A Phase I/II Trial of Brentuximab Vedotin (BV), Ifosfamide (I), Carboplatin (C), and Etoposide (E) for Patients With Relapsed or Refractory Hodgkin Lymphoma (BV-ICE)
Phase: PHASE1
Conditions: Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma
Sponsor: University of Washington

9111 
Protocol Version 5.1 dated 12 November 2019  
 
PROTOCOL  
 
A phase I/II trial of Brentuximab vedotin (BV), Ifosfamide (I),  Carboplatin (C), and 
Etoposide (E) for patients with relapsed or refractory Hodgkin lymphoma (BV-ICE). 
 
Trial of the Fred Hutchinson Cancer Research Center (FHCRC), the University of Washington 
(UW), and the Seattle Cancer Care Alliance (SCCA) 
Supported in part by Seattle Genetics 
 
Current Version Date: 12 November 2019 
 
Previous Version Date: 13 November 2018 
 
 
 
 
Sponsor-Investigator  
Lead Sub-Investigator:    
Ajay K Gopal, MD 
Ryan C. Lynch, MD 
 
Professor, UW 
Assistant Professor, UW  
Member, FHCRC 
Assistant Member, FHCRC 
 
825 Eastlake Ave. E. CE3-300 
825 Eastlake Ave. E. CE3-300 
Seattle, WA  98109 
Seattle, WA  98109 
Telephone: (206) 606-2037 
Telephone: (206) 606-1739 
 
 
This trial is supported in part from the Lymphoma Research Foundation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRO received 06/10/20
FHCRC IRB Approval  
07 09 2020 
Document Released Date

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Protocol Version 5.1 dated 12 November 2019 
 

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Protocol Version 5.1 dated 12 November 2019 
PROTOCOL ACTIVITY 
 
Accrual Activated: 
 
Protocol Revision Record: 
 
Original Version: 
08/01/2014 
 
Amendment #1:  
02/06/2015 
 
Amendment #2: 
05/11/2015 
 
Amendment #3: 
02/17/2017 
 
Amendment #3.1: 
12/01/2017 
 
Amendment #4.0:  
08/29/2018 
 
Amendment #5.0: 
11/13/2018 
 
Amendment #5.1: 
07/25/2019 
 

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Protocol Version 5.1 dated 12 November 2019 
SCHEMA 
Registration 
 
 
 
 
Brentuximab Vedotin, Ifosfamide, Carboplatin, and Etoposide (BV-ICE) 
Given Approximately Every 21 Days for 2 Cycles 
 
Dosing Schema 
Treatment 
 
Dosing Days 1-3 and 8 of each 
Cycle 
 
1 
2 
3 
8 
Brentuximab Vedotin IV 
Dose per escalation schema 
X* 
 
 
X* 
Ifosfamide 5 g/m2 
 
X 
 
 
Mesna 5 g/m2 
 
X 
 
 
Carboplatin AUC 5 IV 
(Cap carboplatin dose  
at 800 mg) 
 
X 
 
 
Etoposide 100 mg/m2  IV 
X 
X 
X 
 
 
G-CSF ≥ 5 µg/kg SQ daily starting on day 4 or 5 and to be continued until absolute neutrophil 
count > 1,000/µL after nadir (pegylated G-CSF may be used when stem cell mobilization is not 
being attempted). 
 
G-CSF is considered standard of care and may be administered at a local clinic upon approval of 
the Sponsor-Investigator or Lead Sub-Investigator. 
 
 
* Brentuximab vedotin administration will be allowed +/- 1 day of these relative dates.   
 
 

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Protocol Version 5.1 dated 12 November 2019 
TABLE OF CONTENTS: 
1.0 
Objectives  ................................................................................................................. 5 
2.0 
Background and Rationale ........................................................................................ 5 
3.0 
Drug Information ....................................................................................................... 7 
4.0 
Staging Criteria .......................................................................................................... 10 
5.0 
Eligibility Criteria  ..................................................................................................... 10 
6.0 
Registration  ............................................................................................................... 12 
7.0 
Treatment Plan  .......................................................................................................... 13 
8.0 
Dosage Modifications  ............................................................................................... 16 
9.0 
Study Calendar  ......................................................................................................... 18 
10.0 
Criteria for Evaluation and Endpoint Definitions ..................................................... 19 
11.0 
Statistical Considerations .......................................................................................... 21 
12.0 
Study Monitoring and Reporting Procedures ............................................................ 23 
13.0 
Elements of Informed Consent  ................................................................................. 27 
14.0 
References ................................................................................................................. 27 
 
  
 

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Protocol Version 5.1 dated 12 November 2019 
1.0 
OBJECTIVES 
 
1.1 
Primary objectives 
1. To determine maximally tolerated dose of brentuximab vedotin that can be 
combined with ifosfamide, carboplatin and etoposide chemotherapy in patients 
with relapsed or refractory Hodgkin lymphoma. 
2. To gain a preliminary assessment of the efficacy of the above regimen. 
 
1.2 
Secondary objectives 
1. To determine the safety and toxicity of the above regimen. 
2. To determine the ability to proceed to peripheral blood stem cell collection 
following the above regimen (the impact of above regimen on stem cell 
reserve). 
3. To assess the impact of this regimen on biomarkers from the microenvironment 
in Hodgkin lymphoma tumors. 
 
 
2.0 
BACKGROUND 
 
Hodgkin lymphoma (HL) was newly diagnosed in about 9,000 people in the United States 
in 2012 [1].  Fortunately, the majority of these patients will be cured with standard 
treatment approaches [2-5].  However, when relapsed or refractory HL is encountered, it 
can be particularly challenging to treat.  To salvage these relapses, several aggressive 
multi-agent regimens have been investigated.  However, the complete response (CR) rates 
to these regimens range from approximately 10 to 50% [6].  Furthermore, for patients who 
are deemed eligible for such an approach, high-dose therapy (HDT) followed by 
autologous stem cell transplantation (ASCT) improves long-term remission rates over 
conventional chemotherapy [7].  The success of this intervention can be predicted by the 
presence of persistent disease at the time of transplant, measured most frequently in the 
modern era by functional imaging with fluorodeoxyglucose-positron emission 
tomography (FDG-PET) [8-11].  Thus, it would be a substantial improvement to develop 
a salvage regimen that has a higher CR rate without leading to prohibitive toxicity. 
 
At the time of relapse, most oncologists employ aggressive cytoreductive chemotherapy 
regimens to determine chemo-responsiveness as well as to optimally debulk patients prior 
to stem cell collection.  Historically, many recent cytoreduction regimens have included 
platinum-based agents because of their considerable activity in lymphoid malignancies.  
One of the first such combination regimens employed Dexamethasone, high dose 
Cytarabine, and Cisplatin (DHAP). This regimen was found to be relatively well tolerated 
with overall response rates (ORR) in the 50-90% range with CRs in the 20-30% range [12, 
13]. In addition, these investigators were able to demonstrate the ability to harvest bone 
marrow or peripheral blood stem cells following treatment.  Despite the encouraging 
efficacy of the DHAP regimen, toxicities including emetogenicity of cisplatin, 
nephrotoxicity of cisplatin, and limited ability to treat older adults with high-dose Ara-C 
prompted other investigators to develop novel platinum-containing combination regimens 
for salvage of lymphoid malignancies. 
 

