Clinical trial NCT02689219
Conditions: Germ Cell Tumors Testis Cancer Testicular Cancer Embryonal Carcinoma Nonseminomatous Germ Cell Tumor
Keywords: Antigens, CD30, Embryonal Germ Cell Tumors
Sponsor: Nabil Adra
Start date: 2016-03-09; Completion date: 2019-01-23
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II study to evaluate the activity of brentuximab vedotin in relapsed/refractory non-seminomatous germ cell tumors (NSGCT).

Detailed description:
Primary Objective To determine the anti-tumor efficacy of brentuximab vedotin in relapsed/ refractory NSGCT.

Secondary Objectives

1. To determine the progression free survival in patients with relapsed/ refractory NSGCT treated with brentuximab vedotin.
2. To determine the overall survival of patients with relapsed/ refractory NSGCT treated with brentuximab vedotin.
3. To determine the safety and tolerability of brentuximab vedotin in this patient population.

Eligible patients will be divided into two cohorts, those who are CD30 positive and those who are CD30 negative/unknown. Both groups will be treated similarly and in parallel but analyzed separately. CD30 status may be unknown in the unlikely case of tumor-marker-only relapse or when a fresh tumor biopsy is not feasible, and archival tumor tissue is not obtainable despite efforts to do so. These patients will be included in the CD30 negative cohort for analysis purposes, since statistically NSGCT are more likely to be CD30 negative. The number of such patients with unknown CD30 status should not exceed 5 patients.

Eligible patients will be treated with brentuximab vedotin at 1.8 mg/kg IV every 3 weeks (maximum dose of 180 mg) indefinitely until disease progression, unacceptable toxicity, or study closure.Eligible patients with grade 2 peripheral neuropathy at enrollment will be treated with brentuximab vedotin at 1.2 mg/kg IV every 3 weeks (maximum dose of 180 mg) indefinitely until disease progression, unacceptable toxicity, or study closure. Response to treatment will be assessed clinically with history, physical exam and tumor markers measurement (BHCG and AFP) on day 1 of each cycle and with CT scans after cycle 2, 4, and every 4 cycles thereafter while receiving treatment.

Arms: arm 1: Brentuximab vedotin, 1.8 mg/kg (1.2 mg/kg in patients with grade 2 peripheral neuropathy at enrollment) will be administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle. arm 2: Brentuximab vedotin, 1.8 mg/kg (1.2 mg/kg in patients with grade 2 peripheral neuropathy at enrollment) will be administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle.
Interventions: intervention 1: Brentuximab Vedotin
Intervention descriptions: intervention 1: Both cohorts will be treated similarly and in parallel but analyzed separately.

Protocol documents:
Prot_SAP_000.pdf: 
IUSCC-0568 
A Multicenter Phase II Study of Brentuximab Vedotin in Relapsed/Refractory 
Germ Cell Tumors 
IUSCC-0568 
Coordinating Center: 
Indiana University Melvin and Bren Simon Cancer Center 
Principal Investigator: 
Nabil Adra, MD 
 (Indiana University) 
Co-Principal Investigator:  
Darren R. Feldman, MD 
(Memorial Sloan Kettering Cancer Center) 
Co-Investigators: 
Mohammad Abu Zaid, MD 
Nasser Hanna, MD 
Robert Motzer, MD 
Lawrence H. Einhorn, MD 
Statistician: 
Susan M. Perkins, PhD 
Support Provided By: 
Seattle Genetics 
Protocol Version Date: 
09/12/2019 
IND #: 129002 
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PROTOCOL SIGNATURE PAGE 
Protocol title: Phase II Study of Brentuximab Vedotin in Relapsed/Refractory Germ Cell 
Tumors 
VERSION DATE:  12SEP2019 
I confirm I have read this protocol, I understand it, and I will work according to this 
protocol and to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable guidelines for good clinical practices, or the applicable laws and 
regulations of the country of the study site for which I am responsible, whichever 
provides the greater protection of the individual.  I will accept the monitor’s overseeing 
of the study.  I will promptly submit the protocol to applicable ethical review board(s). 
____________________________________ 
________________________ 
Signature of Site Investigator 
 Date 
____________________________________ 
Site Investigator Name (printed) 
____________________________________ 
Site Investigator Title 
____________________________________ 
Name of Facility 
____________________________________ 
Location of Facility (City and State) 
PLASE COMPLETE AND EMAIL COPY TO INDIANA UNIVERSITY SIMON 
CANCER CENTER CLINICAL TRIALS OFFICE 
Instructions to the investigator: Please SIGN and DATE this 
signature page. PRINT your name and title, the name and location of 
the facility in which the study will be conducted, and the expected 
IRB approval date. Scan and email the completed form to Indiana 
University Simon Cancer Center and keep a record for your files. 
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SYNOPSIS 
TITLE 
Phase II Study of Brentuximab Vedotin in Relapsed/Refractory Germ Cell 
Tumors 
SHORT TITLE 
ADCETRIS in refractory testicular cancer 
PHASE  
II 
OBJECTIVES 
Primary Objective: To determine the anti-tumor efficacy of brentuximab 
vedotin in relapsed/refractory NSGCT. 
Secondary Objectives:  
1) To determine the progression free survival in patients with 
relapsed/refractory NSGCT treated with brentuximab vedotin. 
2) To determine the overall survival of patients with 
relapsed/refractory NSGCT treated with brentuximab vedotin.  
3) To determine the safety and tolerability of brentuximab vedotin in 
this patient population.  
Exploratory Objectives: 
1) To characterize the intensity and localization (cell wall vs. 
cytoplasmic) of CD30 staining among tumors from patients with 
relapsed or refractory NSGCT enrolling on the study. 
2) To correlate the intensity and localization of tumor staining for 
CD30 with objective response and progression-free survival for 
patients enrolling on the study. 
STUDY DESIGN 
Phase II study with 2 cohorts in parallel using a Simon two-stage design 
ELIGIBILITY 
CRITERIA  
Main Inclusion Criteria: 
1. Age ≥ 18 years at the time of screening. 
2. Patients with histologically or serologically confirmed 
relapsed/refractory non-seminoma germ cell tumor, (i.e. 
embryonal carcinoma, choriocarcinoma, or yolk sac tumors) 
including female GCT and primary mediastinal NSGCT. 
3. Patients must have progressed after prior high dose chemotherapy 
(HDCT) treatment, been deemed not to be a candidate for high 
dose chemotherapy or refused high-dose chemotherapy, and be 
considered incurable by other standard therapies including further 
chemotherapy or surgery. There is no maximum allowable number 
of previous therapies. 
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4. Patients with measurable disease according to RECIST v1.1, or
with rising AFP or BHCG above the upper limit of normal on two
consecutive determinations if no measurable radiologic disease.
5. Patients with brain metastases are allowed onto the study as long as
patients have completed their treatment for brain metastasis, no
longer require corticosteroids, and are asymptomatic. Subjects with
neurological symptoms should undergo a head CT scan or brain
MRI to exclude brain metastasis, at the discretion of the treating
physician.
6. Patients with ECOG performance status of 0-2.
7. Adequate organ and marrow function as detailed in the protocol.
8. Patients who are willing and able to comply with the protocol and
study procedures including willingness to undergo tumor biopsy for
tumor cells before therapy to assess for CD30 status (unless archival
tumor tissue from orchiectomy or other previous sample is not
obtainable despite efforts to do so and a fresh tumor biopsy is not
feasible).
Main Exclusion Criteria: 
1. Patients with pure seminoma.
2. Patients with pure teratoma.
3. Chemotherapy within 2 weeks of initiating study treatment.
4. Major surgery within 3 weeks of starting study treatment. There is
no minimum time requirement for minor procedures such as biopsy
or vascular access placement.
5. Radiation within 2 weeks of starting study treatment.
6.
≥ Grade 3 neuropathy at the time of enrollment.
7. Pregnancy or breast-feeding.
8.
Previous treatment with any anti-CD30 directed therapy.
STATISTICAL 
CONSIDERATIONS 
a) Definition of primary outcome/endpoint:
Objective response rate is the proportion of patients who achieve
either a partial or complete response.
Complete response is defined as disappearance of all target lesions
and normalization of serum tumor markers (AFP and beta-hCG) for
at least 4 weeks. Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to <10 mm. Complete
Response must be confirmed four or more weeks after initial CR is
observed.
In patients whose only evidence of disease is elevated serum tumor
markers (AFP or beta-hCG), then values must fall below the upper
limit of normal for the assay employed and remain at that level for at
least 4 weeks.
Partial response is defined as at least a 30% decrease in the sum of
the diameters of target lesions, taking as reference the baseline sum
diameters. This should be present on at least 2 measurements 1 month
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apart. The serum tumor markers (AFP and beta-hCG) should be 
stable or decreasing. Partial Response must be confirmed four or 
more weeks after initial PR is observed.  
In patients whose only evidence of disease is elevated serum tumor 
markers (AFP or beta-hCG), then values must fall ≥ 90% below 
baseline pretreatment levels for beta-hCG or 50% decrease below 
baseline pretreatment levels for AFP and persist for 6 weeks. If both 
tumor markers are elevated and one falls below 90% the other should 
fall at least below 50% of baseline pretreatment levels.  
b) Definition of secondary outcomes/endpoints:
Progression-free survival (PFS) time is the time measured from the
date of initiation of therapy until disease progression or death,
whichever comes first. Patients alive and progression-free will be
censored at their last follow-up.
Overall survival (OS) is the time measured from the date of initiation
of therapy until death, regardless of cause. Patients alive at the time of
data analysis will be censored at their last date of contact.
c) Analytic plan for primary objective:
The ORR and its 95% exact CI will be summarized for the total
population and by cohort using the F distribution method (Collett
1991).
d) Analytic plan for secondary objectives:
•
Both PFS and OS will be estimates using the methods of Kaplan
and Meier for each cohort separately.
•
Toxicities will be assessed based on the Common Terminology
Criteria for Adverse Events (CTCAE) version 4.0. The maximum
grade of each toxicity will be recorded for each patient over the
course of treatment (all cycles). Toxicities will be recorded up
until 30 days after the last day of treatment. The incidence of
treatment delays, dose reductions, and early discontinuations of
treatment due to toxicity or patient choice, will also be recorded as
a means of assessing the tolerability of treatment for each cohort.
•
CD30 staining will be characterized by intensity (0 to 3+) and by
localization (cell wall vs. cytoplasmic) and correlated with
response using logistic regression and with PFS using proportional
hazards regression.
e) Sample size justification:
An optimal Simon two-stage design will be used for each cohort of
patients to differentiate between the null hypothesis that the response
rate P is ≤ 5% (P<=0.05) and the alternative hypothesis that the
response rate is ≥20% (P>=0.20). Under this design, the probability of
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early termination under the null hypothesis is 0.599. This design yields 
a type I error rate, α (probability of concluding that the drug is not 
effective when it is actually effective) of 0.047 and a power of 0.801 
(type II error rate 0.199) when the true response rate is ≥20%.  In the 
first stage in each cohort, 10 patients will be enrolled. If there are no 
objective responses, then that cohort will terminate. If ≥1 response is 
observed, then an additional 19 patients will be enrolled in the second 
stage for a total sample size of 29 patients per cohort. If 3 or fewer 
responses are observed out of the 29 patients, then brentuximab 
vedotin will be declared as not worthy of further study. If ≥4 objective 
responses are achieved, then brentuximab vedotin will be deemed 
active in refractory/relapsed NSGCT and worthy of further study.  
f)
Accrual estimation:
We estimate enrolling 2 patients/month for the CD30 negative cohort
and 1 patient/month for the CD30 positive patients.
TOTAL  
NUMBER OF 
SUBJECTS 
N = 58 (10 patients in the first stage + 19 patients in the second 
stage= 29 per cohort x 2 cohorts) 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 24 months 
ESTIMATED STUDY 
DURATION  
Estimated 36 months 
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TABLE OF CONTENTS 
 
