continue to the second stage. At the second stage, 12 additional patients will be 
entered. At the end of stage 2, if 15 or more patients out of the total 28 experience a complete response, 
the combination will be considered worthy of further study. If ≤14 patients experience a complete 
response then no further investigation of the combination is warranted. 
Per Amendment dated 05-10-19, the statistical design is being revised. The revisions are motivated by 
the recent published data from the randomized Phase III ECHELON-2 study (n=452)[58]. In the ECHELON-
2 study, previously untreated CD30-positive PTCL patients were randomized to BV+CHP or CHOP for 6-8 
cycles. The CR rate at end of treatment was 56% (95% CI 49%-62%) for CHOP arm and 68% (61%-74%) 
for BV+CHP arm (p=0.007). In our initial design described above, 40% CR rate was considered the 
baseline rate for CHOP-like induction thearpy. Given the ECHELON-2 data results, the study is being 

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revised to consider a baseline rate of 56% instead of 40%, and to increase the total study accrual to 48 
evaluable patients. Patients enrolled during the Safety Lead-in segment who are treated at the final 
dose deemed tolerable will be included in the Phase 2 response evaluation provided that they are also 
evaluable for response. The sample size of 48 is based on the desire to discriminate a promising CR rate 
of 71% from a disappointing CR rate of 56%, using a type I error rate of 0.10 and power of 80% based on 
an exact binomial test. The design will require 32 or more CR among the 48 patients to consider the 
outcome encouraging. 
At the time of this amendment, this study has already passed the initial/previous design Stage I efficacy 
rule and is at Stage 2 accrual. Among the 16 Stage I patients, there have been 9 end of induction CR, 1 
end of induction PR, 2 interim CR and 2 interim PR pending end of induction response, and 2 pending 
any response evaluations. Given the efficacy of BV+CHP established by ECHELON-2 study and the 
preliminary efficacy data we observe with CHEP-BV on this study, this revised design is a single stage 
design without an interim monitoring rule.       
12.1.2 Safety Lead-in 
Prior to formally initiating the Phase 2 response evaluations, a patient safety lead-in segment will be 
conducted to ensure there are no unexpected toxicities. The safety lead-in segment will follow standard 
3+3 dose escalation/de-escalation/expansion rules based on observed toxicity during Induction Cycle 1. 
The unacceptability toxicities are defined in Section 11.2. Patients evaluable for unacceptable toxicities 
during the Safety Lead-in are defined in Section 12.2.  
Initially up to 3 patients can be enrolled and treated with CHEP-BV induction therapy at brentuximab 
vendotin dose level of 1.8 mg/kg (dose level 1). After 3 patients are treated and evaluated for 
unacceptable toxicities during Cycle 1, if ≤1 out of 3 patients experience unacceptable toxicities, up to 3 
additional patients will be enrolled and treated at 1.8 mg/kg to bring the total number of patients 
treated to 6. If ≤1/6 patients experience unacceptable toxicities during Cycle 1, brentuximab vedotin at 
1.8 mg/kg will be considered tolerable for the CHEP-BV therapy and the brentuximab vedotin 
consolidation therapy. If ≥2/3 (after the initial 3) or ≥2/6 (after the total 6 in 2 cohorts) patients 
experience unacceptable toxicities during Cycle 1, 1.8 mg/kg will be considered not tolerable, and the 
study will then evaluate the safety and tolerability of the lower dose level of brentuximab vedotin at 1.2 
mg/kg (dose level -1).  
A similar “3+3” design will be used to evaluate the dose level of 1.2 mg/kg if 1.8 mg/kg is not tolerable. 
Up to 6 patients will be enrolled in cohort of 3 patients. If ≤1/6 patients experience unacceptable 
toxicities during Cycle 1, 1.2 mg/kg will be considered tolerable. If ≥2/3 (after the initial 3) or ≥2/6 (after 
the total 6 in 2 cohorts) patients experience unacceptable toxicities during Cycle 1, 1.2 mg/kg will be 
considered not tolerable, and the study accrual will be suspended. 
12.2 Evaluable Participants and Participant Replacement 
o Evaluable toxicity: Patients who receive at least one dose of protocol therapy are evaluable for 
toxicity. 
o Evaluable for unacceptable toxicity during Safety Lead-in: Patients evaluable for unacceptable 
toxicity (defined in Section 11.2) are: 
1) Those who receive the dose of brentuximab vedotin, the dose of cyclophosphamide, the 
dose of doxorubicin,  all doses of Etoposide, and at least 80% doses of prednisone  
during Induction Cycle 1 OR  