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Protocol Version 5.1 dated 12 November 2019 
In order to reduce the nephrotoxicity and emetogenicity, a second platinum-based 
combination chemotherapy regimen for lymphoid malignancies was developed containing 
Ifosfamide, Carboplatin and Etopside (ICE). This regimen demonstrated promising 
response rates with ORR of 70-90% and CR in up to 60% [11, 13, 14]. Furthermore, 
successful peripheral blood stem cell collection was accomplished in a majority of 
patients. Finally, as was the goal of this combination regimen, significant nephrotoxicity 
was not observed. This regimen has become the national standard for use prior to 
transplantation. 
 
Despite the activity of this regimen, the majority of patients do not attain complete 
remissions and nearly 30% of patients do not respond [13, 14]. As noted above, the 
inability to achieve CR prior to transplantation portends a poor outcome after transplant.  
In B-cell non-Hodgkin lymphoma (B-NHL), investigators have successfully added 
rituximab to ICE (RICE) with promising results based on its single agent activity, potential 
synergy with chemotherapy, and lack of overlapping toxicity [15].  This strategy increased 
the CR rate to 53% in transplant-eligible patients that had only received 1 prior regimen 
and who had never received rituximab. Unfortunately, further escalation with more 
traditional cytotoxic agents is not possible due to the considerable hematologic toxicity 
and non-hematologic toxicity of the RICE regimen [15].  Thus, the addition of a 
monoclonal antibody to an established cytotoxic chemotherapy regimen can be effective 
for relapsed/refractory B-NHL.  To date, however, this approach has not been fully 
realized for relapsed/refractory HL. 
 
We propose to address this need by adding brentuximab vedotin (BV) to the standard 
salvage regimen, ICE.  BV is an anti-CD30 antibody conjugated to the anti-microtubule 
agent monomethyl auristatin E (MMAE).  It was shown in a phase II study to yield a 
single-agent objective response rate of 75% with CR observed in 34%, comparable as 
monotherapy to the multiagent chemotherapy regimens noted above [6, 16].  On this basis, 
it was approved by the United States Food and Drug Administration (FDA) for the 
treatment of relapsed or refractory HL following ASCT or at least 2 prior multi-agent 
systemic therapies.  In terms of toxicity, this phase II study noted NCI Common 
Terminology Criteria for Adverse Events (CTCAE) grade 3 or worse toxicity in 55 patients 
(56% of the total cohort) when administered at 1.8 mg/kg every 3 weeks to a median of 9 
cycles (range: 1-16).  Most of these events were either peripheral neuropathy (PN) or 
hematologic/laboratory abnormalities, with no deaths attributed to study drug.  More 
recently, a phase I study investigated the safety of more frequent administration (i.e., 
weekly for 3 out of 4 weeks) of BV [17].  Using this dosing schedule, the maximum 
tolerated dose (MTD) was established at 1.2 mg/kg.  The toxicity profile was similar to 
that seen with the every 3 week schedule, with the median number of cycles administered 
across all dose levels of 4 (range: 1-12).  Again, no treatment-related deaths were observed.   
 
Given the encouraging results with BV and the need to improve the therapeutic options 
for patients with relapsed/refractory HL, broader application of this agent is needed.  
Preliminary data from a prospective study of PET-adapted sequential BV followed by 
augmented ICE as first salvage of HL suggest excellent efficacy without prohibitive 
toxicity [18].  In a more straightforward approach, we will investigate the safety and 
efficacy of BV given concurrently with ICE (BV-ICE) for first salvage of HL.  As the 
patients in both of the above-cited studies with single-agent BV were (in general) more 

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Protocol Version 5.1 dated 12 November 2019 
heavily pretreated than the patients that would be enrolled in this study, and since they 
received significantly more of this agent over the course of these studies than what is 
proposed here, we hypothesize that patients will be able to tolerate higher doses of BV 
when given over fewer cycles.  We are thus including a dose-escalation portion of the 
study to increase the delivery of this agent with the hope of achieving a higher CR rate in 
a shorter interval.  Details of this study are described below. 
 
As treatment regimens have improved, efforts are also underway to identify biomarkers 
associated with risk of relapse following established treatments.  Such features may allow 
us to individualize treatment based on specific biological features of the lymphoma.  One 
potential avenue for these efforts is with factors identified within the tumor 
microenvironment of HL, which vastly over-represents the malignant Hodgkin Reed 
Sternberg (HRS) cells [19].  In particular, the degree of MΦ infiltration into HL tumors is 
associated with outcome from both primary and secondary treatment [20, 21].  What 
makes this biomarker particularly desirable is that it is relatively easy to assess with 
immunohistochemistry (IHC) for surface markers such as CD68 and CD163 [22].  Other 
biomarkers associated with the inflammatory microenvironment in HL include gene 
expression profiling of tumors as well as levels of pre-treatment serum cytokines [23, 24], 
which potentially represent a particularly innovative approach to the risk-stratification of 
relapsed/refractory HL.    
 
The primary objectives of this study are to determine the MTD of brentuximab vedotin 
that can be combined with ifosfamide, carboplatin, and etoposide, and to preliminarily 
assess the efficacy of this combination.  We will also be evaluating the safety of this 
regimen in this particular patient population as well as the ability to collect peripheral 
blood stem cells following cytoreduction with this approach.  Lastly, we also will explore 
how factors in the inflammatory microenvironment may impact the results from this 
regimen. 
 
3.0 
DRUG INFORMATION 
 
3.1  
Ifosfamide, carboplatin, etoposide, and G-CSF must be obtained from commercial 
sources.  Please refer to the current FDA-approved package inserts or the Physician Desk 
Reference for information about possible side effects and instructions for preparation, 
handling, dosing and storage of these drugs.  
 
3.2  
Brentuximab vedotin 
    
3.21  General Information 
BV is a CD30-directed antibody-drug conjugate (ADC) that has been 
approved by the FDA for use in patients with HL after failure of ASCT or 
failure of at least two prior treatment regimens in patients who are not 
candidates for ASCT.  BV is marketed in the United States under the name 
ADCETRIS™ by Seattle Genetics, Inc. 
 
3.22 
Description  
BV is a sterile, preservative-free, white to off-white lyophilized cake for 
reconstitution for IV administration. BV will be supplied by Seattle 

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Protocol Version 5.1 dated 12 November 2019 
Genetics in single-use, Type 1 borosilicate glass vials with FluroTec®-
coated butyl rubber stoppers and aluminum seals. Each vial of the product 
contains BV, trehalose, sodium citrate, and polysorbate 80. The drug 
product vial is reconstituted with the appropriate amount of Sterile Water 
for Injection. 
 
