Conditions: Germ Cell Tumor
Keywords: GCT
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a multi-center phase II study of brentuximab vedotin in combination with bevacizumab for the treatment of refractory CD-30+ germ cell tumors (GCT) after disease progression on imaging and/or tumor marker progression documented by serially rising alpha-fetoprotein (AFP) or beta human chorionic gonadotropin (bHCG) measured on at least 2 consecutive visits and determined by treating physician to be clinically significant. Patients unable to receive 2nd line of platinum-based chemotherapy due to toxicity or refusal would also be eligible.

Detailed description:

Arms:
arm 1: * Bevacizumab will be administered at a dose of 15 mg/kg IV every 21 days; over 90 minutes during 1st infusion, over 60 minutes as 2nd infusion and over 30 minutes for subsequent infusions if prior infusions well tolerated.
* Brentuximab vedotin will be administered first at 1.8 mg/kg (maximum dose of 180 mg) IV over 30 minutes every 21 days.

Interventions: intervention 1: Brentuximab Vedotin intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Dose level 1: 1.8 mg/kg every 21 days (up to 180 mg) Dose level -1 :1.2 mg/kg every 21 days ( up to 120 mg) intervention 2: 15 mg/kg every 21 days

Protocol document:
Prot_SAP_000.pdf: 
Masonic Cancer Center 
University of Minnesota 
 
 
Phase II Study of Brentuximab Vedotin and Bevacizumab in 
Men with Refractory CD-30 Positive Germ Cell Tumors 
CPRC #2015LS190 
IND 133200 
 
 
Principal Investigator/IND Sponsor: 
Shilpa Gupta, MD 
Division of Hematology, Oncology and Transplantation 
Department of Medicine 
University of Minnesota 
MMC 480 Mayo 
420 Delaware Street SE 
Minneapolis, MN 55455 
Phone: 612-626-3003 
Email:  guptash@umn.edu 
Fax:  
612-625-6919 
 
Co-Investigators: 
Gautam Jha, MD 
Badrinath Konety, MD, MBA 
 
 
Biostatistician: 
Joseph Koopmeiners, PhD 
 
 
Version Date: 
May 10, 2017 
 
 
 
 
 


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Revision History 
 
 
 
Revision # 
Version 
Date 
Summary of Changes 
Consent 
Revision 
 
07/08/2016 
Original to CPRC 
n/a 
 
10/10/2016 
In response to CPRC stipulations 
n/a 
 
11/02/2016 
Replace BV with full name at study sponsor’s request 
Original to IRB and FDA 
n/a 
1 
05/10/2017 
Added clarification to follow-up activities, as follows: 
• AEs that are probably or definitely related to study treatment will 
be followed until resolution or until initiation of new anti-cancer 
therapy, whichever is sooner. 
• Follow-up data includes survival and initiation of new cancer 
therapy 
Clarified the proteinuria eligibility criteria and dose hold 
requirements. 
Page 4 - Listed the participating institutions and key personnel. 
Added signature line for IND-sponsor to review eligibility 
checklists from affiliate sites. 
Clarified Study Calendar to state that the pre-screening activity 
does not fall into the 28 day screening window 
Minor clarifications throughout. 
No 
 
 


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Table of Contents 
List of Key Abbreviations ............................................................................................................ 6 
Protocol Synopsis ........................................................................................................................ 7 
1 
Objectives ............................................................................................................................ 8 
1.1 
Primary Objective .......................................................................................................... 8 
1.2 
Secondary Objectives ..................................................................................................... 8 
1.3 
Exploratory Objective ..................................................................................................... 8 
2 
Background and Rationale ...................................................................................................... 8 
2.1 
Refractory Germ Cell Tumors .......................................................................................... 8 
2.2 
CD-30 and VEGF Germ Cell Tumors ............................................................................... 8 
2.3 
Brentuximab Vedotin ...................................................................................................... 9 
2.4 
Bevacizumab ................................................................................................................10 
2.5 
Study Rationale .............................................................................................................10 
3 
Study Design .......................................................................................................................10 
4 
Patient Selection ...................................................................................................................11 
4.1 
Inclusion Criteria ...........................................................................................................11 
4.2 
Exclusion Criteria ..........................................................................................................12 
5 
Patient Registration ..............................................................................................................13 
5.1 
Registration with the University of Minnesota Clinical Trials Office ...................................13 
5.2 
Patients Who Are Registered and Do Not Receive Study Treatment ....................................13 
6 
Study Drug Administration ....................................................................................................14 
6.1 
Bevacizumab ................................................................................................................14 
6.2 
Brentuximab Vedotin .....................................................................................................14 
6.3 
Dose Modifications and Delays .......................................................................................15 
6.4 
Supportive Care ............................................................................................................16 
6.5 
Duration of Treatment ....................................................................................................17 
6.6 
Duration of Study Participation .......................................................................................17 
7 
Study Drug Information ........................................................................................................17 
7.1 
Bevacizumab (Avastin) ..................................................................................................17 
7.2 
Brentuximab Vedotin .....................................................................................................19 
8 
Study Calendar/Procedures ....................................................................................................23 
8.1 
Study Calendar .............................................................................................................23 
8.2 
Correlatives/Special Studies ...........................................................................................24 


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9 
Measurement of Effect ..........................................................................................................25 
9.1 
Definitions ...................................................................................................................25 
9.2 
Disease Parameters ........................................................................................................26 
9.3 
Methods for Evaluation of Measurable Disease .................................................................27 
9.4 
Response Criteria ..........................................................................................................27 
9.5 
Duration of Response .....................................................................................................29 
10 
Adverse Event Monitoring, Documentation and Reporting .....................................................30 
10.1 
Adverse Event Terminology ...........................................................................................30 
10.2 
Adverse Event Monitoring and Documentation .................................................................31 
10.3 
SAE Documentation and Reporting Requirements .............................................................31 
10.4 
Early Stopping Rule Events Documentation and Reporting Requirements ............................32 
10.5 
Other Event Documentation and Reporting Requirements ..................................................32 
10.6 
Institutional Event Reporting Table .................................................................................32 
10.7 
MMC Reporting Requirements .......................................................................................32 
11 
Study Data Collection and Monitoring .................................................................................33 
11.1 
Data Management .........................................................................................................33 
11.2 
Case Report Forms ........................................................................................................33 
11.3 
Data and Safety Monitoring Plan (DSMP) ........................................................................34 
11.4 
Affiliate Site Monitoring ................................................................................................34 
11.5 
Record Retention ...........................................................................................................34 
12 
Statistical Considerations ...................................................................................................35 
12.1 
Study Endpoints ............................................................................................................35 
12.2 
Study Design and Sample Size Considerations ..................................................................35 
12.3 
Analysis .......................................................................................................................35 
12.4 
Safety Monitoring .........................................................................................................36 
13 
Conduct of the Study .........................................................................................................37 
13.1 
Good Clinical Practice ...................................................................................................37 
13.2 
Ethical Considerations ...................................................................................................37 
13.3 
Informed Consent ..........................................................................................................37 
14 
Publications .....................................................................................................................37 
15 
References .......................................................................................................................38 
Appendix I – Eligibility Checklist .................................................................................................40 


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Key Study Personnel Contact Information 
 
Site 
Contact Information 
Role 
Masonic Cancer Center, 
University of Minnesota 
Shilpa Gupta, M.D. 
Division of Hematology, Oncology and Transplantation 
420 Delaware St. SE, MMC 480 
Minneapolis, MN 55455 
Phone: 612-626-3003  
Email: guptash@umn.edu  
IND Sponsor-
Investigator  
Erica A Orcholski 
Clinical Trials Office 
MMC 6 
420 Delaware Street SE 
Minneapolis, MN 55455 
Phone: 612 626-5174 
Email:  eorchols@umn.edu 
Fax: 612 625-6145 
Affiliate Sites 
Manager 
Huntsman Cancer Institute 
Benjamin L. Maughan, M.D., Pharm.D 
Farmington Health Center 
165 N. University Ave. 
Farmington, UT 84025 
Phone:  801-213-3200 
Email:  benjamin.maughan@hci.utah.edu  
Site PI 
City of Hope 
Comprehensive Cancer 
Center 
Przemyslaw W. Twardowski, M.D. 
1500 East Duarte Road 
Duarte, CA, 91010 
Phone: 626-256-4673 
Email: ptwardowski@coh.org 
Site PI 
 
Refer to the Procedures Manual for Affiliate Sites for a complete list of study personnel and contact 
information.  
 
 
 


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List of Key Abbreviations 
 
AE 
adverse event 
AFP 
alpha-fetoprotein 
ANC 
absolute neutrophil count 
bHCG 
beta human chorionic gonadotropin 
CD-30 
antigen-30 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTCs 
circulating tumor cells 
CTO 
Clinical Trials Office 
CYP3A4 
cytochrome P450 3A4 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food And Drug Administration 
GCT 
germ cell tumors 
GFR 
glomerular filtration rate 
IHC 
immunohistochemistry 
IND 
Investigational New Drug  
IV 
intravenous 
Kg 
kilogram 
LDH 
lactate dehydrogenase 
MCC 
Masonic Cancer Center 
MMAE 
Monomethyl auristatin E 
MTD 
maximum tolerated dose 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAEs 
serious adverse event 
SD 
stable disease 
VDGF 
vascular endothelial growth factor 
 
 
 
 


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Protocol Synopsis 
 
Title: 
Phase II Study of Brentuximab Vedotin and Bevacizumab in Men with Refractory 
CD-30 Positive Germ Cell Tumors 
 
Study Phase: 
II 
 
Study Design: 
Multi-center phase II study of brentuximab vedotin in combination with 
bevacizumab for the treatment of refractory CD-30+ germ cell tumors (GCT) in 
men, after prior treatment with 2 or more lines of platinum-based chemotherapy, 
or at least 1 line of platinum-based chemotherapy if patient is ineligible for further 
platinum based chemotherapy or refuses 2nd line platinum based chemotherapy. 
 