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2) Those who experience any unacceptable toxicity during Cycle 1 regardless of actual dose 
received.  
Patients who are not evaluable for unacceptable toxicities will be replaced. 
o Evaluable for response:  
 Evaluable patients are defined as eligible participants who have received at least one cycle of 
CHEP-BV Induction therapy, and have had  at least one disease evaluation. Patients cannot 
proceed to BV consolidation without a response assessment after CHEP-BV induction. 
Patients will be evaluable and be considered non-CR in the primary response evaluation if 
they discontinued study therapy prior to having a response assessment because of 
progressive disease or unacceptable toxicity (rather than withdrawal of consent or 
investigator decision). If a patient discontinues study treatment prior to the first response 
assessment due to progressive disease, the treating physician is encouraged to obtain 
imaging to confirm progression.   
Eligible participants who are not evaluable for response will be replaced and excluded from  
efficacy analyses, but will be included in the general toxicity analyses if they received any 
protocol treatment. 
12.3 Sample Size Accrual Rate 
The Phase 2 response evaluation will require 48 response evaluable patients. The first 6-12 patients 
enrolled on the study will be part of the safety lead-in segment evaluating the two dose levels, as 
described in the Section 12.1.2. The patients enrolled during the safety lead-in segment who are treated 
at the final dose deemed tolerable will be included in the Phase II response evaluation provided that 
they are also evaluable for response.  Accounting for up to 10% inevaluable patients and some of the 
patients treated at the safe dose during the safety lead-in segment not evaluable for response, the 
maximum accrual for the study is estimated to be 53 patients.  In both 2012 and 2013, City of Hope saw 
~160 PTCL patients per year, with ~30 new patients per year (mix of newly diagnosed and relapsed or 
refractory). We expect that about ~50% of patients will be CD30+, therefore, we expect to accrue 10 
patients to this trial in 36 months at COH. Given that this is a multi-center study including 3 high-volume 
PTCL centers, we anticipate completing study accrual within 36 months.  
12.4 Statistical Analysis Plan 
Patient demographics, baseline disease characteristics and prior treatment therapy will be summarized 
using descriptive statistics. For continuous variables, descriptive statistics such as number, mean, 
standard deviation, standard error, median (range) etc. will be provided. For categorical variables, 
patient counts and percentages will be provided. 
CR rate after CHEP-BV induction therapy will be estimated by the proportion of evaluable patients 
achieving CR after CHEP-BV induction therapy, along with the 95% exact binomial confidence interval. 
ORR after CHEP-BV induction therapy and CR rate after BV consolidation will be similarly estimated.  PFS 
and OS will be estimated using the product-limit method of Kaplan and Meier along with the 
Greenwood estimator of standard error. Observed toxicities of CHEP-BV induction therapy, those of BV 
consolidation after CHEP-BV induction and ASCT/radiation, and those of BV consolidation after CHEP-BV 
induction without ASCT/radiation will be summarized by type (organ affected or laboratory 
determination such as absolute neutrophil count), severity (by NCI CTCAE v4.0 and nadir or maximum 
values for lab measures), date of onset, duration, reversibility, and attribution.  