3.23  Toxicity 
For the most up-to-date information, refer to the Investigator’s Brochure 
for BV (most recent version at this amendment = version 16).  The 
following list of side effects corresponds to adverse events which have 
occurred in patients in pivotal phase 2 studies and are considered to have a 
possible association with BV by the Sponsor.   
 
Side Effect 
Incidence 
Abnormal nerve function in arms or legs 
(peripheral neuropathy) 
67% 
Alopecia 
13% 
Back Pain 
12% 
Chills 
13% 
Constipation 
18% 
Cough 
21% 
Diarrhea 
34% 
Dizziness 
13% 
Fever 
31% 
High blood sugar 
6% 
Infection risk 
10% 
Infusion-related reactions 
15% 
Itching 
17% 
Low platelets 
10% 
Low red blood cells 
9% 
Low white blood cells 
35% 
Joint pain 
18% 
Muscle pain 
16% 
Nausea 
41% 
Rash 
18% 
Shortness of breath 
15% 
Tiredness 
43% 
Upper respiratory tract infection 
31% 
Vomiting 
20% 
 
This table presents additional serious or potentially life-threatening events 
that could have possible association to BV.  Events in this section have 
occurred infrequently in patients treated with BV in clinical trials or in the 
commercial setting.   
 
Side Effect 
Incidence 

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Protocol Version 5.1 dated 12 November 2019 
Stevens-Johnson syndrome and toxic 
epidermal necrolysis 
< 0.1% 
Tumor lysis syndrome 
< 0.1% 
Progressive multifocal 
leukoencephalopathy 
< 0.1% 
Acute pancreatitis 
< 0.5% 
Hepatotoxicity 
< 2% 
 
 
Drug interactions:  
In humans, BV did not affect the PK of midazolam, a sensitive CYP3A4 
substrate, suggesting that BV and MMAE are neither inhibitors nor 
inducers of CYP3A4.  In humans, data from co-administration of BV with 
rifampin, a CYP3A4 and P-gp inducer, or ketoconazole, a strong CYP3A4 
and P-gp inhibitor, indicate that MMAE is a substrate of CYP3A4.  This is 
consistent with results from in vitro studies, which show that the 
metabolites of MMAE are produced primarily through the action of 
CYP3A4.  No dose adjustment should be necessary based on co-
administration of a CYP3A4 inducer.  Patients receiving strong CYP3A4 
inhibitors concomitantly with BV should be closely monitored for adverse 
events. 
 
Pregnancy:  
The effects of BV on embryogenesis, reproduction, and spermatogenesis in 
humans are unknown.  In addition, data about the effects of BV in pregnant 
women are unavailable.  Therefore, women of childbearing potential and 
fertile men should be advised to use adequate and effective contraception 
during and after treatment with BV. 
 
3.24 
Storage and Stability 
Vials containing BV must be stored under refrigeration at 2-8°C.  Chemical 
and physical stability of the reconstituted brentuximab vedotin drug 
product has been demonstrated for 24 hours at 2-8°C and 25°C.  However, 
BV does not contain preservatives; therefore, from a microbiological 
standpoint, opened and reconstituted vials should be used immediately. If 
not used immediately, the in-use storage should not be longer than 24 hours 
under refrigeration at 2–8°C.  It is recommended that BV vials and 
solutions be protected from direct sunlight until the time of use. 
 
3.25 
Supplier  
BV used under this study will be provided by Seattle Genetics and will be 
identical to the commercially marketed product. 
 
3.26  Drug Accountability  
The sponsor-investigator, or a responsible party designated by the sponsor-
investigator, must maintain a careful record of the receipt, disposition, and 
return of all drugs received for this study using the study specific 
Investigational Agent Accountability Record form or NCI Drug 
Accountability form. 

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Protocol Version 5.1 dated 12 November 2019 
 
Transfer of Brentuximab Vedotin 
Brentuximab vedotin may not be used outside the scope of this protocol, 
nor can brentuximab vedotin be transferred or licensed to any party not 
participating in this clinical study.  
 
 Return of unused Brentuximab Vedotin 
Only un-dispensed drug supplies should be returned to the UW IDS.  Drug 
returns should be noted on the drug accountability log.  Please send a drug 
return form along with the study drug to:  
 
 
Investigational Drug Services 
 
University of Washington medical Center 
 
1959 NE Pacific St., Rm EA-128 Box 356015 
 
Seattle, WA  98195-6015 
 
 
4.0 
STAGING CRITERIA 
 
4.1 
The Ann Arbor staging criteria will be utilized; staging should be the highest stage 
established, either at diagnosis or relapse of disease.   
 
4.2 
For patients from whom data are available, international prognostic score from the 
time of diagnosis will be documented (per Hasenclever, et al. [25]) as detailed 
below:  
 
1. 
Serum albumin, < 4 g/dl 
 
2. 
Hemoglobin, < 10.5 g/dl 
 
3. 
Male sex 
 
4.  
Stage IV disease 
 
5.  
Age ≥ 45 years 
 
6.  
White-cell count ≥ 15,000/µL 
 
7. 
Lymphocyte count < 600/µL or < 8% of white-cell count 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
5.1 
Inclusion Criteria 
 
5.11 
Patients must have primary refractory or first relapse of CD30+ Hodgkin 
lymphoma.     
 
5.12 
Patients must have measurable disease defined as lesions that can be 
accurately measured in two dimensions by CT, MRI, medical photograph 
(skin or oral lesion), plain x-ray, or other conventional technique and a 
greatest transverse diameter of 1 cm or greater; or palpable lesions with 
both diameters ≥ 2 cm.  Further, at least 1 of these lesions must be positive 
by PET scan (i.e., Deauville score of 4 or more).  Note: CT scans remain 
the standard for evaluation of nodal disease. 

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Protocol Version 5.1 dated 12 November 2019 
 
5.13 
Patients must have a CT of chest, abdomen, and pelvis with PET within 28 
days of enrollment. Patients with evidence of lymphadenopathy in the neck 
must have a dedicated CT of neck. 
 
5.14 
Patients must have an ECOG performance status of 0 or 1. (Performance 
status of 2 will be allowed if poor performance status is thought to be 
directly secondary to patient’s HL.) 
 
5.15 
Patients must be 18 years of age or older.  
 
5.16 
Patients must have adequate bone marrow, renal, and hepatic function as 
defined below. All tests must be performed within 28 days prior to 
registration: 
Bone Marrow Function: ANC  ≥ 1,500/µL, platelets ≥ 100,000/µL (without 
transfusion or growth factor support). 
Renal Function: serum creatinine < 1.5 mg/dl or creatinine clearance (CrCl) 
> 60 mL/min by the following formula  
CrCl = (140-age) (Wt in Kg) x 0.85 (female) OR 1.0 (male) 
    72 x serum Cr 
Hepatic function: total bilirubin < 2 times upper limit of normal (unless due 
to Gilbert’s syndrome), AST < 2.5 times upper limit of normal.  
 