Schema ................................................................................................................................ 9 
1. 
Background and Rationale ........................................................................................ 10 
1.1 
Relapsed and Refractory Germ Cell Tumors .................................................... 10 
1.2 
Current Standard of Care .................................................................................. 10 
1.3 
Brentuximab Vedotin ........................................................................................ 10 
1.4 
Rationale ........................................................................................................... 11 
2. 
Study Objectives and Endpoints ............................................................................... 12 
2.1 
Objectives ......................................................................................................... 12 
2.2 
Endpoints .......................................................................................................... 12 
3. 
Eligibility Criteria ..................................................................................................... 13 
3.1 
Inclusion Criteria .............................................................................................. 13 
3.2 
Exclusion Criteria ............................................................................................. 15 
4. 
Subject Registration .................................................................................................. 16 
5. 
Treatment Plan .......................................................................................................... 16 
5.1 
Treatments Administered .................................................................................. 17 
5.2 
Investigational Study Drug ............................................................................... 17 
5.3 
Concomitant Therapy........................................................................................ 19 
5.4 
Drug Interactions .............................................................................................. 20 
5.5 
Treatment Compliance ...................................................................................... 20 
6. 
Toxicities and Dose Delays/Dose Modifications ...................................................... 20 
6.1 
Dose Delays and Dose Modifications ............................................................... 20 
6.2 
Protocol Therapy Discontinuation .................................................................... 22 
6.3 
Study Withdrawal ............................................................................................. 22 
7. 
Study Calendar & Evaluations .................................................................................. 23 
7.1 
Screening Evaluations ....................................................................................... 25 
7.2 
On Treatment Evaluations ................................................................................ 25 
7.3 
Post Treatment Safety Assessment ................................................................... 26 
7.4 
Long Term Follow-up Evaluations ................................................................... 26 
8. 
Biospecimen Studies and Procedures ....................................................................... 27 
9. 
Criteria for Disease Evaluation ................................................................................. 27 
9.1 
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) will be used 
as follows: ..................................................................................................................... 27 
9.2 
Methods for Evaluation of Measurable Disease: .............................................. 28 
9.3 
Methods of Measurement: ................................................................................ 28 
9.4 
Non-target lesions ............................................................................................. 29 
9.5 
Response Criteria .............................................................................................. 29 
9.6 
Evaluation of best overall response .................................................................. 31 
9.7 
Confirmation ..................................................................................................... 32 
9.8 
Duration of follow-up: ...................................................................................... 32 
9.9 
Definitions of Response Evaluation: ................................................................ 32 
10. 
Drug Information .................................................................................................. 33 
10.1 
Brentuximab vedotin ......................................................................................... 33 
10.2 
Clinical pharmacology ...................................................................................... 33 
10.3 
Supplier ............................................................................................................. 34 
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10.4 
Preparation ........................................................................................................ 35 
10.5 
Storage and Handling ........................................................................................ 35 
10.6 
Packaging and Labeling .................................................................................... 35 
10.7 
Dispensing......................................................................................................... 35 
10.8 
Adverse Events ................................................................................................. 36 
10.9 
WARNINGS AND PRECAUTIONS ............................................................... 36 
11. 
Adverse Events ..................................................................................................... 38 
12. 
Statistical Methods ................................................................................................ 45 
12.1 
Study Design ..................................................................................................... 45 
12.2 
Endpoints .......................................................................................................... 45 
12.3 
Sample Size and Accrual .................................................................................. 45 
12.4 
Analysis Datasets .............................................................................................. 46 
12.5 
Assessment of Safety ........................................................................................ 46 
12.6 
Assessment of Efficacy ..................................................................................... 46 
12.7 
Data Analysis Plans .......................................................................................... 47 
12.8 
Interim Analysis/Criteria for Stopping Study ................................................... 47 
13. 
Trial Management ................................................................................................. 47 
13.1 
Data and Safety Monitoring .............................................................................. 47 
13.2 
Changes to the Protocol and Informed Consent ............................................... 50 
14. 
Multicenter guidelines .......................................................................................... 51 
14.1 
Study Documents .............................................................................................. 51 
14.2 
Study Initiation.................................................................................................. 51 
14.3 
Patient Enrollment ............................................................................................ 51 
14.4 
Data Monitoring ................................................................................................ 51 
14.5 
Record Retention .............................................................................................. 52 
15. 
Ethics..................................................................................................................... 52 
15.1 
Institutional Review Board (IRB) Review ........................................................ 52 
15.2 
Ethical Conduct of the Study ............................................................................ 52 
15.3 
Informed Consent Process ................................................................................ 52 
15.4 
Compliance with Trial Registration and Results Posting Requirements .......... 53 
16. 
References ............................................................................................................. 54 
17. 
Appendices ............................................................................................................ 56 
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SCHEMA 
 
 
 
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1. 
BACKGROUND AND RATIONALE 
1.1 
Relapsed and Refractory Germ Cell Tumors 
Germ cell tumors (GCT) are the most common malignancies among men between ages 
15 and 35. In 2013, 7,920 cases and 370 deaths were estimated to occur in the United 
States.(1) Cisplatin-based chemotherapy has transformed this disease from the most 
common cause of cancer death among young men to a model of curative malignancy.(2) 
Patients who are not cured with initial platinum-based chemotherapy are usually treated 
with salvage chemotherapy. Approximately 50% of these testicular cancer patients will 
subsequently be cured with salvage chemotherapy with tandem transplant of high-dose 
chemotherapy with peripheral stem cell rescue. Today, with modern chemotherapy and 
surgery techniques, 80-90% of patients will survive their disease. For the unfortunate 10-
20% who are not cured by these measures, there is a desperate need for novel therapeutic 
agents. 
 
Germ cell tumors of the ovary are very rare. Relapsed ovarian GCT after chemotherapy 
carries a poor prognosis and there are very few trials that looked at novel therapies for 
this disease.(3) 
1.2 
Current Standard of Care 
Seven phase 2 clinical trials evaluated single-agents activity in 90 refractory GCT patients 
at MSKCC showed median progression free survival (PFS) of 4 weeks and median overall 
survival (OS) of 4 months.(4) Similar experience at Indiana University (IU) showed that 
chemotherapy post-HDCT result in a response rate of less than 20%, with a median survival 
time of 8 months. All deaths occurred within 12 months of HDCT.(5) An average of more 
than 35 years of life is lost when a patient dies from GCT, well over a decade longer than 
any other adult malignancy. Therefore, there is currently no standard of care for patients 
who relapse after high-dose chemotherapy and have no surgically resectable disease. The 
development of novel treatment options for this patient population is needed. 
1.3 
Brentuximab Vedotin 
Brentuximab vedotin (SGN-35 or ADCETRIS) is an antibody-drug conjugate (ADC) 
consisting of 3 components: 1) the antibody cAC10, specific for human CD30; 2) the 
potent antimicrotubule agent monomethyl auristatin E (MMAE); and 3) a protease-
cleavable linker that covalently attaches MMAE to cAC10. The biological activity of 
brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on 
the cell surface initiates internalization of the ADC-CD30 complex, which then traffics to 
the lysosomal compartment. Within the cell, a single defined active species, MMAE, is 
released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule 
network within the cell, induces cell cycle arrest, and results in apoptotic death of the 
CD30-expressing tumor cell. Contributions to the mechanism of action by other 
antibody-associated functions have not been excluded.(6) 
 
 Experience with Brentuximab Vedotin 
To date, more than 700 patients have received brentuximab vedotin in 10 completed 
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clinical studies. 
Two phase 2 studies evaluating the efficacy and safety of brentuximab vedotin as a single 
agent have been performed in patients with relapsed or refractory Hodgkin lymphoma 
(HL; Study SG035-0003) and systemic anaplastic large cell lymphoma (ALCL; Study 
SG035-0004). The objective response rate (ORR) for HL patients was 75%, with 
approximately one-third of patients achieving a complete response/remission (CR) 
(Seattle Genetics, Clinical Study Report No. SG035-0003, 2010). ALCL patients had an 
ORR of 86%, with over 50% of patients achieving a CR (Seattle Genetics, Clinical Study 
Report No. SG035-0004, 2010). In both studies, brentuximab vedotin was generally well 
tolerated with manageable side effects. 
A complete summary of the clinical and nonclinical data relevant to the investigational 
product and its study in human subjects is provided in the Investigator’s Brochure. 
Brentuximab vedotin is currently FDA-approved in relapsed or refractory Hodgkin's 
lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma. 
1.4 
Rationale 
CD30 is expressed in the vast majority of testicular embryonal carcinomas.(7-11) 
Estimates range as high as 93%-98% of cases, with staining in >50% of tumor cells. 
There have been reports of weak expression of CD30 in yolk sac tumors and primary 
mediastinal germ cell tumors,(12, 13) though the percentage of cells in primary 
mediastinal ECs staining positive for CD30 was seen to vary widely, from 5% to >90%. 
A recent retrospective study found that CD30 expression was retained in patients with 
non-seminoma germ cell tumors (NSGCT) even after multiple lines of therapy, 
confirming that it is a reliable treatment target.(14) 
Five patients with refractory GCT were recently enrolled on protocol SGN00-001. This 
study treated CD30-positive nonlymphomatous malignancies with brentuximab vedotin. A 
clinical benefit was observed in 3 of these patients (1 complete response, 1 partial response 
and 1 with stable disease). One of these patients achieved a complete response after 4 cycles 
of treatment and ultimately completed 14 cycles of therapy. He remains disease free at this 
point, despite being off brentuximab vedotin for more than 16 months (J Clin Oncol 31, 
2013 (suppl 6; abstr 327)). A second study is currently evaluating brentuximab vedotin as 
salvage therapy in refractory GCT but it mandates tumor cells to be CD30-positive 
(NCT01851200).  
We propose a phase 2 study to evaluate activity of brentuximab vedotin in 
relapsed/refractory NSGCT. For this study we propose treating patients regardless of the 
tumor’s CD30 status. The rationale for this study in CD30-negative patients is that it is 
unknown whether tumor positivity for CD30 by immunohistochemistry (IHC) is truly 
predictive of benefit with this agent. In a recent study looking at the activity of brentuximab 
vedotin in B cell non-Hodgkin lymphoma(15, 16), there was no statistical correlation 
between response and CD30 expression by central visual IHC or by computer-assisted 
review. Specifically, in 48 DLBCL patients, the median percent of CD30-positive cells by 
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visual central review was 25% in the responders vs. 25% in the nonresponders. Twenty-
one percent of the responders had <10% CD30 expression. Two patients with DLBCL with 
≤1% detectable CD30 expression by central pathologist review achieved CR. Although the 
precise mechanisms underlying this phenomenon remain unknown, some evidence 
indicates a 'bystander effect', whereby free MMAE is released from dying cells in 
concentrations sufficient to kill neighboring tumor cells(17) either directly or indirectly by 
altering the tumor microenvironment.(18) 
 