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For the exploratory objects, descriptive statistics will be used to summarize the correlative study 
measures such as GEP and MRD assessments. For continuous variables, number, mean, standard 
deviation, standard error, median (range) etc., will be provided. For categorical variables, patient counts 
and percentages will be provided. Changes in these measures before, during, and after treatment (when 
measured) will also be summarized by descriptive statistics and tables/plots. Various statistical analyses 
will be used to explore the association between these correlative measures (at different time points and 
the associated changes over time, when measured) with clinical outcomes. For the exploratory 
correlation of these endpoints with response, analyses comparing groups of participants defined by 
response  may be conducted by various two sample tests such as two-sample t-test or Wilcoxon rank 
sum test for the continuous correlative endpoints, or Chi-square test/Fisher’s exact test for the 
categorical correlative endpoints. For the exploratory correlation of these endpoints with survival 
outcomes, survival analysis techniques such as Log rank test will be considered. Appropriate regression 
models will also be considered, such as logistic regression for analyses on response and Cox proportional 
hazards models for survival outcomes.   All these analyses are exploratory in nature and are intended to 
generate hypotheses that may be validated in larger studies; no multiple comparison adjustments will 
be made in these exploratory analyses.  
12.5 Toxicity Monitoring after Safety Lead-in 
Close and continuous monitoring for toxicity will occur throughout the study duration per institutional 
standards. The City of Hope Data Safety Monitoring Committee (DSMC) will review the toxicity data on 
this study quarterly. The expected rate of “unacceptable toxicity” as defined in Section 11.2 should not 
be ≥33%. The stopping rule for “unacceptable toxicity” will be assessed after at least 6 patients are 
treated at the final dose deemed tolerable for Phase 2 evaluation. If “unacceptable toxicity” events 
occur in ≥33% of patients treated at the final dose at the quarterly review, accrual will be halted and a 
full review of these events will be performed by the City of Hope DSMC. Patient accrual will not resume 
until approved by the DSMC to do so. These rules are in addition to the bi-annual review of all toxicities 
submitted to the City of Hope DSMC. Patients with ongoing toxicity will be followed until resolution or 
stability. 

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13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) that are relevant to 
the clinical trial.  The investigator or their designee will prepare and maintain adequate and accurate 
source documents.  These documents are designed to record all observations and other pertinent data 
for each patient enrolled in this clinical trial.  Source documents must be adequate to reconstruct all 
data transcribed onto the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system (EDC) that is compliant 
with 21 CFR Part 11.  
13.3 Case Report Forms/Data Submission Schedule 
Study personnel will enter data from source documents corresponding to a participant’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that visit is 
available.  
The investigator is responsible for all information collected on participants enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the investigator. All case report forms must be completed by designated study personnel.  
The completed case report forms must be reviewed, signed and dated by the Investigator or designee in 
a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Safety Lead-in Induction Cycle 1: Within 7 calendar days of the 
assessment/notification 
Safety Lead-in remaining cycles and Phase 2: Within 10 calendar days of the 
assessment/notification 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms  
Within 10 calendar days of the assessment 
Off Treatment/Off Study 
Forms 
Within 10 calendar days of completing treatment or being taken off study 
for any reason 
Follow up/ Survival Forms 
Within 14 calendar days of the protocol defined follow up visit date or call 

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13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations 
14.0 ADHERENCE TO THE PROTOCOL 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate 
hazard(s) for the protection, safety, and well-being of a research participant. As a result of deviations, 
corrective actions are to be developed by the study staff and implemented promptly. All protocol 
deviations and planned protocol deviations will be reported in accordance with the City of Hope Clinical 
Research Protocol Deviation policy. 
Non-COH Sites: 
Deviations meeting the criteria specified in the City of Hope Clinical Research Protocol Deviation policy 
(available from the DCC) will be reported to the DCC and Study PI within 24 hours of notification that the 
event occurred.  
Procedure for reporting deviations to the COH DCC: 
1. Document the deviation on the Deviation Reporting Coversheet or submit your site-specific 
protocol deviation log if the log format has been approved for use by the DCC. This 
modifiable Microsoft Word document is available from the DCC. An electronic signature on 
this document will be accepted.  
2. Scan and email the Deviation Reporting Coversheet or protocol deviation log to the Study PI 
(aherrera@coh.org) and DCC@coh.org within 24 hours of notification of the deviation with 
the email subject title of “Herrera CHEP-BV Deviation COH IRB #17058”. If an email receipt 
from the DCC is not received within one working day, please email DCC@coh.org.  
Sites are to report to their local IRB and DSMC per their site’s specific institutional and IRB guidelines. As 
soon as possible, non-COH sites will provide to the COH DCC copies of the IRB and/or DSMC submission 
and corresponding response(s).  
15.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
15.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
15.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities are executed in accordance with federal regulations.  