5.17 
All patients must be informed of the investigational nature of this study and 
have given written consent in accordance with institutional and federal 
guidelines. 
 
5.18 
Patients must be anticipated to complete 2 cycles of chemotherapy. 
 
5.2 
Exclusion Criteria 
   
5.21 
Patients known to be positive for HIV. 
 
5.22  Pregnant or nursing women. Men or women of reproductive potential may 
not participate unless they have agreed to use an effective contraceptive 
method.  
 
5.23   Patients with other prior malignancies except for adequately treated basal 
cell carcinoma, squamous cell carcinoma of the skin, breast or cervical 
cancer in situ, or other cancer from which the patient has been disease-free 
for 5 years or greater, unless approved by the protocol Chair or Co-Chair. 
 
5.24  Patients with known allergy, intolerance, or resistance (i.e., remission 
duration less than 6 months or lack of response) to ifosfamide, carboplatin, 
or etoposide. 
 

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Protocol Version 5.1 dated 12 November 2019 
5.25 
Patients with evidence of active central nervous system lymphoma. 
 
5.26 
Patients with prior receipt of brentuximab vedotin. 
 
5.27 
Patients with peripheral neuropathy of > Grade 1. 
 
5.28  Patients who have other medical conditions that would contraindicate 
treatment with aggressive chemotherapy (including active infection, 
uncontrolled hypertension, congestive heart failure, unstable angina 
pectoris, myocardial infarction within the past 6 months,  or uncontrolled 
arrhythmia).  If the patient's cardiac history is questionable, a measurement 
of left ventricular ejection fraction should be obtained within 42 days prior 
to registration. Patients with left ventricular ejection fraction < 50% are not 
eligible. 
 
5.29 
Prior failed (< 5x106 CD34/kg) peripheral blood stem cell (PBSC) 
collection.  
 
5.210   Patients who had pelvic radiation within 12 months.  
 
5.211 Previous chemotherapy/immunotherapy within 3 weeks before study entry. 
 
5.212 Concurrent use of other anti-cancer agents or experimental treatments.  
 
 

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Protocol Version 5.1 dated 12 November 2019 
 
6.0 
REGISTRATION 
 
6.1 
Patients must be registered prior to the start of protocol therapy.  A completed 
eligibility checklist with source documentation, a copy of the signed consent form 
and a signed HIPAA authorization are required for registration.  All of the 
eligibility requirements according to Section 5.0 must have been met. 
 
 
7.0 
TREATMENT PLAN 
 
7.1 
For treatment or dose-modification related questions, please contact Dr. Lynch at 
(206) 606-1739 or Dr. Gopal at (206) 606-2037.  (MedCon may also be used to 
contact MDs at 206-543-5300.) 
 
7.2 
Administration of Brentuximab Vedotin added to Ifosfamide, Carboplatin, and 
Etoposide (BV-ICE).  Each cycle of therapy is given every 21 days +/- 3 days.  
Two cycles of chemotherapy should be administered.  The days noted in the table 
below are to be considered a general timeframe: variations +/- 1 day will be 
permitted for administrative/scheduling flexibility. 
 
Dosing should be based on actual weight except for patients weighing greater than 100kg; 
dose will be calculated based on 100 kg for these individuals. BV dose should be rounded 
to the nearest whole number of milligrams. 
 
Drug 
Dose  
Route 
Days 
Duration 
Brentuximab 
vedotin 
Per assigned dose-
escalation schema 
(cap weight for 
dose calculation at 
100kg) 
 
IV 
1 and 8 
~30 minutes 
Ifosfamide 
5 g/m2 
IV 
2 
Infused over ~24 hrs 
Mesna 
5 g/m2 
IV 
2 
Infused over ~24 hrs 
Carboplatin 
AUC 5 
(cap carboplatin 
dose at 800 mg) 
IV 
2 
~1 hr 
 
Etoposide 
100 mg/m2 
IV 
Days 1, 2, and 3 
~1 hr 
 
Filgrastim  
  OR 
Pegfilgrastim 
≥ 5 mcg/kg/day 
 
6 mg 
SQ 
 
SQ 
Day 4 or 5 
 
Day 4, 5, or 6 x 1 
Daily until ANC >  
1,000 
Once 
 

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Protocol Version 5.1 dated 12 November 2019 
Post Protocol Treatment 
Following the 2 cycles of treatment patients may go on to receive other therapy at the discretion 
of their physician.  It is anticipated that most patients will proceed to HDT and ASCT.  
Brentuximab vedotin will no longer be supplied. 
 
7.21  Brentuximab Vedotin 
Dose level will be assigned at enrollment.  BV is administered 
intravenously on days 1 and 8 (+/- 1 day at each timepoint).  Advice on BV 
reconstitution and administration: 
• Reconstitute lyophilized BV by adding 10.5 mL Sterile Water for 
Injection, USP to the 50 mg vial, directing the stream to the side of 
the vial.   
• Dilute reconstituted product in either 0.9% Sodium Chloride 
Injection, USP, Lactated Ringer’s solution, USP, or dextrose 5% in 
water (D5W), USP.  Gently invert the infusion bag. DO NOT 
SHAKE. 
• The final concentration of BV in infusion bag should be in the range 
of 0.4–1.8 mg/mL.   
• 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. 
• BV should be administered over approximately 30 minutes and 
cannot be mixed with other medications.  In-line filters should not 
be used during the IV administration. 
 
7.22  Carboplatin Dose Calculation and Administration 
 
Carboplatin dose will be calculated for an AUC of 5 using the Calvert 
Formula as described below.  Carboplatin dose should be capped at 800 
mg. 
 
Carboplatin dose = 5 x (GFR* + 25) 
 
* Calculated creatinine clearance (CrCl) is substituted for GFR based on 
the formula below. Dose is in mg NOT mg/m2. 
 
CrCl = (140-age) (Wt in Kg) x 0.85 (female) OR 1.0 (male) 
 
 
72 x serum Cr** 
 
**Serum creatinine must be obtained within 3 days of receiving 
chemotherapy for each cycle. 
 
7.3 
Peripheral Blood Stem Cell Mobilization and Collection 
 
For patients that plan to go on to consolidative HDT and ASCT, PBSC can be 
mobilized following the 2nd cycle of study therapy at the discretion of the treating 

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Protocol Version 5.1 dated 12 November 2019 
physician.  The following includes general guidelines regarding PBSC 
mobilization and collection.  Deviations from this plan to accommodate particular 
clinical scenarios, logistical issues, etc. will be permitted. 
 