Patients will be enrolled into two cohorts, one for CD30 positive patients and one for CD30 
negative (or CD30 unknown). CD30 status may be unknown in the unlikely case of tumor-
marker-only relapse or when a fresh tumor biopsy is not feasible, and archival tumor tissue 
is not obtainable despite efforts to do so. We would like to enroll such patients if they are 
otherwise eligible for the study and would include them in the CD30 negative cohort for 
analysis purposes, since statistically NSGCT are more likely to be CD30 negative. The 
number of such patients with unknown CD30 status should not exceed 5 patients. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
 Primary Objective 
To determine the anti-tumor efficacy of brentuximab vedotin in relapsed/refractory 
NSGCT. 
 Secondary Objectives 
1) To determine the progression free survival in patients with relapsed/refractory 
NSGCT treated with brentuximab vedotin. 
2) To determine the overall survival of patients with relapsed/refractory NSGCT 
treated with brentuximab vedotin.  
3) To determine the safety and tolerability of brentuximab vedotin in this patient 
population.  
 Correlative/Exploratory Objectives 
1) To characterize the intensity and localization (cell wall vs. cytoplasmic) of CD30 
staining among tumors from patients with relapsed or refractory NSGCT enrolling 
on the study. 
2) To correlate the intensity and localization of tumor staining for CD30 with 
objective response and progression-free survival for patients enrolling on the 
study. 
2.2 
Endpoints 
 Primary Endpoint 
Objective response (CR + PR) measured by RECIST Criteria v1.1 if there is measurable 
disease. In case of no measurable disease (marker-only patients), response can be 
assessed by either a reduction of BHCG by >90% (with no rise in AFP on two 
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consecutive measures) or a reduction of AFP by >50% (with no rise in BHCG on two 
consecutive measures). 
Secondary Endpoints 
1.
Progression-free survival time defined from the start of the treatment until death,
criteria for disease progression are met, or last follow-up visit. Overall survival time
defined from the start of the treatment until death or last follow-up visit.
2.
Toxicity measured by Common Toxicity Criteria 4.0 and need for treatment delay,
dose reduction, or early discontinuation.
3.
Correlation between tumor CD30 staining intensity/localization and objective
response and progression-free survival.
3.
ELIGIBILITY CRITERIA
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this 
study: 
1. Age ≥ 18 years at the time of informed consent.
2. Patients with histologically or serologically confirmed relapsed/refractory non-
seminoma germ cell tumor, (i.e., embryonal carcinoma, choriocarcinoma, or yolk
sac tumors) including female GCT and primary mediastinal NSGCT.
3. Patients must have progressed after prior high dose chemotherapy (HDCT)
treatment, been deemed not to be a candidate for high dose chemotherapy or refused
high-dose chemotherapy, and be considered incurable by other standard therapies
including further chemotherapy or surgery. There is no maximum allowable
number of previous therapies.
“Failure” of prior therapy is defined as:
a. A >25% increase in the products of perpendicular diameters of measurable
tumor masses during prior therapy which are not amenable to surgical resection.
b. The presence of new tumors which are not amenable to surgical resection.
c. An increase in AFP or beta-hCG (two separate determinations at least one week
apart are required if rising tumor markers are the only evidence of failure).
NOTE: Patients with clinically growing “teratoma” (normal declining tumor 
markers and radiographic or clinical progression) should be considered for 
surgery. 
4. Patients must have evidence of recurrent or metastatic carcinoma by one or more
of the following:
i)
The appearance of metastatic disease by standard imaging techniques
ii) The appearance of rising serum tumor marker, AFP or beta-hCG
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NOTE: If a rising tumor marker is the only evidence of progressive disease, at 
least 2 consecutive rising values at least one week apart are needed. Patients with 
only evidence of disease is rising tumor marker AFP and beta-hCG will be 
provided alternate causes of increased serum levels of these markers are not 
present, such as cross reaction with luteinizing Hormone (LH) (that can be tested 
if needed by testosterone suppression of LH), hepatitis, use of marijuana or 
second primary tumor, etc.  
5. Patients with primary medistinal non seminomatous germ cell tumor are eligible 
if they have received first line platinum based chemotherapy and their recurrence 
is not amenable to surgical resection based on the treating physician expert 
opinion. 
 
6. Patients with late relapse (>2 years) of non seminomatous germ cell tumors are 
eligible if they have received first line platinum based chemotherapy and their 
recurrence is not amenable to surgical resection based on the treating physician 
expert opinion.  
 
7. Patients with brain metastases are allowed onto the study as long as patients have 
completed their treatment for brain metastasis, no longer require corticosteroids, 
and are asymptomatic. Subjects with neurological symptoms should undergo a 
head CT scan or brain MRI to exclude brain metastasis, at the discretion of the 
treating physician.  
8. Patients with ECOG performance status of 0-2. 
9. Adequate organ and marrow function as defined below: 
a. 
Hemoglobin ≥ 8 g/dL 
b. 
Absolute neutrophil count ≥ 1,000/mm3 
c. 
Platelet count ≥ 75,000/mm3 
d. 
Total bilirubin ≤ 1.5 × ULN except patients with documented Gilbert’s 
syndrome (≤ 3 × ULN) 
e. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 
× ULN 
f. 
Calculated creatinine clearance ≥ 30 mL/min as determined by the 
Cockcroft-Gault equation. 
10. Patients who are willing and able to comply with the protocol and study procedures 
including willingness to undergo tumor biopsy for tumor cells before therapy to 
assess for CD30 status (unless archival tumor tissue from orchiectomy or other 
previous sample is not obtainable despite efforts to do so and a fresh tumor biopsy 
is not feasible). 
 
11. Females of childbearing potential must not be pregnant or breast-feeding. Male 
and female patients of reproductive potential must agree to use two forms of 
highly effective contraception from the screening visit through 28 days after the 
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last dose of study drug unless patient is practicing true abstinence. Acceptable 
forms of effective contraception include: 
• Oral, injected or implanted hormonal methods of contraception. 
• Tubal ligation 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
• Male sterilization (defined as complete retrograde ejaculation or the 
appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate). 
• True abstinence: When this is in line with the preferred and usual lifestyle of 
the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.] 
 
Pregnancy tests for females of childbearing potential are required; must be serum 
at screening and the post treatment safety assessment visit. A positive urine 
pregnancy test must be confirmed by a serum pregnancy test and a pelvic US 
since some NSGCT may secrete beta-hCG and cause a false positive pregnancy. 
A pelvic US does not need to be repeated with each cycle unless the treating 
physician thinks it is necessary to do so. 
12. Potential subject must have the ability to understand (as judged by the treating 
physician) and willingness to provide written informed consent and HIPAA 
authorization for release of personal health information.  
 
NOTE: HIPAA authorization may be included in the informed consent or 
obtained separately. Written informed consent must be obtained from a potential 
subject prior to the conduct of any study-specific procedures. 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Patients with pure seminoma. 
2. Patients with pure teratoma. 
3. Chemotherapy within 2 weeks of initiating study treatment. There is no maximum 
allowable number of previous therapies. 
4. Major surgery within 3 weeks of starting study treatment. There is no minimum 
time requirement for minor procedures such as biopsy or vascular access 
placement.  
5. Radiation within 2 weeks of starting study treatment. 
6.  ≥ Grade 3 neuropathy at the time of enrollment. 
7. Pregnancy or breast-feeding. 
8. Previous treatment with any anti-CD30 directed therapy. 
 
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4.
SUBJECT REGISTRATION
All patients will be registered with the Indiana University Cancer Center Clinical Trials
Office. Regulatory files will be maintained by the Clinical Trials Office. Applicable
regulatory documents must be completed and on file prior to registration of any patients.
Potential patients will be identified in the Oncology outpatient clinics or by referrals from
outside physicians. Patients who appear to be eligible for this trial will undergo the
Informed Consent Process and be screened for eligibility utilizing the Eligibility Criteria.
The original signed IRB approved Informed Consent Document and completed eligibility
checklist will be forwarded to the Clinical Trials Office designee for eligibility
verification and registration in the OnCore® database. Notification will be sent to the
principal investigator, treating physician and research nurse when registration is complete
to confirm registration and inform them of patient ID number.
Study data will be collected and stored in OnCore®, developed by Forte Research 
Systems, Inc. (www.forteresearch.com). OnCore® Enterprise Research is a 
comprehensive, web-based, Clinical Trial Management System (CTMS) which utilizes 
an Oracle database.  It has been licensed by Indiana University (IU) to support the 
operations and data capture of clinical research trials. 
The system has been installed and configured within a HIPAA-aligned, Information 
Technology (IT), operations center supported by IU’s IT organization, University 
Information Technology Services (UITS). OnCore® provides users secure access with 
unique IDs/passwords and restricts access by assigned roles, from any location, to record, 
manage, and report on data associated with the operation and conduct of clinical trials. 
The system is comprised of three specific applications—Clinical Research Management 
(CRM), Biospecimen Management (BSM), and Unified Registries Management (URM). 
Indiana University leverages OnCore® to support clinical research operations specifically 
as it relates to the following functions/processes:  electronic Scientific Review 
Committee (SRC), regulatory management, protocol and subject life cycle management, 
coverage analysis, study financials management, subject registration and visit 
management, subject safety monitoring, protocol deviation monitoring, study auditing 
and monitoring, electronic data management, correlative study sample management, 
specimen banking and management, registries management, effort tracking, and 
reporting. 
Subjects must be registered prior to starting protocol therapy. Subjects must be begin 
therapy within 7 business days of registration.  
5.
TREATMENT PLAN
•
Eligible patients will be divided into two cohorts, those who are CD30 positive and
those who are CD30 negative/unknown. Both groups will be treated similarly and in
parallel but analyzed separately.
•
CD30 status may be unknown in the unlikely case of tumor-marker-only relapse or
when a fresh tumor biopsy is not feasible, and archival tumor tissue is not obtainable
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despite efforts to do so. These patients will be included in the CD30 negative cohort 
for analysis purposes, since statistically NSGCT are more likely to be CD30 negative. 
The number of such patients with unknown CD30 status should not exceed 5 
patients. 
• Enrollment to the study does not have to wait for determination of CD30 status prior 
to treatment, unless in the situation where one arm is closed for enrollment or an 
interim assessment of response for the Simon stage I phase is needed. For example: 
o The first 10 patients can enroll on the study and start on therapy without 
waiting for CD30 status assessment. Prior to enrolling patient number 11, 
CD30 status need to be determined for all patients to make sure an interim 
assessment of response for the Simon stage I phase is not needed (i.e. one arm 
is at 10 patients). 
o If an arm has closed for lack of efficacy, CD30 status need to be assessed 
prior to starting therapy to make sure that patients belong to the open arm. 
o If both arms advance to the second stage of the Simon design then enrollment 
can again be pursued without waiting for CD30 status until one arm is closed 
to accrual. 
• Eligible patients will be treated with brentuximab vedotin at 1.8 mg/kg IV every 3 
weeks (maximum dose of 180 mg) indefinitely until disease progression, 
unacceptable toxicity, or study closure. 
• Eligible patients with grade 2 peripheral neuropathy at enrollment will be treated with 
brentuximab vedotin at 1.2 mg/kg IV every 3 weeks (maximum dose of 180 mg) 
indefinitely until disease progression, unacceptable toxicity, or study closure. 
• Response to treatment will be assessed clinically with history, physical exam and 
tumor markers measurement (BHCG and AFP) on day 1 of each cycle and with CT 
scans after cycle 2, 4, and every 4 cycles thereafter while receiving treatment. 
5.1 
Treatments Administered 
Brentuximab vedotin (SGN-35), the investigational agent under study in this protocol, is 
an ADC consisting of the antibody cAC10, specific for human CD30; the potent 
antimicrotubule agent MMAE; and a protease-cleavable linker that covalently attaches 
MMAE to cAC10. 
5.2 
Investigational Study Drug 
For injection: 50 mg of brentuximab vedotin as a sterile, white to off-white lyophilized, 
preservative-free cake or powder in a single-use vial for reconstitution. 
 Dose and Administration 
Brentuximab vedotin, 1.8 mg/kg (1.2 mg/kg in patients with grade 2 peripheral 
neuropathy at enrollment) will be administered by IV infusion given over approximately 
30 minutes on Day 1 of each 21-day cycle. In the absence of infusion-related reactions, 
the infusion rate for all patients should be calculated in order to achieve a 30-minute 
infusion period. If an infusion reaction does occur, infusion rates should be adjusted as 
necessary and documented appropriately in source documents. Brentuximab vedotin must 
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not be administered as an IV push or bolus. Brentuximab vedotin should not be mixed 
with other medications. 
 