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15.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, collaborating investigators, 
site investigators, research nurse, clinical research associate/coordinator, and the study biostatistician, 
is responsible for ongoing monitoring of the data and safety of this study, including implementation of 
the stopping rules for safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) to review study status. The meeting 
is a forum to discuss study related issues including accrual, SAE/AE/UPs experienced, study response, 
deviations/violations, and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed. 
15.4 Quality Assurance 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and regulatory requirements, and that the quality 
and integrity of study data and data collection methods are maintained.  Monitoring for this study will 
be performed by the City of Hope Office of Clinical Trials Monitoring (OCTM), within City of Hope’s 
Office for Safety and Data Quality.  
Details of clinical site monitoring are documented in the OCTM SOP and the Risk Based Monitoring 
(RBM) plan. These documents specify the frequency of monitoring, monitoring procedures, the amount 
of subject data to be reviewed, and the distribution of monitoring reports to the study team and the 
COH DSMC.  
15.5 Risk Determination  
This is a high risk study, as defined in the City of Hope Institutional DSMP.  This determination was made 
because this study involves a COH IND. 
15.6 City of Hope Data and Safety Monitoring Committee 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor study progress, 
compliance, toxicity, safety, and accrual data from this trial via the PMT Progress Report (submitted by 
the Study Principal Investigator according to the frequency outlined in the City of Hope Institutional 
DSMP). The DSMC is composed of clinical specialists who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Protocol 
Management Team.  
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
16.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the 
following considerations: 

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o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 312 – Investigational New Drug Application  
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 
o Applicable institutional research policies and procedures 
16.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 
50, 56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 
(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study. Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the 
study. All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
Each participating non-COH institution must provide for the review and approval of this protocol and the 
associated informed consent documents by an appropriate IRB holding a current US Federal wide 
Assurance issued by and registered with the Office for Human Research Protections (OHRP). The 
protocol and consent will be reviewed and approved by the COH IRB before submission to a 
participating site IRB. 
The IRB’s written unconditional approval of the study protocol and the informed consent document 
must be in the possession of the investigator, and, for external sites, the possession of the DCC, before 
the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
All participating sites must follow the lead institution’s IRB-approved protocol. 
16.4 Informed Consent 
Each participating non-COH institution will be provided with a model informed consent form. Each 
institution may revise or add information to comply with local and/or institutional requirements, but 
may not remove procedural or risk content from the model consent form. Furthermore, prior to 
submission to the site’s IRB (initial submission and amendments), the consent and accompanying HIPAA 
form, if separate to the consent, must be reviewed and approved by the DCC. 