In general, G-CSF is given at a dose of 10 µg/kg/day at least 24 hours after the last 
dose of ICE chemotherapy (adjusted weight may be used at the clinical discretion 
of the treating physician).  Apheresis will proceed as per standard practice and at 
the discretion of the treating physician (large volume apheresis is preferred for all 
collections).  In general, apheresis will commence on the day after the post nadir 
WBC ≥ 1,000/µL and will continue daily for a minimum of 3 days or until the 
target of > 5 x 106 CD34+/kg has been met.  A CD34 count of ≥ 5/μL or preferably 
≥ 10/μL can also be used as a guide as to when to initiate apheresis, in general, 
CD34 counts are obtained starting 24 hours after recovery from nadir.  Additional 
apheresis will be at the discretion of the treating physician with no more than 7 
days of apheresis.  G-CSF will continue until PBSC collection is completed (unless 
WBC is > 100,000/µL in which case G-CSF will be discontinued).  The use of 
adjunctive mobilization agents (e.g., plerixafor) will be left to the discretion of the 
treating physician. 
 
For the secondary endpoint related to PBSC collection, adequate stem cell 
collection will be defined as > 5 x 106 CD34+/kg obtained within 7 days of 
apheresis.   
 
 
G-CSF is considered standard of care and may be administered at a local clinic 
upon approval of the Sponsor-Investigator or Lead Sub-Investigator. 
 
7.4 
Prophylaxis 
7.41 
Nausea/vomiting prophylaxis: Ondansetron 8 mg IV is recommended to be 
given daily before chemotherapy on Days 1-3.  Dexamethasone 10 mg by 
mouth daily is highly recommended before chemotherapy on Days 1-
3.  Other anti-emetics (e.g., lorazepam, promethazine, etc.) should be 
prescribed according to the discretion of the prescribing physician. 
 
7.42 
Infection prophylaxis: Levofloxacin 500 mg by mouth daily (or equivalent) 
is highly recommended to be used once a patient’s ANC is less than or 
equal to 1,000 cells/µL. 
 
7.5  
Patients will be assessed for response as specified in section 10.0, at least 3 weeks 
following the second cycle of chemotherapy.  Criteria for removal from protocol 
treatment: 
 
7.51  Documented progression of disease.  
 
7.52    Development of any related grade 4 non-hematologic toxicity (excluding 
asymptomatic grade 4 laboratory abnormalities) or other dose limiting 
toxicity as defined in Section 11. 
 

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Protocol Version 5.1 dated 12 November 2019 
7.53  Development of any other unacceptable toxicities unless prophylactic 
measures can be taken for subsequent cycles.   
 
7.54 
Delay of treatment for more than 3 weeks due to adverse events.   
 
7.55 
Completion of protocol treatment (maximum of 2 cycles).   
 
7.56 
The patient may withdraw from the treatment at any time for any reason.   
 
 
8.0 
DOSAGE MODIFICATIONS 
 
The dose of brentuximab vedotin will be adjusted according to the dose modification plan 
described in Statistical Considerations (Section 11).  Standard dose adjustments for 
ifosfamide, carboplatin, and/or etoposide during treatment may be made based on changes 
in hepatic and renal function. Parameters for retreatment and treatment modifications are 
as follows: 
 
8.1 
Modifications for Hematologic Toxicity   
 
8.11 
Subsequent cycles of therapy will not begin until the ANC is ≥ 1,000/µL 
and the platelet count is ≥ 50,000/µL. Therapy will be delayed a maximum 
of 3 weeks until these values are achieved.  Patients who fail to recover 
adequate counts within 3 weeks will be removed from study treatment.  
 
8.2  
Modifications for Impaired Renal Function 
 
8.21  Serum creatinine must be < 1.5 mg/dl or an estimated or measured 
creatinine clearance must be > 60 ml/minute on Day 1 of each cycle (lab 
may be drawn up to 3 days prior to day 1).  If these values are not met, 
treatment may be delayed for up to 3 weeks.  If these values do not recover 
within 3 weeks, the patient will be removed from protocol treatment.   
 
 
8.3 
Modifications for Impaired Liver Function 
 
8.31 
Total bilirubin must be < 2 times upper limit of normal, and ALT and AST 
< 2.5 times upper limit of normal on Day 1 of each cycle (lab may be drawn 
up to 3 days prior to day 1). If these values are not met, treatment may be 
delayed for up to 3 weeks.  If these values do not recover within 3 weeks, 
the patient will be removed from protocol treatment.  Please notify the 
Study Chair of any Grade 3 or 4 elevated liver function tests that occur on 
Day 1, prior to starting the next cycle.   
 
8.5 
Modifications for Other Adverse Events 
 
8.51  Any related grade 4 non-hematologic toxicity (excluding asymptomatic 
grade 4 laboratory abnormalities) or other dose-limiting toxicity as defined 

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Protocol Version 5.1 dated 12 November 2019 
in Section 11 will result in the patient being removed from protocol 
treatment.  
 
8.52  Patients should receive appropriate medical management for adverse 
events.  Treatment may be delayed for clinically significant grade 2 or 3 
adverse events and unrelated grade 4 adverse events at the discretion of the 
treating physician.  If treatment is delayed for 3 weeks, the patient will be 
removed from protocol treatment. 
 
8.6   
Concomitant Therapy 
 
Medications used during the course of the study should be documented. 
 
8.61   Prohibited Concomitant Therapy:  
The administration of concurrent medications intended to treat the 
primary cancer is not allowed during protocol therapy.  This includes any 
chemotherapy, investigational agent, biologic agent or other anti-tumor 
agents.  Radiation therapy is also prohibited.  
 
 
8.62   Patients should be strongly discouraged from taking any “alternative” or 
“naturopathic” medications since these agents may interact with study 
treatment. Any use of these medications should be at the judgment of the 
treating physician and should be documented in the patient’s medical 
record. 
 

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Protocol Version 5.1 dated 12 November 2019 
 9.0 
STUDY CALENDAR  
 
Required Studies 
Pre-Entry 
(within 4 weeks 
unless indicated 
otherwise) 
Within 3 
days prior to 
each cycle 
Post 
Therapy6, 11 
Follow-up 
Physical 
 
 
 
 
History and Physical 
X 
X9 
X6,11 
X7 
Performance Status 
X 
X9 
X6,11 
 
Clinical Disease Assessment 
X 
X9 
X6,11 
 
Adverse Event Assessment 
X 
X9 
X6,11 
 
EKG 
X 
 
 
 
CBC, Diff, platelets 
X 
X9 
X6 
 
Serum creatinine, total bilirubin, 
SGOT (AST), electrolytes, glucose  
X 
X9 
X6 
 
Albumin  
X1 
 
 
 
LDH 
X 
 
X6 
 
Bone Marrow Studies 
X2 
 
X2,6 
 
Pregnancy test 
X8 
 
 
 
Laboratory Correlative Studies 
X3 
X3 
X3,6 
X10 
Radiology 
 
 
 
 
CT Chest, abdomen and pelvis; CT 
neck if cervical adenopathy present 
X 
 
X6 
 
Left Ventricular Ejection Fraction 
(LVEF) 
X4 
 
 
 