Dosing is based on patient weight according to the institutional standard; however, doses 
will be adjusted for patients who experience a ≥10% change in weight from baseline. 
Actual weight will be used except for patients weighing greater than 100 kg; dose will be 
calculated based on 100 kg for these individuals. Rounding is permissible within 5% of 
the nominal dose. 
 Required Premedication and Postmedication 
Routine premedication should not be administered for the prevention of infusion-related 
reactions prior to the first dose of brentuximab vedotin. However, patients who 
experience a Grade 1 or Grade 2 infusion-related reaction may receive subsequent 
brentuximab vedotin infusions with premedication as described in Section 5.2.3. Patients 
who experience a Grade 3 or Grade 4 infusion-related reaction may potentially receive 
additional treatment with brentuximab vedotin at the discretion of the Investigator after 
discussion with the Sponsor. 
Patients should be individually evaluated to assess the need for tumor lysis prophylaxis 
prior to the first dose of brentuximab vedotin. Patients should receive prophylaxis as 
appropriate per institutional standards. 
 Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of study treatment. The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis 
should it occur. The patient should be observed for at least 60 minutes following the first 
infusion of study treatment. During this observation period, an IV line should remain 
open for at least 60 minutes to allow administration of IV drugs, if necessary for infusion-
related reactions. All supportive measures consistent with optimal patient care will be 
given throughout the study according to institutional standards. This includes adjusting 
the infusion time if necessary. Medications for infusion-related reactions, such as 
epinephrine, antihistamines, and corticosteroids, should be available for immediate use. 
Patients who experience a Grade 1 or Grade 2 infusion-related reaction may receive 
subsequent study treatment infusions with premedication consisting of acetaminophen 
and diphenhydramine administered 30–60 minutes prior to each 30-minute infusion or 
according to institutional standards. 
If anaphylaxis occurs, brentuximab vedotin administration should be immediately and 
permanently discontinued. 
 Management of Suspected PML 
Signs and symptoms of progressive multifocal leukoencephalopathy (PML) may include 
altered mental status, motor deficits such as hemiparesis or ataxia, visual disturbances, or 
higher cortical dysfunction such as dysphasia or agnosia. See the Investigator’s Brochure 
for further details. 
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If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic 
work-up including (but not limited to): 
• Neurologic examinations, as warranted 
• Brain radiologic features by magnetic resonance imaging (MRI) 
• PCR analysis: John Cunningham virus (JCV) DNA detectable in cerebrospinal 
fluid 
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin. 
5.3 
Concomitant Therapy 
All concomitant medications and blood products will be collected from Day 1 (predose) 
through the safety reporting period. Any concomitant medication given for a study 
protocol-related adverse event should be recorded from the time of informed consent. All 
supportive measures consistent with optimal patient care should be provided throughout 
the study according to institutional standards. 
 Required Concomitant Therapy 
Pneumocystis carinii (jiroveci) pneumonia (PCP) prophylaxis is required for human 
immunodeficiency virus (HIV)-positive patients. Medications that aggravate cytopenias 
(e.g., trimethoprim-sulfamethoxazole) should be avoided. 
All patients should be up-to-date on any recommended vaccinations prior to study entry. 
Additional vaccination(s) during each cycle of study treatment must be approved by the 
medical monitor. 
 Allowed Concomitant Therapy 
Routine premedication should not be administered prior to the first dose of brentuximab 
vedotin. However, patients who experience an infusion-related reaction may receive 
subsequent treatment with premedication as described in Section 5.2.3. 
Prophylactic intrathecal therapy is allowed only after discussion with the Sponsor. 
For HIV-positive patients, highly active anti-retroviral therapy (HAART) according to 
the institutional standard of care is permitted. 
The use of platelet and/or red blood cell supportive growth factors or transfusions when 
applicable is allowed. The use of colony stimulating factors for the treatment of 
neutropenia per institutional practice is permitted during therapy. Prednisone (or 
equivalent) ≤20 mg/day may be used if for reasons other than malignant disease control 
and the patient has been on a stable dose for ≥30 days; doses >20 mg are allowed for 
treatment of hypersensitivity reactions. 
 Prohibited Concomitant Therapy 
Patients may not receive other investigational drugs, immunosuppressive medications 
(excluding steroids as described in Section 5.3.2), radiotherapy, or systemic anti-
neoplastic therapy during the study. 
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5.4 
Drug Interactions  
In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an 
inhibitor of CYP3A4/5. In vitro data indicate that MMAE is also a substrate of the efflux 
transporter P-glycoprotein (P-gp).  
 
 Effect of Other Drugs on Brentuximab vedotin  
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A [see 
Clinical Pharmacology (10.2)]. Co-administration of brentuximab vedotin with 
ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by 
approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly 
with brentuximab vedotin should be closely monitored for adverse reactions. Co-
administration of brentuximab vedotin with rifampin, a potent CYP3A4 inducer, reduced 
exposure to MMAE by approximately 46%.  
P-gp Inhibitors: Co-administration of brentuximab vedotin with P-gp inhibitors may 
increase exposure to MMAE. Patients who are receiving P-gp inhibitors concomitantly 
with brentuximab vedotin should be closely monitored for adverse reactions.  
 Effect of Brentuximab Vedotin on Other Drugs  
Co-administration of brentuximab vedotin did not affect exposure to midazolam, a 
CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical 
concentrations [see Clinical Pharmacology (10.2)]. Brentuximab vedotin is not expected 
to alter the exposure to drugs that are metabolized by CYP3A4 enzymes. 
5.5 
Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to 
grade adverse events.  
Subjects enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study as specified in 
Study Calendar & Evaluations. 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation as specified in Study 
Calendar & Evaluations.   
6.1 
Dose Delays and Dose Modifications 
Intrapatient dose reduction will be allowed depending on the type and severity of toxicity. 
Table 1 describes the recommended dose modifications for study treatment-associated 
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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. Delays of greater than 4 weeks are prohibited without approval of the 
Sponsor. 
Doses reduced for treatment-related toxicity should not be re-escalated without 
discussion with the Sponsor. 
Table 1 Recommended dose modifications for brentuximab vedotin-associated 
toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
Neuropathy 
Continue at 
same dose 
level. 
Reduce 
treatment to 
1.2 mg/kg 
Withhold until 
toxicity 
resolves to ≤ 
Grade 2 or has 
returned to 
baseline; 
resume 
treatment at 
1.2 mg/kg 
Discontinue 
treatment 
Nonhematologic Continue at 
same dose 
level. 
Continue at 
same dose 
level, except in 
the event of 
Grade 2 
neuropathy. 
Withhold dose 
until toxicity is 
≤ Grade 2 or 
has returned to 
baseline, then 
resume 
treatment at 
the same dose 
level.a 
Withhold dose 
until toxicity is 
≤ Grade 2 or 
has returned to 
baseline, then 
reduce dose to 
1.2 mg/kg and 
resume 
treatment, or 
discontinue at 
the discretion 
of the 
Investigator 
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 level.b Consider 
growth factor support (G-CSF or 
GM-CSF) for treatment of 
neutropenia and prophylaxis in 
subsequent cycles. If Grade 4 
neutropenia recurs despite 
growth factor support, consider 
discontinuation or dose 
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Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
reduction to 1.2 mg/kg. 
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.
6.2 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in Section 6.1, 
a subject will also be discontinued from protocol therapy and followed up per protocol 
under the following circumstances: 
•
Evidence of disease progression
•
The treating physician thinks a change of therapy would be in the best interest of
the subject
•
The subject requests to discontinue protocol therapy, whether due to unacceptable
toxicity or for other reasons
•
In case a subject decides to prematurely discontinue protocol therapy (“refuses
treatment”), the subject should be asked if she or he may still be contacted for
further scheduled study assessments. The outcome of that discussion should be
documented in both the medical records and in the eCRF.
•
A female subject becomes pregnant
•
Delays of greater than 4 weeks are prohibited without approval of the Sponsor.
Subjects will be removed from protocol therapy and the site investigator notified when 
any of the criteria listed above apply. The reason for discontinuation of protocol therapy 
will be documented on the electronic case report form (eCRF). 
6.3 
Study Withdrawal 
If a subject decides to withdraw from the study (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as 
possible. The treating investigator should contact the subject or a responsible relative by 
telephone or through a personal visit to establish as completely as possible the reason for 
the study withdrawal. A complete final evaluation at the time of the subject’s study 
withdrawal should be made with an explanation of why the subject is withdrawing from 
the study. If the reason for removal of a subject from the study is an adverse event, it will 
be recorded on the eCRF. 
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7. 
STUDY CALENDAR & EVALUATIONS 
Procedure 
Screening1 (≤ 28 days 
before 1st dose) 
Every Cycle (21 
days ± 3 days) 
Before cycle 3 
& cycle 5 
Before cycle 9 & then 
after every 4 cycles 
Post Treatment Safety 
Assessments6 
Follow-
Up10 
Informed consent and 
medical history 
X 
 
 
 
 
 
Patient Registration 
X 
 
 
 
 
 
Brentuximab vedotin 
administration2 
 
X 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
Physical exam3, vital signs 
X 
X 
 
 
X 
 
Serum AFP and beta-hCG 
X 
X 
 
 
X 
X12 
CBC (differential & 
platelets) 
X 
X4,11 
 
 
X 
 
Complete metabolic panel  
X 
X4 
 
 
X 
 
Magnesium and 
phosphorus 
X 
X4 
 
 
X 
 
Pregnancy test5 
X 
X 
 
 
X 
 
Concomitant medications 
X 
X 
 
 
X 
 
Adverse event monitoring7 
 
X 
 
 
X 
 
Radiologic evaluations8 
X 
 
X 
X 
 
X12 
Archival tissue9 
X 
 
 
 
 
 
Survival 
 
 
 
 
 