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The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document. In addition, they will review the experimental subject’s bill of rights if 
applicable, and the HIPAA research authorization form. Prospective participants will be informed that 
they may withdraw from the study at any time and for any reason without prejudice, including as 
applicable, their current or future care or employment at City of Hope or participating institution or any 
relationship they have with City of Hope or participating institution. Prospective participants will be 
afforded sufficient time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent must 
comply with the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the site investigator and available for 
inspection by sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
16.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures and 
chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review and 
survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research specimens may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form.  Once the PI and site PI is 
notified of this withdrawal of informed consent, the research specimens will not be used in any 
research. At that time, any of the existing specimens will be destroyed. 
16.6 Special and Vulnerable Populations 
16.6.1 Inclusion of Women and Minorities 
The study is open anyone regardless of gender, race or ethnicity.  Efforts will be made to extend the 
accrual to a representative population. If differences in outcome that correlate to gender, racial, or 
ethnic identity are noted, accrual may be expanded or additional studies may be performed to 
investigate those differences more fully.   
Pregnant women are excluded because the effects of brentuximab vedotin and chemotherapy on 
embryogenesis, reproduction, and spermatogenesis in humans are unknown. 

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16.6.2 Exclusion of Pediatric Population 
Pediatric participants (< 18 years old of age) are excluded from this study since safety and effectiveness 
of protocol therapy has not been defined for PTCL. Additional studies may be performed in the pediatric 
population once safety and effectiveness of protocol therapy is defined in the adult PTCL population. 
The incidence of PTCL is rare in the pediatric population. 
16.6.3 Inclusion of HIV Positive Individuals 
Participants with HIV are excluded since safety and effectiveness of brentuximab vedotin therapy has 
not been defined for this population.  
16.6.4 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose 
additional risks for adults lacking capacity than for the general population.  In such instances, informed 
consent will be sought and documented from the prospective participant’s legally authorized 
representative in agreement with institutional policies and local IRB approval. 
16.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any 
study information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, ant the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out 
in accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned patient number. 
Source documents provided to coordinating center for the purpose of auditing or monitoring will be de-
identified and labeled with the study number, subject ID, and if applicable patient initials. 

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The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to 
the extent permitted by the applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research laboratories. The 
specimens will be labeled with the study number, subject ID, date and timepoint of collection. The key 
to the code will be maintained in the COH clinical trials management system which is a secure 
environment.  
16.8 Use of  Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will be either: (a) discarded or (b) placed in a COH IRB approved biorepository with clinical 
information and potentially PHI attached. 
With regard to which option will apply, each site IRB may choose to either: (a) leave the determination 
to the participant via a question in the informed consent document, which would be communicated to 
the study registrar (DCC) at the time of participant registration, OR b) may choose to make a single 
determination on behalf of their respective participants, and communicate that determination to their 
respective participants via the informed consent. 
16.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
16.10 Financial Obligations, Compensation, and Reimbursement of Participants 
Brentuximab vedotin will be provided free of charge to participants. 
Neither the research participant nor the insurance carrier will be responsible for the research 
procedures related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be 
responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures as 
set forth by the insurance carrier.  The participant and/or the insurance carrier will be billed for the costs 
of treatment and diagnostic procedures in the same way as if the participant were not in a research 
study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope or at the non-COH site to the injured participant. There are 
no plans for City of Hope to provide financial compensation in the event of physical injury to a 
participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 

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16.11 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI. Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope and Seattle 
Genetics. The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier. 