PET/CT  
X5 
 
X5,6 
 
 
1 Albumin is used for documenting prognostic criteria 
2 Bone Marrow Studies include aspirate and unilateral or bilateral biopsy.  If all bone marrow studies are negative at 
enrollment, these do not need to be repeated at completion of the study.  Patients who do not have a bone marrow 
study at enrollment with PI’s approval will need to have bone marrow study at completion of treatment to confirm 
CR if needed.  
3 Laboratory correlative studies: In patients from whom a biopsy specimen is available from the time of initial 
diagnosis and/or relapse/progression, tissue blocks and/or slides maybe obtained to perform prognostic/predictive 
correlative studies.  Pre-treatment biopsy to confirm relapsed/refractory disease is recommended, but not required, 
for study enrollment.  Peripheral blood samples may also be obtained prior to Cycle 1 and after study treatment for 
similar correlative analyses (including a satellite vial of patients’ stem cells that will be collected at time of 
apheresis for such analyses). 
4  Measurement of LVEF should be done if medically indicated.  LVEF must be >50% 
5 PET scans should have a Deauville score assigned [26]. 
6 Post therapy studies should be done at least 3 weeks post cycle 2 or after the patient’s last cycle, whichever comes 
first, unless otherwise specified.  
7 Follow-up should be performed as clinically indicated. A typical follow-up schedule would be that follow-up 
assessments are done every 3 months for 1 year then every 6 months for 4 years (total follow-up time 5 years). 
8 Pregnancy test is only required in women of childbearing potential. 
9 For Cycle 1 Day 1, pre-entry H&P, performance status, disease assessment and adverse event assessment may be 
used (these do not need to be repeated within 3 days) and labs done within 14 days are acceptable. 
10 For patients that proceed on to ASCT, an optional blood draw may be performed on or around day 30 post-
transplant for additional correlative studies. 
11 Patients who move on to receive care from the SCCA Transplant Team will be followed via detailed medical records rather 
than having a Post Therapy clinic visit directly with the Sponsor-Investigator or Lead Sub-Investigator. 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 

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Protocol Version 5.1 dated 12 November 2019 
 
Definitions of Disease, Criteria for Evaluation and Endpoint Definitions – response will 
be defined by standard NCI criteria (Cheson, et al.) for lymphoid malignancies [27].   
 
10.1 
Measurability of Lesions: 
 
10.11 Measurable Disease: Lesions that can be accurately measured in two 
dimensions by CT, MRI, medical photograph (skin or oral lesion), plain  x-
ray, or other conventional technique and a greatest transverse diameter of 
1 cm or greater; or palpable lesions with both diameters ≥ 2 cm.  Note: CT 
scans remain the standard for evaluation of nodal disease. 
 
10.12 Non-measurable Disease: All other lesions including uni-dimensional 
lesions, lesions too small to be considered measurable, pleural or 
pericardial effusion, ascites, bone disease, lymphangitis, pulmonitis, 
abdominal masses not confirmed or followed by imaging techniques, or 
disease documented by indirect evidence only (e.g., lab values).  
 
10.2 
Objective Disease Status:  Objective status is to be recorded at each evaluation. 
The three largest measurable lesions at baseline should be identified as target 
lesions and be measured at initial and follow-up imaging.  All remaining lesions 
may remain unmeasured; these lesions should be noted as to site and presence or 
absence on follow-up imaging.  ‘Absence’, in general, will be defined as not 
pathologically enlarged. 
 
10.21 Complete Response (CR):  Complete disappearance of all evidence of 
disease with the exception of nodes for which the following must be true:  
all measurable nodal lesion and nodal masses >1.5 cm in greatest transverse 
diameter (GTD) at baseline must have regressed to ≤1.5 cm in GTD; nodal 
masses that were 1.1 to 1.5 cm in their longest axis and more than 1.0 in 
their short axis before treatment must have decreased to ≤1.0 cm in their 
shortest axis after treatment. A post treatment residual mass of any size is 
permitted as long as it is PET negative (i.e., Deauville score of 3 or less 
[26]). If patients have an isolated site on post-therapy imaging that appears 
to represent persistent disease, but a subsequent biopsy fails to identify 
evidence of Hodgkin lymphoma, such patients shall be defined as CR. PET 
scans should not be performed for at least 3 weeks, and preferably 6 to 8 
weeks after completion of therapy. No new lesions.  Spleen and other 
previously enlarged organs must have regressed in size and must not be 
palpable.  If bone marrow was positive at baseline, it must be negative 
based on biopsy and aspirate at the same site. If a sample that is considered 
negative by immunohistochemistry but that demonstrates a small 
population of clonal lymphocytes (<2%) by flow cytometry will be 
considered a CR.  Normalization of markers (e.g., LDH definitely 
assignable to HL).  All disease must be assessed using the same technique 
as baseline.  
 
 

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Protocol Version 5.1 dated 12 November 2019 
10.22 Partial Response (PR):  At least a 50% decrease in sum of the product of 
the diameters (SPD) for up to six identified dominant lesions.  No new 
lesions and no increase in the size of liver or spleen or other nodes.  Splenic 
and hepatic nodules must have regressed in size by at least 50% in SPD.  
Sites that were PET positive (i.e., Deauville score of 4 or more) pre-
treatment should still be positive in at least 1 site post-treatment.  Bone 
marrow assessment is irrelevant if the sample is positive before treatment. 
All disease must be assessed using the same technique as baseline.  
 
10.23 Stable disease (SD):  Does not qualify for CR, PR, or Relapsed/Progressive 
Disease.  All disease must be assessed using the same technique as baseline.  
 
10.24 Relapsed Disease:  If a CR was achieved at a previous assessment, a 50% 
increase in the SPD of target measurable lesions over the smallest sum 
observed (over baseline if no decrease during therapy) or 50% increase in 
the GTD of any node greater than 1 cm in shortest axis using the same 
techniques as baseline.  Unequivocal progression of non-measurable 
disease in the opinion of the treating physician (an explanation must be 
provided).  Appearance of a new lesion/site.  Death due to disease without 
prior documentation of progression. 
 
10.25 Progressive Disease (PD): If a CR was not achieved at a previous 
assessment, a 50% increase in the SPD of target measurable lesions over 
the smallest sum observed (over baseline if no decrease during therapy) 
using the same techniques as baseline.  Appearance of a new lesion site.  
Lesions should be PET positive unless the lesion is too small to be detected 
with current PET systems (1.5 cm in its long axis by CT).  Unequivocal 
progression of non-measurable disease in the option of the treating 
physician (an explanation must be provided).  
 
10.26 Assessment inadequate, objective status unknown: Progression has not 
been documented and one or more target lesions or other sites of disease 
have not been assessed or inconsistent methods of assessment were used. 
 
10.3 
Bone Marrow Status: Bone marrow status is evaluated as follows:  
 
Positive: Unequivocal cytological or architectural evidence of malignancy.   
 
Negative: No aggregates or only a few well-circumscribed lymphoid  
aggregates.   
 
Indeterminate:  Does not qualify for either Positive or Negative Status.  *Note this 
typically consists of increased number or size of aggregates without cytological or 
architectural atypia. 
 
 
 
11.0  STATISTICAL CONSIDERATIONS 
 

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Protocol Version 5.1 dated 12 November 2019 
11.1  Study Objectives: This study has two primary objectives.  The first is to define the 
maximally tolerated dose (MTD) of BV that can be combined with ICE 
chemotherapy. The MTD will be defined as below, based on the proportion of 
patients that experience a dose-limiting toxicity (DLT).  For the purposes of this 
study, a DLT is defined as: 
• Any non-hematologic grade 4 or 5 NCI CTCAE adverse event (excluding 
asymptomatic grade 4 laboratory abnormalities) that is possibly, probably 
or definitely related to the drug combination within 28 days of the last dose 
of the study drug, with the following exception: Any treatment-emergent 
grade 3 or higher peripheral neuropathy will also be considered a DLT.   
• The patient did not complete one full cycle of therapy due to toxicity from 
the treatment.  Patients choosing to stop study medication for adverse 
events that are not considered medically significant by the Investigators, 
will not be scored as a DLT.  
• Treatment delay of > 3 weeks following cycle 1 due to prolonged recovery 
from observed toxicity (see Section 8 for details) 
 
The second primary objective is to gain a preliminary assessment of the efficacy 
of this regimen.  This will be defined as the percentage of patients that achieve a 
complete remission (CR) following study treatment, as defined above in Section 
10.2.  Further, we will describe the progression-free and overall survival from the 
time of initiation of study therapy and from ASCT (for those who go on to receive 
this treatment). 
 
11.2 
Phase I (Dose Escalation) Design: Dose escalation/de-escalation will be conducted 
by a “3+3” approach.  The starting dose level will be Dose Level 1 (see table 
below). Toxicities occurring in the first or second cycle will be evaluated for DLT. 
If a patient receives only one cycle of therapy, they will still be considered 
evaluable for DLT. Dose escalation will not occur until sufficient time has elapsed 
to evaluate for DLTs in all patients treated at that dose level. We anticipate treating 
9-12 patients in this phase of this study. 
 
Three patients will be entered at Dose Level 1.  The following rules will dictate the 
dose escalation/de-escalation schema: 
• If 0 of 3 patients treated at Dose Level 1 experience a DLT, then the next 3 
patients will be enrolled at Dose Level 2.  If < 1 of these patients 
experiences a DLT, then another 3 patients will be enrolled at Dose Level 
2.  If < 1 of these 6 patients experience a DLT, then Dose Level 2 will be 
declared the MTD and the dose escalation phase will stop.  
• If 1 of 3 patients treated at Dose Level 1 experience a DLT, then another 3 
patients will be enrolled at Dose Level 1.  If < 1 of these 6 patients 
experience a DLT, then Dose Level 1 will be declared the MTD and the 
dose escalation phase will stop. 
• If > 2 of 3 patients treated at Dose Level 1 experience a DLT, then up to 6 
patients will be enrolled at Dose Level -1.  If < 1 of 6 patients treated at 
Dose Level -1 experience a DLT, then Dose Level -1 will be declared the 
MTD and the dose escalation phase will stop. 

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Protocol Version 5.1 dated 12 November 2019 
• If > 2 patients in any group of 6 patients experience a DLT, then the dose 
will be de-escalated by one dose level, 3 patients will be treated at that 
lower dose level, and so forth as above.   
 
If de-escalation is indicated at Dose Level -1, the investigators may submit a 
modification to the IRB to request further dose de-escalation. There will be no 
intra-patient dose escalation.  Based on the above rules, we anticipate treating 9-
12 patients in this phase of the study. 
 
Dose Level 
Brentuximab vedotin dose (mg/kg, each cycle) 
 
Day 1 
Day 8 
-1 
1.8 
none 
1  
(starting dose) 
1.2 
1.2 
2 
1.5 
1.5 
 
11.3 
Phase II (Expansion Cohort) Design: Once the MTD of BV has been determined, 
enrollment will continue with all patients receiving this dose of BV.  The primary 
endpoint of this section will be the CR rate.  We recognize that a precise estimate 
of CR rate will require a larger sample size than possible within the context of this 
trial.  Thus, we will consider the phase II portion a pilot study/MTD expansion 
with a minimum of 36 additional patients treated beyond the 9-12 patients treated 
in the phase I portion.  This means that a total of 42 patients will be treated at the 
MTD (6 patients in the phase I portion plus 36 patients in the phase II portion).  If 
the true CR rate using BV-ICE is 78% and we treat 42 patients at the MTD, this 
would provide 80% power to detect a statistically-significant increase in CR rate 
from a historical rate of 60% [11], based on a one-sample chi-square test with one-
sided significance level of 5%.  Analyses of secondary endpoints (e.g., PBSC yield, 
PFS, and OS) will be primarily descriptive. 
 
Stopping Rules: The dose escalation schema will act as stopping rules unless a 
dose lower than the lowest dose-level is considered the MTD, at which point the 
protocol will be closed. 
 
11.4  Anticipated accrual: We anticipate that accrual will take 3-4 years.      
 
11.5 
Estimated* distribution of study population by gender and race and ethnicity: 
 
 
Ethnic Category 
Females 
Males 
American Indian/Alaska Native 
 
 
Asian 
2 
3 
Native Hawaiian or Other Pacific Islander 
 
 
Black or African American 
1 
2 
White 
12 
25 
More than one race 
 
 
Unknown or not reported 
 
 
Racial Categories: Total of all subjects 
15 
30 
 

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Protocol Version 5.1 dated 12 November 2019 
The exact sample size is not known since it is dependent on the number of 
evaluable patients, but we estimate the total enrollment will be 30.    
 
12.0  STUDY MONITORING AND REPORTING PROCEDURES 
 
 
12.1 
Adverse Event Reporting  
 
AEs of Grade 3 and above, and Serious Adverse Events (SAEs) occurring at 
any grade will be monitored and recorded in study-specific case report forms 
(CRFs) from the time of study enrollment through 30 days following the end 
of study treatment, or until the patient receives an alternative anti-cancer 
therapy, whichever date comes first. AEs related to biopsies  that are done 
solely  for research study screening  purposes will be monitored, recorded, and 
reported  according to  the  same  standards,  with  the  exception  that  
assessment   of  study  drug attribution  will be excluded from reporting criteria. 
 
The NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) will 
be used to classify and grade toxicities. 
   
 
The CTC can be found on the Cancer Therapy Evaluation Program (CTEP) 
homepage at: 
http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.
pdf. 
 
 
12.2  Definitions and descriptions of terms used in adverse event reporting. 
 
Adverse Event (AE) 
An AE is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be 
related to the study. 
 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
 
Serious Adverse Event (SAE) or Adverse Drug Reaction (ADR) 
A Serious Adverse Event or Adverse Drug Reaction means any AE/ADR 
occurring at any dose that results in: 
 
• Death; 
 
• A life-threatening AE/ADR (i.e, the patient/subject was, in the view of the 
initial reporter/investigators, at immediate risk of death from the AE as it 
occurred. It does not refer to an AE that hypothetically might have caused 
death if more severe); 
 

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Protocol Version 5.1 dated 12 November 2019 
• Inpatient hospitalization or prolongation of existing hospitalization(i.e, 
hospitalization was required to treat or diagnose the AE/ADR: excludes 
hospitalization for unrelated reasons); 
 
• A persistent or significant disability or incapacity (disability here means 
that there is a substantial disruption of a person's ability to conduct 
normal life functions; 
 
• A congenital anomaly/birth defect; 
 
• An important medical event (i.e., AEs/ADRs that might not be 
immediately life-threatening, or result in death or hospitalization might be 
considered serious when, based upon appropriate medical and scientific 
judgment, they might jeopardize the patient/subject or might require 
medical or surgical intervention to prevent one of the other serious 
outcomes listed above); 
 
• Any suspected transmission via a medicinal product of an infectious 
agent. 
 
Sponsor-Investigator shall use his/her judgment to determine the relationship 
between the Serious Adverse Drug Experience and the Study Drug. 
 
Grade 
Grade is defined as the severity of the adverse event.  The CTCAE Version 4.0 
must be used to determine the grade of the adverse event. If toxicity is not listed in 
the CTCAE use the following general criteria for grading.   
 
0 – No adverse event or within normal limits 
1 – Mild adverse event 
2 – Moderate adverse event 
3 – Severe adverse event 
4 – Life-threatening or disabling adverse event 
5 – Fatal adverse event 
 
Attribution 
Attribution is defined as the determination of whether an adverse event is related 
to a medical treatment or procedure.  Attribution categories are as follows: 
 
• Unrelated The adverse event is clearly NOT related to therapy 
• Unlikely 
The adverse event is doubtfully related to therapy 
• Possible 
The adverse event may be related to therapy 
• Probable The adverse event is likely related to therapy 
• Definite 
The adverse event is clearly related to therapy 
 
Suspected Adverse Reaction  
Any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event. 

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Protocol Version 5.1 dated 12 November 2019 
 
Unexpected Adverse Event 
An unexpected adverse event is any adverse event for which the specificity or 
severity is not listed in the current Investigator’s Brochure or the package insert or 
the specificity or severity of which is not consistent with the Investigator’s 
brochure or package insert.   
 
12.3 
Routine Reporting 
 
Routine reporting will be conducted in accordance with FHCRC/Cancer 
Consortium IRB policies, applicable FDA regulations, and agreements with Seattle 
Genetics Inc. 
 
Reports may include data after each cycle of therapy and 30 days after the last dose 
of study drugs, or until the patient receives an alternative anti-cancer therapy, 
whichever date comes first.   
 12.4  Expedited Reporting  
 
Expedited reporting will be conducted in accordance with  FHCRC/Cancer 
Consortium IRB policies, applicable FDA regulations, and  agreements 
with 
Seattle Genetics Inc. 
 
12.5 
Reporting to Seattle Genetics, Inc. 
 
 
 
 
 
The study coordinating office will notify the IRB and Seattle Genetics within two 
business days, by facsimile or e-mail, upon learning of the occurrence during the 
Study of: 
 
• All Serious AE/ADRs, regardless of causality; 
 
• Any exposure of a pregnant Study participant to the Study Drug within 
thirty (30) days of exposure; 
 
• A female partner of a male Study participant becoming pregnant within 
thirty (30) days of exposure;    
 
• Any medical event which may reasonably be believed to impair the 
integrity, validity or ongoing viability of the Study.  
 
All such occurrences listed in this section shall be reported to Seattle Genetics 
using an approved local regulatory form.  An aggregate listing of all SAEs will 
also be sent monthly to Seattle Genetics electronically. 
 
In the event the IRB requests additional safety information from the Sponsor-
Investigator, the Sponsor-Investigator shall notify Seattle Genetics of such 
request within one (1) business day. 
 

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Protocol Version 5.1 dated 12 November 2019 
 
12.6  Reporting to the IRB 
 
Institutions should follow the guidelines of their local IRB for reporting serious 
adverse events in a timely manner.   
 
 
12.7 
Data Safety and Monitoring Plan 
All serious adverse events are communicated to the study Sponsor-Investigator and 
regulatory agencies as described above.  A status report including accrual, adverse 
events, and death information will be reviewed by the Sponsor-Investigator and 
the Fred Hutchinson Cancer Research Center (FHCRC) Data Safety Monitoring 
Committee (DSMC) annually.  In addition, the study will be monitored by the 
Research Trials Office according to the Fred Hutchinson Cancer Research Center 
monitoring plan. 
 
 
12.8 
Required Records and Materials 
 Under the supervision of the investigators, research staff will maintain case 
report forms and secured databases on the relevant clinical and laboratory data.   
Records maintained in investigators' offices will be secured with access limited 
to study personnel.  Authorization for access to medical records will be obtained 
from all patients in accordance with provisions of the Health Insurance 
Portability and Accountability Act (HIPAA). 
 
Original signed informed consent forms will be kept within the secured study team 
office, access is limited to study personnel. A copy of the signed informed consent 
form is given to the participant.  Data will be collected on patient characteristics, 
disease characteristics, protocol therapy, response to treatment, adverse events and 
follow-up for relapse and survival.  Copies of the patient’s medical record 
including history and physical exams, documentation of protocol therapy, labs, 
scans, x-rays, hospitalizations, operative reports, pathology reports etc. are 
required.  
 
13.0 
ELEMENTS OF INFORMED CONSENT 
 
All Institutional, NCI, State and Federal regulations concerning informed consent and peer 
judgment will be fulfilled.  Written consent will be obtained from all patients 
entering the study. 
 
14.0 
REFERENCES: 
 
1. 
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Federico, M., et al., ABVD compared with BEACOPP compared with CEC for the initial 
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4. 
Gordon, L.I., et al., Randomized phase III trial of ABVD versus Stanford V with or 
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Mendler, J.H. and J.W. Friedberg, Salvage therapy in Hodgkin's lymphoma. Oncologist, 
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Schmitz, N., et al., Aggressive conventional chemotherapy compared with high-dose 
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Sureda, A., et al., Prognostic factors affecting long-term outcome after stem cell 
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Moskowitz, A.J., et al., Pretransplantation functional imaging predicts outcome 
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Josting, A., et al., Time-intensified dexamethasone/cisplatin/cytarabine: an effective 
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Abali, H., et al., Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP 
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Moskowitz, C.H., et al., A 2-step comprehensive high-dose chemoradiotherapy second-
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Kewalramani, T., et al., Rituximab and ICE as second-line therapy before autologous 
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Steidl, C., et al., Tumor-associated macrophages and survival in classic Hodgkin's 
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