For primary mediastinal germ cell tumors, failure of first-line platinum based 
chemotherapy will be accepted. 
 
Brentuximab vedotin and bevacizumab will be administered every 21 days until 
disease progression or unacceptable toxicity. 
 
Primary 
Objective: 
Objective response rate 
Secondary 
Objectives: 
1. Safety and tolerability of brentuximab vedotin and bevacizumab in CD-30+ 
refractory GCT 
2. To evaluate progression free survival 
3. To determine overall survival 
 
Exploratory 
Objectives: 
1. To study the expression of CD-30 in tumor and blood and VEGF in blood and 
correlate with clinical outcomes 
2. To assess for circulating tumor cells (CTCs) and correlate with clinical 
outcomes. 
 
Enrollment: 
21 patients over 3 years 
 
 
 


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1 
Objectives 
1.1 
Primary Objective 
To determine the efficacy of brentuximab vedotin and bevacizumab when given in 
combination for the treatment of refractory CD-30+ germ cell tumors (GCT) according 
to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.  
1.2 
Secondary Objectives 
• To evaluate safety and tolerability of brentuximab vedotin and bevacizumab in CD-
30+ refractory GCT  
• To evaluate progression free survival  
• To determine overall survival  
1.3 
Exploratory Objective 
• To study the expression of CD-30 in tumor and blood and VEGF in blood and 
correlate with clinical outcomes 
• To assess for circulating tumor cells (CTCs) and correlate with clinical outcomes. 
2 
Background and Rationale 
2.1 
Refractory Germ Cell Tumors 
There is no standard for salvage therapy for refractory germ cell tumors (GCT) after 
failure of 2nd line chemotherapy. Typical second-line chemotherapy regimens include 
vinblastine, ifosfamide, and cisplatin (VeIP) and paclitaxel, ifosfamide, and cisplatin 
(TIP), with gemcitabine, paclitaxel, and oxaliplatin usually reserved for subsequent 
administration and there is no standard for subsequent therapies. (1-16) Complete 
responses with third-line or later salvage chemotherapy for GTCs are seen in only less 
than 10 % patients and are short-lived. Patients progressing after several lines of 
chemotherapy, including high dose chemotherapy have a dismal prognosis and die from 
disease. Novel targeted therapies and combination strategies are urgently needed for this 
patient population with a goal of improving outcomes where currently no curative 
treatment exists. 
2.2 
CD-30 and VEGF and Germ Cell Tumors 
Cluster of Differentiation antigen-30 (CD-30) is expressed in untreated embryonal 
carcinoma, implicating that CD-30 is a rational target in this disease. In addition, CD-
30 staining was retained in over 70% cases of embryonal carcinoma even after various 
lines of chemotherapy and high dose chemotherapy, making this a suitable target for 
refractory CD-30 expressing GCT (embryonal carcinoma or GCT with embryonal 
component) (17)  


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Angiogenesis is essential for tumor growth and metastasis and vascular endothelial 
growth factor (VEGF) expression is involved in tumor development, angiogenesis, and 
metastasis in GCT.(18)  
In an ongoing phase 2 study of monotherapy in patients with CD-30+ heavily pretreated 
GCT (embryonal carcinoma) who were refractory to treatment, there is evidence of 
clinical benefit and was well tolerated. (19)  
Targeting VEGF with bevacizumab, a monoclonal antibody to VEGF has shown 
promising activity in GCT. (20, 21)  
Moreover, inhibition of VEGF can reduce tumor vessel permeability, remodeling the 
tumor vasculature, and restoring tumor interstitial pressure. This may potentially help 
improve drug delivery of other agents. (21) Based on these preclinical and clinical 
findings, combination of brentuximab vedotin and bevacizumab may be synergistic in 
refractory CD-30+ GCT and do not have any potential overlapping toxicities. This 
combination would also help spare heavily pretreated patients with toxicity from 
conventional cytotoxic chemotherapies. 
2.3 
Brentuximab Vedotin 
Brentuximab Vedotin (formerly SGN-35) is a novel antibody drug conjugate that 
combines the agent mono-methyl auristatin E (MMAE) to a CD-30 specific monoclonal 
antibody by a protease-cleavable linker. After binding to CD-30, brentuximab vedotin 
in internalized and processed into lysosomal vesicles leading to the release of MMAE 
from the antibody by reduction or acid hydrolysis within the lysosomes. Subsequently, 
MMAE is released into cytoplasm and inhibits microtubule polymerization leading to 
cell cycle arrest followed by cell death (Figure 1). As HRS cells die, a small amount of 
MMAE is released into the tumor microenvironment which can kill neighboring cells 
by a CD-30-independent manner. It is approved by the FDA for treatment of relapsed 
Hodgkin lymphoma and anaplastic large cell lymphoma. Efficacy data for brentuximab 
vedotin are available from two noncomparative multicentre, phase II trials; one in 
patients with Hodgkin lymphoma who had relapsed after HDCT/ASCT (22) and one in 
patients with relapsed systemic ALCL after at least one prior treatment.(23) In both 
trials, patients received intravenous brentuximab vedotin 1.8 mg/kg every 3 weeks, 
based on results from a phase I, dose-escalation trial in 45 patients with relapsed or 
refractory CD-30-positive haematologic cancers showing this to be the maximum 
tolerated dose (MTD). (24)The most commonly reported treatment-related adverse 
events of any grade were peripheral sensory neuropathy, nausea, fatigue, pyrexia, and 
diarrhea. Treatment-emergent grade 3 adverse events occurring included neutropenia 
(14 %) and peripheral sensory neuropathy (8 %). The only treatment-emergent grade 4 
adverse event that was reported was neutropenia (6 %). No cases of febrile neutropenia 
were reported. No deaths were attributed to brentuximab vedotin treatment. (22, 23) 


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2.4 Bevacizumab  
Bevacizumab is a humanized monoclonal neutralizing antibody binding all 5 isoforms 
of human VEGF. It has been shown to bind to VEGF-A with high affinity and neutralize 
its activity. Inhibition of angiogenesis resulted in reduced tumor growth in many ex vivo 
models of pediatric and adult malignancies. Bevacizumab is an effective therapeutic 
agent in multiple types of human cancer in which VEGF-dependent angiogenesis plays 
an important role in tumor cell survival. (25, 26) Bevacizumab is currently approved for 
a variety of cancers. (27)  
2.5 
Study Rationale 
The preclinical and clinical data of brentuximab vedotin and bevacizumab in GCT 
support the concept that combination of brentuximab vedotin and bevacizumab may be 
synergistic in refractory GCT without potential overlapping toxicities.  
3 Study Design 
This is a multi-center phase II study of brentuximab vedotin in combination with bevacizumab 
for the treatment of refractory CD-30+ GCT after disease progression on imaging and/or tumor 
marker progression documented by serially rising AFP or bHCG measured on at least 2 
consecutive visits and determined by treating physician to be clinically significant. Patients 
unable to receive 2nd line of platinum-based chemotherapy due to toxicity or refusal would also 
be eligible.  
This study will enroll patients with CD-30 expressing GCTs; any level of expression of CD-
30 (> 1%) will be allowed, as there has been no correlation between higher expression of CD-
30 and clinical responses with brentuximab vedotin. The genitourinary pathologists at local 
sites will assess for CD-30 expression as per their standard procedure and report presence of 
CD 30 and scoring if applicable.  
Patients must have received 2 or more lines of platinum-based chemotherapy, or at least 1 line 
of platinum-based chemotherapy if patient is ineligible for further platinum based 
chemotherapy or refuses 2nd line platinum based chemotherapy.  
For primary mediastinal germ cell tumors, failure of first-line chemotherapy will be accepted.  
Brentuximab vedotin and bevacizumab will be given once every 21 days until disease 
progression, unacceptable toxicity or patient refusal. A disease reassessment will be done every 
2 treatment cycles.    
 
 


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4 Patient Selection 
4.1 
Inclusion Criteria 
4.1.1 Male, ≥ 18 years of age 
4.1.2 Diagnosis of CD-30 positive GCT. CD-30 expression will be tested by 
immunohistochemistry (IHC) in archival or fresh tumor tissue as is 
routinely done for diagnosis.  
4.1.3 Disease progression on imaging or tumor marker progression (clinical 
significance of tumor marker progression to be decided per the discretion 
of treating physician) after at least 2 lines of platinum-based chemotherapies 
unless patient is ineligible for further platinum based chemotherapy or 
refuses 2nd line platinum based chemotherapy due to toxicity. For primary 
mediastinal germ cell tumors, failure of first-line chemotherapy will be 
accepted. Prior high dose chemotherapy with hematopoietic stem cell 
rescue is allowed. Prior treatment with bevacizumab is allowed.  
4.1.4 At least 3 weeks should have elapsed since the last treatment (e.g. 
chemotherapy, targeted small molecule therapy, immunotherapy or 
radiation) and must have recovered to grade 1 or better from the acute 
effects of prior therapy.  
4.1.5 Presence of measurable disease according to RECIST 1.1 (Section 9) 
4.1.6 ECOG performance status 0 or 1  
4.1.7 Adequate marrow and organ function within 28 days prior to study 
registration as defined below:  
• Leukocytes > 3,000/µL 
• ANC > 1500/µL 
• Hemoglobin ≥ 9 g/dL 
Note:  Blood transfusion will be allowed for patients with hemoglobin < 9 g/dl and 
G-CSF is allowed for neutropenic patients at time of enrollment. 
• Platelets > 100,000/mm3  
• Creatinine:  ≤3mg/dl OR if serum creatinine > 3 mg/dl, estimated GFR 
>30 mL/min/1.73m2   
• INR: <1.5 x institutional upper limit of normal OR < 3 if on warfarin or 
other anticoagulants. There should be no evidence of active bleeding 
while on anticoagulants.  
• Total bilirubin: ≤ 2 x institutional upper limit of normal (ULN) 
• SGOT (AST) or SGPT (ALT):  < 3 x institutional upper limit of normal 
(< 5 x ULN  if liver metastases present)  
• If patient has proteinuria, it should be <2+ (< 100 mg/dl or per 
institutional guidelines). If proteinuria is 2+ or greater (≥ 100 mg/dl per 


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institutional guidelines), patients should undergo a 24- hour urine 
collection and 24 hour urinary protein should be less than < 2 grams.  
4.1.8 Sexually active men with partners of women of childbearing potential must 
agree to practice effective methods of contraception during the study and 
for 6 months after the last treatment 
4.1.9 Provide voluntary written consent and HIPAA authorization for release of 
personal health information, approved by an Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) 
4.2 Exclusion Criteria 
4.2.1 Prior treatment with BV. 
4.2.2 Known active brain metastases and or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate provided brain 
metastases are stable (without evidence of progression by imaging for at 
least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to study 
registration. This exception does not include carcinomatous meningitis, 
which is excluded regardless of clinical stability. 
4.2.3 History of blood clots, pulmonary embolism, or deep vein thrombosis in 
previous 6 months unless controlled by anticoagulant treatment 
4.2.4 Known history of HIV  
4.2.5 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected) 
4.2.6 Received a live vaccine within 1 week prior to the first dose of study 
treatment 
4.2.7 Has active autoimmune disease that required systemic treatment with use of 
disease modifying agents, corticosteroids or immunosuppressive drugs  
4.2.8 Any clinically significant active infection that requires systemic treatment 
at the time of enrollment.  
4.2.9 Known allergy to bevacizumab or brentuximab vedotin or any of its 
excipients 
4.2.10 Patients who have congestive heart failure (NYHA Class III or IV), unstable 
angina, sustained ventricular tachycardia, ventricular fibrillation, clinically 
significant bradycardia, advanced heart block or a history of acute 
myocardial infarction (MI) within 6 months of study registration 
4.2.11 History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess in previous 6 months 
4.2.12 Prior major surgery within the previous 28 days of study registration and/or 
presence of any non-healing wound, fracture, or ulcer.  


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4.2.13 Use of an investigational agent within the previous 28 days of study 
registration. 
4.2.14 Poorly controlled hypertension [defined as systolic blood pressure (SBP) of 
≥150 mmHg and/or diastolic blood pressure (DBP) of ≥ 90mmHg]. Note: 
Initiation or adjustment of antihypertensive medication(s) is permitted prior 
to study registration 
4.2.15 Arterial thromboembolic events, including transient ischemic attack (TIA), 
cerebrovascular accident (CVA), unstable angina, or MI within 6 months of 
study registration 
4.2.16 History of posterior reversible encephalopathy syndrome 
4.2.17 Other malignancies unless the patient is considered to be disease-free and 
has completed therapy for the malignancy > than 6 months prior to study 
entry 
4.2.18 Any serious and/or unstable pre-existing medical, psychiatric, or other 
condition that could interfere with subject’s safety, provision of informed 
consent, or compliance to study procedures 
4.2.19 Concurrent use of rifampin or ketoconazole 
 
5 Patient Registration 
To be eligible for registration to this study, the patient must meet the criteria listed on the 
eligibility checklist based on the eligibility assessment documented in the patient’s medical 
record.  
5.1 
Registration with the University of Minnesota Clinical Trials Office 
Upon completion of the screening evaluation, eligibility checklist (appendix I) and 
obtaining consent, the Site Study Coordinator or designee will enroll the patient in 
OnCore.  
 
Complete registration information is found in the study’s Procedures Manual for 
Affiliate Sites. 
 
Affiliate sites only:  At the time of registration, the signed consent will be uploaded 
into OnCore as an attachment under the patient’s record within the study.  
 
Affiliates are responsible for fulfilling any local registration requirements. 
 
 
5.2 
Patients Who Are Registered and Do Not Receive Study Treatment 


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If a patient is registered to the study and is later found not able to begin study treatment, 
the patient will be removed from study and treated at the physician’s discretion. The 
reason for removal from study prior to starting study treatment will be clearly indicated 
in OnCore. The patient will be replaced to complete enrollment.  
6 Study Drug Administration 
 Drug 
Administration 
Sequence 
Dose And Frequency 
bevacizumab  
1st  
15 mg/kg every 21 days  
brentuximab vedotin  
2nd  
Dose level 1: 1.8 mg/kg every 21 days (up to 180 mg)  
Dose level -1 :1.2 mg/kg every 21 days ( up to 120 mg) 
Infusions may be given +/- 3 days for reasons such as observed holidays, inclement weather, 
scheduling conflicts, etc. 
6.1 Bevacizumab 
Bevacizumab will be administered at a dose of 15 mg/kg IV every 21 days; over 90 
minutes during 1st infusion, over 60 minutes as 2nd infusion and over 30 minutes for 
subsequent infusions if prior infusions well tolerated.  
If infusion-related adverse reactions occur, subsequent infusions should be 
administered over the shortest period that is well-tolerated. Patients may receive 
premedication with diphenhydramine 25 to 50 mg intravenously 30 minutes prior to 
bevacizumab if they have previously experienced allergic reactions. Stop infusion if a 
grade 3, or 4 infusion reaction occurs and administer appropriate medical therapy per 
institutional standards. 
6.2 Brentuximab Vedotin  
Brentuximab vedotin will be administered first at 1.8 mg/kg (maximum dose of 180 
mg) IV over 30 minutes every 21 days.  
Dosing is based on patient’s weight according to the institutional standard and actual 
weight will be used except for patients weighing greater than 100 kg. The dose for 
patients with weight greater than 100 kg will be calculated based on 100 kg (180 mg).  
Patients will be monitored for infusion related reactions. If anaphylaxis occurs, 
brentuximab vedotin will be immediately and permanently discontinued and 
appropriate medical therapy will be administered with 100 mg methylprednisolone IV, 
diphenhydramine 25 mg IV, or 0.3cc epinephrine (1:1000) IV.  


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If any other infusion related reaction occurs, infusion should be stopped and appropriate 
medical management initiated and then infusion may be resumed. Patients who 
experience infusion-related reactions should receive premedication which may include 
acetaminophen, antihistamine and corticosteroid for subsequent infusions.  
 
6.3 Dose Modifications and Delays 
Bevacizumab:  No intra-patient dose reduction will be allowed for bevacizumab; the 
dose will be 15 mg/kg. 
Brentuximab Vedotin: One intra-patient dose reduction will be allowed. The 
brentuximab vedotin dose may be reduced to 1.2 mg/kg if patients are unable to tolerate 
1.8 mg/kg dose. If a further dose reduction is needed, treatment will be permanently 
discontinued.  
If one of the study drugs cannot be administered due to reversible toxicity, the patient 
can receive only the other drug per schedule for up to 3 consecutive cycles. Any patient 
who cannot resume one of the study drugs after 3 consecutive cycles, will be taken off 
study. Treatment delays of any particular cycle will be allowed for up to 4 weeks for 
toxicity or adverse events related or unrelated to study drugs.  
6.3.1 Bevacizumab Related Toxicity 
Complete list of adverse event can be found in the package insert. (27) 
 
No intra-patient dose reduction will be allowed for bevacizumab; the dose will be 15 
mg/kg. 
Discontinue bevacizumab permanently per package insert guidelines for: 
• 
gastrointestinal perforations 
• 
wound dehiscence and wound healing complications requiring medical 
interventions.  
• 
serious hemorrhage (i.e., requiring medical intervention)  
• 
life-threatening (grade 4) venous thromboembolic events, including pulmonary 
embolism  
• 
posterior reversible encephalopathy syndrome (pres)  
• 
nephrotic syndrome 
• 
arterial thromboembolism 
 
Hold bevacizumab temporarily for: 
• 
4 weeks prior to elective surgery  
• 
severe hypertension not controlled with medical management  
• 
proteinuria: 


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o If result is 2+ on dipstick urinalysis (≥ 100 mg/dL but ≤ 200 mg/dl or as reported 
per Institutional guidelines) can give dose per treating physician’s discretion. 
Proceed with a 24 hour urine collection prior to next dose. 
o If result is 3+ on dipstick urinalysis (> 200 mg/dl or as reported per Institutional 
guidelines), withhold dose and recheck 24 hour urine within 3 days prior to next 
scheduled dose.  Resume when proteinuria is < 2 gm/24 hours. 
• 
venous thrombosis: If superficial, continue bevacizumab. If grades 3 or 4 DVT, 
hold for 2 weeks; restart bevacizumab after 2 weeks if therapeutic dose 
anticoagulation is stabilized, if no grade 3 or 4 hemorrhage has occurred, and if the 
tumor does not appear to abut on any major vessel. 
6.3.2 Brentuximab Vedotin Related Toxicity 
Complete list of adverse events can be found in the pharmacy instructions (version 9, 
dated October 2015) provided by Seattle Genetics. Refer to it and the Investigator 
Brochure (version 13, dated October 12, 2015). 
The most common adverse reactions (≥20%) are neutropenia, peripheral sensory 
neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, 
pyrexia, rash, thrombocytopenia, cough, and vomiting. 
Peripheral Neuropathy: For new or worsening Grade 2 or 3 neuropathy, brentuximab 
vedotin should be held until neuropathy improves to Grade 1 or baseline and then 
restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, brentuximab vedotin should 
be discontinued. 
Neutropenia: Brentuximab vedotin should be held for Grade 3 or 4 neutropenia until 
resolution to baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent 
cycles in patients who experience Grade 3 or 4 neutropenia in the previous cycle. In 
patients with recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis, 
consider dose reduction to 1.2 mg/kg. 
Renal Insufficiency:  Hold brentuximab vedotin if creatinine clearance is < 30 ml/min. 
Restart once creatinine clearance is > 30 ml/min 
Hepatic Impairment:  For Child Pugh A hepatic impairment, decrease brentuximab 
vedotin dose to 1.2 mg/kg, hold brentuximab vedotin for Child Pugh- B and C hepatic 
impairment. 
6.4 Supportive Care 
Supportive care will be provided per institutional guidelines and investigator’s 
discretion.  
G-CSF is permitted and is recommended for patients experiencing grade 3 and 4 
neutropenia. 


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Appropriate antibiotics, blood products, fluids, electrolytes and general supportive care 
may be used as medically appropriate.  
No other anti-cancer therapy is permitted during the study period (through the end of 
treatment visit).  
6.5 Duration of Treatment 
Treatment may continue until one of the following criteria applies: 
• Disease progression, as defined in Section 9 
• Prolonged intercurrent illness that prevents further administration of treatment  
• Unacceptable AEs 
• Treatment delays necessitating taking patient off study, as specified in Section 6.3 
• Patient decides to withdraw from the study  
• Any changes in patient’s condition that render him unacceptable for further 
treatment in the judgement of the investigator.  
6.6 Duration of Study Participation  
A final end of treatment visit will occur 28 days (+ /-7 days) after the last dose of BV. 
However, Adverse Events that are determined to be probably or definitely related to 
study treatment will be followed until resolution to baseline or until initiation of new 
anti-cancer therapy, whichever is sooner.  
All patients, regardless of disease status at the end of treatment, will be followed for 
survival and for initiation of new cancer therapy every 3 months for 2 years.  Follow-
up may be done by record review or patient contact. 
7 Study Drug Information 
7.1 Bevacizumab (Avastin)  
7.1.1 Description  
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 
and KDR) on the surface of endothelial cells. The interaction of VEGF with its 
receptors leads to endothelial cell proliferation and new blood vessel formation in in 
vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models 
of colon cancer in nude (athymic) mice caused reduction of microvascular growth and 
inhibition of metastatic disease progression.  
Bevacizumab is classified as a recombinant humanized monoclonal IgG1 antibody that 
binds to and inhibits the biologic activity of human vascular endothelial growth factor.  
 


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7.1.2 Availability 
Commercial supplies of bevacizumab will be used in this study and billed to third party 
payers. Based on available data of efficacy of bevacizumab in GCT, this is usually 
approved by third-party payers.  
7.1.3 How Supplied 
Bevacizumab is supplied in sterile single-use vials individually packaged in a carton 
(one vial to a carton) containing either 100 mg per 4 mL vial (NDC: 50242-060) or 400 
mg per 16 mL vial (NDC: 50242-061).  
7.1.4 Storage, Handling, and Accountability 
Unopened vials of bevacizumab are stable until the expiration date indicated on the 
package when stored at 2° to 8ºC (36° to 46ºF). Bevacizumab vials should be protected 
from light. Do not freeze or shake. Diluted bevacizumab solutions may be stored at 2° 
to 8ºC (36° to 46ºF) for up to 8 hours. Store in the original carton until time of use. No 
incompatibilities between bevacizumab and polyvinylchloride or polyolefin bags have 
been observed.  
7.1.5 Description 
Bevacizumab is supplied in a sterile form for intravenous use only. Bevacizumab is a 
clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for 
intravenous infusion. Bevacizumab is supplied in 100 mg and 400 mg preservative-
free, single-use vials to deliver 4 mL or 16 mL of bevacizumab (25 mg/mL). The 100 
mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate 
(monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg 
polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 
mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 
19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for 
Injection, USP.  
7.1.6 Administration  
Use appropriate aseptic technique. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration. Withdraw 
necessary amount of bevacizumab and dilute in a total volume of 100 mL of 0.9% 
Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the 
product contains no preservatives. Do not administer as an intravenous push or bolus. 
Administer only as an IV infusion, as specified in Section 6.1  
 
 


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7.2 Brentuximab Vedotin 
7.2.1 Description  
Brentuximab vedotin (formerly SGN-35) is a CD-30-directed antibody-drug conjugate 
(ADC) consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific 
for human CD-30; 2) the microtubule-disrupting agent monomethyl auristatin E 
(MMAE); and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10.  
 
Each antibody molecule has, on average, two of its interchain disulfides reduced and 
the resulting cysteine residues alkylated with SGD-1006 Intermediate (enzyme-
cleavable linker + MMAE), leading to a molar ratio of four drugs per antibody. 
Brentuximab vedotin is a heterogeneous mixture of a range of drug-load variants and 
isoforms. The overall average drug-to-antibody mole ratio (MRD) is approximately 4. 
The calculated molecular mass for the nominal form of brentuximab vedotin is 
approximately 153 kDa. 
 
The anticancer activity of brentuximab vedotin is due to the binding of the ADC to CD-
30-expressing cells, followed by internalization of the ADC-CD-30 complex, and the 
release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the 
microtubule network within the cell, subsequently inducing cell cycle arrest and 
apoptotic death of the cell. 
7.2.2 Availability 
Brentuximab vedotin will be supplied by Seattle Genetic for the purposes of this study. 
7.2.3 Product Description 
Brentuximab vedotin is a sterile, preservative-free, white to off-white lyophilized cake 
or powder, supplied in single-use vials. Brentuximab vedotin drug product is 
reconstituted with water for injection (WFI), USP, or equivalent. The reconstituted 
brentuximab vedotin drug product is a clear to slightly opalescent, colorless solution 
with no visible particulate matter. 
 
The reconstituted solution is subsequently diluted in sterile 0.9% Sodium Chloride for 
Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection for intravenous (IV) 
administration. The diluents should be USP grade or equivalent. 
 
Brentuximab vedotin is the United States Adopted Name (USAN) and the International 
Nonproprietary Name (INN) assigned to SGN-35. Drug product vials may be labeled 
as SGN-35 or as brentuximab vedotin; the 2 names can be used interchangeably.  
 
 


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7.2.4 Formulation 
Each vial contains 55 mg SGN-35 for Injection (brentuximab vedotin), trehalose, 
sodium citrate, and polysorbate 80. The 5 mg overfill in each vial is to ensure that the 
labeled quantity of 50 mg SGN-35 may be withdrawn. The drug product vial is 
reconstituted with the appropriate amount of Sterile Water for Injection. The pH of 
reconstituted product is approximately 6.6.  
7.2.5 Vial Storage and Handling  
Refrigeration should be set at 2–8°C for storage of vials and solutions containing 
brentuximab vedotin. Chemical and physical stability of the reconstituted brentuximab 
vedotin drug product has been demonstrated for 24 hours at 2–8°C and 25°C. However, 
brentuximab vedotin does not contain preservatives; therefore, from a microbiological 
standpoint, opened and reconstituted vials should be used immediately. If not used 
immediately, the in-use storage should not be longer than 24 hours. It is recommended 
that brentuximab vedotin vials and solutions be protected from direct sunlight until the 
time of use. Recommended safety measures for the handling and preparation of 
brentuximab vedotin for Injection include masks, protective clothing, gloves, and 
vertical laminar airflow safety cabinets. 
7.2.6 Reconstitution  
Reconstitute lyophilized brentuximab vedotin by adding 10.5 mL Sterile Water for 
Injection, USP, or equivalent to the 50 mg vial, directing the stream to the side of the 
vial. The concentration of reconstituted brentuximab vedotin is 5 mg/mL with a total 
volume of 11 mL. Gently swirl the vial until contents are completely dissolved. The 
vial must not be shaken. Slight “bubbling” of the solution upon reconstitution may be 
observed. Allow the reconstituted vial to settle for a minute to allow bubbles to 
dissipate. The reconstituted product should be a colorless, clear to slightly opalescent 
solution with no visible particulates. Refrigeration should be set at 2–8°C for storage 
of the reconstituted vials. The reconstituted vials must be administered within 24 hours 
of vial reconstitution. Protect infusion bag from direct sunlight until time of use. 
7.2.7 Dose Preparation 
1. Transfer the required volume of reconstituted product to a 100 mL to 250 mL 
infusion bag. (A glass, sterile bottle may be used instead of an infusion bag.) It 
is recommended that the infusion bag be labeled with the patient number or 
name, and the drug name and lot number (or kit number in the case of a blinded 
study). The infusion bag size should allow enough diluent to achieve a 
concentration of 0.4–1.8 mg/mL. The following bag types are compatible with 
brentuximab vedotin: polyvinylchloride (PVC), ethylene vinyl acetate (EVA), 
polyolefin, polypropylene, or polyethylene. Discard any 
remaining 
reconstituted product.  


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2. Dilute reconstituted product in either 0.9% Sodium Chloride Injection, Lactated 
Ringer’s solution, or dextrose 5% in water (D5W). The diluents should be USP 
grade or equivalent. The final concentration of brentuximab vedotin in infusion 
bag should be in the range of 0.4–1.8 mg/mL.  
• Total dose = patient weight x dose level. Note that for patients weighing 
more than 100 kg, total dose will be calculated using 100 kg.  
• Volume of reconstituted product required = total dose/5 mg per mL  
• Final concentration = total dose/total volume of infusion. 
3. Gently invert the infusion bag. DO NOT SHAKE or expose the prepared dosing 
solution to excess vibration at any time when transferring or transporting the 
reconstituted product. Pneumatic tube systems are not recommended.  
4. Prior to administration, inspect the prepared dosing solution (in infusion bag) 
for any particulate matter or discoloration.  
5. Do not prepare a single dose of brentuximab vedotin using vials from different 
lots or kits. Use vials from the same lot or kit number for a given dose.  
6. Refrigeration should be set at 2–8°C for storage of the prepared dosing solution. 
The solution must be used within 24 hours.  
7.2.8 Disposal 
Any partially used vials or prepared dosing solutions may be discarded according to 
institutional drug disposal procedures. Partially used vials may not be used to provide 
treatment for a different patient. See the Pharmacy Binder for instructions for disposing 
of unused vials. 
7.2.9 Drug Interactions 
CYP3A4 Inhibitors/Inducers: Monomethyl auristatin E (MMAE) is primarily 
metabolized by CYP3A. 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 Monomethyl auristatin E (MMAE). Patients who are receiving 
P-gp inhibitors concomitantly with brentuximab vedotin should be closely monitored 
for adverse reactions. 
 


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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. Brentuximab vedotin 
is not expected to alter the exposure to drugs that are metabolized by CYP3A4 
enzymes. 
 
 
 


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8 Study Calendar/Procedures  
8.1 Study Calendar 
All schedules procedures/visits can be performed +/- 3 days unless specifically mentioned. 
 
 
 
Screening 
28 days prior to 
starting C1 
Cycle 1 
Day 1 
 
Cycles 2-6 
Day 1 
(+/- 3 days) 
Cycle 7 and 
beyond 
Day 1 
(+/- 3 days) 
End of 
Treatment 
visit within 
28 days (+/- 7 
days) of last 
treatment 
Follow-up for 
2 years 
pre-screening 
consent 1 
X 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
screening 
assessment 
X 
 
 
 
 
 
demographics 
X 
 
 
 
 
 
medical history 
X 
X 
 
 
X 
 
concurrent 
medications 
X 
X 
X 
X 
X 
 
physical exam 
X 
X 
X 
X 
X 
 
vital signs 
X 
X 
X 
X 
X 
 
weight 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
X 
X 
X 
 
CBC with diff 
X 
X 
X 
X 
X 
 
AFP, bHCG, LDH 
X 
X 
X 
X 
X 
 
CMP 6, uric acid, 
magnesium, phos 
X 
X 
X 
X 
X 
 
coagulation studies 
including PT, 
PTT,INR 
X 
X 
X 
X 
X 
 
Urinary protein 
X 
X 
X 
X 
X 
 
Adverse event 
evaluation 
 
X 
X 
X 
X 
X7 
Radiologic 
evaluation 2, 3 
X 
 
X 
X 
X 
 
Brentuximab 
Vedotin 
 
X 
X 
X 
 
 
Bevacizumab 
 
X 
X 
X 
 
 
Follow-up  
 
 
 
 
 
X8 (every 3 
months by 
record review 
or phone) 
Archival tissue  
X1, 4 
 
 
 
 
 
Tumor Biopsy 
X1, 4 
 
 
 
R5 
 
Serum CD-30 
 
R (on day of  
cycle 1 prior to 
treatment 
R (on day of  
cycle 3 prior to 
treatment) 
 
R 
 
Plasma VEGF 
 
R (on day of  
cycle 1 prior to 
treatment) 
R (on day of 
cycle 3 prior to 
treatment ) 
 
R 
 
Circulating tumor 
cell (CTC) Biocept 
CTC send out kits 
 
R(on day of  
cycle 1 prior to 
treatment) 
R (on day of 
cycle 3 prior to 
treatment) 
 
 
 


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1 Not applicable if the subject’s pathology report provides documentation of CD-30 positive expression. The 28 day screening 
window does not apply to the pre-screening consent. 
2 CT scan of Thorax, Abdomen and Pelvis will be performed after cycle 2, prior to starting cycle 3 and every 2 cycles subsequently. 
3 Scans will be done at end of treatment visit unless they were done 3 weeks prior to end of treatment visit. Bone scans will be done 
in patients with known bone metastases along with CT thorax, abdomen, and pelvis.  
4 CD-30 expression in archival or fresh tissue (if archival tissue not available) is a requirement for enrollment in the study. The 28 
day screening window does not apply to the pre-screening test for CD-30 expression. 
5 Tumor biopsy for patients is strongly encouraged at treatment discontinuation to evaluate for changes in CD-30 expression from 
baseline.  
6 CMP (comprehensive metabolic panel) consists of albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, creatinine, glucose, lytes (CO2, Cl, Na, K), total bilirubin, 
and total protein 
7 Adverse Events that are determined to be probably or definitely related to study treatment will be followed until resolution to 
baseline or until initiation of new anti-cancer therapy, whichever is sooner. 
8 Follow-up is for survival and for initiation of new cancer therapy 
R denotes research related procedures 
 
8.2 Correlatives/Special Studies  
8.2.1 CD-30 Expression 
CD-30 is expressed in untreated and refractory GCT (embryonal carcinoma or GCT 
with embryonal features), making it a potential rational therapeutic target. (17) CD-
30+ tumors have a poorer prognosis compared to CD-30- tumors. (17)  From 
Angiogenesis is essential for tumor growth and metastasis and VEGF expression is 
involved in tumor development, angiogenesis, and metastasis in GCT.(18)  
This study would aim to correlate CD-30 expression in tumor tissue with clinical 
response to brentuximab vedotin and bevacizumab. Archival tissue from formalin-
fixed, paraffin-embedded, tumor specimen from orchiectomy or any other surgical site 
will be used for CD-30 evaluation by IHC. If these archival tissues are unavailable or 
insufficient, a fresh core needle or incisional biopsy from a metastatic lesion would be 
used for CD-30 evaluation.  
Any level of expression (1% or more) will be considered positive for determining 
eligibility. If pathology report states tumor is CD-30+, that would be sufficient for 
deeming eligibility.  
For correlating responses with expression of CD-30, a scale of 0-3 will be used to score 
the CD-30 staining (0: no staining; 1+: 1–10% of staining, 2+:  11–50% of staining; 
3+:  >50% of staining). The pathologists at local sites can evaluate the level of 
expression. Levels of CD-30 expression in tumor tissue will be tested at baseline and 
end of study tissue biopsy (if applicable) to correlate with clinical outcomes as well as 
evaluate changes in CD-30 expression after treatment with brentuximab vedotin and 
bevacizumab.  
8.2.2 Serum CD-30 Levels 


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Serum CD-30 levels on day of cycle 1, cycle 3 and at end of treatment will be measured 
and correlated with clinical outcomes.  
8.2.3 Plasma VEGF Levels 
Plasma VEGF level on day of cycle 1, cycle 3 and at end of treatment will be measured 
and correlated with clinical outcomes. 
8.2.4 Circulating Tumor Cells (CTCs)  
We propose to assess for CTCs in using a novel CTC and CTDNA detection platform 
(Biocept) with capability to capture even CTCs with low levels of epithelial markers. 
(28) CTCs will be assessed on day of cycle1 and cycle 3 prior to treatment with study 
drugs and will be correlated with clinical outcomes.  
9 Measurement of Effect  
Patients will be evaluated for response at the end of every 2 cycles (6 weeks). 
Response and progression will be evaluated in this study using the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
In addition to CT scan to assess for disease evaluation, whole body bone scans will be done for 
patients with known or suspected bone metastases to assess for bone lesions. 
Serologic tumor markers, including AFP, b-HCG and LDH will be measured at baseline and at 
every cycle. AFP and b-HCG will be used for determining tumor markers trend. Patients with a 
PR on imaging and normalized or decreasing tumor markers will be classified as PR. PD will be 
defined as serially rising AFP or bHCG measured on at least 2 consecutive visits (as long as 
checked at least 3 weeks or later after cycle 1 to avoid false positives form flare-up) or disease 
progression per RECIST on radiologic imaging, except when there is pathologic evidence of a 
growing teratoma syndrome. If after an initial response in tumor markers and PR on imaging, there 
is serial rise in AFP or bHCG, measured on at least 2 consecutive visits, (not explained by any 
other reasons for a spurious rise in tumor markers), it would constitute as PD.  
The decision to continue on study would be based on treating physician’s discretion and in case 
where patients are deriving clinical benefit, they would be allowed to continue on study. 
9.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with brentuximab vedotin and bevacizumab.  
 


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Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response. These patients will have 
their response classified according to the definitions stated below.  
9.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with 
CT scan, MRI or calipers by clinical exam.  
 
Note:  Tumor lesions that are situated in a previously irradiated area would be 
considered measurable if lesion has grown in size since radiation.  
 
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 <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/pulmonitis, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable. 
 
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, 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. 
 
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, 


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but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
9.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation. 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. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Conventional CT Scans: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans).  
9.4 Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
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. (Note:  the appearance of one 
or more new lesions is also considered progression). 
 
Serologic tumor markers, including AFP, b-HCG and LDH will be measured at 
baseline and at every cycle. AFP and b-HCG will be used for determining tumor 
markers trend. Patients with a PR on imaging and normalized or decreasing tumor 
markers will be classified as PR. PD will be defined as serially rising AFP or bHCG 
measured on at least 2 consecutive visits (as long as checked at least 3 weeks or later 
after cycle 1 to avoid false positives form flare-up) or disease progression per RECIST 
on radiologic imaging, except when there is pathologic evidence of a growing teratoma 
syndrome. If after an initial response in tumor markers and PR on imaging, there is 
serial rise in AFP or bHCG, measured on at least 2 consecutive visits, (not explained 
by any other reasons for a spurious rise in tumor markers), it would constitute as PD. 
Treatment continuation decision would be based on treating physician’s discretion, 
what constitutes a clinically significant progression and the decision to continue on 


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study if patient is deriving clinical benefit. Treatment beyond progression would be 
allowed if patient deriving clinical benefit.  
 
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.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). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 
 
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.    
 
Treatment continuation decision would be based on treating physician’s discretion, 
what constitutes a clinically significant progression and the decision to continue on 
study if patient is deriving clinical benefit. Treatment beyond progression would be 
allowed if patient deriving clinical benefit.  
 
 
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). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 


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Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
It would be up to treating physician’s discretion to determine overall response after 
integrating tumor markers as discussed above. 
9.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
Overall Survival 
Overall survival is the duration of time from enrollment until death from any cause. 
 
 


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10 Adverse Event Monitoring, Documentation and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported on the schedule below. A 
copy 
of 
the 
CTCAE 
can 
be 
downloaded 
from 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
The following definitions of adverse events (AEs) and serious adverse events (SAEs) will 
determine whether the event requires expedited reporting via the OnCore SAE Report Form in 
addition to routine documentation in the OnCore AE case report form (CRF).  
The reporting timeframes for SAEs and other reportable events are located in Section 10.6 
10.1 
Adverse Event Terminology 
Adverse Event:  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Serious Adverse Event:  An adverse event is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization for more than 24 hours or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
Unexpected 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. 
Thus, adverse events that occur as part of the disease process (including relapse and 
death from such) or underlying medical conditions are considered unexpected; and 
will be reportable per Section 10.3. 
 
Critical and Major Clinical (Protocol/Patient) Deviations as defined by the 
Masonic Cancer Center: 


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Critical Deviations: 
• Causes subject harm, puts subject at immediate risk of harm or requires medical 
intervention to prevent harm 
• Done to eliminate apparent immediate harm caused by the protocol 
• Affects subject’s rights or welfare 
• Significantly increases risk to subject 
• Non-adherence to significant protocol requirements, regulations or GCP 
guidelines 
Major Deviations: 
• Changes risk or benefit to one or more subjects 
• Leads to a change in the protocol, consent form or study process 
• Deviation which is not trivial but does put a subject at immediate risk of harm, 
or requires medical intervention to prevent harm (pertains to non-adherence to 
protocol requirements, regulations or GCP guidelines) 
10.2 
Adverse Event Monitoring and Documentation 
The monitoring for adverse events will begin with the 1st dose of study drug through 
the end of treatment visit. 
 
Since a key outcome parameter of this study is to characterize the toxicities of 
brentuximab vedotin and bevacizumab when used in combination, adverse event 
documentation requirements will be determined based on grade, expectedness and 
relationship to each study drug. In addition, unexpected events and expected events that 
are not listed in protocol or the consent form must be documented. 
All adverse events are to be recorded in the AE Log case report form found in OnCore 
beginning with the 1st dose of study drug through the end of treatment visit.   Adverse 
Events that are determined to be probably or definitely related to study treatment will 
be followed until resolution to baseline or until initiation of new anti-cancer therapy, 
whichever is sooner.   
 
10.3  SAE Documentation and Reporting Requirements 
All SAEs are documented using the MCC OnCore SAE Report Form and reported 
within the timeframes indicated in Section 13.7. 
 
Expedited SAE Reporting Requirements:   
Report Within 24 Hours:  A subset of SAE’s must be reported expeditiously to the 
Masonic Cancer Center Affiliate Sites Manager within 24 hours of knowledge.  
 
Any event that is both serious and unexpected and at least possibly related to the study 
treatment requires expedited reporting  


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10.4 Early Stopping Rule Events Documentation and Reporting Requirements 
The following event count toward an early study stopping rule and must be reported to 
the MCC Affiliate Sites Manager using the Event Form found OnCore under the reports 
tab: 
• Any grade 4 or 5 event with the exception of grade 4 hypertension that is related 
to study drugs 
An event that counts toward an early stopping rule does not necessarily constitute a 
SAE and should be reported as such only if they meet the criteria for reporting as 
defined in Section 10.3. 
10.5 
Other Event Documentation and Reporting Requirements 
Deaths, including due to disease, will be recorded as an SAE and reported per Section 
10.6. Deaths due to disease should be recorded as a Grade 5 Neoplasm. In addition, the 
death date and cause must be reported in the patient follow-up tab in OnCore using the 
comment field in the survival status section to record the cause.  
10.6 
Institutional Event Reporting Table 
Individual institutional sites will be responsible for reporting any event meeting local 
reporting requirements to their institutional IRB and/or other research oversight 
committees. 
Event Type 
Reporting Timeframe 
OnCore Form to 
Use 
Report to 
SAEs 
Requiring 
Expedited Reporting 
Within 24 hours of knowledge 
SAE Report Form 
Masonic Cancer Center (MCC) 
Affiliate Sites Manager  
eorchols@umn.edu 
 
Local institutional IRB or other 
entities per institutional policies 
and guidelines 
All other SAEs 
Not required  
n/a 
Stopping Rule Events 
Within 24 hours of knowledge 
Event Form 
Major and Critical 
Clinical Deviations 
 
 
Within 5 working days of 
knowledge 
Deviation 
Report 
Form 
 
Safety events of interest that may require expedited reporting and/or safety evaluation 
include, but are not limited to overdose, medication error with or without subject/patient 
exposure to brentuximab vedotin or bevacizumab.  
10.7 MMC Reporting Requirements 
As the study sponsor, the Masonic Cancer Center has the following expedited reporting 
responsibilities for events reported in Section 10.6: 
Agency 
Criteria for reporting 
Timefra
me 
Form to 
Use 
Submission 
address/ 
Copy to: 


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The SAE Coordinator will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on the 
individual SAE (as reported or in a summary format). 
11 Study Data Collection and Monitoring 
11.1 Data Management 
This study will report clinical data using The Online Enterprise Research Management 
Environment (OnCoreTM), a web based Oracle® database utilizing study specific 
electronic case report forms. Key study personnel are trained on the use of OnCore and 
will comply with protocol specific instructions embedded within the OnCore. Patient 
demographics, patient specific study treatment calendars, adverse events and other 
information required for IND annual reporting will be placed in OnCore and other 
databases maintained by the Cancer Center. 
11.2 
Case Report Forms 
Participant data will be collected using protocol specific electronic case report forms 
(e-CRF) developed within OnCore based on its library of standardized forms. The e-
CRF will be approved by the study’s Principal Investigator and the Biostatistician prior 
to release for use. The Institutional Study Coordinator or designee will be responsible 
fax 
numbers 
FDA 
 
Unexpected and fatal or unexpected and  life 
threatening suspected adverse reaction 
no later 
than 
7 
Calendar 
Days 
MCC 
SAE 
Submit 
to 
FDA as an 
amendment 
to IND  
Seattle Genetics  
Drug Safety by: 
Facsimile (425) 
527-4308 
or 
(866) 333-6627 
(USA only toll 
free) 
Email: 
drug.safety@se
agen.com 
 
1) Serious and unexpected suspected adverse 
reaction or 
2)  increased occurrence of serious suspected 
adverse reactions over that listed in the protocol 
or investigator 
brochure or 
3) findings from other sources (other studies, 
animal or in vitro testing) 
no later 
than 
15 
Calendar
-Days 
Masonic 
Cancer 
Center 
SAE 
Coordinator 
Events that count toward the early study stopping 
rule. 
At time 
of 
reporting 
Event 
Form 
SAE 
Coordinator 
mcc-
saes@umn
.edu 
Not applicable 
Seattle 
Genetics 
Aggregate listing of all SAEs - SAE log must 
include SAEs reported expeditiously to FDA and 
Seattle Genetics, in addition al all other SAEs. 
Subject identifier, event term, start date and 
attribution to treatment must match the expedited 
report information to allow Drug Safety staff at 
Seattle Genetics to match reports 
monthly 
Summary 
format 
IST@seage
n.com 
or 
portal  
 
with a copy to 
each 
participating 
institution 
 


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for registering the patient into OnCore at time of study entry, completing e-CRF based 
on the patient specific calendar, and updating the patient record until patient death or 
end of required study participation.  
11.3 
 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the University 
of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP)  
For the purposes of data and safety monitoring, this study is classified as high risk 
(under a locally held IND – Dr. Gupta as the Sponsor/Investigator (S/I)). Therefore the 
following requirements will be fulfilled: 
 
The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the study’s progress at least quarterly. 
 
The S/I will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 
The S/I will oversee the submission of all reportable adverse events per the 
definition of reportable in Section 10.7 to the Masonic Cancer Center’s SAE 
Coordinator, the University of Minnesota IRB, Seattle Genetics, and the FDA.  
 
The S/I with assistance with the MCC Clinical Trials Office will oversee affiliate 
site monitoring who will, at a minimum, adhere to the University of Minnesota 
Masonic Cancer Center’s DSMP. 
 
In addition, at the time of the continuing review with the University of Minnesota IRB, 
a copy of the report with any attachments will be submitted to the Cancer Protocol 
Review Committee (CPRC). 
11.4 
 Affiliate Site Monitoring 
The PI (Dr. Gupta) with the CTO has oversight responsibility for trial monitoring at 
affiliate sites. Affiliate sites must self-monitor following the University of Minnesota 
Masonic 
Cancer 
Center 
Data 
and 
Safety 
Monitoring 
Plan 
(DSMP 
- 
http://z.umn.edu/dmsp) and the CTO Affiliate Site Monitoring SOPs.  
The investigator will permit study-related monitoring, audits, and inspections by the 
study’s Principal Investigator and/or IND sponsor and/or any designees, the local IRB, 
government regulatory bodies, and University of Minnesota compliance groups. The 
investigator will make available all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data, etc.). The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.) will be available for trial related monitoring, 
audits, or regulatory inspections. 
11.5 
 Record Retention 


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The investigator will retain study records including source data, copies of case report 
form, consent forms, HIPAA authorizations, and all study correspondence in a secured 
facility for at 6 years after the study file is closed with the IRB and FDA.  
Please contact the CTO before destroying any study related records. 
12 Statistical Considerations 
12.1 
Study Endpoints 
12.1.1 Primary Endpoint 
Disease response rate, as defined by the RECIST 1.1 criteria (as defined in Section 
9), integrated with tumor marker response.  
12.1.2 Secondary Endpoints 
• Progression-free survival (as defined in Section 9) 
• Overall survival (as defined in Section 9) 
• Adverse Events 
12.1.3 
Correlative Endpoints 
• Expression of CD-30 in tumor tissue 
• Plasma CD-30 levels  
• Serum VEGF levels 
• CTCs 
12.2 
Study Design and Sample Size Considerations 
This trial will use Simon’s two-stage Minimax design. 30 For the purposes of the design, 
we specify a null response rate of 0.05 and an alternative hypothesis of 0.20. A total of 
21 subjects will be enrolled. In stage 1, we will enroll 12 subjects and the study will 
stop for futility if 0 out of 12 subjects have a tumor response. In stage 2, we will enroll 
an additional 9 subjects (for a total of 21 subjects) and reject the null hypothesis if at 
least 2 of 21 subjects have a tumor response. This design will provide 80% power to 
reject the null hypothesis of a response rate of 0.05, assuming an alternative hypothesis 
of a response rate of 0.20 and a type-I error rate of 0.1.  
 
12.3 
Analysis 
12.3.1 General Considerations 
All statistical analyses will be completed using SAS 9.1 (Cary, NC, USA) or the R 
statistical programming language. 31 P-values less than 0.05 will be considered 
statistically significant unless otherwise noted. 
12.3.2 Description of the Study Population 


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The study population will be described by summarizing demographic and baseline 
clinical covariates. Categorical variables will be summarized by counts and 
percentages, while continuous variables will be summarized by the mean and 
standard deviation or median and interquartile range, as appropriate. 
12.3.3 Analysis of Primary Endpoint 
Tumor response will be summarized by the tumor response rate as estimated by the 
sample proportion with exact 95% confidence intervals. Hypothesis testing of the 
tumor response rate will be as dictated by Simon’s two-stage design (as described 
in Section 12.2). Secondary analyses of the tumor response rate will involve 
univariate tests of the association between demographic and baseline clinical and 
correlative covariates and the tumor response rate using Fisher’s exact test or the 
two-sample t-test, as appropriate. Multivariate analyses will not be completed given 
the small sample size of the trial. 
12.3.4 Analysis of Secondary Endpoints 
The primary analysis of secondary endpoints will be primarily descriptive. Survival 
endpoints (progression-free and overall survival) will be summarized by the 
Kaplan-Meier curve. In addition, we will also complete a secondary analysis to 
evaluate the univariate association between demographic and baseline clinical 
covariates and survival endpoints using Cox proportional hazards regression. 
Adverse events will be tabulated and the adverse event rate will be summarized by 
the sample proportion with exact 95% confidence intervals.  
12.3.5 Analysis of Correlative Endpoints 
We will evaluate the association between expression of CD-30 and VEGF and the 
primary and secondary outcomes. The association between CD-30 and VEGF 
expression and tumor response will be analyzed using logistic regression and the 
association between CD-30 and VEGF expression and survival endpoints 
(progression-free and overall survival) will be analyzed using Cox proportional 
hazards regression. 
12.4 
Safety Monitoring 
Pocock-type sequential stopping boundaries will be used to monitor the adverse event 
rate and accrual will be halted if excessive number of grade 4 or 5 AEs are observed. 
29 That is, accrual will be halted if 2 grade 4 or 5 AEs are observed in the first 2 patients, 
3 in the first 6 patients, 4 in the first 11 patients, 5 in the first 17 patients or 6 at any 
point in the trial. This boundary was chosen such that the probability of crossing the 
stopping boundary is at most 0.05 when the true rate of AEs is equal to the acceptable 
rate of 0.1. The acceptable rate of adverse events reflects the expected adverse event 
rates based on the adverse event rate for each agent, individually, and assuming no 
synergistic AEs. The probability of crossing the stopping boundary is 0.74, assuming 


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a true Grade 4 or 5 AE rate of 0.30 (related to study drugs), with the exception of grade 
4 hypertension from bevacizumab.  
13 Conduct of the Study 
13.1 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be 
established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations.  
13.2 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients. The study will only 
be conducted at sites where IRB approval has been obtained. The protocol, consent, 
written information given to the patients, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB by the investigator.  
13.3 
Informed Consent 
All potential study participants will be given a copy of the IRB-approved consent to 
review. The investigator or designee will explain all aspects of the study in lay language 
and answer all questions regarding the study. If the participant decides to participate in 
the study, he/she will be asked to sign and date the consent document. Patients who 
refuse to participate or who withdraw from the study will be treated without prejudice. 
14 Publications 
The study of these patients and results of all laboratory studies are considered private and 
confidential. The progress and results of this study will not be presented without approval by 
the Principal Investigator. 
 
 


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15 References 
1. 
Baniel J, Foster RS, Gonin R et al. Late relapse of testicular cancer. J Clin Oncol 1995;13:1170.  
2. 
McCaffrey JA, Mazumdar M, Bajorin DF et al. Ifosfamide- and cisplatin-containing chemotherapy as first-line 
salvage therapy in germ cell tumors: Response and survival. J Clin Oncol 1997;15:2559.  
3. 
Pico JL, Rosti G, Kramar A et al. A randomised trial of high-dose chemotherapy in the salvage treatment of 
patients failing first-line platinum chemotherapy for advanced germ cell tumors. Ann Oncol 2005;16:1152–1159.  
4. 
Motzer RJ, Bajorin DF, Schwartz LH et al. Phase II trial of paclitaxel shows antitumor activity in patients with 
previously treated germ cell tumors. J Clin Oncol 1994;12:2277–2283.  
5. 
Bokemeyer C, Beyer J, Metzner B et al. Phase II study of paclitaxel in patients with relapsed or cisplatin-
refractory testicular cancer. Ann Oncol 1996;7:31–34.  
6. 
Kondagunta GV, Bacik J, Donadio A et al. Combination of paclitaxel, ifosfamide, and cisplatin is an effective 
second-line therapy for patients with relapsed testicular germ cell tumors. J Clin Oncol 2005;23:6549–6555.  
7. 
Mead GM, Cullen MH, Huddart R et al. A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as 
second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: A medical research 
council trial. Br J Cancer 2005;93:178–184.  
8. 
Mardiak J, Salek T, Sycova-Mila Z et al. Paclitaxel plus ifosfamide and cisplatin in second-line treatment of 
germ cell tumors: A phase II study. Neoplasma 2005;52:497–501.  
9. 
Einhorn LH, Stender MJ, Williams SD. Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 
1999;17:509–511.  
10. Bokemeyer C, Gerl A, Schoffski P et al. Gemcitabine in patients with relapsed or cisplatin-refractory testicular 
cancer. J Clin Oncol 1999;17: 512–516.  
11. Hinton S, Catalano P, Einhorn LH et al. Phase II study of paclitaxel plus gemcitabine in refractory germ cell 
tumors (E9897): A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2002;20:1859–1863.  
12. Kollmannsberger C, Rick O, Derigs HG et al. Activity of oxaliplatin in patients with relapsed or cisplatin-
refractory germ cell cancer: A study of the German Testicular Cancer Study Group. J Clin Oncol 2002;20:2031–
2037.  
13. Kollmannsberger C, Beyer J, Liersch R et al. Combination chemotherapy with gemcitabine plus oxaliplatin in 
patients with intensively pretreated or refractory germ cell cancer: A study of the German Testicular Cancer 
Study Group. J Clin Oncol 2004;122:108–114.24.  
14. Pectasides D, Pectasides M, Farmakis D et al. Gemcitabine and oxaliplatin (GEMOX) in patients with cisplatin-
refractory germ cell tumors: A phase II study. Ann Oncol 2004;15:493–497.  
15. Kollmannsberger C, Rick O, Klaproth H et al. Irinotecan in patients with relapsed or cisplatin-refractory germ 
cell cancer: A phase II study of the German Testicular Cancer Study Group. Br J Cancer 2002;87:729–732.  
16. Puc HS, Bajorin DF, Bosl GJ et al. Phase II trial of topotecan in patients with cisplatin-refractory germ cell 
tumors. Invest New Drugs 1995;13: 163–165.  
17. Patrizia Giannatempo, Andrea Necchi, Maurizio Colecchia et al. Persistence of CD30 expression by embryonal 
carcinoma (EC) in the treatment time course: A retrospective series of multirelapsing germ cell tumors (GCT).J 
Clin Oncol 31, 2013 (suppl 6; abstr 329) 
18. Souichirou Fukuda, Tsutomu Shirahama, Yoshiharu Imazono et al. Expression of vascular endothelial growth 
factor in patients with testicular germ cell tumors as an indicator of metastatic disease. Cancer. 1999 Mar 
15;85(6):1323-30  
19. Costantine Albany, Darren Richard Feldman, Lawrence E. Garbo, Lawrence H. Einhorn; Antitumor activity of 
brentuximab vedotin in CD30 positive refractory germ cell tumors. J Clin Oncol 31, 2013 (suppl 6; abstr 327)  
20. Jain A1, Brames MJ, Vaughn DJ, Einhorn LH.Phase II clinical trial of oxaliplatin and bevacizumab in refractory 
germ cell tumors. Am J Clin Oncol. 2014 Oct;37(5):450-3.  
21. Yago Nieto, Nizar M et al. Phase II trial of bevacizumab (BEV)/high-dose chemotherapy (HDC) for refractory 
germ-cell tumors (GCT). J Clin Oncol 30, 2012 (suppl; abstr 4533) 


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22. (Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients 
with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9.  
23. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic 
anaplastic large cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6. 
24. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive 
lymphomas. N Engl J Med. 2010;363(19):1812–21 
25. Presta LG, Chen H, O'Connor SJ, et al: Humanization of an anti-vascular endothelial growth factor monoclonal 
antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593-9, 1997 
26. Ferrara N, Hillan KJ, Gerber HP, et al: Discovery and development of bevacizumab, an antiVEGF antibody for 
treating cancer. Nat Rev Drug Discov 3:391-400, 2004 
27. http://www.gene.com/download/pdf/avastin_prescribing.pdf 
28. Pecot, C.V., et al., A novel platform for detection of CK+ and CK- CTCs. Cancer Discov, 2011. 1(7): p. 580-6. 
29. Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in phase II trials in oncology. 
Biometrics 61: 540-545. 
30. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 1989; 10:  
1 - 10. 
31. http://www.R-project.org  
 
 
 


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Appendix I – Eligibility Checklist 
Phase II Study of Brentuximab Vedotin and Bevacizumab in Men with Refractory CD-30 
Positive Germ Cell Tumors (CPRC 2015LS190) 
Patient Eligibility Checklist – page 1 of 3 
Patient initials:  ______     
 
 
Patient Sequence ID# ____________________ 
 
INCLUSION CRITERIA  
A "NO" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
1. Male, ≥ 18 years of age 
    
 
2. Diagnosis of CD-30 positive GCT. CD-30 expression will be tested by immunohistochemistry (IHC) in 
archival or fresh tumor tissue as is routinely done for diagnosis  
    
 
3. 
Disease progression on imaging or tumor marker progression (clinical significance of tumor marker 
progression to be decided per the discretion of treating physician) after at least 2 lines of platinum-based 
chemotherapies unless patient is ineligible for further platinum based chemotherapy or refuses 2nd line 
platinum based chemotherapy due to toxicity. For primary mediastinal germ cell tumors, failure of first-line 
chemotherapy will be accepted. Prior high dose chemotherapy with hematopoietic stem cell rescue is 
allowed. Prior treatment with bevacizumab is allowed. 
    
 
4. 
At least 3 weeks should have elapsed since the last treatment (e.g. chemotherapy, targeted small molecule 
therapy, immunotherapy or radiation) and must have recovered to grade 1 or better from the acute effects of 
prior therapy                                         
    
 
5. Presence of measurable disease according to RECIST 1.1 
    
 
6. ECOG performance status 0 or 1 
    
 
7. 
Adequate marrow and organ function within 28 days prior to study registration as defined below:  
• Leukocytes > 3,000/µL 
• ANC > 1500/µL 
• Hemoglobin ≥ 9 g/dL 
Note:  Blood transfusion will be allowed for patients with hemoglobin < 9 g/dl and G-CSF is allowed for neutropenic patients at 
time of enrollment. 
• Platelets > 100,000/mm3  
• Creatinine:  ≤3mg/dl OR if serum creatinine > 3 mg/dl, estimated GFR >30 mL/min/1.73m2   
• INR: <1.5 x institutional upper limit of normal OR < 3 if on warfarin or other anticoagulants. There should 
be no evidence of active bleeding while on anticoagulants.  
• Total bilirubin: ≤ 2 x institutional upper limit of normal (ULN) 
• SGOT (AST) or SGPT (ALT):  < 3 x institutional upper limit of normal (< 5 x ULN  if liver metastases 
present)  
• If patient has proteinuria, it should be <2+ (< 100 mg/dl or per institutional guidelines). If proteinuria is 
2+ or greater (≥ 100 mg/dl per institutional guidelines), patients should undergo a 24- hour urine collection 
and 24 hour urinary protein should be less than < 2 grams. 
    
 
8. Sexually active men with partners of women of childbearing potential must agree to practice effective 
methods of contraception during the study and for 6 months after the last treatment 
    
 
9. Provide voluntary written consent and HIPAA authorization 
    
 
 
 


Phase II Study of Brentuximab Vedotin And Bevacizumab In Men with Refractory CD-30+ Germ Cell Tumors  
 
 
 
 
May 10, 2017 
Page 41 of 42 
CPRC #2015LS190 
Phase II Study of Brentuximab Vedotin and Bevacizumab in Men with Refractory CD-30 
Positive Germ Cell Tumors (CPRC 2015LS190) 
 
Patient Eligibility Checklist – page 2 of 3 
Patient initials:  ______     
 
 
Patient Sequence ID# ____________________   
 
EXCLUSION CRITERIA 
A "YES" response to any of the following disqualifies the patient from study entry. 
 
 
Yes      No 
10.  Prior treatment with BV 
    
 
11.  Known active brain metastases and or carcinomatous meningitis. 
    
 
12.  History of blood clots, pulmonary embolism, or deep vein thrombosis in previous 6 months unless 
controlled by anticoagulant treatment 
    
 
13.  Known history of HIV 
    
 
14.  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) 
    
 
15.  Received a live vaccine within 1 week prior to the first dose of study treatment 
    
 
16.  Has active autoimmune disease that required systemic treatment with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs 
    
 
17.  Any clinically significant active infection that requires systemic treatment at the time of enrollment 
    
 
18.  Known allergy to bevacizumab or brentuximab vedotin or any of its excipients 
    
 
19.  
Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular 
tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history 
of acute myocardial infarction (MI) within 6 months of study registration.  
    
 
20.  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess in previous 6 months 
    
 
21.  Prior major surgery within the previous 28 days of study registration and/or presence of any non-healing 
wound, fracture, or ulcer 
    
 
22.  Use of an investigational agent within the previous 28 days of study registration 
    
 
23.  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 mmHg and/or diastolic 
blood pressure (DBP) of ≥ 90mmHg] 
    
 
24.  Arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular accident 
(CVA), unstable angina, or MI within 6 months of study registration 
    
 
25.  History of posterior reversible encephalopathy syndrome 
    
 
26.  Other malignancies unless the patient is considered to be disease-free and has completed therapy for the 
malignancy > than 6 months prior to study entry 
    
 
27.  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with 
subject’s safety, provision of informed consent, or compliance to study procedures 
    
 
28.  Concurrent use of rifampin or ketoconazole 
    
 
 
 


Phase II Study of Brentuximab Vedotin And Bevacizumab In Men with Refractory CD-30+ Germ Cell Tumors  
 
 
 
 
May 10, 2017 
Page 42 of 42 
CPRC #2015LS190 
Phase II Study of Brentuximab Vedotin and Bevacizumab in Men with Refractory CD-30 
Positive Germ Cell Tumors (CPRC 2015LS190) 
 
Patient Eligibility Checklist – page 3 of 3 
Patient initials:  ______     
 
 
Patient Sequence ID# ____________________    
 
 
 
Statement of Eligibility 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this 
patient is eligible. 
 
 
 
 
 
 
 
 
 
 
 
Printed name of enrolling investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of enrolling investigator 
 
 
 
 
Date 
 
 
 
 
For Affiliate Sites Only: University of Minnesota Review of Patient Eligibility Checklist 
Patient is deemed: 
 Eligible 
 Ineligible – reason for ineligibility: ___________ 
 
 
 
 
 
 
 
 
 
 
 
Printed name of IND Sponsor-Investigator or Representative 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of IND Sponsor-Investigator or Representative 
 
Date