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Weisenburger, D.D., et al., Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from 
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Smith, S.M., et al., Hematopoietic cell transplantation for systemic mature T-cell non-Hodgkin lymphoma. J 
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Coiffier, B., et al., Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory 
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Thompson, C.A., Belinostat approved for use in treating rare lymphoma. Am J Health Syst Pharm, 2014. 
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Reimer, P., et al., Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: 
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Corradini, P., et al., Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front 
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Ahn, J.-S., et al., Frontline Autologous Stem Cell Transplantation As Intensive Consolidation in Patients with 
Peripheral T Cell Lymphomas: Multicenter Phase II Trial in Korea. ASH Annual Meeting Abstracts, 2011. 
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Rodriguez, J., et al., Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: 
a prospective study from The Gel-Tamo Study Group. Eur J Haematol, 2007. 79(1): p. 32-8. 
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d'Amore, F., et al., Up-Front Autologous Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: NLG-T-
01. Journal of Clinical Oncology, 2012. 30(25): p. 3093-9. 
30. 
Nademanee, A., et al., High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in 
Peripheral T Cell Lymphoma (PTCL): Analysis of Prognostic Factors. Biology of Blood and Marrow 
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31. 
Bossard, C., et al., Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell 
lymphomas: high correlation with mRNA levels. Blood, 2014. 124(19): p. 2983-6. 
32. 
Weisenburger, D.D., et al., Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from 
the International Peripheral T-cell Lymphoma Project. Blood, 2011. 117(12): p. 3402-8. 
33. 
Sabattini, E., et al., CD30 expression in peripheral T-cell lymphomas. Haematologica, 2013. 98(8): p. e81-2. 
34. 
Delabie, J., et al., Enteropathy-associated T-cell lymphoma: clinical and histological findings from the 
international peripheral T-cell lymphoma project. Blood, 2011. 118(1): p. 148-55. 
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Kim, W.Y., et al., Prognostic implications of CD30 expression in extranodal natural killer/T-cell lymphoma 
according to treatment modalities. Leuk Lymphoma, 2014: p. 1-9. 
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Li, P., et al., CD30 expression is a novel prognostic indicator in extranodal natural killer/T-cell lymphoma, 
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Lunning, M.A.e.a., CD30 Is a Potential Therapeutic Target in Patients with HTLV1 Associated Adult TCell 
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38. 
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. 
39. 
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. 
40. 
Pro, B., et al., Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic 
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Fanale, M.A., et al., Brentuximab Vedotin in the Front-Line Treatment of Patients With CD30+ Peripheral T-
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Moskowitz, C.H., et al., Brentuximab vedotin as consolidation therapy after autologous stem-cell 
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43. 
Iqbal, J., et al., Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and 
prognostication in angioimmunoblastic T-cell lymphoma. Blood, 2010. 115(5): p. 1026-36. 
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Iqbal, J., et al., Gene expression signatures delineate biological and prognostic subgroups in peripheral T-
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45. 
Piccaluga, P.P., et al., Molecular profiling improves classification and prognostication of nodal peripheral T-
cell lymphomas: results of a phase III diagnostic accuracy study. J Clin Oncol, 2013. 31(24): p. 3019-25. 
46. 
Faham, M., et al., Deep-sequencing approach for minimal residual disease detection in acute 
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Ladetto, M., et al., Next-generation sequencing and real-time quantitative PCR for minimal residual 
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Logan, A.C., et al., Minimal residual disease quantification using consensus primers and high-throughput 
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Oki, Y., et al., Detection of classical Hodgkin lymphoma specific sequence in peripheral blood using a next-
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Roschewski, M., et al., Circulating tumour DNA and CT monitoring in patients with untreated diffuse large 
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APPENDIX A: PERFORMANCE STATUS 
ECOG Performance Scale [59] 
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 B: 2014 LUGANO RESPONSE CRITERIA 
Response 
Site 
CT-Based Response 
PET-CT Based Response 
Complete 
Response 
 
Complete radiologic response 
(all of the following) 
Complete metabolic response (even 
with a persistent mass) 
Lymph nodes and 
extralymphatic 
sites 
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter (LDi).  
No extralymphatic sites of 
disease. 
Score ≤ 3* with or without a residual 
mass on 5-point scale†. 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., with 
chemotherapy or myeloid 
colony-stimulating factors), 
uptake may be greater than 
normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response 
may be inferred if uptake at sites 
of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal by morphology; if 
indeterminate, IHC negative 
No evidence of FDG-avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes and 
extralymphatic 
sites 
≥ 50% decrease in SPD of up to 
6 target measurable nodes 
and extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 
mm X 5 mm as the default 
value 
When no longer visible, 0 X 0 
mm 
For a node > 5 mm X 5 mm, but 
smaller than normal, use 
actual measurement for 
calculation 
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings 
indicate residual disease 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ enlargement 
Spleen must have regressed by 
> 50% in length beyond 
normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan 
No response 
or stable 
disease 
 
