Clinical trial NCT02429375
Conditions: Hodgkin Lymphoma
Keywords: Mocetinostat (MGCD0103) Brentuximab Vedotin (SGN-35) Relapsed Refractory
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2015-04-22; Completion date: 2021-02-17
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out how safe and effective treatment with a new combination of drugs, mocetinostat and brentuximab vedotin, is in treating cancer. There will be 2 parts to this trial: a phase I part and a phase II part.

Brentuximab vedotin is approved by the U.S. Food and Drug Administration (FDA) to be given to patients with Hodgkin Lymphoma. Mocetinostat is an experimental drug that has been given to patients with Hodgkin lymphoma in another clinical trial. When given alone, mocetinostat caused lymphoma to shrink in about 1 out of 4 patients with Hodgkin lymphoma. This is the first study that will give mocetinostat and brentuximab vedotin together.

Detailed description:

Arms: arm 1: Patients with relapsed or refractory Hodgkin lymphoma will receive brentuximab vedotin combined with mocetinostat. For the phase I portion of the study, patients will be enrolled in a traditional 3 + 3 phase 1 design on sequential dosing cohorts in order to determine the maximum tolerated dose (MTD) of mocetinostat when given with brentuximab vedotin. Once the MTD is determined, (up to) an additional 26 patients will be enrolled on to the phase II portion of the study at the MTD to determine the response rate and toxicity associated with treatment. The phase Ib and II study will include a lead-in with mocetinostat alone for 1 week followed by the combined treatment beginning day 15 following initiation of mocetinostat.
Interventions: intervention 1: Mocetinostat Plus Brentuximab Vedotin
Intervention descriptions: intervention 1: All patients will receive a 1-week lead-in with mocetinostat alone (administered days 1, 3, and 5). Patients with palpable peripheral lymph nodes will undergo FNA before and after this 1 week treatment. Cycle 1 will then begin 15 days (+/-3 days) following initiation of the lead-in.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 1 of 33 
 
 
 
 
MSK PROTOCOL COVER SHEET 
 
Brentuximab Vedotin (SGN-35) in Transplant Eligible Patients with Relapsed or Refractory Hodgkin 
Lymphoma 
 
Principal Investigator/Department: Alison Moskowitz / Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 3 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................................ 9 
4.1 
Design ...................................................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 10 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................. 14 
6.1 
Subject Inclusion Criteria ........................................................................................................ 14 
6.2 
Subject Exclusion Criteria ....................................................................................................... 15 
7.0 
RECRUITMENT PLAN ........................................................................................................................ 15 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 16 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................................ 18 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................................... 22 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............................ 23 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 24 
14.0 
BIOSTATISTICS ................................................................................................................... 25 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 26 
15.1 Research Participant Registration ............................................................................................. 26 
16.0 
DAT A M ANAGEMENT ISSUES ............................................................................................ 26 
16.1 
Quality Assurance .................................................................................................................. 27 
16.2 
Data and Safety Monitoring ......................................................................................................... 27 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................ 28 
17.1 
Privacy ................................................................................................................................... 29 
17.2 
Serious Adverse Event (SAE) Reporting .................................................................................... 29 
17.2.1 
SAE reporting information to Seattle Genetics ................................................................... 30 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................................... 31 
19.0 
REFERENCES .......................................................................................................................... 31 
20.0 
APPENDICES ....................................................................................................................... 33 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
In this study, we plan to treat patients with 2 cycles of weekly brentuximab vedotin (SGN-35); 
patients who achieve FDG-PET/CT normalization will proceed directly to autologous stem 
cell transplant (ASCT) and avoid salvage treatment with ifosfamide, carboplatin, and 
etoposide (ICE). Patients with persistent FDG-PET/CT abnormalities will receive 2 cycles of 
augmented ICE chemotherapy followed by repeat FDG-PET/CT.  We aim to evaluate the 
rate of FDG-PET/CT normalization following 2 cycles of weekly brentuximab vedotin with or 
without augmented ICE in transplant eligible patients with relapsed or refractory HL. This 
study will enroll 46 patients. 
 
 
 
 
 
 
 
 
Expansion Cohort 
 
We will expand this study to include 20 additional patients.  The expansion would again   
enroll patients who fail their front-line therapy for HL; however they will receive 3 cycles of 
weekly BV followed by reassessment by FDG-PET.  Those who score Deauville 2 or better 
will proceed to ASCT while all others will receive 2 cycles of augmented ICE prior to 
consideration for ASCT.  We aim to evaluate the rate of FDG-PET/CT normalization following 
3 cycles of weekly brentuximab vedotin with or without augmented ICE in transplant eligible 
patients with relapsed or refractory HL. 
 
 
 
 
 
 
 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
FDG-PET 
normalization 
Autologous stem 
cell transplant 
FDG-PET 
abnormal 
AugICE x 2 cycles 
SGN-35 x3 cycles 
FDG-PET 
abnormal 
FDG-PET 
normalization 
Autologous stem 
cell transplant 
Further treatment 
according to 
treating physician 
FDG-PET 
normalization 
Autologous stem 
cell transplant 
FDG-PET 
abnormal 
AugICE x 2 cycles 
SGN-35 x2 cycles 
FDG-PET 
abnormal 
FDG-PET 
normalization 
Autologous stem 
cell transplant 
Further treatment 
according to 
treating physician 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 4 of 33 
 
 
 
 
Primary objectives 
 
1. Determine the rate of FDG-PET/CT normalization following salvage therapy with 
brentuximab vedotin (SGN-35) alone or followed by augmented ICE chemotherapy 
Secondary objectives 
 
1. Rate of FDG-PET/CT normalization with respect to the presence of previously 
determined prognostic factors: extranodal disease, bulk ≥ 5cm, relapse within 
previously radiated fields, relapse within 1 year of initial treatment, and presence of B 
symptoms at relapse 
2. Determine overall response rate (CR and PR) rate to brentuximab vedotin alone 
3. Toxicity from brentuximab vedotin alone and followed by augmented ICE 
chemotherapy 
4. Evaluate progression free survival (PFS) and overall survival (OS) with this treatment 
program and their correlation with: ΔSUVmax, expression of CD68, FoxP3, and TIA-1 
by immunohistochemistry, serum cytokine levels, and the clinical factors listed in 
secondary objective #1. 
5. Determine number of CD34 cells collected following this treatment program. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
Introduction 
We have reported that patients with relapsed or refractory Hodgkin lymphoma (HL) who 
achieve FDG-PET/CT normalization prior to autologous stem cell transplant (ASCT) have an 
excellent outcome with 5 year progression free survival of 75%.  Current standard salvage 
regimens for relapsed and refractory HL include ICE or DHAP chemotherapy.  These 
regimens are associated with significant hematologic toxicity and therefore effective and less 
toxic treatments are needed.  Brentuximab vedotin (SGN-35) is well tolerated and highly 
active in patients with relapsed or refractory HL who have failed ASCT.  Weekly 
administration of this agent has yielded complete responses in patients after only 2 cycles (8 
weeks) making this an attractive agent to test as a pre-ASCT salvage regimen. 
 
 
Pre-transplant FDG-PET in Hodgkin lymphoma 
 
The majority of patients with Hodgkin’s Lymphoma (HL) are cured with radiation therapy 
and/or combination chemotherapy. However, patients who relapse after attaining a complete 
remission with chemotherapy and those with primary refractory disease have a poor outcome 
with conventional salvage regimens.  Randomized studies have established high dose 
chemotherapy followed by autologous stem cell transplant (ASCT) as the standard treatment 
for relapsed or refractory (rel/ref) HL1, 2  following response to salvage chemotherapy (ST). 
Unfortunately, about 50% of patients with rel/ref HL will fail ASCT and the prognosis for these 
patients is grim3.  Since 1994, 4 consecutive phase II studies have been performed at 
MSKCC using ICE (ifosfamide, carboplatin, and etoposide)-based salvage therapy (ST) 
followed by ASCT for patients demonstrating chemosensitivity.  In the earliest studies, 


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IRB Number: 14-232 A(5) 
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protocols 94-68 and 97-51, all patients with rel/ref HL received uniform ST with ICE followed 
by ASCT and multivariate analysis identified 3 factors that predicted for outcome: B 
symptoms, extranodal disease, and complete remission less than 1 year from induction 
therapy4.  The next study, 98-71, employed risk stratified salvage therapy based upon the 
presence of the 3 risk factors (RFs) identified in the earlier studies.  Patients with 0-1 RFs 
received standard ICE, 2 RFs received increased dose ICE (“augmented ICE”) and patients 
with all three RF received tandem transplants.  This risk stratified approach diminished the 
prognostic difference between low risk and higher risk patients.  Furthermore, an important 
finding from this study was that functional imaging (gallium or FDG-PET) status before ASCT 
strongly predicted outcome following transplant.  A combined analysis of patients from 
protocols 94-68, 97-51, and 98-71 revealed a 5 year EFS of 75% for patients with functional 
imaging (FI)–normalization compared to 31% for patients with persistent abnormalizations on 
FI-suggesting that normalization of FI following ST should be a goal for patients proceeding 
to ASCT for rel/ref HL.5    These findings led to the design of our most recent study in rel/ref 
HL, 04-047, in which patients are again treated with risk stratified ST; however those with 
persistent abnormalities on FI (FDG-PET/CT primarily used in this study) receive additional 
non-cross resistant gemcitabine-based (GND) chemotherapy before ASCT.  FDG-PET/CT 
was repeated after GND and those with responding disease proceeded to ASCT.  Of 98 
patients enrolled on this study, 33 received GND for persistent FDG-PET/CT abnormalities; 
17 subsequently achieved FDG-PET/CT normalization following GND and had similar 
favorable outcomes to those who achieved FDG-PET/CT normalization from ICE alone6. 
These findings confirm the notion that normalization of FDG-PET/CT should be the goal of 
ST prior to ASCT in rel/ref HL.  Our combined analysis of the 3 protocols, 94-68, 97-51, and 
98-71 also revealed that patients with persistent pre-ASCT FI abnormalities who are 
ineligible for involved field radiation (due to previous radiation therapy or extranodal disease) 
have particularly poor outcomes suggesting that alternatives to autologous stem cell 
transplant (such as allogeneic stem cell transplant) should be evaluated.5 
Factors that predict response to ICE salvage therapy 
 
All patients have received ICE-based ST for rel/ref HL at our institution since 1994; therefore 
we recently pooled this data to identify factors predictive of FI normalization following ICE. 
Between 9/1994 and 4/2010, 277 patients with rel/ref HL were treated on 1 of 4 studies 
described above.  Two hundred and seventy-one patients underwent evaluation with FI 
before and after ST; 62% of these patients were evaluated with FDG-PET/CT.  One hundred 
sixty-five (60%) patients achieved normalization of functional imaging following ST.  
Univariate and multivariate analysis to identify factors associated with failure to normalize FI 
was performed and four factors remained significant by multivariate analysis: bulk ≥ 5cm, 
relapse within previously radiated fields, relapse within 1 year of initial treatment, and 
presence of B symptoms at relapse.   The numbers of patients with 0, 1, 2, 3, or 4 risk factors 
were 31, 100, 83, 38, and 4 and the rate of FI normalization by risk factor group was 87%, 
76%, 50%, 34%, and 0% respectively.   Patients with 0-1 risk factors have a high rate of FI 
normalization with ICE ST and may be candidates for less intense therapy.  In contrast, 
patients with 3-4 risk factors are at high risk for persistent FI abnormalities following ICE 
treatment and therefore may benefit from more novel salvage therapy, such as an antibody- 
drug conjugate.  As described below, brentuximab vedotin (SGN-35) is a highly effective 
treatment in rel/ref HL that is generally well tolerated and therefore may represent a better 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 6 of 33 
 
 
 
 
option for patients both at low risk and high risk of failing to normalize FI following ICE-based 
treatment, therefore we plan to treat all risk cohorts with brentuximab vedotin with or without 
augmented ICE and analyze the results according to risk group. 
The majority of patients enrolled on the MSKCC studies described above had 0-2 risk factors 
(risk factors = b symptoms, extranodal disease, and relapse within 1 year).  Since 2004, 
patients with all 3 risk factors were enrolled on a different study evaluating allogeneic stem 
cell transplant and therefore are not well represented in our ICE database.  The true rate of 
FDG-PET/CT normalization following ICE chemotherapy is therefore likely lower than 60%. 
On this protocol, we will enroll patients with 0-3 risk factors and therefore we assumed a 
lower rate of FDG-PET/CT normalization from ICE chemotherapy in our biostatistics. 
Brentuximab vedotin (SGN-35) 
 
Antibody-drug conjugates (ADCs), which consist of cytotoxic agents or toxins chemically 
conjugated to a monoclonal antibody, potentially represent an advantage over treatment with 
chemotherapy because they are designed to deliver the cytotoxic agent specifically to tumor 
cells thereby resulting in an improved safety profile. 
Brentuximab vedotin (cAC10-vcMMAE [4]) is a novel ADC that binds to the cell-surface 
marker CD30. After binding to CD30-positive cells, brentuximab vedotin is internalized 
releasing free MMAE that leads to cell death. CD30 was originally identified on RS cells, the 
malignant cell in HL, and is now used as a diagnostic marker for the disease.  Brentuximab 
vedotin induces growth inhibition of HL cell lines in vitro and inhibits disease progression in 
both disseminated and subcutaneous HL xenograft models in immunodeficient mice. 
Two phase I studies (evaluating different treatment schedules) and a phase II study 
demonstrated high efficacy with acceptable toxicity for brentuximab vedotin in rel/ref HL.  The 
first phase I study enrolled 45 patients (42 with HL, 2 with systemic ALCL, 1 with 
angioimmunoblastic T-cell lymphoma) treated at dose levels of 0.1 to 3.6 mg/kg administered 
intravenously every 3 weeks7. The most common adverse events were fatigue, pyrexia, 
diarrhea, nausea, neuropathy peripheral, and neutropenia. Dose related peripheral 
neuropathy and neutropenia were observed. Notable serious adverse events considered at 
least possibly related to treatment included anaphylaxis, myocardial infarction, and peripheral 
neuropathy. One patient treated with 3.6 mg/kg died of septic shock (no organism identified) 
and febrile neutropenia that were considered treatment related. The maximum tolerated dose 
of brentuximab vedotin was 1.8 mg/kg administered every 3 weeks. Evidence of objective 
responses in this study led to the phase II study with brentuximab vedotin 1.8 mg/kg q3week 
in relapsed or refractory HL8.  This study enrolled 102 patients with relapsed and refractory 
HL following ASCT.  The overall response rate was 75% and complete response rate 34%, 
establishing brentuximab vedotin as a highly effective therapy in rel/ref and heavily pre- 
treated HL. 
The second phase I study evaluated weekly administration of brentuximab vedotin (day 1, 8, 
and 15 of 28 day cycles)9. The study enrolled 44 patients, 86% with HL.  The maximum 
tolerated dose was determined to be 1.2mg/kg and the dose limiting toxicities were diarrhea 
and hyperglycemia.  The incidence of peripheral neuropathy seen with this dosing schedule 
was similar to that seen with every 3 week dosing.  About 50% of patients experienced 
peripheral neuropathy, mostly grade 1 or 2.  Five patients experienced grade 3 peripheral 


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Approval date: 22-Oct-2020 
Page 7 of 33 
 
 
 
 
neuropathy, 3 with motor neuropathies after 4-9 months of treatment with brentuximab 
vedotin.  Thirteen CRs and 9 PRs were seen with an overall response rate of 56%.  Most 
notable was that the majority of the complete responses were seen at the first restaging 
performed 8 weeks into treatment (following 2 cycles).  The tolerability, efficacy, and early 
responses seen with this dosing schedule make this an attractive agent to test as a salvage 
therapy prior to ASCT in rel/ref HL. 
Rationale for salvage therapy with brentuximab vedotin 
 
Standard salvage regimens administered before ASCT, such as ICE or DHAP, are inpatient 
therapies, associated with significant hematologic toxicity, and risk of myelodysplastic 
syndrome and infertility.  A therapy that is less toxic but can still achieve the same rate of 
response is desirable.  In particular, avoiding ICE chemotherapy, but achieving a similar rate 
of chemosensitivity using less toxic therapy would be considered a success.  Weekly 
brentuximab vedotin is an attractive regimen to test in this setting because it is associated 
with encouraging response rates, and complete responses are seen after only 8 weeks, 
which is desirable for a salvage therapy leading to ASCT.  In this study, transplant-eligible 
patients with rel/ref HL will receive 2 cycles of weekly brentuximab vedotin.  FDG-PET/CT will 
be performed following 2 cycles and patients with PET-normalization will proceed to 
transplant.  Patients with persistent abnormalities on FDG-PET/CT will receive standard 
salvage treatment with 2 cycles of augmented ICE chemotherapy prior to proceeding to 
ASCT. 
Rationale for expansion cohort in patients who fail front-line therapy with brentuximab 
vedotin 
As of April 2013, this study had accrued 37 of the planned 46 patients and 32 patients were 
evaluable for response. Of the 32 evaluable patients enrolled on this study, 9 (28%) achieved 
normalization of FDG-PET (referred to as “excellent responders”) and proceeded to ASCT. 
The remainder of the patients went on to receive augmented ICE.  Although most patients  
did not score Deauville 2 on their post-BV PET, the majority of them achieve marked 
reduction in their disease burden following 2 cycles of BV (see table).  In fact, 4 of the  4 
patients who scored Deauville 3 and 10 of the 17 who scored Deauville 4 achieved greater 
than 66% reduction in SUV max on PET or had residual FDG-avidity of SUV 4 or less 
(referred to as “good responders”).  Overall, there were 14 “good responders” and they 
represent a group of patients who may have achieved normalization of FDG-PET following 
BV if they were given an additional cycle of weekly BV. 
We therefore propose an expansion to our current study for 20 additional patients.  The 
expansion would again enroll patients who fail their front-line therapy for HL; however they  
will receive 3 cycles of weekly BV followed by reassessment by FDG-PET.  Those who score 
Deauville 2 or better will proceed to ASCT while all others will receive 2 cycles of augmented 
ICE prior to consideration for ASCT.  We hypothesize that administration of 3 cycles of BV  
will convert more “good responders” into “excellent responders” and allow more patients to 
avoid ICE chemotherapy prior to consolidation with ASCT. 


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IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
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Deauville 
score 
n=32 
Delta SUV (%) 
range* 
Post-BV SUV 
max** 
Excellent 
responders 
Good 
responders 
1 
5 
-95 to -84 
1 
5 
0 
2 
4 
-90 to -80 
2.3 
4 
0 
3 
4 
-77 to -67 
2.9-3.7 
0 
4 
4 
17 
-86 to -32 
2.2-6.2 
0 
10 
5 
2 
-63 to -13 
n/a 
0 
0 
*calculated for patients with baseline PET SUV max of ≥ 10 
**shown only for patients with baseline PET SUV max of <10 
 
 
Rationale for correlative studies 
 
Immunohistochemical studies 
 
All patients enrolled on this study will be required to have biopsy proven relapsed or 
refractory HL.  This gives us the opportunity to prospectively analyze several markers on the 
biopsy specimens by immunohistochemistry.  Based upon the recent report of the prognostic 
significance of CD68 (a marker of tumor associated macrophages)10 on outcome in newly 
diagnosed HL, we will look at this marker in our relapsed/refractory population.  In addition, 
immunohistochemical analysis of HL biopsy specimens have shown high expression of TIA-1 
(markers of cytotoxic t cells) and low expression of FOXP3 (markers of regulatory T cells) to 
be associated with poor prognosis both following primary treatment11  and in the 
relapsed/refractory setting12.  We aim to confirm these observations and evaluate differences 
following treatment failure by analyzing these markers in both initial biopsies and 
relapsed/refractory biopsies for each patient. 
 
ΔSUVmax analysis 
 
For the purpose of this study, FDG-PET/CT scans will be interpreted by visual analysis  
where areas with uptake greater than the mediastinal blood pool will be considered positive. 
Visual analysis of early interim FDG-PET/CT may not represent the most accurate method of 
interpretation. Evaluation of changes in FDG uptake over time, rather than assessment of 
findings at a single time point, has been proposed as an alternative assessment. Intensity of 
FDG uptake can be measured as standardized uptake value, SUV, usually measured as 
highest activity concentration per lesion, or SUVmax. Treatment induced changes in SUV 
over time are referred to as ΔSUVmax. In patients with previously untreated diffuse large B- 
cell lymphoma, it has been suggested that these changes in SUV from baseline to interim 
scan after 2 cycles of chemotherapy may be more accurate than visual assessment of a 
single scan13. These authors founds that a ΔSUVmax of -67.5% between FDG-PET/CT 
scans performed before and after 2 cycles of chemotherapy reduced the number of false 
positive results and improved the prognostic value of FDG-PET/CT compared to visual 
analysis. We plan to explore ΔSUVmax between FDG-PET/CT scans performed before 
brentuximab vedotin, after two cycles of brentuximab vedotin and after augmented ICE (if 


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given) as a predictor of outcome. This will be done by retrospective analysis of the data set. 
No ΔSUVmax will be defined a priori for determination of treatment strategy. 
Serum cytokines 
 
Serum levels of various cytokines and TNF receptor family members in patients with HL have 
been shown to have prognostic influence on disease outcome.  Sarris et al. reported the 
prognostic significance of serum IL-10 levels in previously untreated HL patients.  Among  
101 patients evaluated, 3 year failure free survival (FFS) for patients with high verse normal 
serum IL-10 levels was 60% and 91% respectively14.  Casasnovas et al. described a cytokine 
prognostic index that predicted disease related outcome in HL15.  They evaluated serum 
levels of TNF receptors (TNFα, TNF-R1, TNF-R2, CD30), and cytokines (IL-6, IL-10, IL1-RA) 
in 519 patients with untreated classical HL.  Elevated levels of TNFα, TNF-R1, TNF-R2, IL1- 
RA, IL-10, IL6, and soluble CD30 (sCD30) were associated with inferior event-free survival 
(EFS) and overall survival (OS).  Furthermore, a cytokine prognostic index which stratified 
patients based upon elevated serum levels of sCD30, IL-6, and IL1-RA was a strong 
independent predictor of EFS.  The prognostic significance of cytokine and TNF expression 
has not been evaluated in patients with relapsed and primary refractory HL.  We will evaluate 
serum levels of IL-10, IL-6, IL-1, and TNFα before and after 2 cycles of brentuximab vedotin. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
Patients with relapsed or refractory HL who are eligible for ASCT will be enrolled.  Patients 
will receive 2 cycles of weekly brentuximab vedotin and then undergo evaluation with FDG- 
PET/CT.  Patients with pre-treatment positive bone marrow biopsies will have repeat bone 
marrow biopsies if the PET scan is negative.  Patients with normalization of FDG-PET/CT 
and negative bone marrow biopsies will proceed to ASCT.  Patients with persistent 
abnormalities on FDG-PET/CT will receive 2 cycles of augmented ICE chemotherapy 
followed by repeat FDG-PET/CT prior to ASCT.  Following augmented ICE, patients with 
negative FDG-PET/CT will proceed to ASCT.  Those with persistent abnormalities on FDG- 
PET/CT will be treated according to their physician’s recommendations. 
4.2.1 
Design: Expansion Cohort 
 
Patients with relapsed or refractory HL who are eligible for ASCT will be enrolled.  Patients 
will receive 3 cycles of weekly brentuximab vedotin and then undergo evaluation with FDG- 
PET/CT.  Patients with pre-treatment positive bone marrow biopsies will have repeat bone 
marrow biopsies if the PET scan is negative.  Patients with normalization of FDG-PET/CT 
and negative bone marrow biopsies will proceed to ASCT.  Patients with persistent 
abnormalities on FDG-PET/CT will receive 2 cycles of augmented ICE chemotherapy 
followed by repeat FDG-PET/CT prior to ASCT.  Following augmented ICE, patients with 
negative FDG-PET/CT will proceed to ASCT.  Those with persistent abnormalities on FDG- 
PET/CT will be treated according to their physician’s recommendations. 


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4.3 
Intervention 
 
Patients will receive 2 cycles of weekly brentuximab vedotin, 1.2mg/kg on days 1, 8, and 15 
of each 28 day cycle.  FDG-PET/CT will be repeated after 2 cycles of treatment within 1 
week of the last dose of cycle 2.  Patients with normalization of FDG-PET/CT (and negative 
bone marrow biopsy) after brentuximab vedotin will proceed to arm A.  Patients with 
persistent FDG-PET/CT abnormalities will proceed to arm B. 
Arm A: Patients with normalization of FDG-PET/CT following 2 cycles of brentuximab 
vedotin will undergo stem cell mobilization in preparation for ASCT. 
Stem cell mobilization and collection will be performed as per standard MSKCC guidelines. 
 
Arm B: Patients with persistent abnormalities on FDG-PET/CT following 2 cycles of 
brentuximab vedotin will receive 2 cycles of augmented ICE.  The first cycle of augmented 
ICE will be initiated 7-14 days after the last dose of SGN-35.  FDG-PET/CT will be repeated 
within 21 days following the second cycle of augmented ICE.  Stem cell mobilization can be 
performed following the first or second cycle of augmented ICE. 
4.3.1 
Intervention: Expansion Cohort 
 
Patients will receive 3 cycles of weekly brentuximab vedotin, 1.2mg/kg on days 1, 8, and 15 
of each 28 day cycle.  FDG-PET/CT will be repeated after 3 cycles of treatment within 1 
week of the last dose of cycle 3.  Patients with normalization of FDG-PET/CT (and negative 
bone marrow biopsy) after brentuximab vedotin will proceed to arm A.  Patients with 
persistent FDG-PET/CT abnormalities will proceed to arm B. 
Arm A: Patients with normalization of FDG-PET/CT following 3 cycles of brentuximab 
vedotin will undergo stem cell mobilization in preparation for ASCT. 
Stem cell mobilization and collection will be performed as per standard MSKCC guidelines. 
 
Arm B: Patients with persistent abnormalities on FDG-PET/CT following 3 cycles of 
brentuximab vedotin will receive 2 cycles of augmented ICE.  The first cycle of augmented 
ICE will be initiated 7-14 days after the last dose of SGN-35.  FDG-PET/CT will be repeated 
within 21 days following the second cycle of augmented ICE.  Stem cell mobilization can be 
performed following the first or second cycle of augmented ICE. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC  AGENTS 
Brentuximab vedotin (SGN-35) 
SGN-35, the investigational treatment in this protocol, is an antibody-drug conjugate 
consisting of the anti-CD30 antibody cAC10 conjugated to MMAE,  an anti-tubulin agent. 
SGN-35 is a sterile, preservative-free, white to off-white lyophilized cake for reconstitution for 
IV administration. SGN-35 is supplied by Seattle Genetics in single-use, Type 1 borosilicate 
glass vials with FluroTec®-coated butyl rubber stoppers and aluminum seals. Each vial of the 
product contains SGN-35, trehalose, sodium citrate, and polysorbate 80.  See the Pharmacy 
Manual for further information (Appendix 1). 
 
Dose and Administration 


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SGN -35 will be administered on Day 1, 8, and 15 of each 28-day cycle. The dose of SGN-35 
is 1.2 mg/kg and is administered by outpatient IV infusion given over approximately 30 
minutes. In the absence of infusion toxicities, the infusion rate for all patients must be 
calculated in order to achieve a 30-minute infusion period. SGN-35 must not be administered 
as an IV push or bolus. SGN-35 should be administered through a dedicated IV line. SGN-35 
cannot be mixed with other medications. 
 
Dosing should be based on actual weight except for patients weighing greater than 100 kg; 
dose will be calculated based on 100 kg for these individuals. SGN-35 dose should be 
rounded according to institutional standards. 
 
 
Required Premedication and Postmedication 
Routine premedication should not be administered prior to the first dose of SGN -35. 
However, patients who experience a Grade 1 or Grade 2 infusion-related reaction may 
receive subsequent SGN-35 infusions with premedication as described below. Patients who 
experience a Grade 3 or Grade 4 infusion-related reaction may potentially receive additional 
treatment with SGN-35 at the discretion of the Investigator. 
 
Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of SGN-35. The infusion should be 
administered at a site properly equipped and staffed to manage anaphylaxis should it occur. 
The patient should be observed for 60 minutes following the first infusion of SGN-35. During 
this observation period, the IV line should remain open for at least 1 hour to allow 
administration of IV drugs if necessary. All supportive measures consistent with optimal 
patient care will be given throughout the treatment according to institution standards. 
Medications for infusion-related reactions, such as epinephrine, antihistamines, and 
corticosteroids, should be available for immediate use. 
A patient who experiences a Grade 1 or Grade 2 infusion-related reaction may receive 
subsequent SGN-35 infusions with premedication consisting of acetaminophen (650 mg 
orally) and diphenhydramine (25-50 mg orally or 10-25 mg IV) or according to institutional 
standards, administered 30-60 minutes prior to each 30-minute SGN-35 infusion. The routine 
use of steroids as premedication is discouraged. 
Dose Modifications 
Intrapatient dose reduction to 0.8 mg/kg will be allowed depending on the type and severity 
of toxicity. The following table describes the recommended dose modifications for study 
treatment-associated toxicity. 
The start of the next cycle may be delayed for up to 3 weeks if additional time is required for 
the patient to recover from study treatment-associated toxicity experienced during the current 
cycle. Doses reduced for drug-related toxicity should generally not be re-escalated. However, 
intrapatient re-escalation to the previous dose level may be permitted at the discretion of the 
treating physician. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 12 of 33 
 
 
 
 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-hematologic 
Continue 
at same 
dose 
level. 
Continue at same 
dose level, except in 
the event of Grade 2 
neuropathy. 
For Grade 2 
neuropathy,  reduce 
dose to 0.8mg/kg. 
For the second 
occurrence of Grade 
2 neuropathy, 
withhold dose until 
toxicity is ≤ Grade 1 
or has returned to 
baseline, then 
resume at 0.8 
mg/kg. 
Withhold dose 
until toxicity is ≤ 
Grade 1 or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose level 
a. 
For Grade 3 or 
higher 
neuropathy, 
discontinue 
treatment at the 
discretion of the 
investigator. 
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to 
baseline, then reduce 
dose to 0.8 mg/kg and 
resume treatment, or 
discontinue at the 
discretion of the 
investigator a. 
Hematologic 
Continue 
at same 
dose 
level. 
Continue at same 
dose level. 
Withhold dose 
until toxicity is ≤ 
Grade 2, or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose 
levelb.  Consider 
growth factor 
support (G-CSF 
or GM-CSF) for 
treatment of 
neutropenia and 
prophylaxis in 
subsequent 
cycles. 
Withhold dose until 
toxicity is ≤ Grade 2, 
then resume treatment 
at the same dose level. 
Consider growth factor 
support (G-CSF or GM- 
CSF) for treatment of 
neutropenia and 
prophylaxis in 
subsequent cycles.  For 
the second occurrence 
of Grade 4 toxicity (if 
neutropenia, while 
receiving growth factor 
support), withhold dose 
until toxicity is ≤ Grade 
2, then reduce the dose 
to 0.8 mg/kg and 
resume treatmentb. 
 
a. Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study 
treatment without interruption. 
b. Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without 
interruption. 
 
Storage and Handling 
Vials containing SGN-35 must be refrigerated at 2-8°C in an appropriate locked room 
accessible only to the pharmacist, the investigator, or a duly designated person. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 13 of 33 
 
 
 
 
 
Reconstituted SGN-35 should not be stored at room temperature. The effect of light on SGN- 
35 has not been assessed; therefore, it is recommended that SGN-35 vials and solutions be 
stored in the dark until the time of use. Reconstituted vials must not be shaken. Drug 
accountability logs must be maintained.  . 
Preparation 
SGN-35 vials are provided via single-use containers. Any partially used vials or diluted 
dosing solutions should be discarded using appropriate institutional drug disposal 
procedures. 
SGN -35 should be reconstituted with the appropriate amount of Sterile Water for Injection, 
USP. The vial should be GENTLY swirled until the contents are completely dissolved. The 
vial must not be shaken or vigorously swirled; excess agitation may cause aggregate 
formation. The reconstituted drug product should be inspected visually for any particulate 
matter and discoloration. 
The appropriate amount of reconstituted SGN-35 should be withdrawn from the vial(s) and 
diluted in an infusion bag containing 0.9% Sodium Chloride Injection, USP. 
There are no known incompatibilities between SGN-35 and polyviny1chloride  bags. The bag 
should be gently inverted to mix the solution. The bag must not be shaken; excess 
agitation may cause aggregate formation. Prior to administration, the reconstituted and 
diluted drug product should be inspected visually for any particulate matter and discoloration. 
 
Ifosfamide (Ifex®) 
Mechanism of action: Ifosfamide is activated in the liver by microsomal enzymes and the 
subsequent ifosfamide mustard causes direct alkylation of DNA. 
Formulation: Ifosfamide is supplied in single dose vials for constitution and administration by 
IV infusion. Each contains 1 gram or 3 grams of sterile ifosfamide. 
Preparation: Injections are prepared by adding sterile water to the vial. The 1-gram dose is 
mixed with 20 mL and the 3-gram dose with 60 mL for a final concentration of 50 mg/mL. 
Storage: The dry powder may be stored at room temperature. 
Supplier: Bristol-Myers Squibb 
 
Carboplatin (Paraplatin®) 
Mechanism of action: Carboplatin binds to DNA and causes cross-linking with a non-cell 
cycle dependent tumor cell lysis. It inhibits DNA synthesis by altering the template via the 
formation of intrastrand cross-links. 
Formulation: Paraplatin® is supplied as a sterile lyophilized powder available in single-dose 
vial containing 50 mg, 150 mg, and 450 mg of carboplatin for administration by IV infusion. 
Each vial contains equal parts of carboplatin and mannitol. 
Preparation: Immediately before use the content of each vial must be reconstituted with 
sterile solution: 50 mg strength with 5 mL, 150 mg with 15 mL and 450 mg with 45 mL. These 
solutions produce a concentration of 10 mg/mL. The solution is stable for 8 hours at room 
temperature. 
Storage: Unopened vials are stable for the life indicated on the insert if protected from light. 
Supplier: Bristol-Myers Squibb 
 
VP-16 (etoposide, VePesid®) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 14 of 33 
 
 
 
 
 
Mechanism of action: Induction of an irreversible blockade of cells in the premitotic phases of 
the cell cycle leading to accumulation of cells in late S or G2 phases. This mechanism is 
secondary to interference of the scissors-reunion reaction of the enzyme topoisomerase II. 
Formulation: VP-16 injection is available in 100-mg (5-mL) sterile multiple-dose vials. The pH 
is 3-4. Each mL contains 20-mg etoposide, 2-mg citric acid, 30-mg benzyl alcohol, 80-mg 
polysorbate 80, 650-mg polyethylene  glycol 300 and 30.5% alcohol. 
Preparation: The computed dose is diluted in 500 mL of normal saline and given by 
intravenous infusion over 1 hour. 
Storage: Unopened vials of VP-16 are stable for 24 months at room temperature. Vials are 
diluted as recommended to a concentration of 0.2 or 0.4 mg/mL and are stable for 96 and 48 
hours respectively, at room temperature under normal light in both plastic and glass 
containers. 
Supplier: Bristol-Myers Squibb 
 
Mesna (Mesnex®) 
Mechanism of action: Mesna was developed as a prophylactic agent to inhibit hemorrhagic 
cystitis induced by ifosfamide and is analogous to the cysteine-cystine system; mesna is 
rapidly metabolized to mesna disulfide and acts as a free radical scavenger. 
Formulation: Mesna is a sterile preservative free aqueous solution of clear, colorless 
appearance in clear glass ampules for IV administration. Mesna injection contains 100 mg/ml 
Mesna, 0.25 mg/ml acetate disodium, and sodium hydroxide to maintain pH 6.5-8.5. 
Preparation: For IV administration the drug is diluted in sterile solution to make a final 
concentration of 20 mg/ml. 
Storage: Diluted solutions are chemically and physically stable for 24 hours at room 
temperature. It is recommended that solutions be refrigerated and used within 6 hours. 
Supplier: Bristol-Myers Squibb 
 
G-CSF (Neupogen, Filgrastim) 
Mechanism of action: Filgrastim is a human protein, which is involved in the promotion of the 
growth and maturation of neutrophil/granulocyte  progenitors. 
Formulation: Available as a recombinant DNA product supplied as 1 or 1.6 ml vials 
containing clear colorless sterile protein solution. 
Storage: It can be stored at 2-6°C and is stable for at least 30 months. 
Supplier: Amgen, Inc. 
 
G-CSF (Neulasta, Pegfilgrastim) 
Mechanism of action: Pegfilgrastim is a human protein, which is involved in the promotion of 
the growth and maturation of neutrophil/granulocyte progenitors. 
Formulation: Available as a recombinant DNA product supplied as 6 mg/0.6 ml containing 
clear colorless sterile protein solution. 
Storage: It can be stored at 2-6°C and is stable for at least 30 months. 
Supplier: Amgen, Inc. 
 
 
6.1 
CRITERIAFOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Histologic diagnosis of cd30 positive classical Hodgkin’s lymphoma. 
 
• 
Primary refractory or relapsed disease proven by biopsy or fine needle aspiration 
(cytology) of an involved site.  Pathology must be reviewed at MSKCC. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 15 of 33 
 
 
 
 
 
• 
Relapse or refractory disease following doxorubicin or nitrogen mustard containing front- 
line therapy 
• 
Fluorodeoxyglucose (FDG)-avid disease by FDG-PET/CT and measurable disease of at 
least 1.5 cm by spiral CT, as assessed by the site radiologist. 
• 
Cardiac ejection fraction of greater than 45%, measured since last chemotherapy. 
 
• 
Hemoglobin-adjusted diffusing capacity for carbon monoxide of greater than 50% on 
pulmonary function testing, measured since last chemotherapy 
 
• 
Serum creatinine <1.5 mg/dl; if creatinine >1.5 mg/dl then the measured 12- or 24-hour 
creatinine clearance must be >60 ml/minute. 
• 
ANC>1000/μl  and Platelets>50,000/μl 
• 
Total bilirubin < 2.0 mg/dl in the absence of a history of Gilbert’s disease. 
• 
Females of childbearing age must be on an acceptable form of birth control. 
• 
Age between 12 and 72 
• 
HIV I and II negative. 
 
6.3 
Subject Exclusion Criteria 
 
• 
Received more than 1 prior treatment (combined modality therapy represents 1 
treatment) for Hodgkin Lymphoma 
• 
Hepatitis B surface antigen positive or hepatitis B core antibody positive. 
• 
Known pregnancy or breast-feeding. 
 
• 
Medical illness unrelated to Hodgkin’s Lymphoma, which, in the opinion of the attending 
physician and/or principal investigator, makes participation in this study inappropriate. 
• 
Peripheral neuropathy > grade 1 
 
7.0 
RECRUITMENT PLAN 
 
Patients seen in the inpatient or outpatient setting who meet eligibility criteria will be recruited 
to this study. An attending physician of the Lymphoma or Hematology service will evaluate all 
patients. 
 
 
8.1 PRETREATMENT EVALUATION 
Prior to initiating treatment: 
• 
Obtain tissue blocks or unstained slides (10) to confirm relapsed or refractory disease 
and to stain for CD68, TIA-1, and FOXP3 
• 
Obtain tissue block or unstained slides (10) from initial diagnostic biopsy to stain for 
CD68, TIA-1, and FOXP3 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 16 of 33 
 
 
 
 
 
• 
Bone marrow biopsy to be performed after the most recent treatment for Hodgkin 
lymphoma.  Bilateral bone marrow biopsies to be performed if previously positive unless 
there was a bone marrow biopsy performed since the last treatment that was positive 
(then the unilateral bone marrow biopsy is sufficient). 
 
Within 2 weeks prior to initiating treatment: 
 
• 
CBC 
 
• 
ESR 
 
• 
Electrolytes (Na, K, Cl, CO2), BUN, Cr, bilirubin, total protein, albumin, AST, ALT, 
alkaline phosphatase, uric acid, and LDH 
 
• 
Hemoglobin (Hgb) A1c 
 
• 
Serum ß-HCG (premenopausal females only) to assess for pregnancy 
 
• 
Creatinine clearance by 12- or 24-hr urine collection if serum Cr>1.5 mg/dl 
 
• 
Modified  Total Neuropathy Score (mTNS) and European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire for chemotherapy-induced 
peripheral neuropathy (CIPN-20) 
 
Within 4 weeks prior to initiating treatment: 
 
• 
CT scan of the chest, abdomen, and pelvis 
 
• 
18F-fluorodeoxyglucose-PET/CT  scan 
 
• 
Echocardiogram or MUGA scan 
 
• 
Pulmonary Function Testing 
 
Within 6 months of initiating treatment 
• 
Hepatitis B surface antigen 
• 
Hepatitis B core antibody 
• 
Hepatitis C serology 
• 
HIV I/II antibodies 
 
9.0 
TREATMENT/INTERVENTION  PLAN 
 
Patients will receive 2 cycles of weekly brentuximab vedotin, 1.2mg/kg on days 1, 8, and 15 
of each 28 day cycle.  See section 5.0 for dosing and administration of brentuximab vedotin. 
FDG-PET/CT will be repeated after 2 cycles of treatment within 1 week of the last dose of 
cycle 2.  Patients with pre-treatment positive bone marrow biopsies will have repeat bone 
marrow biopsies if the PET scan is negative.  Patients with normalization of FDG-PET/CT 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 17 of 33 
 
 
 
 
and negative bone marrow biopsies after brentuximab vedotin will proceed to arm A. 
Patients with persistent FDG-PET/CT abnormalities will proceed to arm B. 
Arm A: Patients with negative FDG-PET/CT following 2 cycles of brentuximab vedotin will 
undergo stem cell mobilization in preparation for ASCT. 
Stem cell mobilization and collection will be performed as per standard MSKCC guidelines. 
 
Arm B: Patients with persistent abnormalities on FDG-PET/CT following 2 cycles of 
brentuximab vedotin will receive 2 cycles of augmented ICE.  The first cycle of augmented 
ICE will be initiated 7-14 days after the last dose of SGN-35.  FDG-PET/CT will be repeated 
within 21 following the second cycle of augmented ICE.  Stem cell mobilization can be 
performed following the first or second cycle of augmented ICE. 
Augmented ICE will be administered as follows: 
 
Ifosfamide (5,000 mg/m2) mixed with Mesna (5,000 mg/m2) IVCI x 2 starting on day 1 
Carboplatin (AUC 5 [maximum dose 800 mg]) IVPB x 1 on day 3 
Etoposide (200 mg/m2) IVPB Q 12 hours x 3 doses starting on day 1 
 
The second cycle of augmented ICE will be initiated no sooner than 17 days after the first 
cycle.  ANC must be ≥1000/μl and platelet count must be ≥50,000/μl for ICE to be 
administered. Treatment will be held until these criteria are met. No dose reductions will be 
allowed. 
For non-collection cycles, either pegfilgrastim 6 mg on day after hospital discharge 
(completion of chemotherapy) or filgrastim 300 mcg (for patients under 70 kg) or 480 mcg 
(for patients over 70 kg) on days +5 to +12 will be given. 
For collection cycles, Filgrastim at 10 mcg/kg/day will be given on day +5 and continue until 
stem cell collection completed (approximated to the nearest increment of Filgrastim 600 mcg, 
780 mcg, 960 mcg, 1260 mcg, or 1,440 mcg). 
Stem cell mobilization and collection will be performed as per standard MSKCC guidelines. 
Pediatric patients will be treated in the Pediatric Day Hospital. 
9.0.1 
EXPANSION  COHORT: TREATMENT INTERVENTION/PLAN 
 
Patients will receive 3 cycles of weekly brentuximab vedotin, 1.2mg/kg on days 1, 8, and 15 
of each 28 day cycle.  See section 5.0 for dosing and administration of brentuximab vedotin. 
FDG-PET/CT will be repeated after 3 cycles of treatment within 1 week of the last dose of 
cycle 3.  Patients with pre-treatment positive bone marrow biopsies will have repeat bone 
marrow biopsies if the PET scan is negative.  Patients with normalization of FDG-PET/CT 
and negative bone marrow biopsies after brentuximab vedotin will proceed to arm A. 
Patients with persistent FDG-PET/CT abnormalities will proceed to arm B. 
Arm A: Patients with negative FDG-PET/CT following 3 cycles of brentuximab vedotin will 
undergo stem cell mobilization in preparation for ASCT. 
Stem cell mobilization and collection will be performed as per standard MSKCC guidelines. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 18 of 33 
 
 
 
 
Arm B: Patients with persistent abnormalities on FDG-PET/CT following 3 cycles of 
brentuximab vedotin will receive 2 cycles of augmented ICE.  The first cycle of augmented 
ICE will be initiated 7-14 days after the last dose of SGN-35.  FDG-PET/CT will be repeated 
within 21 days following the second cycle of augmented ICE.  Stem cell mobilization can be 
performed following the first or second cycle of augmented ICE. 
 
 
Augmented ICE will be administered as follows: 
 
Ifosfamide (5,000 mg/m2) mixed with Mesna (5,000 mg/m2) IVCI x 2 starting on day 1 
Carboplatin (AUC 5 [maximum dose 800 mg]) IVPB x 1 on day 3 
Etoposide (200 mg/m2) IVPB Q 12 hours x 3 doses starting on day 1 
 
The second cycle of augmented ICE will be initiated no sooner than 17 days after the first 
cycle.  ANC must be ≥1000/μl and platelet count must be ≥50,000/μl for ICE to be 
administered. Treatment will be held until these criteria are met. No dose reductions will be 
allowed. 
For non-collection cycles, either pegfilgrastim 6 mg on day after hospital discharge 
(completion of chemotherapy) or filgrastim 300 mcg (for patients under 70 kg) or 480 mcg 
(for patients over 70 kg) on days +5 to +12 will be given. 
For collection cycles, Filgrastim at 10 mcg/kg/day will be given on day +5 and continue until 
stem cell collection completed (approximated to the nearest increment of Filgrastim 600 mcg, 
780 mcg, 960 mcg, 1260 mcg, or 1,440 mcg). 
Stem cell mobilization and collection will be performed as per standard MSKCC guidelines. 
Pediatric patients will be treated in the Pediatric Day Hospital. 
10.1 
EVALUATION  DURING TREATMENT/INTERVENTION 
 
Tests to be performed day 1 of each cycle of brentuximab vedotin 
 
• 
History and physical exam 
 
• 
CBC (may be drawn within 24 hours pre-treatment) 
 
• 
Comprehensive metabolic panel 
 
• 
ESR 
 
• 
Cytokine levels (one 8.5 mL SST speckled red top tube  - IL-10, IL-6, IL-1, TNFα ): 
***cycle 1 only 
 
• 
Modified  Total Neuropathy Score (mTNS) and European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire for chemotherapy-induced 
peripheral neuropathy (CIPN-20): ***cycle 2 only 
 
Tests to be performed day 8 and 15 of each cycle of brentuximab vedotin 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 19 of 33 
 
 
 
 
 
• 
History and physical exam 
 
• 
CBC (may be drawn within 24 hours pre-treatment) 
 
Tests to be performed at the completion of 2 cycles of brentuximab vedotin: 
 
• 
FDG-PET/CT (1-7 days after the last dose of brentuximab vedotin, between days 44 and 
50). All studies will be obtained on dedicated PET/CT cameras. Patients must fast for 6 
hrs prior to PET imaging, but intake of water or other non-caloric beverages is 
encouraged. When the patient arrives at one of the nuclear medicine imaging sites, a 
fingerstick blood glucose measurement will be obtained; patient with blood glucose levels 
> 200mg/dl are ineligible. Approximately 12 mCi of 18F FDG will be injected 
intravenously. Following an approximately 60-80 min uptake time, CT and PET images 
will be obtained from skull base to upper thigh using standard clinical imaging protocols. 
For a given patient, all serial PET/CT scans will be obtained on the same camera model. 
• 
CT chest, abdomen, pelvis (1-7 days after the last dose of brentuximab vedotin, between 
days 44 and 50) 
Within 1 week of last dose of SGN-35 (+/- 4 days) 
 
• 
Hemoglobin A1c 
• 
Cytokine levels (one 8.5 mL SST speckled red top tube - IL-10, IL-6, IL-1, TNFα) 
• 
Modified  Total Neuropathy Score (mTNS) and European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire for chemotherapy-induced 
peripheral neuropathy (CIPN-20) 
• 
Bone marrow biopsy (if BM was involved before treatment and post-SGN-35 PET scan is 
negative) 
 
Interventions while receiving brentuximab vedotin (SGN-35) 
Treatment days 
Test/treatment 
Pretreatment 
1 
8 
15 
22 
29 
36 
43 
44-50 
SGN-35 
x 
x 
x 
x 
x 
x 
History and Physical 
x 
x 
x 
x 
x 
x 
CBC 
x 
x* 
x* 
x* 
x* 
x* 
x* 
Comprehensive 
Metabolic  Panel 
x 
x 
x 
ESR 
x 
x 
x 
Uric acid 
x 
Lactate 
dehydrogenase 
x 
Creatinine 
clearance** 
x 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 20 of 33 
 
 
 
 
 
Hemoglobin A1c 
x 
x 
Serum β-HCG*** 
x 
Hep B, C, HIV 
x 
Cytokines 
x 
x 
Neuropathy 
Questionnaire 
x 
x 
x 
BM Bx 
x 
x**** 
FDG-PET/CT and CT 
CAP 
x 
x 
Echo or MUGA 
x 
PFTs 
x 
*may be drawn within 24 hours pre-treatment; ** if creatinine >1.5; ***premenopausal females; ****if 
previously positive 
 
 
The following applies to patients receiving augmented ICE: 
 
• 
A CBC and basic metabolic panel will be obtained upon each admission for 
chemotherapy and a 12-hour urine collection for creatinine clearance will be obtained 
prior to receiving carboplatin. Other laboratory evaluations during admission for ICE 
chemotherapy may be performed at the discretion of the inpatient attending physician. 
When receiving ifosfamide, urine will be monitored for hematuria by urinalysis. 
The following will be performed within 21 days following the completion of augmented 
ICE: 
 
• 
CT scan of the chest, abdomen, and pelvis 
• 
FDG-PET/CT scan 
• 
Bone marrow biopsy (if BM was involved before treatment and post-ICE PET scan is 
negative) 
 
10.1.1 EXPANSION COHORT: EVALUATION  DURING TREATMENT/INTERVENTION 
Tests to be performed day 1 of each cycle of brentuximab vedotin 
• 
History and physical exam 
 
• 
CBC (may be drawn within 24 hours pre-treatment) 
 
• 
Comprehensive metabolic panel 
 
• 
ESR 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 21 of 33 
 
 
 
 
• 
Cytokine levels (one 8.5 mL SST speckled red top tube  - IL-10, IL-6, IL-1, TNFα ): 
***cycle 1 only 
 
• 
Modified  Total Neuropathy Score (mTNS) and European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire for chemotherapy-induced 
peripheral neuropathy (CIPN-20): *** cycle 3 only 
 
Tests to be performed day 8 and 15 of each cycle of brentuximab vedotin 
 
• 
History and physical exam 
 
• 
CBC (may be drawn within 24 hours pre-treatment) 
 
Tests to be performed at the completion of 3 cycles of brentuximab vedotin: 
 
• 
FDG-PET/CT (1-7 days after the last dose of brentuximab vedotin). All studies will be 
obtained on dedicated PET/CT cameras. Patients must fast for 6 hrs prior to PET 
imaging, but intake of water or other non-caloric beverages is encouraged. When the 
patient arrives at one of the nuclear medicine imaging sites, a fingerstick blood glucose 
measurement will be obtained; patient with blood glucose levels > 200mg/dl are 
ineligible. Approximately 12 mCi of 18F FDG will be injected intravenously. Following an 
approximately 60-80 min uptake time, CT and PET images will be obtained from skull 
base to upper thigh using standard clinical imaging protocols. For a given patient, all 
serial PET/CT scans will be obtained on the same camera model. 
• 
CT chest, abdomen, pelvis (1-7 days after the last dose of brentuximab vedotin) 
 
Within 1 week of last dose of SGN-35 (+/- 4 days) 
 
• 
Hemoglobin A1c 
• 
Cytokine levels (one 8.5 mL SST speckled red top tube - IL-10, IL-6, IL-1, TNFα) 
• 
Modified  Total Neuropathy Score (mTNS) and European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire for chemotherapy-induced 
peripheral neuropathy (CIPN-20) 
• 
Bone marrow biopsy (if BM was involved before treatment and post-SGN-35 PET scan is 
negative) 
 
Interventions while receiving brentuximab vedotin (SGN-35) 
Treatment days 
Test/treatment 
Pretreatment 
1 
8 
15 
22 
29 
36 
43 
50 
57 64 71 
72-78 
SGN-35 
x 
x 
x 
x 
x 
x 
x 
x 
x 
History and 
Physical 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC 
x 
x* 
x* 
x* 
x* 
x* 
x* 
x* 
x* 
x* 
Comprehensive 
Metabolic  Panel 
x 
x 
x 
x 
ESR 
x 
x 
x 
x 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 22 of 33 
 
 
 
 
 
Uric acid 
x 
Lactate 
dehydrogenase 
x 
Creatinine 
clearance** 
x 
Hemoglobin A1c 
x 
x 
Serum β-HCG*** 
x 
Hep B, C, HIV 
x 
Cytokines 
x 
x 
Neuropathy 
Questionnaire 
x 
x 
x 
BM Bx 
x 
x**** 
FDG-PET/CT 
and CT CAP 
x 
x 
Echo or MUGA 
x 
PFTs 
x 
*may be drawn within 24 hours pre-treatment; ** if creatinine >1.5; ***premenopausal females; ****if 
previously positive 
 
 
The following applies to patients receiving augmented ICE: 
 
• 
A CBC and basic metabolic panel will be obtained upon each admission for 
chemotherapy and a 12-hour urine collection for creatinine clearance will be obtained 
prior to receiving carboplatin. Other laboratory evaluations during admission for ICE 
chemotherapy may be performed at the discretion of the inpatient attending physician. 
When receiving ifosfamide, urine will be monitored for hematuria by urinalysis. 
The following will be performed within 21 days following the completion of augmented 
ICE: 
 
• 
CT scan of the chest, abdomen, and pelvis 
• 
FDG-PET/CT scan 
• 
Bone marrow biopsy (if BM was involved before treatment and post-ICE PET scan is 
negative) 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-232 A(5) 
Approval date: 22-Oct-2020 
Page 23 of 33 
 
 
 
 
Brentuximab vedotin: Fatigue, fever, diarrhea, nausea, peripheral neuropathy, neutropenia, 
alopecia, rash 
Ifosfamide: Alopecia, nausea and vomiting, hematuria, gross hematuria, CNS toxicity, 
infection, renal dysfunction, allergic reactions and at high doses, cardiotoxicity, and 
myelosuppression. 
Carboplatin: Myelosuppression, nausea, vomiting, peripheral neuropathy, ototoxicity, hepatic 
toxicity, electrolyte abnormalities, hypomagnesemia, hypocalcemia, and allergic reactions. 
Etoposide: Myelosuppression, mucositis, alopecia, nausea, vomiting, headache, fever, 
hypotension, anorexia, and allergic reactions. Possible secondary leukemia. 
Mesna: Nausea, vomiting, diarrhea. 
 
Neupogen® (Filgrastim): Bone pain; exacerbation of preexisting autoimmune disorders; 
transient and reversible changes in alkaline phosphatase, uric acid and LDH; peripheral 
edema. 
Neulasta® (Pegfilgrastim): bone pain, flu-like symptoms, nausea/vomiting, adult respiratory 
distress syndrome, sickle cell crises, splenic rupture (rare) 
Placement of leukapheresis catheter: pneumothorax, deep venous thrombosis, infection, and 
bleeding. 
12.0 
CRITERIAFOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Criteria for interim FDG-PET/CT assessment 
Patients enrolled in this study will receive salvage treatment with brentuximab vedotin and 
those who achieve FDG-PET/CT normalization will proceed directly to ASCT without 
receiving standard salvage chemotherapy such as ICE or DHAP.  Because this treatment 
strategy represents, for some patients, a departure from standard practice, or de-escalation 
of treatment, stringent criteria are required to designate those most appropriate for avoiding 
ICE chemotherapy.  A five-point scale for assessing response on interim FDG-PET/CT 
scans, referred to as the “London criteria”, was developed by international experts in Nuclear 
Medicine and Oncology for use in diffuse large B cell lymphoma and HL17  and validated for 
use as interim assessment in HL patients.18    The 5-point scale is displayed in the following 
table. 
 
Score 
FDG-PET/CT scan result 
1 
No uptake above background 
2 
Uptake ≤ mediastinum 
3 
Uptake > mediastinum but ≤ liver 
4 
Uptake moderately more than liver uptake, 
at any site 
5 
Markedly increased uptake at any site or 
new sites of disease 


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The score on this scale used to define a normal or abnormal scan depends upon the 
particular clinical strategy planned.  For example, when escalation of treatment is planned 
based upon FDG-PET/CT results, defining an abnormal FDG-PET/CT by a score of 4 or 5 is 
appropriate to avoid overtreating patients.  Conversely, when de-escalation of treatment is 
planned based upon FDG-PET/CT results, defining a persistently abnormal FDG-PET/CT by 
a score of 3, 4, or 5 is appropriate in order to avoid undertreating patients. 
For the purpose of this study, a score of 1 or 2 will be considered a “normal” FDG-PET/CT 
scan because de-escalation of treatment is anticipated.  All scores (1 through 5) will be 
recorded for each FDG-PET/CT scan and scans will be reviewed by either Dr. Grewal or Dr. 
Schöder. 
Progression free survival (PFS) and overall survival (OS) will be calculated from the time of 
initiation of brentuximab vedotin. 
The response criteria developed by the International  Harmonization Project for response 
assessment in lymphoma will be used to define complete response, partial response, and 
progression of disease in this study19.  The definitions for response are detailed in the table 
below. 
 
 
 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be followed on study until progression of disease or 2 years following autologous 
stem cell transplant. 
 
The following patients will be removed from study: 


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• Patients who have progression of disease while on treatment. These patients may 
be offered alternate treatments. 
• Patients who develop unacceptable toxicity. 
• Patients who request that they be removed from study. This will not compromise the 
care they receive at this institution. 
• Patients who are non-compliant with treatment or follow-up. 
 
14.0 
BIOSTATISTICS 
 
For the primary objective of this study, we will employ a Simon two stage design. Currently, 
the FDG-PET/CT normalization rate for ICE alone is between 50-60% therefore for a new 
treatment regimen, we would consider a normalization rate of 40% unacceptable.   The goal 
of this study is to replace an intense inpatient regimen with an effective, less toxic regimen 
without impacting efficacy. Thus, we will set the desirable FDG-PET/CT normalization rate aa 
60% for the new treatment regimen (i.e., SGN-35 with or without ICE) and we will use 40%  
as our null hypothesis in employing the Simon two stage design. In the first stage, we will 
enroll 18 relapsed or refractory Hodgkin lymphoma patients who meet the criteria in Section 
6. If 7 or fewer patients achieve FDG-PET/CT normalization either after SGN-35 alone or 
after SGN-35 combined with ICE, no additional patients will be enrolled and the regimen will 
be considered not promising in this cohort of patients. 
If 8 or more patients are FDG- 
PET/CT negative either after SGN-35 alone or after SGN-35 with ICE, then an additional 28 
patients will be enrolled for the second stage. Among the total 46 patients, If 23 or more 
patients achieve FDG-PET/CT normalization either after SGN-35 alone or after SGN-35 with 
ICE, this treatment regimen will be declared effective. This decision rule has both type I error 
(declaring the new treatment regimen promising while it is actually not) and type II error 
(declaring the new treatment regimen not promising while it actually is) rate as 0.10. The 
early stopping (i.e., stop after the first stage with 18 patients) probability is 0.56 when the 
FDG-PET/CT normalization rate is 40%, and is 0.06 when the FDG-PET/CT normalization 
rate is 60%.  We expect it will take 2-3 years to enroll 46 patients. 
Furthermore, additional stopping rules are in place if we observe an unacceptable amount of 
toxicity due to SGN-35 or an unacceptable rate of relapse following transplant in the SGN- 
35-only group among the first 18 patients.  We have defined an unacceptable rate of toxicity 
as grade 3 or more neuropathy occurring in 5 of the first 18 patients enrolled.  We have 
defined an unacceptable relapse rate as a 50% rate of relapse within 3 months of transplant 
among the SGN-35-only patients. 
As an additional criterion, we require that at least 7 out of the total 46 patients (15%) achieve 
FDG-PET/CT normalization after SGN-35 to call this new regimen a success. The purpose of 
this criterion is to exclude the situation that all patients may fail SGN-35 (i.e., persistent PET 
abnormalities) and hence must receive ICE salvage therapy, yet accidently pass the above 
two-stage design. The threshold 15% was chosen because the previous phase I data show 
that about 30% of patients may achieve CR with SGN-35, and thus we believe it would be 
clinically meaningful to require at least 15% of patients to achieve PET normalization after 
SGN-35 to call it a success. 
For the secondary objectives, we will report the stratified FDG-PET/CT normalization rates  
as sample proportions with their confidence intervals. Overall response rate to SGN-35 alone 
will be reported similarly. Toxicities will be summarized and tabulated. PFS and OS (see 


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definition in Section 12) will be analyzed using standard survival tools such as Kaplan-Meier 
estimation, log-rank tests and/or Cox regression models to incorporate various factors (such 
as ∆SUVmax, CD68, FoxP3, TIA-1, serum cytokine, etc.) and assess their correlation with 
PFS and/or OS. Competing risks analysis will be conducted if competing risk(s) exists (such 
as death without progression). Lab results including CD34 cell yield following mobilization will 
be reported as summary statistics. 
14.0.1  EXPANSION COHORT: BIOSTATISTICS 
 
This study would be an expansion of our current study and therefore the data will ultimately 
be analyzed along with the data from our current study in which patients are receiving 2 
cycles of BV.  The goal of this expansion study is to determine whether the rate of FDG-PET 
normalization is improved with 3 cycles of BV when compared to 2 cycles. So far, we have 
observed a 28% rate of FDG-PET normalization following 2 cycles of BV; however an 
additional 14 patients (44%) were "good responders" to 2 cycles of BV and likely had the 
potential to achieve FDG-PET normalization had they received an additional cycle of BV. 
Based upon this, we estimate that the rate of FDG-PET normalization following 3 cycles of 
BV will be around 50%. 
Allowing for type I and type II error rates of 0.2, and assuming a FDG-PET normalization rate 
of 28% with 2 cycles of BV, the number of patients required to show an improvement in FDG- 
PET normalization rate to 50% is 20. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. 


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The data collected for this study will be entered into the Clinical Research Database (CRDB). 
Source documentation will be available to support the computerized patient record. 
Data to be collected will include: 
 
1. Patient related features: 
- age 
- sex 
 
2. Disease related features 
- prior therapy 
- disease status- relapsed vs. primary refractory 
 
- results of all tests related to the study 
 
- disease status at long-term follow-up 
 
3. Treatment related 
- duration of treatment 
- stem cell yields 
 
- response to treatment 
 
- toxicities of treatment 
 
16.2 
Quality Assurance 
 
Registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
Retention of Records: All documentation of adverse events, records of study drug receipt 
and dispensation, and all IRB correspondence will be retained for at least 3 years after the 
investigation is completed. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at  
http://www.cancer.gov/clinicaltrials/conducting/dsm -guidelines. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 


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and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb5.mskcc.org/intranet/html/99073.cfm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring  Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
Section 16.3 Regulatory Documentation 
 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
 
Participating sites that are conducting data analysis should submit this protocol to their IRB 
according to local guidelines. Copies of any site IRB correspondence should be forwarded to 
MSK. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
Potential Risks 
Traditionally, we have used ICE chemotherapy as the initial salvage therapy in 
relapsed/refractory HL.  In this study, ICE chemotherapy is either eliminated or delayed until 
treatment with SGN-35 is completed.  In the phase II studies described above, SGN-35 was 
associated with tumor reduction in over 90% of patients with relapsed/refractory HL.  While 
delaying or eliminating ICE chemotherapy represents a potential risk for patients enrolled in 
this protocol, this potential risk is minimal given the high activity of SGN-35. 
Potential Benefits 
 
While ICE-based salvage treatment is commonly administered for relapsed/refractory HL it is 
associated with significant toxicity.  Patients enrolled on this trial who achieve FDG-PET/CT 
negativity following 2 cycles of SGN-35 will proceed directly to ASCT.  Therefore, a portion of 
patients enrolled on this study may avoid ICE-based treatment.  Furthermore, Seattle 
Genetics is supplying SGN-35 free of charge. 
Provisions for preventing and treating adverse events 
 
Assessment for neuropathy will be performed before each cycle of brentuximab vedotin. 
Treatment of febrile neutropenia, cytopenias, ifosfamide-related gross and microscopic 


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hematuria, and catheter related sepsis, thrombosis, and pneumothorax will be in accordance 
with standard medical practices employed at MSKCC. 
Patients will receive standard anti-emetics as prophylaxis against nausea and vomiting. 
 
Alternatives/Options for treatment 
 
For patients eligible, alternative therapy would consist of ICE-based salvage therapy or 
DHAP chemotherapy. 
Costs 
 
The patient will be responsible for all costs related to treatment and complications of 
treatment, including G-CSF, pegfilgrastim, FDG-PET scans, and all hospitalizations. 
SGN-35 will be supplied by Seattle Genetics free of charge.  The patient will not be 
responsible for the cost of correlative studies. 
Participation in this study is voluntary and patients will not be paid for participation. 
 
Privacy and confidentiality 
 
Confidentiality will be maintained within the limits of the law. Only qualified individuals from 
MSKCC; the National Cancer Institute; the FDA; Seattle Genetics; will be able to review 
patients' medical records. Neither the patients' names nor other identifying information will be 
used in reports or publications arising from this study. After all patients have completed 
treatment on study and primary data analysis is complete, FDG-PET/CT scans will be de- 
identified (only patient weight and study ID number will be shared) and sent on a CD via mail 
to LYSA Imaging at Hôpitaux Universitaires Henri Mondor, France for data analysis. 
 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 


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• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
17.2.1 
SAE reporting information to Seattle Genetics 
 
• 
Reporting Timeframe: The Principal Investigator will report to Seattle Genetics 
 
Drug Safety by facsimile (425) 527-4308 or (866) 333-6627 (USA only toll free) 
any Serious Adverse Event (SAE) that occurs in a study subject within 24 hours 
of first awareness of the event. 
• 
Reporting Forms: The Principal Investigator will report such SAEs using the 
Seattle Genetics SAE Report Form or the approved local regulatory form 
SAEs should be reported as soon as they are determined to meet the 
definition, even if complete information is not yet available. 
• 
Reporting Period: The reportable events that are subject to this provision are 
those that occur from the start of administration of the first dose of the Product 
through thirty (30) days after discontinuation of the Product. SAEs occurring 
more than thirty (30) days after discontinuation of the Product that are assessed 
by the Investigator as related to the Product should also be reported. 


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• 
Follow-up Information: The Principal Investigator will assist Seattle Genetics in 
investigating any SAE and will provide any follow-up information reasonably 
requested by Seattle Genetics. 
• 
Regulatory Reporting: Reporting an SAE to Seattle Genetics does not relieve 
the Principal Investigator conducting the study of the responsibility for reporting it 
to the FDA, local regulatory authority, or IRB/IEC as required. 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.1 
REFERENCES 
 
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Moskowitz AJ, Yahalom J, Kewalramani T, Maragulia JC, Vanak JM, Zelenetz 
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Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero- 
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Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Klasa R, Connors JM, 
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20.0 
APPENDICES 
 
Appendix 1: Pharmacy manual 
Appendix 2: mTNS questionnaire 
Appendix3:  EORTC neuropathy questionnaire