X 
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Footnotes: 
1 
All procedures are to be performed ≤ 28 days prior to study drug administration. Screening assessments may be used in place of the Cycle 1 
Day 1 assessments if performed within 7 days prior to the Day 1 visit. Standard of care procedures may be used for screening requirements 
if performed within 28 days prior to study drug administration.   
2 
Brentuximab vedotin is administered on Day 1 of each Cycle. First dose must be administered within 7 days of registration. 
3 
Complete physical exam to be performed within 28 days of first study drug administration (for screening requirements), Day 1 
Cycle 1 and at Final Safety Follow-up. At other time-points, a brief symptom-directed exam and ECOG performance evaluation are 
sufficient. At Screening, height is recorded and body surface area (BSA) calculated 
4 
Hematologic and chemistry parameters (including serum creatinine, AST, ALT, BUN, phosphate, bilirubin, calcium & magnesium) to be 
performed on Day -3 to Day 1 of every cycle. 
5 
Females of childbearing potential only. Pregnancy tests must be serum at screening and the post treatment safety assessment visit. Urine 
pregnancy tests are required on Day 1 of each Cycle. A positive urine pregnancy test must be confirmed by a serum pregnancy test and a 
pelvic US since some NSGCT can secrete beta-hCG. A pelvic US does not need to be repeated with each cycle unless the treating physician 
thinks it is necessary to do so. 
6 
The post-treatment safety assessment will be done 21 ± 7 days after the last dose of study drug. 
7 
All SAEs should be collected from C1D1 until the post-treatment safety assessment. SAEs related or possibly related to study treatment 
or a study procedure should be reported until the patient is off study. Any death occurring within 30 days after study treatment discontinuation 
must be reported as an SAE regardless of attribution. 
8 
Appropriate radiographic diagnostic procedures (CT scan of chest, abdomen & pelvis) for evaluation of measurable disease at baseline within 
28 days of initiation of the study. CT scans and Chest X-ray will be performed as clinically indicated to follow disease per RECIST 
1.1. A confirmation CT scan of response will be performed per RECIST as outlined in the protocol. Patients will be followed for progression 
every 2 months ± 2 weeks for first year from registration. NOTE: existing scans that are no older than 30 days may be used for the screening 
scan. RECIST 1.1 Guidelines will be used to evaluate response (see Section 9.0). 
9 
Previous surgical specimens or biopsy samples will be collected for CD30 staining. If none is available, the patient will be offered a repeat 
biopsy to determine CD30 status. 
10 Follow up for disease progression and survival will be every 2 months ± 2 weeks for first year from registration. Patients who have progressed 
will be followed for resolution of all study related toxicity. 
11 CBC should be done between Day 8 and Day 15 of Cycle 1. This lab can be done locally with results faxed to the study team. Detailed 
instructions and orders will be provided to patients. 
12 This will be documented for all patients whenever possible as some patients will not have this information available. 
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7.1 
Screening Evaluations 
 Within 28 days prior to registration for protocol therapy 
• Informed consent 
• Study eligibility per inclusion/exclusion criteria 
• Medical history and prior disease therapies including ECOG performance status 
• Vital signs including height, weight, blood pressure, temperature, pulse and BSA 
• Physical examination including testicular examination if appropriate 
• Complete blood counts (CBC) with differential 
• Chemistry panel (CMP) including serum creatinine, AST, ALT, BUN, phosphate, 
bilirubin, calcium & magnesium 
• Tumor marker measurements including serum alpha-fetoprotein (AFP) and beta 
human chorionic gonadotropin (BHCG) 
• Serum pregnancy test for women of childbearing potential 
• Concomitant medication use 
• Appropriate radiographic diagnostic procedures (for example CT scan of chest, 
abdomen & pelvis) for evaluation of measurable disease at baseline within 28 
days of initiation of the study. NOTE: Existing scans that are no older than 30 
days may be used for the screening scan. 
• Previous surgical specimens or biopsy samples will be collected for CD30 
staining. If none are available, the patient will be required to do a repeat biopsy to 
determine CD30 status. 
7.2 
On Treatment Evaluations 
 Cycle 1 Day 1 
• Complete physical examination including testicular examination if appropriate 
• ECOG performance status 
• Vital signs including weight, blood pressure, temperature and pulse 
• Complete blood counts with differential 
• Chemistry panel including serum creatinine, AST, ALT, BUN, phosphate, 
bilirubin, calcium & magnesium 
• Tumor marker measurements including serum alpha-fetoprotein (AFP) and beta 
human chorionic gonadotropin (BHCG) 
• Urine pregnancy test for women of childbearing potential 
• Concomitant medication use 
• Adverse Event Assessment 
 Cycle 1 Day 8 (+7 days) 
• Complete blood counts with differential 
 Cycle 2 Day 1 and all subsequent cycles 
• Symptom-directed physical examination including testicular examination if 
appropriate 
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•
ECOG performance status
•
Vital signs including weight, blood pressure, temperature and pulse
•
Complete blood counts with differential
•
Chemistry panel including serum creatinine, AST, ALT, BUN, phosphate,
bilirubin, calcium & magnesium
•
Tumor marker measurements including serum alpha-fetoprotein (AFP) and beta
human chorionic gonadotropin (BHCG)
•
Urine pregnancy test for women of childbearing potential
•
Concomitant medication use
•
Adverse Event Assessment
Before cycle 3 & cycle 5 (D-7 to D1)
•
Appropriate radiographic diagnostic procedures (CT scan of chest, abdomen &
pelvis) for assessment of response per RECIST 1.1 criteria. Assessments should
be the same modality as used for screening.
Before cycle 9 & then after every 4 cycles (D-7 to D1)
•
Appropriate radiographic diagnostic procedures (CT scan of chest, abdomen &
pelvis) for assessment of response per RECIST 1.1 criteria. Assessments should
be the same modality as used for screening.
7.3 
Post Treatment Safety Assessment 
Subjects discontinued from the treatment phase of the study for any reason will be 
evaluated 21 days (± 7) after the last dose of study drug.  This visit should include the 
following: 
•
Complete physical examination
•
ECOG performance status
•
Vital signs including weight, blood pressure, temperature and pulse
•
Complete blood counts with differential
•
Chemistry panel including serum creatinine, AST, ALT, BUN, phosphate,
bilirubin, calcium & magnesium
•
Tumor marker measurements including serum alpha-fetoprotein (AFP) and beta
human chorionic gonadotropin (BHCG)
•
Serum pregnancy test for women of childbearing potential
•
Concomitant medication use
•
Adverse Event Assessment
7.4 
Long Term Follow-up Evaluations 
Patients who achieve a complete remission and are off treatment will be followed every 2 
months ± 2 weeks for first year from date of registration. Follow up visits will be done 
per institutional standard of care. Patients who are discontinued from the treatment for 
other reasons and are not in remission will be followed for long-term survival and 
subsequent therapy. 
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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
 Source and Timing of Biospecimen Collections 
Archival tumor tissue will be collected (orchiectomy and metastatic tumor) if available, 
and a fresh biopsy of tumor if archival tissue is not available will be attempted, for 
assessment of CD30 expression using immunohistochemistry with anti-CD30 BerH2. All 
tissues will be sent to the Indiana University Simon Cancer Center Clinical Trials Office 
Laboratory, 535 Barnhill Dr., RT 355, Indianapolis, Indiana, 46202 where it will be 
catalogued, and then transferred to the Department of Pathology and Laboratory 
Medicine at IU Health for IHC by Dr. Liang Cheng. The CD30 results from the original 
archival tissue pathology report will also be collected. 
Please see Study Procedure Manual for additional processing and shipping information. 
 Storage of Biospecimens 
Any remaining specimens will be stored for future research.  
 
9. 
CRITERIA FOR DISEASE EVALUATION 
Patients will be assessed every cycle by physical examination for response for disease 
progression and by serum AFP and beta-hCG. Patients will have appropriate radiographic 
diagnostic procedures (CT scan of chest, abdomen and pelvis) for evaluation of 
measurable disease at baseline within 28 days of initiation of the study. Imaging can be 
repeated if required to evaluate the disease (i.e. no elevation of serum tumor markers) 
before cycle 3, 5 and then every 4 cycles thereafter, at completion of treatment or 
as clinically indicated. Patients with stable disease or partial or complete response will 
be eligible for continued therapy. 
9.1 
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) will be 
used as follows: 
 Measurable disease: 
Lesions that can be accurately measured in at least one dimension 
with longest diameter >20 mm using conventional techniques or >10 
mm with spiral CT scan. 
 Malignant lymph nodes: 
To be considered pathologically enlarged and measurable, a lymph node 
must   be 
>15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
 Non-measurable disease: 
All other lesions (or sites of disease), including small lesions (longest 
diameter 
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<10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonis, inflammatory breast disease, and abdominal masses (not 
confirmed and followed by CT or MRI), are considered non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non- measurable) since they are, by definition, simple 
cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
9.2 
Methods for Evaluation of Measurable Disease: 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed within 28 days before the 
beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Clinical lesions will 
only be considered measurable when they are superficial (e.g., skin nodules and palpable 
lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
9.3 
Methods of Measurement: 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Baseline documentation of “Target” and “Non-Target” lesions: 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, 
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but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will 
be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
9.4 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression 
of each should be noted throughout follow-up. 
9.5 
Response Criteria 
Evaluation of target lesions or serum tumor biomarker 
Complete Response (CR): 
Disappearance of all target and normalization of serum tumor 
markers (AFP and beta-hCG) for at least 4 weeks. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. Complete Response must be 
confirmed four or more weeks after initial CR is observed. 
In patients whose only evidence of disease is elevated serum tumor 
markers (AFP or beta-hCG), then values must fall below the 
upper limit of normal for the assay employed and remain at that 
level for at least 4 weeks. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. This 
should be present on at least 2 measurements 1 month apart. The 
serum tumor markers (AFP and beta-hCG) should be stable or 
decreasing. Partial Response must be confirmed four or more 
weeks after initial PR is observed. 
In patients whose only evidence of disease is elevated serum tumor 
markers (AFP or beta-hCG), then values must fall ≥ 90% below 
baseline pretreatment levels for beta-hCG or 50% decrease below 
baseline pretreatment levels for AFP and persist for 6 weeks. If 
both tumor markers are elevated and one falls below 90% the other 
should fall at least below 50% of baseline pretreatment levels. 
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Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study); in addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm OR the appearance of one or more new 
lesions OR unequivocal progression of non-target or non-
measurable lesions (e.g. worsening bone pain requiring radiation or 
significant increase in pain medications) OR increase ≥ 50% in 
serum tumor markers AFP or beta-hCG in 2 samples at least 1 week 
apart compared to nadir values 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study AND/OR stable serum tumor markers, 
or change that does not qualify as CR, PR or progressive disease. 
To be assigned a status of stable disease, measurements must have 
met the stable disease criteria at least once after study entry at a 
minimum interval (in general, not less than 6-8 weeks). 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis). 
Note: If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the 
normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the Principal Investigator. 
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Note: In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the complete response status. 
9.6 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). In general, the patient’s best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. Overall responses for all possible combinations of tumor responses 
in target and non-target lesions are summarized below 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks.
Confirmation** 
CR 
Non-CR/ 
Non-PD 
No 
PR 
>4 wks.
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/ 
Non-PD/ 
not evaluated 
No 
PR 
SD 
Non-CR/ 
Non-PD/ 
not evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline**
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
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*
See RECIST 1.1 manuscript for further details on what is evidence of a new
lesion.
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
9.7 
Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it should 
be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate. 
In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval (in general, not less than 6-8 weeks) that is 
defined in the study protocol. 
9.8 
Duration of follow-up: 
All patients, including those who discontinue protocol therapy early, will be followed for 
disease progression, and survival until death. Follow up for disease progression and 
survival will be every 2 months ± 2 weeks for the first year from the date of registration, 
every 4 months ± 2 weeks during year 2, and every 6 months ± 4 weeks for years 3-5. 
Patients who progress will be followed for resolution of all study related toxicity. 
9.9 
Definitions of Response Evaluation: 
Progression-Free Survival Time 
Definition: A measurement from the start of the treatment until death or 
criteria for disease progression are met. Surviving patients without progression 
are treated as censored at last date known alive. 
Overall Survival Time 
Definition: A measurement from the start of the treatment until death. Patients 
surviving are treated as censored at last date known alive. 
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Time to Remission 
Definition: A measurement from the start of the treatment until the confirmed 
criteria for disease remission (PR + CR) are met. Patients not in remission are 
treated as censored at last date known alive. 
Duration of Remission (Among Remitters, PR + CR) 
Definition: A measurement from the earliest time when confirmed remission 
criteria are met until death or progression. Patients continuing in remission at 
the end of the study are treated as censored. 
Follow-Up Time 
Definition: The time from start of treatment until last date known alive among 
surviving patients with patients considered censored at death. 
10.
DRUG INFORMATION
Please refer to the latest version of the Investigator’s Brochure (IB), provided as a
document separate from this protocol.
10.1 
Brentuximab vedotin 
Brentuximab vedotin is a sterile, preservative-free, white to off-white lyophilized cake or 
powder supplied by Seattle Genetics in single-use vials for reconstitution for IV 
administration. Each vial of the product contains brentuximab vedotin (SGN-35), 
trehalose, sodium citrate, and polysorbate 80.  
10.2 
Clinical pharmacology 
 Mechanism of Action  
Brentuximab vedotin is an ADC. The antibody is a chimeric IgG1 directed against CD30. 
The small molecule, MMAE, is a microtubule disrupting agent. MMAE is covalently 
attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity 
of brentuximab vedotin is due to the binding of the ADC to CD30-expressing cells, 
followed by internalization of the ADC-CD30 complex, and the release of MMAE via 
proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network 
within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells.  
 Pharmacodynamics  
QT/QTc Prolongation Potential  
The effect of brentuximab vedotin (1.8 mg/kg) on the QTc interval was evaluated in an 
open-label, single-arm study in 46 evaluable patients with CD30-expressing hematologic 
malignancies. Administration of brentuximab vedotin did not prolong the mean QTc 
interval >10 ms from baseline. Small increases in the mean QTc interval (<10 ms) cannot 
be excluded because this study did not include a placebo arm and a positive control arm.  
 Pharmacokinetics  
The pharmacokinetics of brentuximab vedotin were evaluated in phase 1 trials and in a 
population pharmacokinetic analysis of data from 314 patients. The pharmacokinetics of 
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three analytes were determined: the ADC, MMAE, and total antibody. Total antibody had 
the greatest exposure and had a similar PK profile as the ADC. Hence, data on the PK of 
the ADC and MMAE have been summarized.  
Absorption  
Maximum concentrations of ADC were typically observed close to the end of infusion. A 
multiexponential decline in ADC serum concentrations was observed with a terminal 
half-life of approximately 4 to 6 days. Exposures were approximately dose proportional 
from 1.2 to 2.7 mg/kg. Steady-state of the ADC was achieved within 21 days with every 
3-week dosing of brentuximab vedotin, consistent with the terminal half-life estimate. 
Minimal to no accumulation of ADC was observed with multiple doses at the every 3-
week schedule.  
The time to maximum concentration for MMAE ranged from approximately 1 to 3 days. 
Similar to the ADC, steady-state of MMAE was achieved within 21 days with every 3 
week dosing of brentuximab vedotin. MMAE exposures decreased with continued 
administration of brentuximab vedotin with approximately 50% to 80% of the exposure 
of the first dose being observed at subsequent doses.  
Distribution  
In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%. MMAE 
is not likely to displace or to be displaced by highly protein-bound drugs. In vitro, 
MMAE was a substrate of P-gp and was not a potent inhibitor of P-gp.16  
In humans, the mean steady state volume of distribution was approximately 6–10 L for 
ADC.  
Metabolism  
In vivo data in animals and humans suggest that only a small fraction of MMAE released 
from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE 
metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using 
human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP 
isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of 
human hepatocytes.  
Elimination  
MMAE appeared to follow metabolite kinetics, with the elimination of MMAE appearing 
to be limited by its rate of release from ADC. An excretion study was undertaken in 
patients who received a dose of 1.8 mg/kg of brentuximab vedotin. Approximately 24% 
of the total MMAE administered as part of the ADC during a brentuximab vedotin 
infusion was recovered in both urine and feces over a 1-week period. Of the recovered 
MMAE, approximately 72% was recovered in the feces and the majority of the excreted 
MMAE was unchanged. 
10.3 
Supplier 
Brentuximab vedotin will be supplied by Seattle Genetics. Please see Study Procedures 
Manual for instructions on ordering initial and subsequent drug supply shipments. 
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10.4 
Preparation  
Brentuximab vedotin vials are provided via single-use containers. Any partially used 
vials or diluted dosing solutions should be discarded using appropriate institutional drug 
disposal procedures. 
 
Brentuximab vedotin should be reconstituted with the appropriate amount of Sterile 
Water for Injection, United States Pharmacopeia (USP) (or equivalent; see Pharmacy 
Manual for details). 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 required volume of reconstituted drug product should be transferred to an infusion 
bag. There are no known incompatibilities between brentuximab vedotin and 
polyvinylchloride (PVC) ethylene vinyl acetate (EVA), polyolefin, or polyethylene bags. 
The reconstituted drug product should be diluted (see Pharmacy Manual for details) and 
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. 
 
Detailed drug preparation instructions are provided in the Pharmacy Manual. 
10.5 
Storage and Handling 
Refrigeration should be set at 2-8°C for storage of vials and solutions containing 
brentuximab vedotin. The controlled location must be accessible only to the pharmacist, 
the investigator, or a designated person. Brentuximab vedotin (SGN-35) for Injection 
does not contain preservatives; therefore, from a microbiological standpoint, opened and 
reconstituted vials of brentuximab vedotin should be used immediately. If not used 
immediately, the in-use storage should not be longer than 24 hours. It is recommended 
that brentuximab vedotin vials and solutions be stored protected from direct sunlight until 
the time of use. Reconstituted vials must not be shaken.  
 
Drug accountability instructions are provided in the Study Procedures Manual. 
10.6 
Packaging and Labeling 
Vialed drug product may be labeled as brentuximab vedotin, the United States adopted 
name (USAN) and the International Nonproprietary Name (INN), or as SGN-35, the 
compound code; the 2 names can be used interchangeably. 
10.7 
Dispensing 
Brentuximab vedotin must be dispensed only from official study sites and to eligible 
subjects under the supervision of the site investigator. Brentuximab vedotin should be 
stored in a secure area according to local regulations.  It is the responsibility of the site 
investigator to ensure that study drug is only dispensed to subjects. 
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10.8 
Adverse Events 
The following serious adverse reactions are discussed in greater detail in other sections 
of the prescribing information: 
• Peripheral Neuropathy [see Warnings and Precautions (10.9.1)] 
• Anaphylaxis and Infusion Reactions [see Warnings and Precautions (10.9.2] 
• Hematologic Toxicities [see Warnings and Precautions (10.9.3)] 
• Serious Infections and Opportunistic Infections [see Warnings and Precautions 
(10.9.4)] 
• Tumor Lysis Syndrome [see Warnings and Precautions (10.9.5)] 
• Increased Toxicity in the Presence of Severe Renal Impairment [see 
Warnings and Precautions (10.9.6)] 
• Increased Toxicity in the Presence of Moderate or Severe Hepatic 
Impairment [see Warnings and Precautions (10.9.7)] 
• Hepatotoxicity [see Warnings and Precautions (10.9.8)]) 
• Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions 
(10.9.9)] 
• Pulmonary Toxicity [see Warnings and Precautions (10.9.10)] 
• Serious Dermatologic Reactions [see Warnings and Precautions (10.9.11)] 
• Embryo-Fetal Toxicity [see Warnings and Precautions (10.9.12)] 
 
Please refer to the most current IB or package insert(s) for the comprehensive list of 
adverse events. 
10.9 
WARNINGS AND PRECAUTIONS 
 Peripheral Neuropathy 
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. 
Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced 
peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of 
patients experienced any grade of neuropathy. Of these patients, 49% had complete 
resolution, 31% had partial improvement, and 20% had no improvement.  Of the 
patients who reported neuropathy, 51% had residual neuropathy at the time of their last 
evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, 
hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or 
weakness. Patients experiencing new or worsening peripheral neuropathy may require a 
delay, change in dose, or discontinuation of ADCETRIS [see Dose Modification (6.1)]. 
 Anaphylaxis and Infusion Reactions 
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. 
Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently 
discontinue administration of ADCETRIS and administer appropriate medical therapy. 
If an infusion-related reaction occurs, the infusion should be interrupted and appropriate 
medical management instituted. Patients who have experienced a prior infusion-related 
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reaction should be premedicated for subsequent infusions. Premedication may include 
acetaminophen, an antihistamine, and a corticosteroid. 
 Hematologic Toxicities 
Prolonged (≥1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or 
anemia can occur with ADCETRIS. Febrile neutropenia has been reported with 
treatment with ADCETRIS. Complete blood counts should be monitored prior to each 
dose of ADCETRIS and more frequent monitoring should be considered for patients 
with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia 
develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with 
subsequent ADCETRIS doses [see Dose Modification (6.1)]. 
 Serious Infections and Opportunistic Infections 
Serious infections and opportunistic infections such as pneumonia, bacteremia, and 
sepsis or septic shock (including fatal outcomes) have been reported in patients treated 
with ADCETRIS. Patients should be closely monitored during treatment for the 
emergence of possible bacterial, fungal, or viral infections. 
 Tumor Lysis Syndrome 
Patients with rapidly proliferating tumor and high tumor burden may be at increased 
risk of tumor lysis syndrome.  Monitor closely and take appropriate measures. 
 Increased Toxicity in the Presence of Severe Renal Impairment 
The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with 
severe renal impairment compared to patients with normal renal function. Due to 
higher MMAE exposure, ≥Grade 3 adverse reactions may be more frequent in patients 
with severe renal impairment compared to patients with normal renal function. Avoid 
the use of ADCETRIS in patients with severe renal impairment [creatinine clearance 
(CLcr) <30 mL/min]. 
 Increased Toxicity in the Presence of Moderate or Severe Hepatic 
Impairment 
The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with 
moderate and severe hepatic impairment compared to patients with normal hepatic 
function. Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or 
severe (Child-Pugh C) hepatic impairment. 
 Hepatotoxicity 
Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients 
receiving ADCETRIS. Cases were consistent with hepatocellular injury, including 
elevations of transaminases and/or bilirubin. Cases have occurred after the first dose of 
ADCETRIS or after ADCETRIS rechallenge. Preexisting liver disease, elevated 
baseline liver enzymes, and concomitant medications may also increase the risk. 
Monitor liver enzymes and bilirubin. 
Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, 
change in dose, or discontinuation of ADCETRIS. 
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 Progressive Multifocal Leukoencephalopathy 
JC virus infection resulting in PML and death has been reported in ADCETRIS-treated 
patients. In addition to ADCETRIS therapy, other possible contributory factors include 
prior therapies and underlying disease that may cause immunosuppression. Consider the 
diagnosis of PML in any patient presenting with new-onset signs and symptoms of central 
nervous system abnormalities. 
Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS 
dosing if a diagnosis of PML is confirmed. 
 Pulmonary Toxicity 
Pulmonary toxicity has been reported in patients receiving ADCETRIS. A causal 
association with single-agent ADCETRIS has not been established. In the event of new 
or worsening pulmonary symptoms (e.g., cough, dyspnea), perform a prompt diagnostic 
evaluation and institute appropriate medical therapy. 
 Serious Dermatologic Reactions 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal 
outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue 
ADCETRIS and administer appropriate medical therapy. 
 Embryo-Fetal Toxicity 
There are no adequate and well-controlled studies of ADCETRIS in pregnant women. 
However, based on its mechanism of action and findings in animals, ADCETRIS can 
cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused 
embryo-fetal toxicities, including significantly decreased embryo viability and fetal 
malformations, in animals at maternal exposures that were similar to human exposures at 
the recommended doses for patients with HL and sALCL. If this drug is used during 
pregnancy, or if the patient becomes pregnant while receiving the drug, the patient 
should be apprised of the potential hazard to the fetus. 
11. 
ADVERSE EVENTS 
11.1 
Definitions of Adverse Events 
11.1.1 Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. An adverse 
event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of a drug, without any judgment about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, 
use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. Adverse events will be graded 
according to the NCI Common Toxicity Criteria, Version 4.0 (Appendix I). 
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11.1.2 Suspected Adverse Reaction (SAR) 
Suspected adverse reaction is any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. Suspected adverse reactions are the 
subset of all adverse events for which there is a reasonable possibility that the drug 
caused the event. 
 
Examples of types of evidence that would suggest a causal relationship between the 
drug and the adverse event: 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to the 
drug (e.g., tendon rupture). 
• An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical 
control group. 
11.1.3 Adverse Reaction (AR) 
An adverse reaction is any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions where there is reason to conclude that the 
drug caused the event. 
11.1.4 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if it results 
in any of the following outcomes: 
• 
Results in death  
• 
Is life-threatening. Life-threatening is defined as an adverse event or 
suspected adverse reaction that places the subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death.  
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to first administration of study drug 
 Hospitalization for elective treatment of a pre-existing condition 
unrelated to the study medication 
• 
Results in persistent or significant disability/incapacity 
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•
Is a congenital anomaly or birth defect
•
Is an important medical event (defined as a medical event(s) that may not
be immediately life-threatening or result in death or hospitalization but,
based upon appropriate medical and scientific judgment, may jeopardize
the patient or may require intervention (e.g., medical, surgical) to prevent
one of the other serious outcomes listed in the definition above).
Examples of such events include, but are not limited to, intensive
treatment in an emergency room or at home for allergic bronchospasm;
blood dyscrasias or convulsions not resulting in hospitalization; or the
development of drug dependency or drug abuse.
Pregnancy 
•
Pregnancy of a patient or of the female partner of a male patient during
the study or within 30 days after the last dose of study drug should be
reported via an SAE report.  Should pregnancy occur in a female
participant during the treatment period, study drug should be
discontinued and Seattle Genetics notified immediately.  Should a
pregnancy occur in a female companion of a male participant during the
treatment period, the male participant can continue treatment and Seattle
Genetics notified immediately.  Any such pregnancy is to be followed
until final outcome.
11.1.5 Unexpected Adverse Event 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if 
the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral 
vascular accidents. "Unexpected," as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation.  
This definition relies entirely on the adverse events or suspected adverse reactions 
listed in the investigator brochure for the particular drug under investigation (or 
elsewhere in the general investigational plan if an investigator brochure is not 
required or available) as the basis for determining whether newly acquired 
information generated from clinical trials or reported from other sources is 
unexpected. This means that events not listed for the particular drug under 
investigation in the investigator brochure are considered “unexpected” and those 
listed are considered “expected.” When new adverse event information is 
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received, it is the sponsor’s responsibility to determine whether the event is 
“unexpected” for IND safety reporting purposes. In the clinical trial setting, there 
has been some confusion with the term “expected” as it has been used to mean 
“anticipated” for the disease being treated or population being studied rather than 
“listed in the investigator brochure.” For example, some adverse events can be 
anticipated to occur as a result of a disease or in an older population (e.g., cancer-
related deaths in a cancer trial, strokes or acute myocardial infarctions in an older 
population). However, for reporting purposes, these anticipated events are not 
“expected” because they are not listed in the investigator brochure (i.e., the test 
drug is not suspected or known to cause them). 
 
Adverse events listed in the investigator brochure as occurring with members of 
the same class of drugs, or as anticipated from the pharmacological properties of 
the drug, would be considered unexpected until they have been observed with the 
drug under investigation. For example, although angioedema is anticipated to 
occur in some patients exposed to drugs in the angiotensin-converting enzyme 
(ACE) inhibitor class and angioedema would be described in the investigator 
brochure as a class effect, a case of angioedema observed with the drug under 
investigation should be considered unexpected for reporting purposes until it is 
included in the investigator brochure as occurring with the drug under 
investigation. 
 
11.1.6 Determining Attribution to the Investigational Agent(s) 
Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE does not define an AE as necessarily “caused by a 
therapeutic intervention”. After naming and grading the event, the clinical 
investigator must assign an attribution to the AE using the following attribution 
categories: 
 
Relationship 
Attribution 
Description 
Unrelated to 
investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
11.2 
Adverse Event (AE) Reporting Requirements: 
 
Adverse events (AEs) will be recorded from the time of first study drug 
administration and for at least 30 days after treatment discontinuation, regardless 
of whether or not the event(s) are considered related to trial medications.  AEs 
occurring after the post-treatment safety assessment visit can be collected by 
telephone or other means of communication. All AEs considered related to trial 
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medication will be followed until resolution, return to baseline, or deemed 
clinically insignificant, even if this occurs post-trial. 
11.2.1 Participating Site Reporting Responsibilities 
11.2.1.1 
Reporting to the IU Simon Cancer Center 
Any serious adverse event or unanticipated problem occurring within 30 days of the 
last dose of study drug must be reported to the IU Simon Cancer Center within 1 
business day of notification or discovery of the incident, using the MedWatch Form 
3500A (Mandatory Reporting).  SAEs that occur greater than 30 days from last dose 
of study drug must be reported to the IU Simon Cancer Center if the event is possibly, 
probably, or definitely related to the study drug. This form must be accompanied by a 
cover letter which:  identifies the event, is signed by the local principal investigator or 
treating physician, includes the applicable study number and title, and contains the 
following: 
•
Site assessment of the event attribution to investigational product or study
procedure
•
Site assessment of event expectedness (expected vs. unexpected)
•
Assessment of whether or not the research places subjects at a greater risk of harm
than was previously known or recognized
•
Assessment of the event’s affect on the risk to benefit ratio
•
Statement as to whether the informed consent statement should reflect changes in
the potential risks involved
•
Statement as to whether the event has been reported previously, and if so, whether
the frequency is considered unusually high
Send to: 
IUSCC Clinical Trials Office 
ATTN: Multicenter coordinator/ IUSCC-0568 
Fax: (317) 274-8022 
E-mail: IUSCCSAE@iu.edu
The Multicenter Network Associate Administrator, or designee, will distribute the 
reports to all participating sites, the FDA and to Seattle Genetics as per section 11.2.2 
below. Copies of all serious adverse event reports or unanticipated problems reports 
will be kept on file in the IU Simon Cancer Center Clinical Trials Office. 
11.2.1.2 
Reporting to the IRB 
Each participating site will report adverse events and unanticipated problems to their 
IRB per local guidelines. Any event that requires expedited reporting to the local IRB 
will also be submitted to the IU Simon Cancer Center for distribution to the Funder.  
11.2.2 Coordinating Center Reporting Responsibilities 
In addition to the responsibilities above, the Coordinating Center will also be 
responsible for reporting events to the Funder and the FDA. 
11.2.2.1 
Reporting to Seattle Genetics 
SAEs 
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IUSCC will report to Seattle Genetics all SAEs that are sent to the FDA at the time of 
submission to the FDA. Follow-up information will be provided to Seattle Genetics as 
reasonably requested. Send SAE reports on the MedWatch Report Form to:  
Seattle Genetics Drug Safety  
Facsimile: (425) 527-4308 or (866) 333-6627 
Email: drug.safety@seagen.com 
A study-specific cumulative SAE line listing of all SAEs with assessment of causality 
to investigational product will be sent monthly to IST@seagen.com.  
Study Initiation 
IUSCC will provide the following to Seattle Genetics prior to initiation of Seattle 
Genetics support (provision of Product and/or funding): 
•
Final study protocol
•
Fully executed IST Agreement
•
Regulatory Response Documentation (IND or CTA documentation if applicable)
•
IRB/IEC approval
Study Maintenance
Throughout the study, IUSCC will provide the following to Seattle Genetics:
•
At least one safety study status update per year, to include information on
enrollment and study completion dates.
•
Notification of any amendment to the original protocol after the research has
begun; and immediate notification of any amendments made due to safety
reasons.
Study Closure 
IUSCC will provide Seattle Genetics a copy of the IND Annual Report. Upon study 
closure, IUSCC will certify that all safety reporting obligations were met. 
11.2.2.2 
Reporting to the FDA 
Per CFR 312.32 (c), the sponsor-investigator of the IND (Dr. Adra) must notify the 
Food and Drug Administration (FDA) and all participating investigators in a written 
IND safety report of any adverse experience that meets the criteria outlined below.  
There are two types of reports to the FDA: 7-day and 15-day reports. 
7-Day Reports:
The investigator-sponsor of the IND must notify the FDA and all participating 
investigators in a written IND safety report of any adverse experience: 
•
fatal or life-threatening experience that is both
•
suspected to be associated with use of the drug and
•
unexpected (as defined in 11.1.5)
The FDA will be notified as soon as possible but no later than 7 calendar days after 
the investigator-sponsor’s initial receipt of the information. 
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15-Day IND Reports:
The investigator-sponsor of the IND must notify the FDA and all participating
investigators in a written IND safety report of any adverse experience:
•
suspected to be associated with use of the drug that is both
•
serious and
•
unexpected  (as defined in 11.1.5)
The FDA will be notified as soon as possible but no later than 15 calendar days after 
the investigator-sponsor’s initial receipt of the information.   
Report Content: 
Each written notification may be submitted on FDA Form 3500A or in a narrative 
format and must bear prominent identification of its contents, i.e., “IND Safety 
Report”.  For purposes of this protocol, the MedWatch Report Form (FDA 3500A 
mandatory reporting), along with FDA Form 1571, and a cover letter submitted 
to the appropriate FDA division, will serve as the written IND safety report.  Follow-
up information to a safety report should be submitted as soon as the relevant 
information is available. Submit to the FDA: 
•
MedWatch Report Form (FDA 3500A)
•
FDA Form 1571
•
Cover Letter
Notify the FDA via phone or fax using MedWatch 3500A (mandatory reporting form) 
•
Phone: 1-888-463-6332, option #1
•
Fax: 1-800-FDA-0178
The IUSCC Protocol Development Coordinator should be contacted to assist with all 
FDA submissions and will be provided with a copy of all events that are reported to 
the FDA.  All IND submissions will be maintained in a master file in the Clinical 
Trials Office of the IU Simon Cancer Center. 
11.2.2.3 
Reporting to Participating Sites  
Seattle Genetics will send IND safety reports from external studies that involve the 
study drug to the Multicenter Network Associate Administrator, or designee. The 
Multicenter Network Associate Administrator, or designee, will forward the safety 
reports to the sponsor-investigator, or designee, who will review these reports and 
determine if revisions are needed to the protocol or consent. IUSCC will forward 
these reports to participating sites every 2 weeks.  
For IND safety reports originating from this study, IUSCC will distribute reports 
which are serious, unexpected and associated with the study intervention (possibly, 
probably or definitely related) to all participating sites in the form of an Expedited 
Safety Report (external safety/IND safety report) within 15 calendar days from 
determination that the suspected adverse reaction qualifies for reporting. Copies of 
these External Safety Reports will be kept on file in the IU Simon Cancer Center 
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Clinical Trials Office. Upon receipt from IUSCC, site investigators, or designees, are 
responsible for submitting these safety reports to their respective IRBs, as per their 
IRB policies. 
12. 
STATISTICAL METHODS 
12.1 
Study Design 
This is an open label, single agent, multicenter, phase II study with 2 cohorts evaluating 
the efficacy of brentuximab vedotin in “CD30 positive” and “CD30 negative/unknown” 
relapsed/refractory NSGCT who are otherwise considered non-curable.  Both cohorts will 
be treated similarly and in parallel but analyzed separately. 
12.2 
Endpoints 
 Definition of Primary Endpoint 
Objective response rate is the proportion of patients who achieve either a partial or 
complete response  
Complete response is defined as disappearance of all target lesions and normalization of 
serum tumor markers (AFP and beta-hCG) for at least 4 weeks. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Complete Response must be confirmed four or more weeks after initial CR is observed.  
In patients whose only evidence of disease is elevated serum tumor markers (AFP or 
beta-hCG), then values must fall below the upper limit of normal for the assay employed 
and remain at that level for at least 4 weeks. 
Partial response is defined as at least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. This should be present on at least 
2 measurements 1 month apart. The serum tumor markers (AFP and beta-hCG) should be 
stable or decreasing. Partial Response must be confirmed four or more weeks after initial 
PR is observed.  
In patients whose only evidence of disease is elevated serum tumor markers (AFP or 
beta-hCG), then values must fall ≥ 90% below baseline pretreatment levels for beta-hCG 
or 50% decrease below baseline pretreatment levels for AFP and persist for 6 weeks. If 
both tumor markers are elevated and one falls below 90% the other should fall at least 
below 50% of baseline pretreatment levels.  
 Definition of Secondary Endpoints 
Progression-free survival (PFS) is the time measured from the date of initiation of 
therapy until disease progression or death, whichever comes first. Patients alive and 
progression-free will be censored at their last disease assessment. 
 
Overall survival (OS) is the time measured from the date of initiation of therapy until 
death, regardless of cause. Patients alive at the time of data analysis will be censored at 
their last date of contact. 
12.3 
Sample Size and Accrual 
An optimal Simon two-stage design will be used for each cohort of patients to 
differentiate between the null hypothesis that the response rate P is ≤ 5% (P<=0.05) and 
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the alternative hypothesis that the response rate is ≥20% (P>=0.20). These values were 
chosen for both arms based on what is clinically relevant per the investigators’ 
experiences. There is no available data at this time for CD30-negative/unknown patients 
as brentuximab vedotin has not been tested for such patients. Under this design, the 
probability of early termination under the null hypothesis is 0.599. This design yields a 
type I error rate, α (probability of concluding that the drug is not effective when it is 
actually effective) of 0.047 and a power of 0.801 (type II error rate 0.199) when the true 
response rate is ≥20%. In the first stage in each cohort, 10 patients will be enrolled. If 
there are no objective responses, then that cohort will terminate. If ≥1 response is 
observed, then an additional 19 patients will be enrolled in the second stage for a total 
sample size of 29 patients per cohort. If 3 or fewer responses are observed out of the 29 
patients, then Brentuximab will be declared as not worthy of further study for that cohort. 
If ≥4 objective responses are achieved, then brentuximab vedotin will be deemed active 
in refractory/relapsed NSGCT and worthy of further study. 
We estimate enrolling 2 patients/month for the CD30 negative cohort and 1 patient/month 
for the CD30 positive patients. 
12.4 
Analysis Datasets 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study.  
Efficacy 
The efficacy population comprises all patients who have 
received at least one dose of the study medication. This 
population will be used for efficacy analysis. 
Safety 
The safety population comprises all patients who have 
received at least one dose of the study medication. This set 
will be used for safety analysis. 
12.5 
Assessment of Safety 
Toxicities will be assessed based on the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. The maximum grade of each toxicity will be recorded for each 
patient over the course of treatment (all cycles). Toxicities will be recorded up until 30 
days after the last day of treatment. The incidence of treatment delays, dose reductions, and 
early discontinuations of treatment due to toxicity or patient choice, will also be recorded 
as a means of assessing the tolerability of treatment for each cohort. 
12.6 
Assessment of Efficacy 
All subjects who have received at least one cycle of treatment and have their disease re-
evaluated will be evaluable for assessment of objective response using the criteria for 
response detailed in Section 9. 
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12.7 
Data Analysis Plans 
 Analysis Plans for Primary Objective 
The ORR and its 95% exact CI will be summarized by cohort using the F distribution 
method (Collett 1991). This endpoint may also be tabulated by covariates, such as sex, 
age, race, categorized weight, categorized disease burden at baseline, prior treatment, and 
performance status. The maximum percent reduction in the sum of the products of the 
largest diameters of the nodes or nodal masses being followed for response assessment 
will be graphically displayed. ORR by intensity and pattern of CD30 expression will be 
tabulated by cohort.  
Analysis Plans for Secondary Objectives 
•
Both PFS and OS will be estimates using the methods of Kaplan and Meier for each
cohort separately.
•
Toxicities will be summarized by by cohort using frequencies and rates calculated
as the proportion of patients in the safety population experiencing SAEs, and treatment
delays, reductions, and discontinuations due to AEs, and SAEs.  Two sets of tables will
be generated: one for the overall toxicities and one for toxicities related to the study
medication (possibly related, probably related and definitely related). Toxicities will be
grouped by system using MedRA preferred terminology. Grade 1 to 4 will be reported
individually and also as grade 3/4. Deaths will be reported individually.
Analysis Plans for Exploratory Objectives 
•
CD30 staining will be characterized by intensity (0 to 3+) and by localization (cell
wall vs. cytoplasmic) using descriptive statistics and correlated with objective response
using logistic regression and with PFS using proportional hazards regression.
12.8 
Interim Analysis/Criteria for Stopping Study 
Each cohort will be evaluated after 10 patients enroll on the study to that cohort. If no 
responses are seen then that cohort will be closed for lack of efficacy. 
13.
TRIAL MANAGEMENT
13.1 
Data and Safety Monitoring 
 Data Safety Monitoring Committee 
The Data Safety Monitoring Committee (DSMC) of the Indiana University Simon Cancer 
Center (IUSCC) is responsible for patient safety and privacy protection, compliance with 
required reporting, and study integrity for all trials conducted at IUSCC. Members are 
subject matter experts from multiple disciplines including medical oncology, pediatrics, 
biostatistics, behavioral oncology, radiation oncology, urology, surgery, gynecologic 
oncology, data and project management and research administration who are appointed by 
the DSMC Chair. The DSMC will provide independent oversight of the clinical trial so 
that study integrity is assured. However, the DSMC is not serving as a Data and Safety 
Monitoring Board (DSMB) for this study. The DSMC will meet per the currently approved 
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DSMP, led by the DSMC Chair and Coordinator, and will review all adverse events, 
monitoring and auditing reports, unanticipated problems and study non-compliance events 
that require expedited reporting.  Meeting minutes will be maintained in the IUSCC 
Clinical Trials Office (CTO). Specifically the DSMC has the following responsibilities:  
• Assessment of the adequacy of trial-specific Data Monitoring and Safety Plan 
(DSMP) of studies that are not subject to external monitoring, including 
investigator initiated studies, and establish risk based monitoring determination 
of trial specific DSMB. 
• Review safety data for investigator initiated trials including all adverse events, 
unanticipated problems and study non-compliance events requiring expedited 
reporting. 
• Conduct routine study monitoring and auditing in compliance with the IUSCC 
data quality control review process.  
  Data Safety Monitoring Plan 
This trial will comply with the current requirements of the Data and Safety Monitoring 
Plan (DSMP) of the IUSCC.  The CTO of the IUSCC will be the Coordinating Center for 
this multicenter phase 2 trial.  
In accordance with the DSMP of the IUSCC, investigators will conduct continuous review 
of data and patient safety. Monthly review meetings for Phase 2 trials are required and will 
include the:  principal investigator, clinical research specialist, and/or research nurse data 
manager and/or study coordinator, and other members as per the principal investigator’s 
discretion. In addition, conference calls with investigators and staff at participating sites 
will be scheduled at least monthly (and more often as needed) to discuss study progress. 
If there are no patients on treatment or in follow-up, email communication will be used in 
lieu of a teleconference. Monthly meeting summaries will include and document review 
of data and patient safety by including for each dose level:  the number of patients, 
significant toxicities as described in the protocol, dose adjustments, responses observed, 
eligibility of patients enrolled at each site, serious adverse events (SAEs) or unanticipated 
problems (UPs) (both IUSCC and those reported from other institutions), dose adjustments, 
and protocol deviations.  Meeting minutes will be submitted and reviewed by the DSMC.  
• Study Auditing and Monitoring: All trials are subject to auditing and/or 
monitoring per the currently approved DSMC Charter. 
• Reporting Guidelines: The DSMC has streamlined the reporting process by 
utilizing reports from OnCore®. This has allowed the direct view of reports within 
the Clinical Trial Management System (CTMS); thus discontinuing paper reports. 
SAE reports are entered into OnCore® and reviewed by the DSMC chair and/or 
coordinator monthly. Findings will be reported to the full DSMC at the time of 
study review. 
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• Reporting Death: Death will be captured in the Case Report Form and reported 
per local IRB reporting guidelines. 
• Study Accrual Oversight: Accrual data will be entered into the IU Simon Cancer 
Center OnCore® system. The Protocol Progress Committee (PPC) reviews study 
accrual twice per year while the PPC coordinator reviews accrual quarterly.  
• Continuing Review: All Continuing Reviews (CR) will be reviewed annually or 
as dictated by the Institutional Review Board.  Participating sites will submit a copy 
of the CR with attachments to the IUSCC Multicenter Network Associate 
Administrator, or designee. 
• Protocol Deviations: Investigators are required to submit protocol deviations to 
the DSMC via the OnCore® database.  
• Early Study Closure: At any time during the conduct of the trial, if it is the opinion 
of the investigators that the risks (or benefits) to the patient warrant early closure 
of the study, this recommendation should be made in writing to the DSMC.  
Alternatively, the DSMC may initiate suspension or early closure of the study based 
on its review. 
  Data Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB) that will review and 
monitor study progress, toxicity, safety and other data from this trial. The board is 
chaired by an independent medical oncologist or another qualified individual external to 
this trial. Questions about participant safety or protocol performance will be addressed 
with the Principal Investigator, statistician and study team members. Should any major 
concerns arise, the DSMB will offer recommendations regarding whether or not to 
suspend the trial.  
The DSMB will meet once a year to review accrual, toxicity, response and other 
information reported to the IRB. Information to be provided to the DSMB may include: 
participant accrual, treatment regimen information, adverse events and serious adverse 
events reported by category, summary of any deaths on study, audit and/or monitoring 
results.  
The DSMB will provide a written recommendation to the PI and team after all 
information is reviewed. The report will indicate one or more of the following decisions:  
• Continuation of the trial without change 
• Continuation of protocol/project with modifications as outlined by the Board 
• Immediate suspension of trial for safety reasons with recommended plan of 
follow up to minimize subject harm 
• Study placed on clinical hold  
• Termination of trial 
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The IUSCC will submit the DSMB report(s) to the participating sites as well. The DSMB 
report(s) should be provided to the local IRB at the time of continuing review. 
  Data Acquisition  
Case Report Forms and Data Submission: This study will utilize electronic Case 
Report Form completion in the OnCore® database. A calendar of events and required 
forms are available in OnCore® at https://cancer.iu.edu/oncore. The OnCore® database 
is a comprehensive database used by the IUSCC CTO and supported by the Indiana 
University Cancer Center. Access to data through OnCore® is restricted by user accounts 
and assigned roles. Once logged into the OnCore® system with a user ID and password, 
OnCore® defines roles for each user which limits access to appropriate data.   
All source documents are to remain in the patient’s clinic file. All documents should be 
kept according to applicable federal guidelines. Clinical trial data in OnCore® are 
periodically monitored by the IU Simon Cancer Center per the DSMC Charter.  
13.2 
Changes to the Protocol and Informed Consent 
Study procedures will not be changed without the mutual agreement of the sponsor-
investigator and Seattle Genetics. Except for an emergency situation in which proper care 
for the protection, safety, and well-being of the study subject requires alternative 
treatment, the study shall be conducted exactly as described in the approved protocol. 
 Emergency Modifications 
Site investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IUSCC or their respective 
institution’s IRB approval. As soon as possible after the modification has been made, the 
implemented deviation or change and the reasons for it should be submitted to IUSCC, 
and to the site’s IRB for review and approval. 
 Other Protocol Deviations/Violations 
If a deviation or violation occurs, the deviation should be reported in OnCore®. Any 
protocol violation that occurs must be reported to the IRB per institutional policies and 
reported to IUSCC as soon as possible. IUSCC will determine if the violation affects the 
safety of the study subject and integrity of the data. 
 Amendments 
If it is necessary for the study protocol to be amended, the amended protocol will be 
generated by IUSCC and must be approved by the sponsor-investigator, Seattle Genetics 
prior to implementation (IST@seagen.com), the FDA (if applicable), and each site’s IRB. 
If applicable, also the local regulatory authority. Local requirements must be followed. 
The site investigator is responsible for the distribution of these documents to his or her 
IRB, and to the staff at his or her center. The distribution of these documents to the 
regulatory authority will be handled according to local practice. 
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Seattle Genetics willingness to supply study drug is predicated upon the review of the 
protocol. IUSCC agrees to provide written notice to and approval from Seattle Genetics 
of any modifications to the protocol prior to implementation. 
14. 
MULTICENTER GUIDELINES 
14.1 
 Study Documents 
Each participating site must submit regulatory documents (informed consents, 1572s, 
Financial Disclosures, IRB approval documents, Continuing Reviews, Amendments, 
patient brochures or recruitment material etc.) to the Coordinating Center. The 
Coordinating Center will provide each site with a comprehensive list of the required 
documents prior to study start-up, throughout the duration of the study and upon study 
close-out. It is the responsibility of the participating site to maintain copies of all 
documentation sent to the Coordinating Center. 
14.2 
 Study Initiation  
Before activating the clinical trial at each participating site, the IUSCC CTO Multicenter 
Network Associate Administrator, or designee will ensure that: 
• Full Institutional Review Board (IRB) approval has been obtained.  
• Research staff at the participating site has been trained in data entry into 
OnCore®  
• A start-up meeting with each institution has taken place via telephone 
conference. The start-up meeting will cover protocol details (including 
eligibility criteria, treatment plan, etc.), responsibilities of the participating 
investigators, and reporting procedures. 
• A financial conflict of interest statement from each investigator has been 
obtained. 
14.3 
 Patient Enrollment 
After eligibility is confirmed by the participating site staff, a completed eligibility 
checklist, supporting source documentation, and signed consent will be sent to IUSCC for 
verification.  The Multicenter Network Associate Administrator, or designee, will assign 
the patient a study number and return the enrollment information to the site.  The site 
staff will then register the patient in OnCore®. Additional details of this process can be 
found in the Study Procedure Manual.   
14.4 
 Data Monitoring 
All multicenter investigator initiated trials conducted at the IUSCC are subject to data 
monitoring by the Multicenter Network Associate Administrator, or designee. External 
sites will be notified of upcoming monitoring visits and will be expected to provide the 
Multicenter Network Associate Administrator, or designee, with de-identified source 
documents for remote monitoring of patients. Queries will be issued in OnCore® and a 
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detailed monitoring report will be provided to the participating site.  The IUSCC will also 
forward any monitoring and/or auditing reports to the DSMC.  
When a patient enrolled on this trial, or the trial itself, is selected for local monitoring or 
auditing, the participating site will forward the results to the Multicenter Network 
Associate Administrator, or designee. In addition, if a participating site patient is selected 
for local auditing by the IUSCC DSMC, the site will be responsible for sending IUSCC 
de-identified source documents.  
14.5 
 Record Retention 
All documentation of adverse events, records of study drug receipt, dispensation, 
destruction, and all IRB correspondence will be stored in accordance with all applicable 
federal guidelines. 
Following closure of the study, each participating site will maintain a copy of all site 
study records in a safe and secure location. The Coordinating Center will inform the 
investigator at each site at such time that the records may be destroyed. 
15. 
ETHICS 
15.1 
Institutional Review Board (IRB) Review 
The final study protocol and the final version of the informed consent form must be 
approved in writing by an IRB. The site investigator must submit written approval by the 
IRB to IUSCC before he or she can enroll subjects into the study. 
 
The site investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by 
the IRB as local regulations require.  
 
Progress reports and notifications of adverse events will be provided to the IRB 
according to local regulations and guidelines. 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study.  Subjects 
must also be notified they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
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The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
15.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator 
of the trial is solely responsible for determining whether the trial and its results are 
subject to the requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov. The sponsor-investigator has delegated responsibility to 
IUSCC Clinical Trials Office for registering the trial and posting the results on 
clinicaltrials.gov. Information posted will allow subjects to identify potentially 
appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and study site 
contact information. 
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APPENDICES
Appendix 1 
A copy of the Common Toxicity Criteria Version 4.0 can be obtained from the NCI 
website at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
Protocol 1601349135 IRB Approved - Do Not Enroll Subjects