Stable disease 
No metabolic response 
Target nodes/nodal 
masses, 
extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria 
for progressive disease are 
met 
Score 4 or 5† with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 
Organ enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires at 
least 1 of the following 
Progressive metabolic disease 
Individual target 
nodes/nodal 
masses 
PPD progression: 
Score 4 or 5† with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal lesions 
An individual node/lesion must 
be abnormal with: 
Longest diameter (LDi) > 1.5 cm 
and 
Increase by ≥ 50% from PPD 
nadir and 
An increase in LDi or shortest 
New FDG-avid foci consistent with 
lymphoma at interim OR 
 End-of-treatment assessment 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
diameter (SDi) from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, 
the splenic length must 
increase by > 50% of the 
extent of its prior increase 
beyond baseline (e.g., a 15-
cm spleen must increase to 
>16 cm). If no prior 
splenomegaly, must 
increase by at least 2 cm 
from baseline 
New or recurrent splenomegaly 
Nonmeasured 
lesion 
New or clear progression of 
preexisting nonmeasured 
lesions 
None 
New lesions 
Regrowth of previously 
resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm 
in any axis; if < 1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable 
to lymphoma 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation).  
If uncertain regarding etiology of 
new lesions, biopsy or interval 
scan may be considered. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG-avid foci 
Measured dominant lesions:  
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly 
measurable in two diameters. Nodes should preferably be from disparate regions of the body and should 
include, where applicable, mediastinal and retroperitoneal areas.  
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation.  
Nonmeasured lesions:  
Any disease not selected as measured, dominant disease and truly assessable disease should be considered 
not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well 
as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or 
in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, 
with marrow activation as a result of chemotherapy or myeloid growth factors). 

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*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider 
a score of 3 as inadequate response (to avoid undertreatment).  
 
†PET 5-point scale:  
1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to 
be related to lymphoma. 
Abbreviations:   
CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse 
diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross 
product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the 
product of the perpendicular diameters for multiple lesions. 

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APPENDIX C: NYHA CARDIAC GRADING CRITERIA 
 
Modified from Dolgin et al., 1994 [60] 
 
New York Heart Association Classification of Heart Failure 
Class I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not cause fatigue 
or dyspnea. 
Class II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking uphill, walking 
or stair climbing after meals, in cold weather, in wind or when under emotional stress causes undue 
fatigue or dyspnea. 
Class III 
Symptoms with less than ordinary physical activity. Walking one to two blocks on the level and 
climbing more than one flight of stairs in normal conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea. 
 

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APPENDIX D-1: CORRELATIVE TISSUE FORM (FOR ALL SITES)  
 
A copy of this form should accompany the sample shipments to COH Pathology Core. 
Non-COH sites: refer to Appendix D-2 for shipping instructions to COH Pathology Core. 
 
COH IRB number: 17058 
Shipping date (MM-DD-YYYY):   ________/________/________ 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
Date of collection/ biopsy (MM-DD-YYYY):    ________/________/________ 
Time point:     
  Baseline       
  Progression 
Diagnosis: 
Tissue type (FFPE scrolls, slides, biopsies): 
Number of scrolls: 
Number of slides: 
 
 
 
 
 
 
CRA/Study Coordinator/Nurse Printed Name:   
CRA/Study Coordinator/Nurse Signature:   
Contact Number: 
 

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APPENDIX D-2: TISSUE SHIPPING GUIDELINES FOR EXTERNAL NON-COH SITES  
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
 
1. Aim to ship samples on a Monday through Wednesday. If this is not feasible, advance 
arrangements should be made with City of Hope Pathology Core (DL-PATHCORE-
BiospecimenSupport@COH.org).   
2. Notify City of Hope Pathology Core (DL-PATHCORE-BiospecimenSupport@COH.org) of 
impending shipment. To request a FedEx shipping label, email DCC@coh.org and indicate the 
planned shipment date. 
3. Slides/ Blocks: Batch ship at room temperature via FedEx. During extreme heat, include 
refrigerated (not frozen) gel packs or gel insulators. 
It is recommended to ship samples via FedEx overnight (for a delivery by 3 pm or earlier the next 
day) or FedEx 2-day (with a morning delivery). During extreme heat, ship via FedEx overnight 
(for a delivery ideally by 10.30 am, or 3 pm the next day). 
4. Frozen samples should be batch shipped on dry ice via FedEx overnight (for a delivery by 10.30 
am the next day). The shipment should contain enough dry ice to last at least 72 hours. 
5. On the day of shipment, email the sample shipment information to City of Hope Pathology Core 
(DL-PATHCORE-BiospecimenSupport@COH.org). 
6. Ship samples with a copy of the correlative tissue form (Appendix D-1) and a copy of the 
pathology report to: 
 
Karen Miller 
COH Pathology Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Familian Science (Building 084), Room 1207 
Duarte, CA 91010 
Telephone: 626-218-8408 
Email: DL-PATHCORE-BiospecimenSupport@COH.org 
 

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APPENDIX D-3: CORRELATIVE BLOOD COLLECTION FORM (NON-COH SITES) 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
Blood samples will be collected into Cell-free BCT® DNA tubes from an indwelling venous catheter or by 
venipuncture.  Refer to Section 9.3 for details.  
Sample # 
Timepoint of 
Collection 
Expected 
Volume 
Tube Type  
Collected 
Volume 
Time of Collection 
Date of Collection 
Induction CHEP-BV 
1. 
 Cycle 1 Day 1 
(baseline) 
~20 mL 
BCT®  tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
2. 
 Cycle 3 Day 15 
~20 mL 
BCT®  tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
3. 
 Cycle 6 Day 15 OR 
 Cycle 5 Day 15* 
~20 mL 
BCT®  tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
Consolidation BV 
4. 
 Cycle 5 Day 1 
~20 mL 
BCT®  tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
5. 
 30-days post last-
dose  
~20 mL 
BCT®  tube 
_____ mL 
____:____ AM/ PM 
____/____/____ 
* For patients who qualify for receiving only 5 cycles of CHEP-BV. 
 
A copy of this form should accompany the sample shipments to COH APCF. Refer to Appendix D-4 for 
shipping instructions COH APCF. 
 
CRA/Study Coordinator/ Nurse:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 
 

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APPENDIX D-4: BLOOD SHIPPING GUIDELINES FOR EXTERNAL NON-COH SITES  
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 - Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety Biosafety Branch. 
If applicable also follow International Air Transport Association (IATA) guidelines. 
When to ship and 
temperature of shipment: 
Promptly but no later than 3 days post-collection via overnight courier at ambient 
temperature. 
 
Days to ship: 
Monday-Wednesday for receipt Tuesday-Friday by the laboratory.  
If this is not feasible, advance arrangements should be made with Leslie Smith-
Powell (LSmith-Powell@coh.org) or Stephanie Lee (stlee@coh.org) or their 
representative. 
Notification on the day of 
shipment 
Email the FedEx shipment # with a copy of Appendix D-3. 
 
Leslie Smith-Powell (LSmith-Powell@coh.org) or  
 
Stephanie Lee (stlee@coh.org) or their representative  
 
What to include with the 
shipment 
 
Copy of Appendix D-3  
 
Copy of the latest CBC results (with differential) and the date of the test  
Shipment address 
Dr. Tim Synold 
Analytical Pharmacology Core Facility  
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
 
 
 
 

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APPENDIX E: DCC REGISTRATION COVERSHEET 
COH Protocol #17058: A Phase 2 Study of Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, 
Etoposide, and Prednisone (CHEP-BV) Followed by BV Consolidation in Patients with CD30-Positive Peripheral 
T-cell Lymphomas 
 
 
Data Coordinating Center  
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-218-7904  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare