A Phase 1/2 Study of Brentuximab Vedotin (SGN35) in Combination With Gemcitabine for Pediatric and Young Adult Patients With Relapsed or Refractory Hodgkin Lymphoma
Phase: PHASE1
Conditions: Recurrent Adult Hodgkin Lymphoma, Recurrent Childhood Hodgkin Lymphoma, Refractory Childhood Hodgkin Lymphoma
Sponsor: National Cancer Institute (NCI)



 
 
 
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1 
Version Date: 11/18/2015 
 
Activated: 
1-14-2013 
Version Date: 
11-18-2015 
Closed: 
 
Amendment #: 
5 
 
CHILDREN’S ONCOLOGY GROUP 
 
AHOD1221 
 
A PHASE 1/2 STUDY OF BRENTUXIMAB VEDOTIN (SGN35, IND# 117117) IN 
COMBINATION WITH GEMCITABINE FOR PEDIATRIC AND YOUNG ADULT PATIENTS 
WITH RELAPSED OR REFRACTORY HODGKIN LYMPHOMA 
 
Phase 1*:  
Participation Limited to the COG Phase 1 Consortium  
and the following institutions: 
*As of amendment 4, Phase I was completed. 
Children’s Hospital of Los Angeles, Los Angeles, CA 
 
     Dr. Leo Mascarenhas 
Children’s Hospital and Research Center at Oakland, Oakland, CA 
     Dr. Carla B. Golden 
Dana-Farber Cancer Institute, Boston, MA  
 
 
     Dr. Carlos Rodriguez-Galindo 
Johns Hopkins University, Baltimore, MD 
 
 
     Dr. Kenneth J. Cohen 
Loma Linda University Medical Center, Loma Linda, CA   
     Dr. Albert Kheradpour 
Lucile Packard Children’s Hospital Stanford University, Palo Alto, CA   Dr. Neyssa M. Marina 
Montefiore Medical Center- Moses Campus, Bronx, NY 
 
     Dr. Peter Cole 
Nationwide Children’s Hospital, Columbus, OH  
 
     Dr. Mark Ranalli 
University of Kentucky, Lexington, KY  
 
 
     Dr. Lars Wagner 
Vanderbilt University, Nashville, TN 
 
      
 
     Dr. Howard Katzenstein 
 
Phase 2:  
Open to COG Institutions Groupwide 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC 
INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR 
CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND 
SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED 
MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN THIS PROTOCOL 
ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE 
TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO 
CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR 
HEALTHCARE INSTITUTION. 
 
NCI Supplied Agent:  
Brentuximab Vedotin (SGN-35, IND #117117, NSC# 749710) 
IND sponsor for Brentuximab Vedotin: DCTD, NCI 
 
STUDY CHAIR 
 
The Children’s Hospital at Montefiore 
111 E 210 St 
Bronx, NY 10467 
 
 
 
  
 
For Group Operations and Statistics & Data Center Contacts  
See: http://members.childrensoncologygroup.org 

 
 
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TABLE OF CONTENTS  
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary/Exploratory Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction: Relapsed/Refractory HL. 
9 
2.2 
Gemcitabine/Vinorelbine 
10 
2.3 
Rationale for the substitution of brentuximab vedotin for vinorelbine 
10 
2.4 
Preclinical Studies with brentuximab vedotin 
10 
2.5 
Adult Studies of brentuximab vedotin 
10 
2.6 
Pediatric Studies of brentuximab vedotin 
11 
2.7 
Pulmonary Toxicity 
12 
2.8 
Progressive multifocal leukoencephalopathy (PML) 
12 
2.9 
Rationale for Complete Response (CR) as Primary Response Endpoint 
12 
2.10 
Background for Exploratory Correlative Studies 
13 
2.11 
Overview of Proposed Pediatric Study 
14 
2.12 
Amendment Expanding Enrollment at Dose Level 2 (August 2013) 
14 
2.13 
Amendment Opening Phase 2 (Part B) 
14 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
15 
3.1 
Patient Registration 
15 
3.2 
IRB Approval 
15 
3.3 
Reservation Requirements 
16 
3.4 
Study Enrollment 
16 
3.5 
Timing 
17 
3.6 
Institutional Pathology Report 
17 
4.0 
PATIENT ELIGIBILITY CRITERIA 
18 
4.1 
Inclusion Criteria 
18 
4.2 
Exclusion Criteria 
21 
5.0 
 TREATMENT PLAN 
23 
5.1 
Overview of Treatment Plan 
23 
5.2 
Therapy Delivery Map 
25 
5.3 
Dose Escalation Schema 
27 
5.4 
Grading of Adverse Events 
27 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
28 
6.1 
Dose Modifications for Hematological Toxicity 
29 
6.2 
Dose Modifications for Non-Hematological Toxicity 
29 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
34 
7.1 
Concurrent Anticancer Therapy 
34 
7.2 
Investigational Agents 
34 
7.3 
Supportive Care 
34 
7.4 
Growth Factors 
34 
7.5 
Concomitant Medications 
35 

 
 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
35 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
35 
8.2 
Required Observations Following Completion of Protocol Therapy 
37 
8.3 
Radiology Studies 
37 
8.4 
Mobilization and Collection of Peripheral Blood Stem Cells 
39 
8.5 
Correlative Biology Studies (As of amendment 4, Part A was completed. This section is 
for Part B.) 
41 
9.0 
DRUG INFORMATION 
42 
9.1 
Brentuximab vedotin 
42 
9.2 
Agent Ordering and Agent Accountability 
47 
9.3 
Clinical Drug Request 
47 
9.4 
Agent Inventory Records 
48 
9.5 
Gemcitabine 
48 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
51 
10.1 
Criteria for Removal from Protocol Therapy 
51 
10.2 
Off Study Criteria 
51 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
52 
11.1 
Sample Size and Study Duration 
52 
11.2 
Definitions for Part A 
52 
11.3 
Dose Escalation and Determination of MTD (Part A) 
53 
11.4 
Evaluation of Expansion Cohort at Dose Level 2 Using Revised DLT Definitions 
(Amendment #2) 
54 
11.5 
Response Analysis for Part A 
54 
11.6 
Study Design for Part B 
54 
11.7 
Methods of Analysis for Part B 
55 
11.8 
Evaluability for Response for Part B 
55 
11.9 
Evaluability for Toxicity 
56 
11.10 Inclusion of Children, Women and Minorities 
57 
11.11 Gender and Minority Accrual Estimates 
57 
12.0 
EVALUATION CRITERIA 
58 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
58 
12.2 
Imaging Lesion Evaluation 
58 
12.3 
Response Criteria 
61 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
63 
13.1 
Purpose 
63 
13.2 
Determination of reporting requirements 
63 
13.3 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
64 
13.4 
When to Report an Event in an Expedited Manner 
67 
13.5 
General Instructions for Expedited Reporting via CTEP-AERS 
67 
13.6 
Definition of Onset and Resolution of Adverse Events 
68 
13.7 
Other Recipients of Adverse Event Reports 
69 
13.8 
Reporting Secondary AML/MDS 
69 
13.9 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
70 
13.10 Routine Adverse Event Reporting 
71 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
71 
14.1 
Categories of Research Records 
71 
14.2 
CDUS 
72 

 
 
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14.3 
CRADA/CTA 
72 
14.4 
Data and Safety Monitoring Plan 
73 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
74 
15.1 
Pregnancy 
75 
15.2 
Recommended Technique 
75 
15.3 
FDG Dosing and Injection 
76 
15.4 
PET Scanning Protocol 
76 
15.5 
After Completion of the PET Scan 
77 
15.6 
FDG Handling and Dose Documentation 
77 
15.7 
PET Imaging Quality Control Standards 
77 
REFERENCES 
79 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
82 
APPENDIX II: CTEP AND CTSU REGISTRATION PROCEDURES 
83 
APPENDIX III: CORRELATIVE STUDIES GUIDE (AS OF AMENDMENT 4, PART A IS CLOSED. 
THIS IS ONLY FOR PART B.) 
85 
APPENDIX IV: GUIDELINES FOR PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION 
PROCEDURE (AS OF AMENDMENT 4, PART A IS CLOSED. THIS IS ONLY FOR PART 
B.) 
86 
APPENDIX V: PERIPHERAL BLOOD STUDIES FORM (AS OF AMENDMENT 4, PART A IS 
CLOSED. THIS IS ONLY FOR PART B.) 
88 
APPENDIX VI: BPC SPECIMEN TRANSMITTAL FORM FOR PERIPHERAL BLOOD STUDIES 
(AS OF AMENDMENT 4, PART A IS CLOSED. THIS IS ONLY FOR PART B.) 
89 
APPENDIX VII: PREGNANCY INFORMATION FORM 
90 
APPENDIX VIII:  CYP3A4 INDUCERS AND INHIBITORS 
91 
APPENDIX IX:  POSSIBLE DRUG INTERACTIONS 
92 
APPENDIX X: YOUTH INFORMATION SHEETS 
93 
 

 
 
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STUDY COMMITTEE 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
   
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
   
  
 
  
 
  
 
   
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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STUDY COMMITTEE, cont. 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
  
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
  
 
 
  
 
 
   
  
   
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
NCI-Supplied Agent: 
 
 
Brentuximab Vedotin (SGN-35, NSC #749710, IND# 117117) 
 
 
IND Holder: DCTD, NCI 
  
 
 
Commercial Agent : 
 
Gemcitabine (Gemzar, NSC # 613327) 
 
 
 
 
SEE APPENDIX V FOR SPECIMEN SHIPPING ADDRESSES 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will 
help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of 
information about subjects collected during the course of our covered studies. The researchers involved in the studies 
cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the 
federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings.  
However, the subject or the researcher may choose to voluntarily disclose the protected information under certain 
circumstances. For example, if the subject or his/her guardian requests the release of information in writing, the 
Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA 
request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others. 
 
ABSTRACT 
Brentuximab vedotin (previously known as SGN35; currently marketed under the brand name Adcetris) is 
an antibody-drug conjugate containing an anti-CD30 murine/human chimeric monoclonal antibody 
(cAC10; brentuximab) linked to monomethylauristatin E (MMAE; vedotin). After binding CD30, a 
transmembrane receptor highly expressed in both Hodgkin Lymphoma (HL) and anaplastic large cell 
lymphoma (ALCL), brentuximab vedotin is internalized and MMAE is released into the cytoplasm where 
it causes M-phase cell cycle arrest and apoptosis. Brentuximab vedotin has been evaluated in adults, at the 
MTD of 1.8 mg/kg every three weeks. The observed complete response (CR) rate was 34% among patients 
with HL (95% CI, 25-45%) and 53% (95% CI: 40-67%) among patients with ALCL. The most common 
treatment related toxicity was peripheral sensory neuropathy (44%). Based partly on these results, the FDA 
has approved brentuximab vedotin for the treatment of patients with refractory HL or ALCL.  
 
This COG trial will study brentuximab vedotin in the context of a novel combination regimen, with 
gemcitabine, for pediatric patients with high-risk relapsed or refractory Hodgkin lymphoma. The primary 
objectives of this study are to define the appropriate dose of brentuximab vedotin when given in 
combination with gemcitabine, to describe the toxicity associated with this regimen, and to determine the 
CR rate among patients with relapsed or refractory HL treated with this combination. Exploratory objectives 
include describing the proportion of patients able to mobilize stem cells after treatment with this regimen 
and describing the relationship between disease response and changes in serum TARC and miRNA profiles. 
 
Part A will enroll patients with relapsed/refractory HL in a phase 1 dose finding study of brentuximab 
vedotin in combination with gemcitabine. Gemcitabine will be administered on days 1 and 8 of a 21 day 
cycle at a fixed dose. Brentuximab vedotin will be investigated at a starting dose of 1.4 mg/kg administered 
on day 1 and escalated if tolerated. As of amendment 4, Part A was completed. 
 
Part B will evaluate the response rate in patients with HL to the combination of gemcitabine and 
brentuximab vedotin at the dose defined in Part A. 
 
 

 
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Version Date: 11/18/2015 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose of brentuximab vedotin in combination with gemcitabine administered every 
three weeks to children with relapsed or primary refractory Hodgkin lymphoma 
(HL). 
 
1.1.2 
To define and describe the toxicities of brentuximab vedotin in combination with 
gemcitabine administered on this schedule. 
 
1.1.3 
To determine the CR rate after treatment with four cycles of gemcitabine with 
brentuximab vedotin among patients with relapsed or refractory HL. 
 
 
1.2 
Secondary/Exploratory Aims 
 
1.2.1 
To preliminarily define the antitumor activity of brentuximab vedotin in 
combination with gemcitabine within the confines of a Phase 1 study. 
 
1.2.2 
To describe the overall response rate (ORR) after 4 cycles of therapy among 
patients with relapsed or refractory HL. 
 
1.2.3 
To describe the proportion of patients with HL able to mobilize an adequate yield 
of CD34+ stem cells after gemcitabine with brentuximab vedotin. 
 
1.2.4 
To describe the relationship between disease response among patients with HL and 
changes in TARC during treatment, and to determine if specific miRNA profiles 
correlate with response to treatment. 
 
1.2.5 
To describe the frequency of the FcγRIIIa-158 V/F polymorphism among patients 
who experience pulmonary toxicity on this protocol. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction: Relapsed/Refractory HL. 
A minority of patients with advanced stage HL will fail to achieve a CR with first-line 
therapy, and as many as 30% of those who initially respond will subsequently relapse. 
Multiple second-line chemotherapy regimens have been associated with high overall 
response rates for patients with refractory or relapsed HL, and have been the subject of 
recent reviews.1,2 Some patients with low-risk relapses (limited-stage initial disease and 
late relapse more than one year after completion of therapy) may be cured with 
conventional chemotherapy alone. For those patients with primary refractory disease or 

 
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higher risk relapse (early relapse; advanced stage disease), long-term disease-free survival 
remains relatively low. 
 
High-dose therapy with autologous stem cell rescue (ASCR) appears to significantly 
improve outcome relative to treatment with standard-dose chemotherapy alone for patients 
with refractory disease or high-risk relapses. However, lack of a CR after reinduction 
therapy, indicated by residual FDG avidity on PET scanning, portends an increased risk of 
relapse after ASCR.3-6 Therefore, it is critically important to identify a retrieval regimen 
that will maximize the CR rate for patients with relapsed or refractory HL prior to ASCR. 
 
Patients with second or subsequent relapse, or recurrence after ASCR, will be excluded 
from this Phase I/II trial due to the concern that this more heavily treated patient population 
will be at an increased risk of hematologic toxicity from this experimental regimen. 
 
2.2 
Gemcitabine/Vinorelbine 
The Children’s Oncology Group (COG) has demonstrated the safety and efficacy of 
combination chemotherapy with Gemcitabine/Vinorelbine (GV) for pediatric patients with 
relapsed/refractory HL (76% overall response rate by CT criteria; 45% CR by PET 
criteria).7,8 Successful mobilization of stem cells for subsequent autologous transplantation 
has also been demonstrated following this regimen.9 The COG HL Committee is interested 
in further developing GV (1) as a backbone for testing novel retrieval strategies and (2) for 
incorporation within therapeutic protocols for patients with newly diagnosed HL. 
Compared to alternative intensification and retrieval regimens, this combination offers the 
advantage of avoiding the addition of agents that are associated with late treatment 
sequelae, such as anthracyclines or alkylators. 
 
2.3 
Rationale for the substitution of brentuximab vedotin for vinorelbine 
As described below, the antibody-drug conjugate brentuximab vedotin exerts its cytotoxic 
effect through a mechanism similar to vinorelbine. However, a greater overall response 
rate has been described after treatment with brentuximab vedotin (76%, with 34% CRs) 
than has been reported for vinorelbine (50%, with few CRs).10-12 The clinical study of the 
combination of gemcitabine with brentuximab vedotin is further supported by preclinical 
data demonstrating that CD30 targeting will sensitize lymphoma cells to gemcitabine.13,14 
 
2.4 
Preclinical Studies with brentuximab vedotin 
Brentuximab vedotin (previously known as SGN35) is an antibody-drug conjugate 
containing an anti-CD30 murine/human chimeric monoclonal antibody (cAC10; 
brentuximab) covalently linked to monomethylauristatin E (MMAE; vedotin) by an 
enzyme-cleavable peptide linker. CD30 is a transmembrane receptor highly expressed in 
both HL and ALCL. After binding to CD30, brentuximab vedotin is internalized and is 
transported to lysosomes, where the peptide linker is selectively cleaved, releasing MMAE 
into the cytoplasm. Like vinorelbine, MMAE exerts its antineoplastic effect through 
inhibition of tubulin polymerization, leading to M-phase arrest and apoptosis. 
 
2.5 
Adult Studies of brentuximab vedotin 
The safety and efficacy of brentuximab vedotin has been evaluated in adults with HL or 
ALCL, using the MTD of 1.8 mg/kg every three weeks. Treatment related toxicity included 
peripheral sensory neuropathies (44%), fatigue (42%), nausea (41%), diarrhea (34%), 
pyrexia (31%), neutropenia (21%) and vomiting (20%). Among 102 patients with HL, the 
observed ORR was 76% (95% CI 65-83%), with a CR rate of 34% (95% CI 25-45%).15 
The median time to objective response was 5.7 weeks (range, 5.1 to 56 weeks), and the 

 
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median time to CR was 12 weeks (range, 5.1 to 56 weeks). Among the 102 patients 
enrolled, the median number of cycles on this study was 9 (range, 1 to 16 cycles), the mean 
number of cycles was 10. 
 
Following the recommended intravenous (IV) dose of 1.8 mg/kg every 3 weeks, maximum 
concentrations were typically observed at the end of infusion. A multi-exponential decline 
in brentuximab vedotin serum concentrations was observed with a terminal half-life of 
approximately 4 to 6 days. Exposures were approximately dose proportional. After 
multiple-dose administration of brentuximab vedotin, steady-state was achieved by 21 
days, consistent with the terminal half-life estimate. Minimal to no accumulation was 
observed with multiple doses at the q3wk (every 3 weeks) schedule. 
 
 
 
 
 
 
 
Brentuximab vedotin is being investigated for use in earlier lines of therapy for adults with 
HL. Ongoing studies include a phase 3 randomized, placebo-controlled trial evaluating 
brentuximab vedotin for the treatment of HL patients at high risk for relapse after 
autologous stem cell transplant (SCT), a phase 2 study evaluating the efficacy and safety 
of retreatment with brentuximab vedotin, a phase 2 study evaluating the efficacy and safety 
of brentuximab vedotin in patients with CD30-positive NHL, a phase 2 study evaluating 
the efficacy and safety of brentuximab vedotin in patients with CD30-positive non-
lymphomatous malignancies, a phase 1 study evaluating the safety of brentuximab vedotin 
in combination with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or AVD 
(doxorubicin, vinblastine, dacarbazine) for patients with newly-diagnosed HL, and a phase 
1 study evaluating the safety of brentuximab vedotin in sequence and in combination with 
multi-agent chemotherapy for patients with newly diagnosed CD30-positive mature T-Cell 
and NK-Cell neoplasms, including systemic ALCL.  
 
2.6 
Pediatric Studies of brentuximab vedotin 
There have been no pediatric-specific trials of brentuximab vedotin. Nine patients on the 
early phase trials of brentuximab vedotin were less than 18 years old (5 HL, 4 ALCL; age 
range 12-17 years).16 Four of the nine had undergone prior ASCT. All nine patients were 
treated with brentuximab vedotin as a single agent on either phase I or phase 2 trials, given 
either weekly (0.8-1.2 mg/kg/dose from between 6-9 doses) or every three weeks (1.2 – 
1.8 mg/kg/dose for 6-26 cycles). Six of these were treated with 1.8 mg/kg every 3 weeks, 
for a median of 15 cycles.16 
 
 
 
 
 
 
  
 
 

 
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2.7 
Pulmonary Toxicity 
 
2.7.1 
Pulmonary toxicity due to gemcitabine is rare  
When gemcitabine is administered alone, severe pulmonary toxicity is rare 
(~1%).17 Gemcitabine induces pulmonary toxicity at greater frequency only when 
combined with other therapies known to cause lung injury, such as bleomycin.18 
No cases of noncardiogenic pulmonary edema were observed among pediatric 
patients treated with gemcitabine and vinorelbine on AHOD0321.8 
 
2.7.2 
Pulmonary toxicity after gemcitabine with SGN30  
It is possible that the combination of gemcitabine with brentuximab vedotin will 
be associated with unacceptable pulmonary toxicity. Grade 3-5 pneumonitis was 
observed among five adults (aged 36-62) out of 23 treated with the unconjugated 
anti-CD30 antibody (SGN30), in combination with gemcitabine, vinorelbine, and 
pegylated liposomal doxorubicin.19 Of note, all five patients with pulmonary 
toxicity had a V/F polymorphism in the FcγRIIIa gene (p = 0.008). 
 
Nevertheless, clinical data suggest that pulmonary toxicity may be less frequent 
among pediatric lymphoma patients treated with the combination of gemcitabine 
and brentuximab vedotin. The dose of the unconjugated anti-CD30 antibody 
(SGN30) that was associated with pulmonary toxicity (12 mg/kg on days 1 and 8 
of each 21-day cycle, a total of 24 mg/kg/cycle) was significantly higher than the 
phase 2 dose of brentuximab vedotin (1.8 mg/kg/cycle, given every 3 weeks). No 
clinically meaningful pulmonary toxicity signal has been associated with 
brentuximab vedotin monotherapy at this dose.15,20  
 
2.7.3 
Pulmonary toxicity from brentuximab vedotin in combination with bleomycin. 
Severe pulmonary toxicity has been described in 10 of 25 patients treated with 
brentuximab vedotin in combination with doxorubicin, bleomycin, vinblastine, 
and dacarbazine (ABVD).21 Patients presented with cough and dyspnea. Interstitial 
infiltration and/or inflammation were observed on plain films and/or computed 
tomography of the chest. Five patients had a maximum severity ≥ Grade 3 (3 with 
Grade 3 and 2 with Grade 4). Most patients responded favorably to corticosteroid 
therapy. In contrast, no further pulmonary toxicity was observed among patients 
treated with brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine 
(AVD),22 suggesting that brentuximab vedotin can be successfully combined with 
chemotherapy agents not frequently associated with pulmonary toxicity. 
 
2.8 
Progressive multifocal leukoencephalopathy (PML) 
In January 2012, the US Food and Drug Administration (FDA) issued a warning to health 
care professionals noting that three cases of progressive multifocal leukoencephalopathy 
(PML) have been described among patients treated with brentuximab vedotin, including 
two diagnosed with PML after the FDA approval of brentuximab vedotin for patients with 
relapsed/refractory lymphoma. A mechanism by which brentuximab vedotin causes PML 
is not known. Due to the serious nature of PML, a new Boxed Warning highlighting this 
risk has been added to the drug label. The FDA recommends that healthcare professionals 
suspend brentuximab vedotin dosing if PML is suspected, and discontinue the drug therapy 
if a diagnosis of PML is confirmed. 
2.9 
Rationale for Complete Response (CR) as Primary Response Endpoint 

 
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Among patients with primary refractory disease or early relapse of lymphoma, high-dose 
therapy with autologous stem cell rescue improves outcome relative to patients treated with 
standard-dose chemotherapy alone. However, lack of a CR after reinduction therapy, 
indicated by residual FDG avidity on PET scanning, portends an increased risk of relapse 
after autologous SCT.3-6 Therefore, identifying a retrieval regimen that will allow the 
greatest number of patients to achieve a CR prior to autologous SCT is an objective with 
greater clinical relevance than maximizing ORR. 
 
2.10 
Background for Exploratory Correlative Studies 
 
 
2.10.1 TARC as a biomarker for response among patients with HL 
Hodgkin’s Reed–Sternberg (HRS) cells typically reside among a background of 
reactive inflammatory cells, consisting of a dense infiltrate of T cells, histiocytes, 
eosinophils, and plasma cells. These inflammatory cells support the HRS cells by 
secreting both immunosuppressive factors and pro-survival factors. HRS cells 
appear to attract these cells to the microenvironment by secreting type 2 helper T 
chemokines and cytokines, such as thymus and activation-regulated chemokine 
(TARC, or CCL17).23 Serum levels of TARC correlate with disease activity in 
patients with HL.24-26 Recent data from University Medical Center Groningen, 
(n=60) showed that using plasma TARC, response to chemotherapy can be 
assessed after one cycle of chemotherapy in both early and advanced stage HL 
patients.27 In this study, plasma will be collected from patients prior to the start of 
therapy and at the end of each cycle to determine if TARC can provide an early 
measure of disease response in pediatric HL. 
 
2.10.2 Prognostic value of circulating miRNA  
MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene 
expression via post-transcriptional suppression of mRNA translation. Recently, it 
has been shown that tumor cells release miRNAs into the circulation where they 
can be detected in serum or plasma.28 Moreover, these studies showed that 
miRNAs in serum or plasma remain stable after shipment. Circulating miRNAs 
have been described as disease specific biomarkers in patients with pancreatic, 
gastric, breast, ovarian and colorectal cancer and even in other diseases states such 
as acute myocardial infarction.29 Previous work has identified differential 
expression of 38 circulating miRNAs (including miR-9, miR-19a and miR-20a) in 
adult HL patients compared to tissue derived from reactive lymph nodes,30 and 30 
miRNAs in microdissected HRS cells compared to CD77+ progenitor cells.31 
miRNAs appear to regulate several growth pathways involved with H/RS cell 
proliferation, including p21 and NF-κB.32,33 We propose to explore the significance 
of circulating miRNA in pediatric HL patients by collecting serum prior to start of 
treatment and at the end of each cycle. 
 
2.10.3 FcγRIIIa-158 receptor single nucleotide polymorphisms (SNPs) 
The FcγRIIIa receptor 158 valine (V) allotype displays a higher affinity for human 
immunoglobulin G1 and increased antibody-dependent cellular cytotoxicity 
(ADCC).34 As described above (section 2.7.2) this polymorphism was present in 
five of five patients who experienced Grade 3 or 4 pulmonary toxicity after 
treatment with SGN30 in combination with gemcitabine, vinorelbine, and 
pegylated liposomal doxorubicin.19 To determine if there is a similar association 

 
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between FcγRIIIa (V/F) heterozygosity and pulmonary toxicity after treatment 
with gemcitabine plus brentuximab vedotin, peripheral blood mononuclear cells 
will be banked for retrospective analysis. If pulmonary toxicity is observed during 
this trial, analysis of this SNP will be performed on all patients with available 
sample. 
 
2.11 
Overview of Proposed Pediatric Study 
This is a single-arm, nonrandomized trial studying the combination of brentuximab vedotin 
with gemcitabine. The optimal dose of brentuximab vedotin for use in combination with 
gemcitabine will be determined in the Phase 1 portion of the study, Part A. Two dose levels 
will be tested. The Phase 2 portion, Part B, will test the efficacy of gemcitabine in 
combination with brentuximab vedotin at the dose level identified as optimal in the Phase 
1 portion.  
 
In both phases, brentuximab vedotin and gemcitabine will be administered in three-week 
cycles. Therapy will be interrupted if there is evidence of progressive disease or drug 
related dose-limiting toxicity that requires removal from therapy. Response will be 
evaluated after every two cycles. 
 
After the first two cycles, patients with CR are allowed the option of going off protocol 
therapy for stem cell transplantation (See Section 8.4). Patients with PD will be removed 
from protocol therapy. All other patients will continue on therapy to cycles three and four. 
 
After every subsequent response evaluation (i.e. after cycle 4, and every subsequent even-
numbered cycle), patients without PD have the option of either continuing treatment or 
going off protocol therapy for alternative treatment, such as stem cell transplantation. 
Therapy may otherwise continue for up to a total of 16 cycles (approximately 12 months 
from study enrollment). 
 
2.12 
Amendment Expanding Enrollment at Dose Level 2 (August 2013) 
As of August 2013, 9 patients have been treated on AHOD1221: three at dose level 1 and 
six at dose level 2. None of the patients treated at dose level 1 experienced dose limiting 
toxicity. Two patients treated at dose level 2 experienced non-hematologic dose limiting 
toxicity. One patient presented to the emergency room with suspected sepsis and was found 
to be hypotensive, requiring medical management (Grade 3 hypotension). This patient was 
subsequently demonstrated to have pre-existing, steroid-induced adrenal insufficiency, 
which likely contributed to the hypotension. The other patient developed asymptomatic 
Grade 3 elevation of liver enzymes on Day 8 of the first treatment cycle, which decreased 
to eligibility criteria by Day 21 of the cycle. Both patients had resolution of all toxicity, 
and continued on study treatment with dose reduction as prescribed by protocol. We 
therefore plan to accrue an additional six patients at dose level 2 to further evaluate toxicity. 
 
 
2.13 
Amendment Opening Phase 2 (Part B) 
Six patients enrolled in the dose level 2 expansion cohort. None of these six patients 
experienced a non-hematologic dose limiting toxicity (DLT). One of these was found to be 
ineligible for evaluation of hematologic DLT, because filgrastim was administered during 
the first cycle of therapy in preparation for stem cell harvesting. None of the five remaining 
patients experienced a hematologic DLT.  
 
After Amendment 3, criteria were defined for the evaluation of the dose level 2 expansion 
cohort (See Section 11.4). Per this section, dose level 2 is determined to be the 

 
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recommended phase 2 dose (RP2D), because the number of DLTs in this expansion cohort 
did not exceed one. Phase 1 (Part A) can close and the protocol can proceed to Phase 2 
(Part B). Patients treated on the Phase 1 component at dose level 2 will be included in 
analysis of response for Part B provided that they are eligible and evaluable for response. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
Note: This study is not on the CTSU Menu (i.e. it is not posted to the CTSU web site) but is 
supported by the CTSU Regulatory Office, OPEN and Rave. 
 
3.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry system once authorization for the release of 
protected health information (PHI) has been obtained. The COG patient ID number is used 
to identify the patient in all future interactions with COG. If you have problems with the 
registration, please refer to the online help.  
 
In order for an institution to maintain COG membership requirements, every newly diagnosed 
patient needs to be offered participation in ACCRN07, Protocol for the Enrollment on the 
Official COG Registry, The Childhood Cancer Research Network (CCRN). 
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. 
Each patient will be assigned only one BPC number per COG Patient ID. For additional 
information about the labeling of specimens please refer to the Pathology and/or Biology 
Guidelines in this protocol. 
 
Please see Appendix II for detailed CTEP Registration Procedures for Investigators and 
Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures including: how 
to download site registration documents; requirements for site registration, submission of 
regulatory documents and how to check your site’s registration status. 
 
3.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB approval and 
supporting documentation to the CTSU Regulatory Office before they can be approved to 
enroll patients. Allow 3 business days for processing. The submission must include a fax 
coversheet (or optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). 
The CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval 
letter. All CTSU forms can be located on the CTSU web page (https://www.ctsu.org). Any 
other regulatory documents needed for access to the study enrollment screens will be listed 
for the study on the CTSU Member’s Website under the RSS Tab. 
 
IRB/REB approval documents may be faxed (1-215-569-0206), 
E-mailed (CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office. 
When a site has a pending patient enrollment within the next 24 hours, this is considered a 
“Time of Need” registration. For Time of Need registrations, in addition to marking your 
submissions as ‘URGENT’ and faxing the regulatory documents, call the CTSU 
Regulatory Helpdesk at: 1-866-651-CTSU. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the Regulatory 
Support System (RSS) site registration status page of the CTSU members’ web site by 

 
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entering credentials at https://www.ctsu.org. For sites under the CIRB initiative, IRB data 
will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to the 
CTSU Regulatory Office for initial, continuing or amendment review. This 
information will be provided to the CTSU Regulatory Office from the CIRB at the time 
the site’s Signatory Institution accepts the CIRB approval. The Signatory site may be 
contacted by the CTSU Regulatory Office or asked to complete information verifying the 
participating institutions on the study. Other site registration requirements (i.e., laboratory 
certifications, protocol-specific training certifications, or modality credentialing) must be 
submitted to the CTSU Regulatory Office or compliance communicated per protocol 
instructions. 
 
3.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be made 
following the steps below. Reservations may be obtained 24 hours a day through the 
Oncology Patient Enrollment Network (OPEN) system.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Registration system in OPEN. Prior to discussing protocol entry with 
the patient, site staff must use the CTSU OPEN Slot Reservation System to ensure that a 
slot on the protocol is available for the patient. Once a slot-reservation confirmation is 
obtained, site staff may then proceed to enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and password.  
2) In order to make a reservation, the patient must have an OPEN patient number. Click 
on the ‘Slot Reservation’ tab to create an OPEN patient number, under ‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the COG 
Patient ID, and choose the required stratum (if applicable) in order to obtain a 
reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under the ‘Help’ tab 
in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_QuickReferen
ce_SiteUserGuide_102612.pdf&ftype=PDF 
3.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the lead protocol 
organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient position in the Rave database. OPEN can be accessed at https://open.ctsu.org or 
from the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  
 

 
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Prior to accessing OPEN, site staff should verify the following: 
 

All eligibility criteria have been met within the protocol stated timeframes. 

All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
 
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL (https://open.ctsu.org). For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
3.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is projected 
to start must be no later than five (5) calendar days after the date of study enrollment. 
Patients who are started on protocol therapy on a Phase II study prior to study 
enrollment will be considered ineligible.  
 
3.6 
Institutional Pathology Report 
Immediately following enrollment, the most recent institutional pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into RAVE. The 
report must include the associated study number and COG patient registration and 
accession numbers. Personal identifiers, including the patient’s name and initials must be 
removed from the institutional pathology report prior to submission. Note that, as detailed 
in Section 4.1.2, all patients must have histologic verification of Hodgkin disease at the 
time of relapse, and the institutional pathology report from this biopsy should be submitted. 
No additional biopsy is required for patients with primary refractory disease (i.e. no prior 
CR); for these patients, the initial diagnostic pathology report should be sent. 
 
 

 
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4.0 
PATIENT ELIGIBILITY CRITERIA  
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
must be no older than seven (7) days at the start of therapy. Laboratory tests need not be 
repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility. If a post-
enrollment lab value is outside the limits of eligibility, or laboratory values are older than 7 
days, then the following laboratory evaluations must be re-checked within 48 hours prior to 
initiating therapy: CBC with differential, bilirubin, ALT (SGPT) and serum creatinine. If the 
recheck is outside the limits of eligibility, the patient may not receive protocol therapy and 
will be considered off protocol therapy. Imaging studies must be obtained within 14 days 
prior to start of protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th. 
 
See Section 8.1 for required studies to be obtained prior to starting protocol therapy. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age: Patients must be > than 12 months and  30 years of age at the time of 
study enrollment. 
 
4.1.2 
Diagnosis: Patients must have had histologic verification of the malignancy at 
original diagnosis. Patients must have histologic verification of recurrent 
Hodgkin disease at the time of relapse. No additional biopsy is required for 
patients with primary refractory disease (i.e. no prior CR). 
 
4.1.2.1 Parts A and B- Patients with Hodgkin lymphoma (HL) are eligible for both 
the phase 1 and 2 portions, if they are in one of the following categories: 
• 
Primary refractory disease (i.e. no prior CR)  
• 
Very early relapse (< 6 months from the end of initial therapy, 
including chemotherapy ± radiation) 
• 
Advanced stage (III or IV) at diagnosis who relapse less than one 
year from the end of initial therapy. 
 
Note that patients with low-stage disease (IA or IIA) at initial diagnosis, 
who were treated with radiation alone or fewer than four cycles of 
chemotherapy will NOT be eligible (See Section 4.2.6) 
 
4.1.3 
Disease Status:  
Patients must have measurable disease, documented by clinical and radiographic 

 
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criteria. See Section 12 for criteria for measurable disease. 
 
4.1.4 
Life Expectancy: Patients must have a life expectancy of ≥ 8 weeks (≥ 56 days). 
 
4.1.5 
Performance Level: Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I). Patients who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
4.1.6 
Prior Therapy 
 
4.1.6.1 Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer chemotherapy. 
 
a. Myelosuppressive chemotherapy: 
At least 14 days after the last dose of myelosuppressive chemotherapy 
(28 days if prior nitrosourea). Note: Cytoreduction with hydroxyurea 
can be initiated and continued for up to 24 hours prior to the start of 
therapy. 
b. Hematopoietic growth factors: At least 14 days after the last dose of a 
long-acting growth factor (e.g. Neulasta) or 7 days for short-acting 
growth factor. For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur. The 
duration of this interval must be discussed with the study chair.  
c. Biologic (anti-neoplastic agent): At least 7 days after the last dose of 
a biologic agent. For agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur. The 
duration of this interval must be discussed with the study chair. 
d. Immunotherapy: At least 42 days after the completion of any type of 
immunotherapy, e.g. tumor vaccines. 
e. Monoclonal antibodies: At least 3 half-lives of the antibody after the 
last dose of a monoclonal antibody. (See table on DVL homepage 
listing monoclonal antibody half-lives: 
https://members.childrensoncologygroup.org/_files/disc/dvl/Half-
lifetableforeligibility.pdf.) 
f. 
XRT: 
At least 14 days after local palliative XRT (small port); At least 150 
days must have elapsed if prior TBI, craniospinal XRT or if  50% 
radiation of pelvis; At least 42 days must have elapsed if other 
substantial BM radiation. 
g. Stem Cell Infusion without TBI: Patients with prior autologous or 
allogeneic Stem Cell Transplant (SCT) are excluded from this study. 
h. Bleomycin: At least 28 days must have elapsed since the most recent 
dose of bleomycin, to allow adequate time to detect evidence of 
bleomycin-related pulmonary toxicity. 

 
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4.1.7 
Organ Function Requirements 
 
4.1.7.1 Adequate Bone Marrow Function Defined as: 
As of amendment 4, Part A was completed. 
a. Part A: For patients without known bone marrow involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/L 
- 
Platelet count  100,000/L (transfusion independent, defined as 
not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. Part B: For patients without known bone marrow involvement: 
- 
Peripheral absolute neutrophil count (ANC)  750/L 
- 
Platelet count  75,000/L (transfusion independent, defined as 
not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
c. 
Patients with lymphoma metastatic to bone marrow who have 
granulocytopenia, anemia, and/or thrombocytopenia will be 
eligible for study but not evaluable for hematologic toxicity (In 
Part A, there will be a maximum of one per cohort). Such patients 
must meet the blood counts in 4.1.7.1.a (may receive transfusions 
provided they are not known to be refractory to red cell or platelet 
transfusions). If dose-limiting hematologic toxicity is observed, 
all subsequent patients enrolled in Part A must be evaluable for 
hematologic toxicity. 
 
4.1.7.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR35 (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
4.1.7.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. For the 
purpose of this study, the ULN for SGPT is 45 U/L.  
- 
Serum albumin  2 g/dL. 
 
 

 
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4.1.7.4 Adequate Pulmonary Function Defined as: 
- 
No evidence of dyspnea at rest, no exercise intolerance due to 
pulmonary insufficiency, and a pulse oximetry > 92% while 
breathing room air. 
- 
FEV1/FVC > 60% by pulmonary function test (PFT), unless due to 
large mediastinal mass from HL. Carbon monoxide diffusion 
capacity (DLCO), FEV1, and Forced Vital Capacity all > 50% 
predicted value. Note: Pulmonary function testing is not required 
for children < 8 years old, or for any child who is developmentally 
unable to comply with pulmonary function testing. 
 
4.1.7.5 Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Nervous system disorders (CTCAE v4) resulting from prior therapy 
must be  < Grade 2. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal or teratogenic toxicities as seen in animal/human studies. Pregnancy tests 
must be obtained in girls who are post-menarchal. Males or females of 
reproductive potential may not participate unless they have agreed to use an 
effective contraceptive method during protocol therapy and for at least 30 days 
after the last dose of brentuximab vedotin. Abstinence is an acceptable method of 
birth control. 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids: Patients receiving stable or decreasing corticosteroids for 
other concurrent conditions (e.g. asthma, autoimmune diseases, rash, 
documented adrenal insufficiency) are eligible for this study. 
 
4.2.2.2 Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
4.2.2.3 Anti-cancer Agents: Patients who are currently receiving other anti-cancer 
agents are not eligible. 
 
 

 
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4.2.3 
Infection: Patients who have an uncontrolled infection are not eligible. 
 
4.2.4 
Patients with an immunodeficiency that existed prior to diagnosis, such as primary 
immunodeficiency syndromes, organ transplant recipients and children on current 
systemic immunosuppressive agents are not eligible. 
 
4.2.5 
Patients known to be positive for HIV are not eligible. 
 
4.2.6 
Prior Therapy 
 
4.2.6.1 Patients with prior exposure to brentuximab vedotin are not eligible. 
NOTE: Prior exposure to gemcitabine is NOT an exclusion criterion. 
 
4.2.6.2 Patients who have undergone prior autologous or allogeneic SCT are not 
eligible. 
 
4.2.6.3 Patients with HL who were stage IA or IIA at initial diagnosis and treated 
with either radiation alone or < 4 cycles of chemotherapy are not eligible. 
 
4.2.7 
Patients who have received a prior solid organ transplantation are not eligible.  
 
4.2.8 
Patients with known hypersensitivity to E.coli-derived proteins, Filgrastim, or 
any component of Filgrastim are not eligible. 
 
4.2.9 
Patients who in the opinion of the investigator may not be able to comply with 
the safety monitoring requirements of the study are not eligible. 
 
4.2.10 Regulatory Requirements  
 
4.2.10.1 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
4.2.10.2 All institutional, FDA, and NCI requirements for human studies must 
be met. 
 
 

 
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5.1.1 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 21 days if the patient has at least stable disease and 
has again met laboratory parameters as defined in the eligibility section, Section 
4.0 except for the following repeat cycle modified starting criteria: ANC ≥ 750/L, 
platelets ≥ 50,000/L. Patients with lymphoma metastatic to bone marrow at study 
enrollment, who have granulocytopenia and/or thrombocytopenia due to disease 
on scheduled start of Cycle 2 may begin, regardless of blood counts. All 
subsequent cycles, if given, should not begin until the ANC is  750/L and the 
platelet count is  50,000/L (transfusion independent, defined as at least 2 days 
after last platelet transfusion). 
 
Response will be evaluated after every even-numbered cycle. Patients with CR 
after any cycle may go off protocol therapy for stem cell transplantation (See 
Section 8.4) or continue with two more cycles per investigator decision. After 
every subsequent response evaluation (i.e. after cycle 4, and every subsequent 
even-numbered cycle), patients have the option of going off protocol therapy for 
alternative treatment, such as stem cell transplantation. Therapy may otherwise 
continue for up to a total of 16 cycles (approximately 12 months from study 
enrollment). Therapy will be interrupted if there is evidence of progressive disease 
or drug related toxicity that requires removal from therapy. 
 
 

 
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5.2.2 
Required Observations  
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
1  History; Physical Exam with vital signs 
2 
Performance Status; Electrolytes including Ca++, PO4, Mg++ 
3 
CBC, differential, platelets 
4 
Correlative biology studies. See Section 8.5and Appendix III for specifics on 
the correlative biology studies. 
5 
Height, weight, BSA 
6 
Creatinine, ALT, bilirubin 
7 
 Sedimentation Rate (ESR) 
8 
Tumor Disease Evaluation; Imaging Studies (CT scan, FDG-PET). See 
Sections 12.2, 12.3 and 15. Response will be evaluated between Days 15 and 
21 of every even-numbered cycle and as clinically indicated 
9 
Bone marrow biopsies (at least 2 sites) every even-numbered cycle. 
10 Pulmonary Function Tests (PFTs) and Pulse Oximetry should be obtained 
between Days 15 and 21 of cycles 2 and 4 and then every 4 cycles. (Pulmonary 
function testing is not required for children < 8, or for any child who is 
developmentally unable to comply with pulmonary function testing.) If 
pulmonary toxicity occurs, study therapy should be held, and the Study 
Chair and Research Coordinator should be notified within 48 hours. 
11 PBSC Collection in patients. See Section 8.4 and Appendix IV for details. 
Peripheral blood stem cells can be collected after any cycle except for patients 
with bone marrow involvement. Patients who had bone marrow involvement 
at the time of study entry must undergo repeat bone marrow biopsies (at least 
two sites) until negative prior to stem cell collection. If the bone marrow 
biopsies are positive after 2 cycles of therapy, the patient can be harvested the 
end of the next two cycles of therapy. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE. See Section 8.1 
 
 

 
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5.3 
Dose Escalation Schema  
 
PART A: Per amendment 4, Part A was completed.  
Phase 1 dose-finding study (Phase 1 Consortium plus limited institutions) 
 
5.3.1 
Inter-Patient Escalation for Brentuximab vedotin  
Per amendment 4, Part A was completed. 
The starting dose will be 1.4 mg/kg with dose levels for subsequent groups of 
patients as follows. 
 
Dose Level 
Brentuximab vedotin 
Dose (mg/kg) 
Maximum Dose of 
Brentuximab vedotin 
  1* 
1.4 
140 mg 
2 
1.8 
180 mg 
*starting dose level 
 
There will be no escalations beyond dose level 2 (1.8 mg/kg). 
 
5.3.2 
Intra-Patient Escalation Per amendment 4, Part A was completed. 
 
Part A: Patients treated at dose level 1 (1.4 mg/kg) who have not experienced DLT 
in any cycle of therapy, and who do not have a CR after two cycles of therapy are 
allowed to escalate to dose level 2 (1.8 mg/kg) for all subsequent cycles. At the 
discretion of the treating physician, they may also continue treatment at dose level 
1. 
 
Part B: No intra-patient escalation of phase in the phase 2 portion of the study as 
patients will be treated at the MTD or recommended phase 2 dose as established 
in Part A. 
 
PART B: Phase 2 component of the study (COG Groupwide) 
 
5.3.3 
Patients on Part B of the study will be receive brentuximab vedotin at 
1.8 mg/kg/day (the recommended phase 2 dose as determined in Part A). 
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or confirmed 
dose-limiting toxicity should be reported immediately (within 24 hours) to the Study Chair. 
 
Definition of Dose-Limiting Toxicity (DLT)  
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. The DLT observation period for the purposes of dose-
escalation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently. 

 
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5.4.1 
Non-Hematological Dose-Limiting Toxicity 

Any Grade 3 or greater non-hematological toxicity, except for the following: 
- Grade 3 nausea and/or vomiting of < 3 days duration 
- Grade 3 or 4 fever < 5 days duration 
- Grade 3 infection < 5 days duration 
- Grade 3 rash < 5 days duration 
- Grade 3 pruritis < 5 days duration 
- Grade 3 fatigue < 5 days duration 
- Grade 3 non-hematologic laboratory abnormalities that resolve within 
14 days to grade 1, or to initial eligibility criteria, or to baseline (if the 
patient entered the study with existing toxicity). Note: for the purposes 
of this study the ULN for ALT is defined as 45 U/L. 
- Grade 3 infusion reactions < 24 hours duration (See Section 6.2.4) 
- Grade 3 hypophosphatemia, hypokalemia, hypocalcemia, or 
hypomagnesemia responsive to oral supplementation. 
 

Grade ≥ 2 pancreatitis (See Section 6.2.8 for dose modifications and 
instructions on subsequent treatment). 
 

Any other Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption will also be considered a DLT.  

Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
5.4.2 
Hematological Dose Limiting Toxicity  
5.4.2.1 Hematological dose limiting toxicity is defined as: 
 
In patients evaluable for hematologic toxicity (See Section 4.1.7.1): 

Grade 4 neutropenia or thrombocytopenia that does not resolve to an 
ANC of ≥ 500/L and platelets ≥ 20,000/L within 7 days after the next 
scheduled dose of brentuximab vedotin. 
 
5.4.2.2 Note: Grade 4 febrile neutropenia will not be considered a dose-limiting 
toxicity.  
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
Note that these dose modifications apply to brentuximab vedotin only. The dose of 
gemcitabine will not be modified for toxicity. 
 
The Study Chair must be notified of any use of myeloid growth factor for hematologic toxicity 
and of any other dosage modification described below. 
 
The Study Chair and Research Coordinator must be notified within 48 hours of detection of 
pulmonary toxicity, as described in Section 6.2.6. 
 
 

 
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6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
Patients who have thrombocytopenia meeting the definition for DLT in Section 
5.4.2.1: Grade 4 thrombocytopenia that does not resolve to platelets ≥ 20,000/L 
mm3 within 7 days of the next scheduled dose of brentuximab vedotin) should 
receive subsequent cycles at a reduced dose of brentuximab vedotin, 1.2 mg/kg, 
maximum dose 120 mg.  
 
Patients who have neutropenia meeting the definition for DLT in Section 5.4.2.1 
(Grade 4 neutropenia that does not resolve to an ANC of ≥ 500/mL within 7 days 
of the next scheduled dose of brentuximab vedotin) should receive the same dose 
of brentuximab vedotin in the next cycle with myeloid growth factor support. Each 
subsequent course of brentuximab vedotin with gemcitabine, after the first, should 
begin no sooner than Day 21 of the preceding course, and should not begin unless 
the ANC is ≥ 750/mL. GCSF may be administered at a dose of 5 mg/kg daily 
beginning on day 9, and continuing for a minimum of 7 days and until the post-
nadir neutrophil count increases to ≥ 1,500/mL. Note that higher doses of GCSF 
(10-16 micrograms/kg/day) are recommended for use during cycles (post cycle 2 
or higher) when stem cell collection is being attempted (See Section 8.4.3). The 
use of Neulasta is not allowed. 
 
If neutropenia meeting the definition for DLT in Section 5.4.2.1 recurs after 
myeloid growth factor is added, then the patient should be given a reduced dose of 
brentuximab vedotin for subsequent cycles, 1.2 mg/kg, maximum dose 120 mg. If 
neutropenia recurs in a patient that has received a dose level reduction but has not 
received myeloid growth factor, then myeloid growth factor should be 
administered or the patient should be removed from protocol therapy. 
 
6.1.2 
Patients who experience thrombocytopenia meeting the definition for DLT in 
Section 5.4.2.1 after dose reduction or neutropenia meeting the definition for DLT 
in Section 5.4.2.1 after addition of myeloid growth factor and one dose reduction, 
must be removed from protocol therapy. 
 
6.1.3 
Patients who have a hematological toxicity meeting the definition for DLT in 
Section 5.4.2.1 that does not resolve to baseline within 21 days after the planned 
start of the next treatment cycle must be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
Patients who have any non-hematological toxicity meeting the definition for DLT 
in Section 5.4.1 may continue on protocol therapy upon meeting eligibility lab 
requirements or baseline but should receive subsequent cycles at a reduced dose of 
brentuximab vedotin, 1.2 mg/kg, maximum dose 120 mg.  
 
6.2.2 
If the same non-hematological toxicity meeting the definition for DLT in Section 
5.4.1 recurs after one dose reduction, the patient must be removed from protocol 
therapy. 
 
 

 
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6.2.3 
Patients who have a non-hematological toxicity meeting the definition for DLT in 
Section 5.4.1 that does not resolve to baseline within 21 days after the planned start 
of the next treatment cycle must be removed from protocol therapy. 
 
6.2.4 
Dose modifications for infusion reactions 
Infusion-related reactions (IRR), including anaphylaxis, were uncommon 
(approximately 12%) in adult studies with brentuximab vedotin. Infusion 
interruption for IRR treatment generally led to the successful completion of the 
dose and continued treatment with brentuximab vedotin with or without IRR 
prophylaxis, according to the clinical judgment of the investigator. Although the 
experience with IRRs related to brentuximab vedotin is limited, in part due to the 
low incidence observed to date, data support brentuximab vedotin administration 
by appropriately trained personnel without the need for routine prophylaxis.  
 
If IRR symptoms develop, the infusion should be interrupted and appropriate 
medical management instituted. The infusion may be restarted at a slower rate after 
symptom resolution. Premedication with diphenhydramine should be administered 
for subsequent infusions in patients who have experienced a prior IRR. Dosing of 
diphenhydramine can be according to institutional standards, or 1 mg/kg PO or IV 
(maximum of 50 mg). If anaphylaxis occurs, brentuximab vedotin should be 
immediately and permanently discontinued and appropriate medical management 
instituted. 
 
Suggested dose modification for infusional reactions to brentuximab vedotin 
Therapy modifications for patients who develop infusional reactions to 
brentuximab vedotin should be: 
 
 

 
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Grade 
Action 
Grade 1 
Transient flushing or rash, 
drug fever < 38◦ C 
(<100.4 ◦ F) 
And 
Grade 2 
Rash, flushing, urticaria, 
dyspnea, drug fever ≥ 
38◦ C (≥100.4 ◦ F) 
For first reaction: 

Hold the infusion and wait 30 to 60 minutes 
(depending upon the reaction severity) 

Treat reactions with diphenhydramine 1 mg/kg (max 
50 mg), or follow local institution guidelines. If 
diphenhydramine is not available, a similar 
antihistamine may be used, following local 
institution guidelines. Depending on the reaction 
severity, dexamethasone 0.2 mg/kg (max 10 mg) IV 
should be used 

Upon resolution of the symptoms, at the physician’s 
discretion, it may be possible to resume treatment by 
administering an H2 blocker approximately 30 
minutes 
before 
restarting 
the 
infusion.  
Acetaminophen can also be considered.  

Dosing of SGN-35 should be administered at half 
of the previously administered rate. 
For subsequent doses:  

Utilize 
diphenhydramine 
with 
or 
without 
acetaminophen as pre-treatment for all subsequent 
infusions. If diphenhydramine is not available, a 
similar antihistamine may be used, following local 
institution guidelines. 

Dosing should be administered over the shortest 
period that was well tolerated. 
 
If Grade 1-2 infusion reactions recur despite the above 
measures, 
either 
during 
re-challenge 
or 
subsequent 
treatments: 

Take the measures outlined above 

With subsequent dosing, add dexamethasone 0.2 
mg/kg (max 10 mg) IV or equivalent to medications 
above prior to infusion 
Grade 3 
Symptomatic 
bronchospasm 
with 
or 
without urticaria, allergy-
related edema/ 
angioedema, hypotension 
• Stop infusion immediately 
• Administer diphenhydramine hydrochloride 1 mg/kg IV 
(max 50 mg), dexamethasone 0.2 mg/kg (max 10 mg) IV (or 
equivalent), bronchodilators for bronchospasms, and other 
medications as medically indicated. If diphenhydramine is 
not available, a similar antihistamine may be used, following 
local institution guidelines. Hospital admission should be 
considered. 
•Brentuximab vedotin should not be resumed for that course 
•Subsequent courses of brentuximab vedotin may be 
considered at physicians’ discretion, after a discussion with 
the Study Chair, DVL leadership and CTEP.  
• All subsequent infusions should be given with the following 
dose modifications: 
1. Premedication with diphenhydramine hydrochloride 1 
mg/kg IV (max 50 mg), and dexamethasone 0.2 
mg/kg 
(max 
10 mg) 
IV 
(or 
equivalent). 
If 
diphenhydramine 
is 
not 
available, 
a 
similar 
antihistamine may be used, following local institution 
guidelines. 

 
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Grade 
Action 
2. The infusion should be administered at 50% of the 
previous infusion rate 
Grade 4 
Anaphylaxis 
• Stop infusion immediately 
• Administer diphenhydramine hydrochloride 1 mg/kg (max 
50 mg) IV, dexamethasone 0.2 mg/kg (max 10mg) IV (or 
equivalent), and other anaphylaxis medications as indicated. 
If diphenhydramine is not available, a similar antihistamine 
may be used, following local institution guidelines. 
Epinephrine or bronchodilators should be administered as 
indicated. Hospital admission for observation may be 
indicated 
• Study therapy should be discontinued. 
 
6.2.5 
Dose modifications for Peripheral Neuropathy 
Peripheral neuropathy is an effect of cumulative exposure to brentuximab vedotin. 
In adult studies, the first onset of any grade peripheral neuropathy increased with 
increasing numbers of cycles. Dose delay and reduction appeared to mitigate 
worsening of neuropathy. 
 
All dose modifications should be based on the highest grade toxicity in the 
preceding cycle. 
 

Grade 2-3 neuropathy: Treatment should be delayed until neuropathy 
improves to Grade 1 or baseline. Treatment with brentuximab vedotin in 
subsequent cycles should be reduced, 1.2 mg/kg, maximum dose 120 mg. 
 
If Grade 2 or 3 neuropathy recurs after dose reduction as described above, 
patients will be taken off protocol therapy, and brentuximab vedotin will 
be discontinued. Patients who experience a delay in therapy > 14 days due 
to peripheral neuropathy will be taken off protocol therapy, and 
brentuximab vedotin will be discontinued. 
 

Grade 4 neuropathy: Brentuximab vedotin should be discontinued. 
 
6.2.6 
Dose modifications for pulmonary toxicity 
Pulmonary toxicity requiring modification of therapy will occur for dyspnea ≥ 
Grade 3, hypoxia ≥ Grade 3 and ≥ Grade 3 pneumonitis that is attributable to the 
treatment regimen. Dose modifications will also be considered for Grade 2 
pneumonitis (See below). Factors to consider in assessing the attribution include 
the presence of left atrial hypertension, congestive heart failure, infection, 
metabolic abnormalities, or cancer related causes (e.g. malignant pericarditis). 
Upon occurrence of pulmonary toxicity, as defined above, study therapy 
should be held, and the Study Chair and Research Coordinator should be 
notified within 48 hours. 
 
Patients who develop pulmonary toxicity due to gemcitabine and brentuximab 
vedotin may benefit from treatment with corticosteroids. However, there are no 
published guidelines to suggest the most appropriate dosing or duration of 
treatment. Administration of 100 mg of oral or intravenous prednisolone in single 

 
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daily or two divided doses has been reported to improve symptoms in adults with 
pulmonary toxicity secondary to gemcitabine.46 The suggested dose for patients on 
AHOD1221 who develop pulmonary toxicity is methylprednisolone 1 mg/kg IV 
every 12 hours for a minimum of seven days. 
 
Patients who develop pulmonary toxicity, Grade ≥ 3, attributed to the treatment 
regimen will be taken off protocol therapy. Patients who develop Grade 2 
pneumonitis that resolves to Grade ≤ 1 may be retreated with the study regimen, 
after discussion with the Study Chair. CTEP will be notified within 7 days of study 
chair notification of each instance of pulmonary toxicity. The Study Chair will 
consult with CTEP, the study statistician, and DVL leadership (Part A: As of 
amendment 4, Part A was completed) or Hodgkin committee leadership (Part B) 
to review the history of the affected patient and the pulmonary toxicity for the trial 
as a whole before proceeding with the recommendation to resume protocol therapy 
at a lower dose. Failure to discuss a case of pulmonary toxicity will lead to 
suspension of accrual. 
 
6.2.7 
Dose modifications for Progressive multifocal leukoencephalopathy (PML) 
Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating 
disease of the brain that is caused by the John Cunningham virus (JCV). It typically 
occurs in immunocompromised individuals and can be fatal. Presenting features 
may include altered mental status, motor deficits such as hemiparesis or ataxia, 
visual disturbances, or higher cortical dysfunction such as dysphasia or agnosia. 
Seizures have also been reported in PML patients (approximately 20%). Cognitive 
decline without accompanying deficits in motor or sensory function is uncommon. 
Optic nerve involvement, fever, and spinal cord disease are not typically associated 
with PML. In addition, peripheral neuropathy, which has been reported with 
brentuximab vedotin treatment, is not commonly reported with PML. 
 
If PML is suspected, a diagnostic work-up should be performed. The work-up may 
include, but is not limited to the following: 

Neurologic examinations and neurology consultation, as warranted 

Brain MRI. Features suggestive of PML include presence of unifocal or 
multifocal lesions, mainly of the white matter, which are typically non-
enhancing and do not have mass effect. 

PCR analysis. JCV DNA, detectable in CSF or in a brain biopsy, is suggestive 
of PML. 
 
Brentuximab vedotin dosing should be held if PML is suspected. If PML is confirmed, 
brentuximab vedotin should be permanently discontinued. 
 
 

 
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6.2.8 
Dose modifications for Pancreatitis 
 
Therapy modifications for patients who develop pancreatitis should be: 
 
Grade 
Action 
Grade 2 Pancreatitis 

Withhold dose until toxicity has returned to 
baseline, then continue on protocol therapy but 
should resume at one dose reduction as per 
Section 6.2.1. 

If Grade 2 pancreatitis recurs after one dose 
reduction, the patient must be removed from 
protocol therapy. 
Grade 3-4 Pancreatitis 

Permanently discontinue brentuximab vedotin. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, 
immunomodulating agents (with the exception of corticosteroids) or biologic therapy may 
NOT be administered to patients receiving study drug. If these treatments are administered 
the patient will be removed from protocol therapy.  
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary, with the exception that corticosteroids should 
not be used as antiemetics. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/_files/protocol/Standard/SupportiveCareGuide
lines.pdf. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered in accordance with Section 6.1.1 or for culture proven bacteremia or invasive 
fungal infection. In addition, GCSF is recommended for stem cell mobilization (See 
Section 8.4.3). The use of Neulasta is not allowed. 
 
 

 
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7.5 
Concomitant Medications 
No other cancer chemotherapy or immunomodulating agents can be used.  
 
Corticosteroid therapy is permissible as supportive care, with the exception that 
corticosteroids should not be used as antiemetics. Examples of indications for 
corticosteroid use include, but are not limited to, the following: 

Treatment or prophylaxis for anaphylactic reactions or for treatment of pulmonary 
toxicity (See Section 6.2).  

Clinical sepsis and signs of severe septic shock, if relative adrenal insufficiency is 
suspected.  

Diffuse rash or pruritis (may be treated with topical or systemic corticosteroids) 

Asthma exacerbation. 
 
NSAIDs should be used with caution, due to one reported occurrence of Stevens-Johnson 
Syndrome (SJS) noted in a patient utilizing brentuximab vedotin and a short course of an 
NSAID. The cause of SJS is unknown. 
 
Patients should be monitored for potential drug-interaction when administered drugs 
known to be a strong CYP3A4 inhibitor/inducer with SGN-35. See Appendix VIII for a 
list of CYP3A4 inducers and inhibitors. 
 
 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy. Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility. If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum creatinine. If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies must 
be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary). Patients with bone marrow involvement must also have a bone marrow biopsy 
within 14 days prior to the start of protocol therapy. 
 
 

 
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submitted for central review by IROC Rhode Island (QARC) (See Section 8.3.2). 
 
8.3.2 
Central Review of Imaging Studies (Parts A and B): As of amendment 4, Part 
A was completed. The below information is for Part B. 
Central review of images will be performed to validate data reporting for quality 
assurance. Real time FDG-PET central review can be requested on a case-by-case 
basis for clarification or adjudication of conflicting institutional imaging studies 
which may be helpful for clinical assessment (See Section 12.2). 
 
The following imaging studies and corresponding radiology reports should be 
submitted to IROC Rhode Island (QARC) at the following time points: 
 
 
Pre-study Neck/Chest/Abdomen/pelvis CT; FDG-PET scan 
 
Post cycle 2 Neck/Chest/Abdomen/pelvis CT FDG-PET scan 
 
Post cycle 4 Neck/Chest/Abdomen/pelvis CT; FDG-PET scan 
 
Neck/Chest/Abdomen/pelvis CT; FDG-PET scan at progression (if 
different from the time points above). 
 
Submission of Diagnostic Imaging data in digital format is required. Digital files 
must be in DICOM format. These files can be submitted via sFTP. Information for 
obtaining an sFTP account and submission instructions can be found at 
www.QARC.org. Follow the link labeled digital data. Alternatively, if sFTP is not 
feasible, the imaging may be burned to a CD and mailed to IROC RI (QARC) at 
the address below. Multiple studies for the same patient may be submitted on one 
CD; however, please submit only one patient per CD. Sites using Dicommunicator 
may submit imaging via that application. Contact IROC RI (QARC) with questions 
or for additional information. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created.  
 
Address for submission: 
IROC Rhode Island (QARC)  
640 George Washington Highway, Suite 201 
Building B 
Lincoln, RI  02865-4207  
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
Web: 
http://www.qarc.org 
 
 

 
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8.4 
Mobilization and Collection of Peripheral Blood Stem Cells 
 
8.4.1 
Description of Studies 
One of the secondary aims of this study (See Section 1.2.3) is to document the 
proportion of patients able to mobilize sufficient stem cells after treatment with 
gemcitabine and brentuximab. This is a clinically relevant question because most 
patients eligible for this study will eventually go on to high-dose chemo with stem 
cell rescue. However, it is not yet proven that stem cells can be collected from 
patients treated with this regimen. 
 
Autologous peripheral blood stem cells will be collected from consenting patients 
(both Parts A and B) after any cycle of therapy. Patients who had bone marrow 
involvement at the time of study enrollment must undergo repeat bone marrow 
biopsies (at least two sites) prior to stem cell collection. Stem cells will not be 
collected until the bone marrow biopsies are negative for disease involvement. 
Stem cells may be collected following ANY cycle of therapy, subsequent to the 
demonstration of negative bone marrow biopsies and at least 2 cycles of 
chemotherapy.  
 
Institutional standard operating procedures should be used for the collection 
procedure. The following sections present suggested guidelines. See also 
Appendix IV. 
 
8.4.2 
Catheter Use 
PBSC may be collected using a large bore double lumen central venous catheter 
that will allow the flow rates required for apheresis. Depending on institutional 
practices, an appropriate double-lumen leukapheresis-grade catheter may be 
placed prior to cycle 1 and used for medication administration, intravenous fluids, 
and transfusions, in addition to the apheresis procedure. Alternatively, a temporary 
peripherally inserted central leukapheresis-grade catheter can be placed prior to 
peripheral blood stem cell collection and removed following completion of the 
leukapheresis. 
 
8.4.3 
Stem cell mobilization with chemotherapy and G-CSF 
During the mobilization cycle, treatment with granulocyte colony stimulating 
factor (G-CSF) should be started one day after the second dose of gemcitabine (i.e. 
on day 9). G-CSF should be administered daily, subcutaneously (preferred) or 
intravenously, at a dose of 10-16 micrograms/kg/day, and continuing until 
completion of PBSC collection. It is critical that G-CSF be given daily until PBSC 
collection is complete. If the WBC is > 60,000, decrease G-CSF dose to 5 
micrograms/kg/day. The PBSC collection should be timed with the neutrophil rise. 
Institutions which time collections using circulating CD34 cell counts will 
generally begin when the CD34+ count is > 10 cells/µL. These guidelines are 
summarized in the table below. The use of Neulasta is not allowed. 
 
 

 
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8.5 
Correlative Biology Studies (As of amendment 4, Part A was completed. This section 
is for Part B.) 
 
8.5.1 
Description of Studies and Assay 
Biology studies from peripheral blood in all patients for Part B will be used to 
assess TARC expression and miRNA profiles, as well as to bank host DNA to 
examine FcRIIIγ polymorphisms in the event of brentuximab pulmonary toxicity. 
We hypothesize that TARC expression will correlate with reduction in tumor 
volume and may be a surrogate marker for early PET response. We also 
hypothesize that specific miRNA profiles will correlate with response to therapy.  
 
8.5.1.1 Thymus and Activation-Related Chemokine (TARC)  
TARC will be assessed as an early marker of treatment response and 
compared with functional imaging (PET) as an early marker of disease 
response.  
 
8.5.1.2 Circulating miRNA studies  
miRNAs are found in high abundance in the serum of patients and 
previous studies have shown that specific miRNAs correlate with 
treatment response. 
 
All samples will be sent to the BPC, where they will be processed and batched 
and sent to the laboratory of Anke van den Berg, PhD (University Medical 
Center Groningen, The Netherlands) at the end of the study.  
 
University Medical Center Groningen 
Pathology & Medical Biology  
HPC: EA10  
Hanzeplein 1  
9713 GZ Groningen  
Netherlands  
Phone 00-31-50-3611476 
FAX 00-31-50-3619107  
 
Shipment notification should be sent by the BPC to 
 
. 
 
8.5.2 
Sampling Schedule (See Appendix V)  
Blood samples will be collected at baseline and prior to therapy on Day 1 of each 
subsequent cycle.  
 
8.5.3 
Sample Collection and Handling Instructions 
Blood samples will be collected in all patients for Part B before treatment and prior 
to brentuximab vedotin infusion on Day 1 of each subsequent cycle. 5 mL will be 
collected in a gold-top serum separator tube (If serum separator tubes are 
unavailable, tubes with no preservative may be used instead) and 5 mL will be 
collected in into a heparinized tube (either Na-heparin or Lithium heparin are 
acceptable). 
 

 
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8.5.4 
Sample Processing 
No processing of the samples is required for analysis of TARC or miRNA 
profiling. Samples should be shipped the same day as collected, when possible. 
Samples that cannot be shipped the same day should be stored at 4C and shipped 
as soon as possible. See Appendices V and VI. 
 
8.5.5 
Sample Labeling 
Each tube must be labeled with the, patient’s COG patient ID number, specimen 
type (blood) and the date the sample was drawn. Data should be recorded on the 
Peripheral Blood Studies Form in Appendix V and the Specimen Transmittal Form 
in Appendix VI, both of which must accompany the sample(s). 
 
8.5.6 
Sample Shipping Instructions 
Samples should be shipped the same day they are collected when possible. See 
Appendices V and VI for sample shipping instructions.  
 
 
9.0 
DRUG INFORMATION 
 
Please see Appendix IX for known drug interactions associated with the drugs used in this 
study. 
 
9.1 
Brentuximab vedotin 
(SGN35, AdcetrisTM, NSC#749710, IND# 117117)  
 
 
(11/9/2015) 
 
9.1.1 
Structure and molecular weight  
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) 
consisting of three components: the chimeric IgG1 antibody cAC10, specific for 
human CD30, the microtubule disrupting agent MMAE, and a protease-cleavable 
linker that covalently attaches MMAE to cAC10. Approximately 4 molecules of 
MMAE are attached to each antibody molecule. Brentuximab vedotin is produced 
by chemical conjugation of the antibody and small molecule components. The 
antibody is produced by mammalian (Chinese hamster ovary) cells, and the small 
molecule components are produced by chemical synthesis. Brentuximab vedotin 
has an approximate molecular weight of 153 kDa. 
 
9.1.2 
Supplied by: 
Seattle Genetics, Inc. and the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. 
 
9.1.3 
Formulation 
The agent is supplied as a sterile, white to off-white preservative-free lyophilized 
cake or powder in individually-boxed single-use vials containing 50 mg 
brentuximab vedotin per vial. 
 
 

 
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9.1.4 
Storage 
Store vial dry under refrigeration at 2-8°C (36-46°F) in the original carton to 
protect from light until reconstitution and use. 
 
9.1.5 
Solution Preparation 
Use appropriate aseptic technique for reconstitution and preparation of dosing 
solutions. 
 
Please note that the dose for patients weighing greater than 100 kg should be 
calculated based on a weight of 100 kg. 
Preparation consists of 2 steps: dilution of the stock solution and dilution of the final 
solution. 
Step 1: Make a 5 mg/mL concentration. Use vials from the same Lot number for 
each dose. 
1. Reconstitute the 50 mg lyophilized powder SGN-35 with 10.5 mL Sterile 
Water for Injection, USP. Final concentration is 5 mg/mL (Note: total 
volume is 11 mL). 
2. Swirl the vial gently. Do not shake. 
3. Let the reconstituted vial settle for one minute to eliminate bubbles. The 
reconstituted solution should be colorless, clear to slightly opalescent and 
should NOT have visible particulates. 
4. Store the reconstituted vial under refrigeration (2° – 8° C) and protect from 
light if not used immediately. Discard after 8 hours. 
Step 2: Further dilute the IV solution. 
1. Withdraw the calculated amount of drug from the 5 mg/mL reconstituted vial 
in step 1. 
2. Inject the required amount of drug into 0.9% NS, Lactated Ringer’s Solution, 
USP, or dextrose 5% in Water (D5W), USP to a final concentration between 
0.4 – 1.8 mg/mL.  
3. SGN-35 solution is compatible in polyvinylchloride (PVC), ethylene vinyl 
acetate (EVA), polyolefin, or polyethylene. 
4. Do not shake. Gently invert the syringe or bag to mix. 
5. The prepared syringe or IV bag is to be stored at refrigeration (2° – 8° C) and 
must be used within 24 hours of initial product reconstitution (or sooner per 
institutional practice for agents without a preservative). Protect the prepared 
IV solution from direct sunlight if not used immediately. 
6. Prior to administration, inspect the syringe or IV bag for discoloration or 
floating particulates. Do not use the IV solution if the solution is discolored 
or/and have particulates. 
 
9.1.6 
Stability:  
The stability testing of the intact vials is ongoing. Reconstituted agent must be 

 
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diluted and administered within 24 hours. 
CAUTION: The single-use lyophilized dosage form contains no antibacterial 
preservatives. Therefore, the reconstituted product (from Step 1) should be 
discarded within 8 hours after initial entry/puncture. 
 
9.1.7 
Administration 
Infuse the prepared IV solution over 30 minutes. Do not mix with other medications. 
Do not administer as an IV push or bolus. Do not use an in-line filter for the IV 
administration. The syringe or IV bag does NOT need light protection during the IV 
administration. 
Potential drug interaction: In vitro data indicates that the active metabolite of 
SGN-35, monomethyl auristatin E (MMAE) is a substrate and an inhibitor of 
CYP3A4 but is neither a sensitive substrate nor a strong inhibitor/inducer of 
CYP3A4. However, patients should be monitored for potential drug-interaction when 
administered drugs known to be a strong CYP 3A4 inhibitor/inducer with SGN-35. 
In vitro, MMAE is a substrate of P-gp transporter and is not an inhibitor of P-gp. See 
Appendix VII for a list of CYP3A4 inducers and inhibitors. 
Patient Care Implications: 

New signs and symptoms of CNS system abnormalities may indicate 
progressive multifocal leukoencephalopathy (PML). 

Tumor lysis syndrome, particularly in patients with highly proliferative 
tumors or high tumor burden prior to treatment. 

Infusion-related reactions, including anaphylaxis, may occur. Refer to 
protocol for the management of infusion-related reactions. 

Signs and symptoms of peripheral neuropathy such as tingling or numbness 
of the hands, feet, or any muscles weakness. 

Steven-Johnson syndrome 

High fever (≥ 100.5° F) or other signs of potential infection. 
 
9.1.8 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for SGN-35 
(brentuximab vedotin, NSC 749710) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  
 
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 555 patients. 
Below is the CAEPR for SGN-35 (brentuximab vedotin). 

 
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Adverse Events also reported on SGN-35 (brentuximab vedotin) trials but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that SGN-35 (brentuximab 
vedotin) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Myocardial infarction; Pericardial effusion; Sinus tachycardia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Infusion related reaction; 
Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (oral candidiasis); Meningitis; 
Pharyngitis; Sepsis; Sinusitis; Skin infection; Urinary tract infection 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; 
Investigations - Other (blood LDH increased); Lymphocyte count decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness; 
Myositis; Neck pain 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome 
NERVOUS SYSTEM DISORDERS - Dysesthesia; Encephalopathy; Seizure; Syncope 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(pyelonephritis) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders 
- Other (groin pain) 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome3; Pleural effusion3; Pneumothorax3; Productive cough; Respiratory, thoracic and mediastinal 
disorders - Other (oropharyngeal pain) 
VASCULAR DISORDERS - Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: SGN-35 (brentuximab vedotin) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
9.2 
Agent Ordering and Agent Accountability 
NCI supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated. PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained.) The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there 
are several participating investigators at one institution, CTEP supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution. 
 
9.3 
Clinical Drug Request 
Active CTEP-registered investigators and investigator-designated shipping designees and 

 
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ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application at https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam) and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, returns, 
or accountability call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
9.4 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of all agents received from DCTD using the 
NCI Drug Accountability Record (DAR) Form. (See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage and to obtain 
a copy of the DARF and Clinical Drug Request form.) 
 
9.5 
Gemcitabine 
2’-deoxy-2’,2’ difluorocytidine monohydrochloride, LY18801,Gemzar®) NSC #613327 
 
 
9.5.1 
Source and Pharmacology 
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S-phase) and also blocking the progression of cells through the G1/S-
phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to 
the cytotoxic diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. 
Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for 
catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA 
synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction 
in the concentrations of deoxynucleotides, including dCTP. Gemcitabine 
triphosphate competes with dCTP for incorporation into DNA. The reduction in the 
intracellular concentration of dCTP (by the action of the diphosphate) enhances the 
incorporation of gemcitabine triphosphate into DNA. After the gemcitabine 
nucleotide is incorporated into DNA, only one additional nucleotide is added to the 
growing DNA strands. After this addition, there is inhibition of further DNA 
synthesis. DNA polymerase epsilon is unable to remove the gemcitabine nucleotide 
and repair the growing DNA strands. In CEM T lymphoblastoid cells, gemcitabine 
induces internucleosomal DNA fragmentation, one of the characteristics of 
programmed cell death. Gemcitabine pharmacokinetics are linear and are described 
by a 2-compartment model. Gemcitabine half-life for short infusions (< 70 minutes) 
ranged from 42 to 94 minutes, and the value for long infusions varied from 245 to 
638 minutes, depending on age and gender, reflecting a greatly increased volume of 
distribution with longer infusions. The lower clearance in women and the elderly 
results in higher concentrations of gemcitabine for any given dose. The volume of 
distribution was increased with infusion length. Volume of distribution of 
gemcitabine was 50 L/m2 following infusions lasting < 70 minutes, indicating that 
gemcitabine, after short infusions, is not extensively distributed into tissues. For long 
infusions, the volume of distribution rose to 370 L/m2, reflecting slow equilibration 
of gemcitabine within the tissue compartment. The maximum plasma concentrations 
of 2'-deoxy-2',2'-difluorodeoxyuridine (dFdU) (inactive metabolite) were achieved 
up to 30 minutes after discontinuation of the infusions and the metabolite is excreted 
in urine without undergoing further biotransformation. Over one week, 92% to 98% 
of a gemcitabine dose is excreted in urine. Unchanged drug constitutes only a small 

 
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portion of urinary excretion (about 5%), the remainder being dFdU. The metabolite 
did not accumulate with weekly dosing, but its elimination is dependent on renal 
excretion, and could accumulate with decreased renal function. 
 
9.5.2 
Formulation and Stability 
Gemcitabine is available as a 200 mg white, lyophilized powder in a 10 mL size 
sterile single use vial and a 1000 mg white, lyophilized powder in a 50 mL size sterile 
single use vial. Store at controlled room temperature (20°-25°C, 68°-77°F). 
Excursions permitted between 15° and 30°C (59° and 86°F). 
 
9.5.3 
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol. 
 
To reconstitute, add 5 mL of NS to the 200 mg vial or 25 mL of NS to the 1000 mg 
vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 
38 mg/mL which includes the accounting for the displacement volume of the 
lyophilized powder. The total volume upon reconstitution will be 5.26 mL or 
26.3 mL, respectively. Complete withdrawal of the vial contents will provide 
200 mg or 1000 mg of gemcitabine, respectively. The appropriate amount of drug 
may be administered as prepared or further diluted with NS to concentrations as low 
as 0.1 mg/mL. Gemcitabine solutions are stable for 24 hours at controlled room 
temperature 20° to 25°C (68° to 77°F). Solutions of reconstituted gemcitabine should 
not be refrigerated, as crystallization may occur. After reconstitution with NS, the 
pH of the resulting solution lies in the range of 2.7-3.3 and can cause irritation if 
administered through a peripheral line.  
 
Previous investigations have shown that cellular accumulation of the active 
metabolite of gemcitabine is saturated at plasma concentrations above 10 to 20 
μM36,37, a concentration that is exceeded when gemcitabine is infused faster than 6 
to 10 mg/m2/min.37,38 Accumulation of higher intracellular dFdCTP concentrations, 
which may result in an enhanced antineoplastic activity, cannot be achieved by 
higher dosage, but only by prolonged infusion time. Prolonged infusions are well-
tolerated39-44 and may provide increased clinical benefit over bolus administration. 
Gemcitabine should therefore be infused over 100 minutes for this study.45 
 
9.5.4 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information. 
 
 

 
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) Adverse Events requiring removal from protocol therapy (See Section 6). 
c) Refusal of further protocol therapy by patient/parent/guardian 
d) Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) Completion of 16 cycles of therapy.  
f) Patients with CR after two cycles may go off protocol therapy for stem cell 
transplantation.  
g) Patients with SD or any response may go off protocol therapy after the fourth cycle or 
after the response evaluation following any subsequent cycle of therapy. 
h) Physician determines that continuing study therapy is not in the patient’s best interest. 
i) Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of brentuximab vedotin and gemcitabine (See Section 8.1). 
j) Development of second malignancy. 
k) Study is terminated by Sponsor. 
l) Pregnancy 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.6.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events attributable to protocol 
therapy that emerge after the patient is removed from protocol therapy, but within 30 days 
of the last dose of investigational agent, must be followed and reported via RAVE and 
CTEP-AERS (if applicable). Serious adverse events that occur during the follow-up period 
(more than 30 days after the last administration of investigational agent) and have an 
attribution of possible, probable, or definite require reporting per Footnote 1 of Table A. 
Follow-up data will be required unless they meet the off study criteria below. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent (patients on Part A not 
enrolled at the MTD). 
b) 
The fifth anniversary of the date the patient was enrolled on this study (patients on 
Part A enrolled at the MTD and all patients enrolled on Part B) 
c) 
Death 
d) 
Lost to follow-up 
e) 
Withdrawal of consent for any further required observations or data submission. 
f) 
Enrollment onto another COG therapeutic (anti-cancer) study  
 
 

 
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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Part A: Phase 1 dose-finding component  
As of amendment 4, Part A was completed. 
 
Part B: Phase 2 component 
This study includes Part A (Phase 1) and Part B (Phase 2). During Part A, two dose levels 
of brentuximab vedotin were tested: 1.4 mg/kg (dose level 1) and 1.8 mg/kg (dose level 2). 
Initially, three evaluable patients were enrolled on dose level 1 and six on dose level 2. 
Since amendment #2, an expansion cohort of 6 patients have been enrolled onto dose level 
2 using the revised definitions for dose-limiting toxicity. This cohort was evaluated 
separately from the six patients initially enrolled at dose level 2 for the purpose of 
determination of the MTD. None of these six patients experienced a non-hematologic dose 
limiting toxicity (DLT). One of these was found to be ineligible for evaluation of 
hematologic DLT, because filgrastim was administered during the first cycle of therapy in 
preparation for stem cell harvesting. None of the five remaining patients experienced a 
hematologic DLT. Per Section 11.4, dose level 2 is determined to be the recommended 
phase 2 dose, because the number of DLTs in this expansion cohort did not exceed one.  
 
Patients treated on the Phase 1 component at dose level 2 will be included in analysis of 
response for Part B provided that they are eligible and evaluable for response. Part B will 
accrue up to 41 patients evaluable for the primary response endpoint. Considering a 15% 
rate for ineligible/invaluable patients, Part B may enroll a maximum of 48 patients. 
 
The average accrual rate from the 2 prior COG studies on HL patients with first-relapse 
(AHOD00P1 and AHOD0521) was 27-30 patients per year excluding the initial 6 months 
delay for IRB approvals. Part B will be conducted COG group-wide. Given that certain 
relapsed patients with favorable prognosis will be excluded from participation on the study, 
we estimate it would take about 2.5-3 years to complete accrual for Part B (up to 41 
response evaluable patients).  
 
11.2 
Definitions for Part A  
As of amendment 4, Part A was completed. 
 
11.2.1 Evaluable For Adverse Effects 
Any patient who experiences DLT at any time during protocol therapy is 
considered evaluable for Adverse Effects. Patients without DLT who receive at 
least 85% of the prescribed dose per protocol guidelines and had the appropriate 
toxicity monitoring studies performed are also considered evaluable for Adverse 
Effects. Patients who are not evaluable for Adverse Effects at a given dose level 
during Cycle 1 will be replaced. 
 
11.2.2 Maximum Tolerated Dose 
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See Section 5.5) during Cycle 1 of therapy. In the event that 
two DLTs observed out of 6 evaluable patients are different classes of Adverse 
Effects (e.g. hepatotoxicity and myelosuppression), expansion of the cohort to 12 

 
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patients will be considered if all of the following conditions are met:  
•  One of the DLTs does not appear to be dose-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, 
and IND sponsor all agree that expansion of the cohort is acceptable 
 
Expansion will proceed according to the rules of the 3+3 design (Section 11.3): 
Three additional patients will be studied. If none of the initial three additional 
patients experiences DLT, the dose will be escalated.* If one of the initial three 
additional patients experiences DLT, expansion to a total of 12 patients will 
continue. If fewer than 1/3 of patients in the expanded cohort experience dose-
limiting toxicities, the dose escalation can proceed.* 
 
*If the expansion occurs in the last dose level, the recommended phase 2 dose 
has been defined and Part A will be closed. 
 
11.3 
Dose Escalation and Determination of MTD (Part A)  
As of amendment 4, Part A was completed. 
 
11.3.1  Three patients are studied at the first dose level. 
 
11.3.2  If none of these three patients experience DLT, then the dose is escalated to the 
next higher level in the three subsequent patients. 
 
11.3.3  If one of three patients experiences DLT at the current dose, then up to three more 
patients are accrued at the same level. 
 
a)  If none of these three additional patients experience DLT, then the dose is 
escalated in subsequent patients. If there are no further dose escalations, then 
the RP2D has been confirmed. 
 
b)  If one or more of these three additional patients experiences DLT, then patient 
entry at that dose level is stopped. (See Section 11.2.2 for exception to rule). 
Up to three more patients are treated at the next lower dose (unless six patients 
have already been treated at that prior dose). 
 
11.3.4 If two or more of a cohort of up to six patients experience DLT at a given dose 
level, then the MTD has been exceeded and dose escalation will be stopped (see 
Section 11.2.2 for exception to rule). Up to three more patients are treated at the 
next lower dose (unless six patients have already been treated at that prior dose). 
The highest dose with less than two DLTs out of six evaluable patients will be the 
estimated MTD. 
 
11.3.5 Using this dose escalation scheme, the probability of escalating to the next dose 
level, based on the true rate of DLT at the current dose, is given by the following 
table: 
 
 
True Adverse Effects at a Given Dose 
 
10% 
20% 
30% 
40% 
50% 
60% 
Probability of 
Escalating 
.91 
.71 
.49 
.31 
.17 
.08 

 
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Thus, if the true underlying proportion of toxic events is 30% at the current dose, 
there is a 49% chance of escalating to the next dose. 
In addition to determination of the MTD, a descriptive summary of all toxicities 
will be reported. 
 
11.4 
Evaluation of Expansion Cohort at Dose Level 2 Using Revised DLT Definitions 
(Amendment #2) 
 
11.4.1  Three additional patients are studied at Dose Level 2.  
 
11.4.2  If none or one of these three patients experience DLT, then up to three more 
patients are accrued at the same level. 
 
11.4.3  If two or more of a cohort of up to six patients experience DLT at Dose Level 2, 
then the MTD has been exceeded, and the study will be closed to accrual (See 
Section 11.2.2 for exception to rule). 
 
11.4.5 If ≤ one patient out of six experiences DLT, the MTD/RP2D has been defined. 
Part A will be closed and the study will continue to Part B. 
 
11.5 
Response Analysis for Part A 
As of amendment 4, Part A was completed. 
While the primary aim of Part A is to evaluate the toxicity of brentuximab vedotin in 
combination with gemcitabine, patients will have disease evaluations performed as 
indicated in Section 8.1. Disease response will be assessed according to the evaluation 
criteria in Section 12.0, and will be reported descriptively. 
 
All these analyses will be descriptive and exploratory and hypotheses generating in nature. 
 
11.6 
Study Design for Part B 
The primary aim for the Phase 2 component is to evaluate the CR rate among HL patients 
treated with 4 cycles of gemcitabine with brentuximab vedotin. In the adult Phase I and II 
trials, Brentuximab vedotin alone had an estimated CR by PET rate of 34% in HL patients. 
Six of 9 pediatric patients included in these trials achieved CR (2/5 HL and 4/4 ALCL).16 
In the prior COG study on the combination of Gemcitabine/Vinorelbine (AHOD0321), CR 
by CT was achieved in 6/25 (24%) evaluable patients at the end of treatment, and CR by 
PET criteria in 6/13 patients (46%) after 2 cycles. Based on these data, in Part B we expect 
to achieve a CR rate of about 60% after 4 cycles of brentuximab vedotin among HL 
patients, and will consider the study unsuccessful if the data suggests a CR rate that is 
significantly lower than 60% (such as 40%). The study adopts a Simon 2-stage MinMax 
rule: reject this combination and terminate the study if 11 or fewer CR are observed in the 
first 28 evaluable patients, and reject this combination if 20 or fewer CR are observed in a 
total of 41 evaluable patients. Type I error and type II error are both 0.1; in other words, 
this rule will reject gemcitabine with brentuximab vedotin 10% of the time when the true 
CR rate is 60%, and 90% of the time when the true CR rate is 40%. The expected sample 
size is 33.8 if the true CR rate is 40% and is 40.7 if the true CR rate is 60%. 
 
Patients treated on the Phase 1 component, at dose level 2 (1.8 mg/kg) for brentuximab 
vedotin used in the Phase 2 component, will be included in Part B provided that they are 
eligible and evaluable for response (See Section 11.8). Enrollment will be stopped after 
Stage 1 to evaluate response for Stage 1 enrollments, and will only reopen to Stage 2 when 

 
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sufficient responses for Stage 1 are observed. However, if sufficient responses for Stage 1 
are observed prior to reaching Stage 1 accrual target, enrollment will not be stopped after 
Stage 1 and will proceed directly to Stage 2.  
 
The two stage design for Part B is illustrated below: 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 28 evaluable 
patients 
Up to 11 
Terminate the trial because the 
agent is ineffective. 
12 or more 
Proceed to Stage 2. 
Stage 2: Enter 13 additional 
evaluable patients 
Up to 20 
Terminate the trial because the 
agent is ineffective. 
21 or more 
Terminate the trial because the 
agent is effective. 
 
11.7 
Methods of Analysis for Part B 
All patients treated on the phase 1 component, at dose level 2 (1.8 mg/kg) of brentuximab 
vedotin used in the Phase 2 component, will be included in the analyses provided they are 
eligible and evaluable for the particular endpoint (response, toxicity, etc.). CR and ORR 
after 4 cycles and at the end of treatment will be estimated. Toxicities among patients who 
received at least 1 dose of gemcitabine or brentuximab vedotin will be summarized by 
individual toxicity counts and incidence rate. The proportion of patients who were able to 
mobilize sufficient stem cells after treatment with gemcitabine/brentuximab vedotin will 
be estimated. Plasma level of TARC will be considered a continuous variable, and be 
summarized by standard descriptive statistics such as mean, standard deviation, median, 
and range. Plasma level of TARC after each cycle or the change in level of TARC from 
baseline will be compared between patients with CR vs. < CR by two-sample t-test or two-
sample Wilcoxon rank sum test. Specific miRNA levels in serum will also be considered 
continuous variables and summarized by appropriate descriptive statistics. The association 
between response and miRNA profile will be explored by comparing the specific miRNA 
level or change over time between patients with CR vs. < CR by 2-sample tests such as 2-
sample t-test or Wilcoxon rank sum test. Among patients who experience any pulmonary 
toxicity, the frequency of the FcγRIIIa-158 V/F polymorphism will be described. 
 
11.8 
Evaluability for Response for Part B 
In Part B, each patient will receive a minimum of 4 cycles, except that per protocol patients 
might go off study therapy prior to cycle 4 if they have achieved CR or have PD. Primary 
endpoint for Part B is CR by the international harmonization criteria after 4 cycles. 
Complete responders are those who achieve CR any time during/after 4 cycles, except that 
a patient will be considered PD if becoming PD after CR during the first 4 cycles. A 
response of CR or PD prior to 4 cycles will be considered to be carried on as the 4-cycle 
response. Evaluable patients are those with disease evaluation after 4 cycles (including 
those do not actually complete 4 cycles but have a carried-over response of CR/PD), and 
those who complete at least 2 cycles and have disease evaluation after 2 cycles. In other 
words, a patient who had a response of non-CR/PD after cycle 2 but somehow did not 
complete 4 cycles per protocol and went off protocol prior to cycle 4 without a CR/PD will 
be considered evaluable and included in the analysis as non-CR.  
 
 

 
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In addition, all patients treated on Part A, at the dose selected for use in Part B (1.8 mg/kg), 
will be included in the final evaluation of response, provided they meet all eligibility 
criteria for Part B and are evaluable for response, as defined above. 
 
Primary endpoint/analyses will be based on central review of response which will not be 
performed real time; treatment/clinical decisions will be based on institution assessment of 
response. 
 
11.9 
Evaluability for Toxicity 
For Part B, all patients who received at least 1 dose of brentuximab vedotin or gemcitabine 
will be evaluable for toxicity and included in the toxicity tables and summaries. In addition, 
all patients treated on Part A, at the dose selected for use in Part B (1.8 mg/kg), will be 
included in the final toxicity summaries, provided they meet all eligibility criteria for Part 
B and are evaluable for toxicity, as defined above. 
 
Monitoring for Excessive Pulmonary Toxicity during Part B. The incidence of brentuximab 
vedotin-related pulmonary toxicity will be monitored in all patients treated with at least 
one dose of gemcitabine with brentuximab vedotin at the Phase 2 dose level (1.8 mg/kg) 
of brentuximab vedotin on either Phase 1 or Phase 2. Therefore, the 41 response-evaluable 
patients for Part B will be included in this analysis plus some additional patients who were 
not evaluable for response but received at least one dose of the combination; the maximum 
number of patients for the analysis, which is the maximum number of patients on the study 
that can be treated at the final dose of brentuximab vedotin combining Phase 1 and 2, is 
likely 60 patients (up to 48 patients from Phase 2 plus 12 patients from Phase 1 per 
Amendment #2, unless the Phase 1 component at the final dose expands to 12 additional 
(total 18) patients according to Section 11.2.2 per Amendment #2 or there are Phase 1 
patients at the final dose level who received one dose of combination but were not 
evaluable for DLT). Pulmonary toxicity will be defined by dyspnea ≥ Grade 3, hypoxia ≥ 
Grade 3 or pneumonitis ≥ Grade 2. There must be no evidence of other etiologies, including 
left atrial hypertension, congestive heart failure, infection, metabolic abnormalities, or 
cancer related causes (e.g. malignant pericarditis). A Bayesian rule is adopted for this 
monitoring. The prior distribution for the rate of pulmonary toxicity p is a Beta distribution 
with parameters α=1 and β=19. This Beta distribution for the rate of pulmonary toxicity p 
has a mean of 5%; the support for p ≤ 10% is 86%. If given the observed data at interim 
monitoring, the posterior probability of p ≥ 5% is 0.8 or higher, it will be considered 
compelling evidence that the pulmonary toxicity rate is unacceptable and the study will be 
referred to DSMC for review and consideration for early closure. This monitoring will be 
performed for every DSMC report during Part B, which occurs every 6 months during the 
first 2 years and once every year thereafter. Operationally, it will require, for example, ≥ 
2/6, ≥ 3/20, ≥ 5/41, ≥ 5/54, or ≥ 6/60 patients with pulmonary toxicities for the rule to be 
met. The exact rule will depend on the number of patients in the denominator at the time 
of the interim monitoring. The study will tolerate at most 4 patients with pulmonary 
toxicities at the end with 41-54 patients or 5 patients with pulmonary toxicities with 55-60 
patients. With a sample size of n=45, if the true rate of toxicity is 5%, 10%, or 15% 
respectively, the chance of observing 5 or more patients with pulmonary toxicities are 7%, 
47%, and 83% respectively. 
 
 

 
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In addition, Grade 4 or higher toxicities will be reviewed on a case by case basis to see if 
changes in the protocol are warranted.  
 
11.10 Inclusion of Children, Women and Minorities 
The study is open to all participants regardless of gender or ethnicity. Review of accrual to 
past COG studies of new agents demonstrates the accrual of both genders and all NIH-
identified ethnicities to such studies. Efforts will be made to extend the accrual to a 
representative population, but in a trial which will accrue a limited number of patients, a 
balance must be struck between patient safety considerations and limitations on the number 
of individuals exposed to potentially toxic or ineffective treatments on the one hand and 
the need to explore gender, racial, and ethnic aspects of clinical research on the other. If 
differences in outcome that correlate to gender, racial, or ethnic identity are noted, accrual 
may be expanded or additional studies may be performed to investigate those differences 
more fully. 
 
11.11 Gender and Minority Accrual Estimates 
Per Amendment #2, the Phase 1 part of the study may accrue a maximum of 24 patients. The 
Phase 2 part of the study may accrue a maximum of 48 patients. The maximum enrollment 
for the study is therefore 72 patients.  
 
The gender and minority distribution of the study population is expected to be: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
5 
10 
Not Hispanic or Latino 
34 
28 
63 
Ethnic Category: Total of all subjects 
39 
33 
*72 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
4 
5 
Black or African American 
6 
5 
11 
Native Hawaiian or other Pacific Islander 
1 
0 
1 
White 
31 
24 
55 
Racial Category: Total of all subjects 
39 
33 
*72 
 
 
 
 
* These totals must agree 
 
This distribution was derived from AHOD00P1 and AHOD0521. 
 
 

 
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12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
 
12.2 
Imaging Lesion Evaluation 
Imaging guidelines and response criteria have been revised from previous COG protocols, 
including AHOD0831, AHOD0031, AHOD0431, CCG 5942, CCG 59704, POG 9425, and 
POG 9426 and reflect the recent work of the International Lymphoma Working Group’s 
revised recommendations for malignant lymphoma.47,48.  
 
Establishing strict CT size criteria for presumptive lymphomatous nodal enlargement is 
complicated by a number of factors, including substantial size overlap between benign 
reactive 
lymphoid 
hyperplasia 
and 
malignant 
lymphadenopathy, 
interobserver 
measurement variability, obliquity of node orientation to the scan plane, multiplicity of 
criteria for size measurement (volumetric vs. bidimensional vs. unidimensional; short axis 
vs. long axis), variability of normal nodal size with body region and age. For children and 
younger adolescents, there are no established size limits for normal lymph nodes. 
Furthermore, in children reactive hyperplasia is common in the cervical, axillary, 
mesenteric, and inguinal regions, and may be associated with nodes up to 1.5-2 cm in 
diameter. In other anatomic regions, including the supraclavicular, retroperitoneal, iliac, 
mediastinal, and hilar regions, normal nodes are typically less than 1-1.5 cm. Despite these 
limitations, certain features suggest lymphomatous involvement, such as contiguous nodal 
clustering or matting, and nodal FDG avidity.  
 
With these caveats in mind, the nodal size criterion used by previous HL protocols for 
newly diagnosed HL will be used for simplicity and consistency. Bulk disease will continue 
to be defined as a contiguous extramediastinal nodal aggregate that measures > 6 cm in the 
longest transverse diameter (transaxial measurement), a mediastinal mass where the tumor 
diameter is > 1/3 the maximal thoracic diameter, and/or macroscopic splenic nodules. For 
visceral organs (such as liver, spleen, kidney) any focal mass lesion large enough to 
characterize is considered due to lymphomatous involvement unless the imaging 
characteristics indicate an alternative nature (e.g., cyst, hemangioma, abscess, etc.). 
Lesions too small to characterize are considered indeterminate unless follow-up studies 
allow characterization or tissue sampling is performed.  
 
Measurable disease indicates the presence of at least one measurable lesion. Superficial 
lesions (e.g., palpable lymphadenopathy) may be measurable by clinical exam. A 
measurable lesion by CT is a lesion that can be accurately measured in 2 orthogonal 
dimensions. For extranodal sites, this typically involves lesions of at least 1 cm diameter. 
Lymph nodes are considered abnormal if the long axis is  1.5 cm, regardless of the short 
axis. Lymph nodes with a long axis measuring between 1.1-1.5 cm are only considered 
abnormal if their short axis is  1.0 cm.  
 
All measurable lesions should be measured in the axial plane on CT. All measurable 
lesions, up to a maximum of 6 lesions in total, representative of all involved organs, will 
be measured as target lesions at baseline and followed for response. Target lesions will be 

 
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selected on the basis of size (i.e., largest lesions) and suitability for accurate repeated 
measurements by imaging or clinical exam. Lesions will be recorded with size expressed 
as the PPD (product of perpendicular diameters). The PPD is obtained by multiplying the 
longest diameter of the lesion by the maximal diameter perpendicular to the longest 
diameter, and serves as a surrogate measurement of tumor volume, assuming the mass has 
a spherical or ellipsoid shape. The SPPD, or sum of the products of the perpendicular 
diameters, is obtained by adding the products of the perpendicular diameters of measured 
lesions. 
 
Non-measurable assessable lesions include permeative bone lesions, malignant ascites, 
malignant pleural/pericardial effusions, pulmonary or cutaneous lymphangitic spread, and 
lesions too small to accurately measure in 2 dimensions by CT. All non-target and non-
measurable assessable lesions will be recorded at baseline and noted on follow-up. 
 
FDG-PET imaging will be performed as per clinical routine, adhering to the imaging 
guidelines discussed in Section 15. Although these FDG-PET guidelines are 
recommendations, a list of FDG PET imaging issues listed in Section 15 should be adhered 
to as much as possible in this clinical trial to allow for the uniformity of inter- and intra-
patient FDG PET imaging and analysis needed for this study. 
 
On FDG-PET imaging, the level of tumor uptake is assessed subjectively by visual 
inspection, in concordance with the International Working Group criteria.47,48. Semi-
quantitative assessment of response by determination of standardized uptake values 
(SUV) is not utilized in this study. However, SUV measurements will be available for all 
PET scans and can be incorporated into reports as per routine clinical practice. 
 
Part B: Central review of all imaging studies will take place at regular intervals, but not 
on a real-time schedule. Real time FDG-PET central review can be requested on a case-
by-case basis for clarification or adjudication of conflicting institutional imaging studies 
which may be helpful for clinical assessment. Central review will include a visual 
qualitative assessment of tumor FDG PET positive or negative uptake based on the five-
point Deauville scale 49 relative uptake to normal organ FDG activity (1 - no activity above 
surrounding background, 2 ≤ mediastinal blood pool, 3 ≤ liver and > mediastinal blood 
pool, 4 - moderately increased above liver, 5 – markedly increased compared to liver). 
Investigational imaging studies also incorporating semi-quantitative PET tumor SUV-
based assessments will also be performed. 
 
12.2.1 Lymph Nodes or Nodal Masses: 
 
12.2.1.1 FDG-PET negative is defined as: 
a. For moderately sized or large residual masses (≥ 2 cm in greatest 
transverse diameter by CT) regardless of their location, mild and 
diffusely increased FDG uptake with intensity lower than or equal 
to that of mediastinal blood pool structures (i.e. Deauville scale 1 
or 2) should be considered negative. When possible use the 
ascending aorta or aortic arch for reference mediastinal blood 
pool. 
b. For smaller residual masses or normal sized lymph nodes (< 2 cm 
in greatest transverse diameter by CT), any FDG uptake less than 
that of surrounding background activity. 
 

 
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12.2.1.2 FDG-PET positive is defined as: 
a. For moderately sized or large residual masses (≥ 2 cm in greatest 
transverse diameter by CT) regardless of their location, mild and 
diffusely increased FDG uptake with intensity higher than that of 
mediastinal blood pool structures (i.e. Deauville scale 3, 4, or 5) 
should be considered positive. When possible use the ascending 
aorta or aortic arch for reference mediastinal blood pool. 
b. For smaller residual masses or normal sized lymph nodes (< 2 cm 
in greatest transverse diameter by CT), any FDG uptake more than 
that of surrounding background activity. 
 
12.2.2 Lung Nodules: 
 
12.2.2.1 FDG-PET positive is defined as: 
a. For new lung nodules that are ≥ 1.5 cm in greatest transverse 
diameter by CT, FDG uptake exceeding that of mediastinal blood 
pool structures (i.e. Deauville scale 3, 4, or 5) should be 
considered positive. When possible use the ascending aorta or 
aortic arch for reference mediastinal blood pool. 
b. For new lung nodules < 1.5 cm in greatest transverse diameter by 
CT, due to partial volume averaging effects, any uptake is 
considered positive. 
 
12.2.3 Hepatic and Splenic Lesions: 
 
12.2.3.1 FDG-PET positive is defined as: 
a. For hepatic or splenic lesions ≥ 1.5 cm on CT, FDG uptake greater 
than or equal to that of normal liver or spleen parenchyma(i.e. 
Deauville scale 4, or 5), respectively, should be considered 
positive. 
b. For hepatic of splenic lesions < 1.5 cm on CT, FDG uptake greater 
than that of normal liver or spleen parenchyma (i.e. Deauville 
scale 4, or 5), respectively, should be considered positive. 
c. In the absence of focal splenic involvement at diagnosis, diffusely 
increased splenic FDG uptake greater than normal liver 
parenchymal FDG uptake but in the absence of focal lesions seen 
on CT will not be considered for FDG-PET response assessment. 
This is a modification of the IWG criteria as data regarding the 
threshold and significance of this finding is still limited in the 
published literature and potentially complicated by G-CSF effects. 
To balance the competing needs of maintaining time intensity of 
chemotherapy cycles and minimizing the G-CSF effects on FDG-
PET interpretation, the FDG-PET scan should be obtained at the 
specified time points (See Section 8.1). 
 
 

 
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12.2.4 Bone Marrow FDG Uptake: 
12.2.4.1 FDG-PET positive is defined as: 
a. Focal or multifocal FDG uptake in bone marrow. Diffusely 
increased bone marrow FDG uptake, regardless of level of uptake 
– including more intense than liver, is not considered positive. A 
negative bone marrow FDG-PET does not exclude bone marrow 
involvement or preclude a bone marrow biopsy assessment. 
 
12.3 
Response Criteria 
Note: In the instance where there is widespread intense diffuse bone marrow uptake 
secondary to recent G-CSF administration (or other circumstance where the FDG bio-
distribution is abnormal such as brown adipose tissue uptake) the FDG PET studies may 
not be of sufficient quality to adequately assess for response to therapy. In those 
circumstances CT criteria only should be used to assess for response to therapy. See Table 
12.3 below for additional clarification of response criteria definitions. 
 
12.3.1 Complete Response (CR): 
1. Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy.  
2. For patients with bone marrow involvement pre-treatment, negative bone 
marrow biopsies from at least two sites. 
3. HL is typically FDG-avid. Pre-treatment PET scans are required. At sites 
where the PET scan was positive before therapy, a post-treatment residual 
mass of any size is permitted as long as it is PET negative. 
4. The spleen should be normal in size and shape; and pre-therapy nodules should 
have resolved. If the spleen was originally a site of involvement, there should 
be no persistent/residual focal FDG uptake in the spleen. (For assessment of 
diffuse spleen FDG uptake refer to comments on Hepatic and Splenic Lesions 
in Section 12.2.3.) 
5. New FDG-PET positive lung nodules in patients without established 
pulmonary lymphoma at baseline prior to initiation of therapy and evidence of 
complete response at all previously known disease site should be considered 
negative for lymphoma regardless of size or uptake because these typically 
represent infectious or inflammatory lesions. 
 
12.3.2 Partial Response (PR) 
1. At least a 50% decrease in sum of the product of the perpendicular diameters 
(SPPD) of up to 6 of the largest dominant nodes or nodal masses. These nodes 
or masses should be clearly measurable in at least 2 perpendicular dimensions; 
if possible they should be from disparate regions of the body; and they should 
include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved.  
2. There should be no increase in the size of other lymph nodes. 
3. Splenic and hepatic nodules must regress by 50% in their SPPD or, for single 
nodules, in the greatest transverse diameter.  
4. There should be no measurable disease involving other organs.  
5. No new sites of disease. 
6. At sites where the FDG-PET scan was positive before therapy, the post-
treatment PET is positive at one or more of the previously involved sites. 

 
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12.3.5 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). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
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.  
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
13.1 
Purpose 
Adverse event (AE) data collection and reporting which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial. (Please follow directions for routine reporting provided in 
the data collection packet for this protocol). Additionally, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
 
13.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) the characteristics of the adverse event 
including the grade (severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; and 3) whether or not hospitalization 
or prolongation of hospitalization was associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label. Brentuximab vedotin (IND #117117) is the investigational agent in this 
study. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source. The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
 

 
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13.3 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 4.0. The 
descriptions and grading scales found in the revised CTCAE version 4.0 will be 
used for AE reporting. All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
Unrelated, Unlikely, Possible, Probable, and Definite. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported according to the instructions above. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those that 
have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in the current 
Specific Protocol Exceptions to Expedited Reporting (SPEER), as listed in the 
drug information section of the protocol, or as posted as an update on the protocol 
page of the COG Member’s website.  
Step 5:  Review Table A in this section to determine if: 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
there are any protocol-specific exceptions to the reporting requirements. 
 
Table A: Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
 

 
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13.4 
When to Report an Event in an Expedited Manner  

Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.
pdf  
(Telephone the Investigational Drug Branch (IDB) at: 240-276-6565 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 
connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 

Upon occurrence of pulmonary toxicity, as defined in Section 6.2.6, study therapy 
should be held, and the Study Chair and Research Coordinator should be notified 
within 48 hours. 
 

When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 

Expedited AE reporting for this study must only use CTEP-AERS. An expedited AE 
report must be submitted electronically via CTEP-AERS at: https://eapps-
ctep.nci.nih.gov/ctepaers 
 
13.5 
General Instructions for Expedited Reporting via CTEP-AERS 
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located on 
the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.  
 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site. 
 

Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 

Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 

 
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an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 

Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  

Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (eg, H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: 301-230-0159 (back-up: 301-897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax # 626-303-
1768; 
email: 
COGAERS@childrensoncologygroup.org; 
Attention: 
COG 
AERS 
Coordinator).  
 

ALWAYS include the ticket number on all faxed documents. 
 

Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
13.6 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG data 
submission forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.6.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.6.2 If an adverse event progresses through several grades during one course of therapy, 
only the most severe grade should be reported. 
 
 

 
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13.6.3 The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects.  
 
13.6.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than Grade 1, whichever level is higher (note that the resolution 
date may therefore be different from the date at which the grade of the AE 
decreased from its highest grade). If the AE does not return to baseline the 
resolution date should be recorded as "ongoing." 
 
13.6.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
13.7 
Other Recipients of Adverse Event Reports 
 
13.7.1 Events that do not meet the criteria for CTEP-AERS reporting (See Section 13.2) 
should be reported at the end of each cycle using the forms provided in the data 
form packet (See Section 14.1). 
 
13.7.2 COG will forward reports and supporting documentation to the Study Chair, to the 
FDA (when COG holds the IND) and to the pharmaceutical company (for industry 
sponsored trials). 
 
13.7.3 Adverse events determined to be reportable must also be reported according to the 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.8 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients on NCI-sponsored trials following their chemotherapy for cancer must be 
reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation 
Program (CTEP) via CTEP-AERS and included as part of the second malignant neoplasm 
reporting requirements for this protocol (see data submission packet). Submit the 
completed CTEP-AERS report within 14 days of an AML/MDS diagnosis occurring after 
treatment for cancer on NCI-sponsored trials. 
 
Note: The AML/MDS Secondary Reporting form is no longer available on the CTEP 
website. In lieu of this form, AML/MDS events are now to be reported via CTEP-AERS 
(in addition to your routine AE reporting mechanisms). In CTCAE v4.0, the event(s) may 
be reported as either:  
 
1) 
Leukemia secondary to oncology chemotherapy,  
2) 
Myelodysplastic syndrome, or  
3) 
Treatment-related secondary malignancy. 
 
Non-treatment related cases of AML/MDS for CTCAE v4.0 should be reported using 
“Neoplasms benign, malignant and unspecified (including cysts and polyps) - Other, 

 
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specify.” 
To grade a non-life-threatening event for “Myelodysplastic syndrome”, use “Neoplasms 
benign, malignant and unspecified (including cysts and polyps) - Other, specify” where 
the specified term is MDS. 
 
Note: If a patient has been enrolled in more than one NCI-sponsored study, the CTEP-
AERS report must be submitted for the most recent trial. 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
 
13.9 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or Neonatal 
loss”, the Pregnancy Information Form should be completed and faxed along with any 
additional medical information to (301) 230-0159. (Appendix VII). The potential risk of 
exposure of the fetus to the investigational agent should be documented in the “Description 
of Event” section of the CTEP-AERS report. 
 
13.9.1 Pregnancy 

Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
“Pregnancy, puerperium and perinatal conditions - Other (Pregnancy) 
under the Pregnancy, puerperium and perinatal conditions SOC and 
reported as Grade 3. 
 

There is a possibility that the sperm of male patients treated on studies 
involving possible teratogenic agents may have been damaged. For this 
reason, pregnancy in partners of men on study should also be reported and 
followed as described in this section. 
 

Pregnancy should be followed up until the outcome of the pregnancy is 
known at intervals deemed appropriate by her physicians. The “Pregnancy 
Information Form” should be used for all follow-ups. If the baby is born 
with a birth defect or other anomaly, then a second CTEP-AERS report is 
required 
 
13.9.2 Fetal Death 

Fetal death is defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of respiration, 
heartbeat, or definite movement of a voluntary muscle after expulsion 
from the uterus, without possibility of resuscitation.” 
 

 Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.  
 

 A fetal death should NOT be reported as “Fetal death,” a Grade 5 event 

 
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under the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
 
13.9.3 Death Neonatal 

Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
 

A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration- Other (neonatal loss)” under the General 
disorders and administration SOC. 
 

Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event. If reported as 
such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
13.10 
Routine Adverse Event Reporting  
Note: The guidelines below are for routine reporting of study specific adverse 
events on the COG case report forms and do not affect the requirements for CTEP-
AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form 
(CRF) within the study database. For this study, routine reporting will include all 
toxicities reported via CTEP-AERS and all Grade 4 and higher hematologic 
Adverse Events, all Grade 3-4 and higher non-hematologic Adverse Events, and 
all respiratory, peripheral neuropathy, and skin of any grade. 
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information: Roadmaps (Roadmaps were for Part A only), 
Pathology Reports, Surgical Reports. These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data: These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted: All other data will be entered 
in RAVE with the aid of schedules and worksheets (essentially paper copies of the 
OPEN AND RAVE screens) provided in the data form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
 

 
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14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are 
due January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial 
 
14.3 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the provisions in the “Intellectual Property Option to Collaborator” (http:// 
ctep.cancer.gov/industry) contained within the terms of award, apply to the use of the 
Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study. Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI. If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 

 
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(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication. Collaborator(s) will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected. Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting 
or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 

 
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Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 
statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership for 
Part A. This is for Part A only. As of amendment 4, Part A was completed. 
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
Developmental Therapeutics Chair, Vice Chair and Statistician on a weekly 
conference call. 
 
 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 
As of Dec 2009, only CT and MRI guidelines are posted on the COG website so the imaging 
representative on the study committee should be contacted for input. The following COG website 
posted materials may be useful: 
 
CT and MRI guidelines are available on the COG Member site at: 
https://members.childrensoncologygroup.org/_files/reference/RefMaterial/DiagnosticImagingGui
delines_MRI&CT.pdf  
 
For PET scan guidelines please refer to the NCI guidelines for the recommended set of procedures 
for the acquisition and analysis of 18F-FDG PET scans of patients participating in NCI-sponsored 
diagnostic and therapeutic clinical trials, which can be found at the following link: 
http://imaging.cancer.gov/reportsandpublications/publications/Clinical-Trials-Guidelines  
 
The following guidelines are recommendations but follow generally accepted standards for FDG 
PET or PET/CT imaging protocols, allowing for individual institutional variations. However, the 
following generally accepted FDG PET issues and items should be adhered to as much as possible 
in this clinical trial to allow for uniformity of inter- and intra-patient FDG PET imaging and analysis 
needed for this study: 
1) PET/CT, in place of stand-alone PET imaging, should be performed if at all 
possible for anatomical correlation, especially on the follow-up PET imaging. 
2) Patients should be fasted for at least 4 hours before [18F]FDG administration. 

 
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3) After FDG injection, the patient is kept at rest in a warm room through imaging 
to minimize FDG uptake in activated brown adipose tissue or other physiologic 
FDG artifacts. 
4) PET imaging should begin at 60 ± 10 min after injection of [18F]FDG. 
5) For follow-up PET imaging of the same patient, all attempts should be made to 
image the patient on the same PET/CT scanner. 
6) Patient’s measured height and weight on the day of the PET scan be recorded for 
each imaging session. 
7) The following PET parameters should be recorded for each imaging session: 
a. Patient’s weight and height 
b. [18F]FDG dose and time of administration 
c. Start time of PET imaging 
d. Serum glucose level (or verify that level is less than 200 mg/dL) 
8) DICOM PET/CT or PET images be available for transfer to COG for Phase II 
central review.50 
 
Please refer to the American College of Radiology (ACRIN) PET Core Laboratory Standard 
Operating Procedures, which is also adapted from the NCI consensus recommendation,50 at the 
following web link for more detailed information, unless otherwise specified below. 
(http://www.acrin.org/CORELABS/PETCORELABORATORY/PETSOPS/tabid/484/Default.aspx) 
 
15.1 
Pregnancy 
All female patients ≥ 10 years of age should be asked about their pregnancy potential prior 
to FDG injection. Females of reproductive potential may not participate unless they have 
agreed to use an effective contraceptive method. Patients who are sexually active and 
unsure of their pregnancy status should undergo a urine or serum pregnancy test prior to 
FDG injection. Pregnant guardians should not be allowed in the FDG uptake room. 
 
15.2 
Recommended Technique 
Patients should be fasted for at least 4 hours before [18F]FDG administration. Total 
parenteral nutrition and intravenous fluids containing glucose should also be discontinued 
for at least 4 hours before the study. The patient should be well hydrated (oral or 
intravenous fluid administration) before administration of FDG. Fluids administered for 
hydration should not contain glucose. 
 
It is suggested that the patient’s measured height and weight on the day of the PET scan be 
recorded for each imaging session. 
 
If intravenous access is not already in place, this should be obtained, typically in the 
antecubital fossa, for patient hydration (if needed), determination of serum glucose and 
FDG administration. Good hydration is required as the primary route of FDG excretion is 
renal. The patient should drink water or receive intravenous fluids after injection to 
promote urinary FDG excretion. 
 
Venous serum blood glucose will be measured and recorded just prior to injection of the 
FDG and must be ≤ 200 mg/dL. Diabetic patients should be scheduled in the morning after 
an overnight fast before the first meal, and the dose of insulin should be titrated 
appropriately in consultation with the patient’s referring physician to keep the serum 
glucose ≤ 200 mg/dL at the time of scheduled FDG injection. If the serum glucose is 
significantly elevated (> 200 mg/dL) then the test should be rescheduled if at all possible 

 
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with better glucose control or, if necessary, insulin can be used to achieve normoglycemia. 
After regular insulin the patient should wait 2-4 hours (with ultrashort acting glucose 1-2 
hours) prior to administration of FDG in order to minimize physiologic skeletal muscle and 
myocardial FDG uptake. 
 
In patients with tumors in the pelvis, placement of a Foley catheter is recommended. 
Patients in whom a Foley catheter is not placed should be asked to void immediately prior 
to imaging in order to minimize bladder activity and to reduce their radiation exposure. 
 
15.3 
FDG Dosing and Injection 
[18F]FDG is administered intravenously at a dose of 0.140 to 0.200 mCi/kg with a minimum 
dose of 1.0 mCi and maximum dose of 10 mCi. 
 
After injection, the patient is kept at rest in a warm room until imaging. After voiding the 
bladder, whole-body imaging should begin at 60 ± 10 min after injection of [18F]FDG. For 
serial scans of the same patient it is important to start the PET scan with the same delay 
time after injection of the FDG radiotracer. Therefore, it is recommended that all 
subsequent PET scans have approximately the same delay time (± 10 min) as the baseline 
scan. 
 
It is suggested that the net injected FDG dose and time of injection should be recorded. 
The peripheral IV or central line injection site location should also be recorded. 
 
15.4 
PET Scanning Protocol 
A whole body PET imaging protocol is utilized, covering the area from the base of skull/top 
of the ears to the proximal/mid-thigh, just below the pubis. If there is suspicion of 
involvement in the lower extremities, skull, or skull contents, the volume that is imaged 
may be expanded. The patient will be positioned supine, with arms comfortably positioned 
above the head if at all possible (to limit attenuation of the thorax), or at the side of the 
patient if necessary. Scans should proceed upward from the pelvis to diminish the effects 
of accumulation of FDG activity in the bladder. 
 
Transmission scanning matching the areas covered by the emission scan will need to be 
performed for attenuation correction of the emission scan. This will be done after injection 
of FDG. If positron-emitting transmission sources are used, we recommend 2-3 minutes 
per bed position for segmented attenuation correction. With a dedicated NaI PET system, 
attenuation correction should be done with a Cs-137 source per manufacturer 
recommendations. With a combined PET/CT scanner, attenuation correction should be 
done with CT data per manufacturer recommendations. If the COG institution routinely 
adjusts the CT dose used for attenuation correction it can be adjusted to mA based on 
weight of patient using the following guidelines if at all possible to limit the CT radiation 
dose to the patient: 
 
0 to 100 lbs.  
use 40 mA  
 
201 to 300 lbs. use 120 mA 
101 to 150 lbs.  use 60 mA  
 
301 to 400 lbs. use 160 mA 
151 to 200 lbs.  use 80 mA 
 
The 511 KeV-annihilation photons, produced by interaction of positrons with electrons, 
are imaged. Because of the short physical half-life of 1.8 hours and the high photon energy 
of 511 KeV, FDG imaging may follow bone or gallium scintigraphy, or a MUGA study on 
the same day (which use lower energy photons) or FDG imaging may be performed on the 

 
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day preceding any of these other nuclear medicine studies. 
 
Emission data must be collected for at least 5 minutes per bed position for BGO, LSO, and 
GSO systems operated in the 2-D mode; at least 3 minutes per bed position for BGO, LSO, 
and GSO systems operated in the 3-D mode; and at least 6 minutes per bed position for 
NaI systems. Images will be corrected for scatter, random events, and dead-time losses 
using manufacturer's software. Bed positions should be overlapped to avoid large changes 
in sensitivity at the joints between the bed positions. 
 
It is suggested that the following acquisition parameters should be recorded: start time of 
emission scan and type of transmission scan. 
 
It is recommended that PET images be reconstructed with and without attenuation 
correction. It is also recommended that for serial scans of the same patient, image 
reconstruction techniques and parameters be consistent across all scans, including filters 
and application of the attenuation map. 
 
15.5 
After Completion of the PET Scan 
The patient must empty his or her urinary bladder as soon as possible after imaging. Image 
reconstruction will depend on the scanner manufacturer. An iterative reconstruction 
method with parameters chosen to yield 6-8 mm resolution in the reconstructed images is 
recommended. 
 
15.6 
FDG Handling and Dose Documentation 
FDG is to be synthesized by standard methods and tested for pyrogenicity and 
radiochemical purity on each production run, or purchased from nuclear pharmacies 
licensed to sell FDG. The radiochemical purity of the FDG should be > 90%. [18F]FDG 
should be produced in a GMP facility according to FDA required standard-operating-
procedures for clinical use. 
 
15.7 
PET Imaging Quality Control Standards 
FDG-PET imaging will be performed using "state-of-the-art" equipment (either a dedicated 
NaI, BGO, LSO or GSO full-ring PET system), which will have a field of view appropriate 
for body imaging (10 cm), high resolution (FWHM 6.0 mm), high sensitivity, and post-
injection transmission capability. 
 
Daily and monthly steps will be taken to assure quantitative accuracy of PET imaging 
studies and reliable imaging results at all performance sites. Daily quality assurance 
includes a simplified chi-square test to assure consistent performance of the PET scanner. 
The calculation provides a quantitative means of monitoring drift of the scanner electronics 
with time. A blank scan is also performed daily for later attenuation correction. Either of 
these measurements may be viewed routinely as an additional measure of performance. A 
liquid-filled or standardized sealed-source cylinder phantom is used monthly to validate 
the quantitative accuracy of the images against a dose calibrator. The dose calibrator is 
itself calibrated daily against standards for constancy and annually for accuracy using 
NIST-traceable standards. Each month, fine gain calibration of all detectors in the PET 
system will be performed, followed by recalculation of the sensitivity normalization factors 
for the scanner. 
 
 

 
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Transmission scans, each 2-3 minutes in duration for segmented attenuation correction, 
will be obtained with a rotating Ge-68/Ga-68 rod source emission scan (alternatively, 
attenuation measurement may be performed with a Cs-137 source or with CT data from a 
combined PET/CT scanner, in accordance with manufacturer’s recommendations). An 
algorithm to correct for activity in the field of view should be used for processing of these 
post-injection transmission images, if provided by the vendor. Then the corresponding 
emission images can be obtained as appropriate (time per bed position for specific detector 
crystal type and acquisition mode detailed above in the PET Scanning Protocol section). 
Alternatively, the individual emission and transmission scans may be acquired in 
alternating fashion. The PET images will be reconstructed by standard vendor-provided 
reconstruction algorithms, using either filtered back projection with a Hanning filter 
(frequency cutoff 0.6 x Nyquist [Nq] = 0.3 cycle/pixel) or the manufacturer’s 
recommended iterative reconstruction algorithm with an appropriate filter.  
 
Segmentation of transmission images should be used for attenuation correction. Emission 
data will be corrected for randoms, dead-time and scatter using vendor-provided 
algorithms. Multiple-bed position studies must be corrected for radioactive decay. The 
emission images will be reconstructed both with and without attenuation correction. 

 
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10:435-44, 2010 
30. 
Navarro A, Gaya A, Martinez A, et al: MicroRNA expression profiling in classic Hodgkin 
lymphoma. Blood 111:2825-32, 2008 
31. 
Van Vlierberghe P, De Weer A, Mestdagh P, et al: Comparison of miRNA profiles of 
microdissected Hodgkin/Reed-Sternberg cells and Hodgkin cell lines versus CD77+ B-cells reveals 
a distinct subset of differentially expressed miRNAs. British Journal of Haematology 147:686-90, 
2009 
32. 
Gibcus JH, Kroesen BJ, Koster R, et al: MiR-17/106b seed family regulates p21 in Hodgkin's 
lymphoma. J Pathol 225:609-17 
33. 
Paik JH, Jang JY, Jeon YK, et al: MicroRNA-146a downregulates NFkappaB activity via targeting 
TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell 
lymphoma. Clin Cancer Res 17:4761-71 
34. 
Koene HR, Kleijer M, Algra J, et al: Fc gammaRIIIa-158V/F polymorphism influences the binding 
of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H 
phenotype. Blood 90:1109-14, 1997 
35. 
Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr 106:522-6, 1985 
36. 
Grunewald R, Abbruzzese JL, Tarassoff P, et al: Saturation of 2',2'-difluorodeoxycytidine 5'-
triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer 
Chemother Pharmacol 27:258-62, 1991 
37. 
Grunewald R, Kantarjian H, Du M, et al: Gemcitabine in leukemia: a phase I clinical, plasma, and 
cellular pharmacology study. J Clin Oncol 10:406-13, 1992 
38. 
Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular 
pharmacology study of gemcitabine. J Clin Oncol 9:491-8, 1991 

 
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39. 
Akrivakis K, Schmid P, Flath B, et al: Prolonged infusion of gemcitabine in stage IV breast cancer: 
a phase I study. Anticancer Drugs 10:525-31, 1999 
40. 
Patel SR, Gandhi V, Jenkins J, et al: Phase II clinical investigation of gemcitabine in advanced soft 
tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J 
Clin Oncol 19:3483-9, 2001 
41. 
Pollera CF, Ceribelli A, Crecco M, et al: Prolonged infusion gemcitabine: a clinical phase I study 
at low- (300 mg/m2) and high-dose (875 mg/m2) levels. Invest New Drugs 15:115-21, 1997 
42. 
Schmid P, Akrivakis K, Flath B, et al: Phase II trial of gemcitabine as prolonged infusion in 
metastatic breast cancer. Anticancer Drugs 10:625-31, 1999 
43. 
Sezer O, Eucker J, Jakob C, et al: Achievement of complete remission in refractory Hodgkin's 
disease with prolonged infusion of gemcitabine. Invest New Drugs 19:101-4, 2001 
44. 
Touroutoglou N, Gravel D, Raber MN, et al: Clinical results of a pharmacodynamically-based 
strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 9:1003-8, 1998 
45. 
Tempero M, Plunkett W, Ruiz Van Haperen V, et al: Randomized phase II comparison of dose-
intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic 
adenocarcinoma. J Clin Oncol 21:3402-8, 2003 
46. 
Vander Els NJ, Miller V: Successful treatment of gemcitabine toxicity with a brief course of oral 
corticosteroid therapy. Chest 114:1779-81, 1998 
47. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
48. 
Barrington SF, Mikhaeel NG, Kostakoglu L, et al: Role of imaging in the staging and response 
assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas 
Imaging Working Group. J Clin Oncol 32:3048-58, 2014 
49. 
Meignan M, Gallamini A, Itti E, et al: Report on the Third International Workshop on Interim 
Positron Emission Tomography in Lymphoma held in Menton, France, 26-27 September 2011 and 
Menton 2011 consensus. Leuk Lymphoma 53:1876-81, 2012 
50. 
Shankar LK, Hoffman JM, Bacharach S, et al: Consensus recommendations for the use of 18F-
FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J 
Nucl Med 47:1059-66, 2006 
 
 

 
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APPENDIX II: CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP REGISTRATION PROCEDURES 
 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators participating in any NCI-sponsored clinical trial to register and to renew 
their registration annually. 
 
Registration requires the submission of: 
 

a completed Statement of Investigator Form (FDA Form 1572) with an original signature 

a current Curriculum Vitae (CV) 

a completed and signed Supplemental Investigator Data Form (IDF) 

a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator registration.htm>. For questions, please 
contact 
the 
CTEP 
Investigator 
Registration 
Help 
Desk 
by 
email 
at 
<pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate registration.htm>. For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
CTSU REGISTRATION PROCEDURES 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for AHOD1221 Site Registration: 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB) 
• 
CTSU RT Facilities Inventory Form  
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy 

 
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component must participate in the IROQ Houston monitoring program. If this form has been 
previously submitted to CTSU it does not need to be resubmitted unless updates have occurred 
at the RT facility. 
 
Submitting Regulatory Documents: 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration status page 
of the members’ section of the CTSU website. (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 

Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 

Click on the Regulatory tab at the top of your screen 

Click on the Site Registration tab 

Enter your 5-character CTEP Institution Code and click on Go 
 
 

 
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APPENDIX IV: GUIDELINES FOR PERIPHERAL BLOOD STEM CELL (PBSC) 
COLLECTION PROCEDURE (AS OF AMENDMENT 4, PART A IS CLOSED. THIS IS ONLY 
FOR PART B.) 
 
Personnel  
PBSC should be collected by an experienced team that regularly collects apheresis components. The 
collection team should consist of at least one physician and two or more individuals experienced in the 
collection of apheresis components and in the management of apheresis donors. At least one person should 
be experienced in the management of children. The PBSC collections should be performed in a facility with 
a pediatric intensive care unit and adequate provision for the emergency care of children. 
 
Apheresis machine 
The Cobe Spectra or the Fenwal CS 3000+ is recommended because the continuous flow centrifugation 
devices are better tolerated in pediatric patients than discontinuous flow machines. Institutional SOPs for 
the apheresis procedure should be followed. 
 
Priming 
Priming of the machine prior to collection should be with ACD and saline according to manufacturer's 
directions. For patients less than 20-25 kg, a secondary prime with IRRADIATED, leukocyte-reduced red 
blood cells should be done. The use of an in-line blood warmer on the return line is recommended. 
 
Anticoagulant 
Anticoagulant to be used is ACD in a ratio sufficient to prevent extracorporeal clotting. Heparin is not 
recommended for the collection of PBSC unless symptoms of hypocalcemia preclude the use of sufficient 
ACD. 
 
Whole Blood Flow Rate 
In general, it is desirable to process the required volume of blood in the shortest possible time. Catheter size 
and/or tolerance of the citrate anticoagulant may be the rate-limiting factors in children. The following 
guidelines are the whole blood flow rates that can be expected to be achieved in children: 
< 2 years (< 15 kg) 20-30 ml/min 
2-5 yrs (15-20 kg) 30-40 ml/min 
>5 years (> 20 kg) 40-60 ml/min 
 
PBSC Collection Methodology 
Typically apheresis for stem cell collection is established at 2-3x total blood volume (TBV) of 
donor/recipient. This volume will vary, however, and with extended large volume apheresis the cell 
collection can plateau and begin to decline. For optimum collection, twice TBV should be the minimum 
volume processed. Repeated leukaphereses should be performed daily for a maximum of 5 days until 
collection goals are met. Peripheral blood circulating CD34 levels can be monitored to determine optimal 
apheresis time points. When standard volume leukapheresis procedures are used to collect components to 
be infused following myeloablative therapy, 1-5 collections are generally required. Large volume 
eukapheresis procedures are those in which the volume of whole blood processed per procedures is >4-5x 
TBV (>15L TBV). Protocol-specific collection goals may be met with a single collection procedure. 
 
Collection Goals 
The collection goal for autologous PBSC intended to rescue a patient following myeloablative therapy 
(total, all collections) is a minimum of 2 X 106 CD34+ cells/kg. It is suggested that the optimum collection 
goal should be 5 x106 CD34+ cells/kg, stored in at least 2 alliquots of cells, with 2-3 x106 CD34+ cells/kg 
stored as backup for delayed engraftment. 
 
 

 
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Patient Monitoring 
Patients should be observed continuously during the collection procedure by personnel experienced in the 
nursing care of children and familiar with the standard operation of the apheresis device. Care is required 
to ensure that the connections between the patient and the machine are not covered with blankets. Vital 
signs should be taken and recorded, and observations recorded periodically in compliance with institutional 
policy. 
 
Recommended laboratory tests should include of the following: 
Pre-apheresis: WBC, differential; hematocrit, platelet count, serum calcium. 
Post-apheresis: Hematocrit, platelet count, serum calcium. 
 
Vascular Access  
Continuous flow centrifugation machines require two sites of vascular access. Recommended methods of 
achieving this access include: two peripheral venous lines, two central venous lines, one peripheral and one 
central venous line, or one double lumen central venous catheter. One arterial line (for withdrawal) with 
one venous line (for blood return) is acceptable. 
 
PBSC MOBILIZATION WITH CHEMOTHERAPY PLUS GROWTH FACTOR 
Filgrastim administration should begin 24 hours after the second gemcitabine dose in a cycle of 
chemotherapy, at an increased dose of 10-16 mcg/kg/dose until completion of peripheral stem cell 
collection (See Section 8.4). Filgrastim should be discontinued after collections are complete. 
 
PBSC COMPONENTS 
Each PBSC collection should be monitored with the following: 
Culture for bacterial and fungal contamination 
Nucleated cell count and differential 
CD34+ cell enumeration 
 
Each PBSC collection should be processed and cryopreserved on the day of collection. Processing and 
cryopreservation methods to be employed should be those demonstrated to reproducibly result in successful 
hematopoietic reconstitution following marrow ablative therapy. 
 
Positive selection for CD34+ cells, if employed, must be done using a device and reagents approved by the 
FDA for this indication or under an appropriate IND or IDE. 
 
 

 
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APPENDIX VIII:  CYP3A4 INDUCERS AND INHIBITORS 
 
Patients should be monitored for potential drug-interaction when administered drugs known to be a strong 
CYP3A4 inhibitor/inducer with SGN-35. The use of the following medications should be avoided during 
protocol therapy if reasonable alternatives exist. This is not an inclusive list; please refer to other resources 
such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx for additional information. 
 
Strong 
Inhibitors 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Other 
Inhibitors 
Inducers 
Clarithromycin 
Indinavir 
Itraconazole 
Ketoconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telithromycin 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit 
Grapefruit juice 
Verapamil 
Cimetidine 
Amiodarone 
Bocepravir 
Chloramphenicol 
Ciprofloxacin 
Delaviridine 
Fluvoxamine 
Imatinib 
Mifepristone 
Norfloxacin 
Norfluoxetine 
(fluoxetine) 
Star fruit 
Telaprevir 
Voriconazole 
Barbiturates 
Carbamazepine 
Efavirenz 
Glucocorticoids* 
Modanfinil 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s wort 
 
*Refer to Section 7.5 regarding use of corticosteroids. 
 
 

 
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APPENDIX IX:  POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Brentuximab vedotin 
Drugs that may interact with brentuximab vedotin 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
Antifungals  
o Itraconazole, ketoconazole, posaconazole, voriconazole 
Arthritis medications  
o Leflunomide, tofacitinib 
Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir 
Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
Heart medications  
o Nicardipine, verapamil 
Some chemotherapy (be sure to talk to your doctor about this) 
Many other drugs, including the following: 
o Bosentan, deferasirox, dexamethasone, lomitapide, natalizumab, nefazodone 
 
Food and supplements that may interact with brentuximab vedotin* 
Echinacea 
St. John’s Wort 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
 
Gemcitabine 
Drugs that may interact with gemcitabine* 
o Clozapine, natalizumab, leflunomide, tofacitinib, warfarin  
 
Food and supplements that may interact with gemcitabine** 
Echinacea 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Sometimes these drugs are used with gemcitabine on purpose. Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. The list above does not include everything that may interact with your 
chemotherapy. Talk to your doctor before starting any new medications, over-the-counter medicines, or 
herbal supplements and before making a significant change in your diet. 
 
 

 
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APPENDIX X: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY (Part B only) 
(for children from 7 through 12 years of age) 
 
A Study of Brentuximab Vedotin and Gemcitabine for Children with Hodgkin Disease  
 
1. We are asking you to take part in a research study because you have Hodgkin disease that didn’t 
get better with treatment or that has come back after treatment. Hodgkin disease is a type of cancer 
that grows in the tissues in your body that make and store white blood cells. White blood cells help 
protect your body against infections. A research study is when doctors work together to try out new 
ways to help people who are sick.  
 
2. Children who are part of this study will be will be treated with chemotherapy. Everyone in this 
study will be treated with two chemotherapy drugs used to treat Hodgkin disease. These drugs are: 
brentuximab vedotin and gemcitabine. After every 2 cycles of treatment, we will look at changes 
on scans (called CT and PET scans) to measure how the cancer is responding to therapy.  
 
3. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that your cancer 
will go away but we don’t know for sure if there is any benefit of being part of this study. 
 
4. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may not get rid of 
your cancer as well as a non-study treatment. Other things may happen to you that we don’t yet 
know about. 
 
5. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
6. As part of this study, we will collect additional blood. These studies will help us better understand 
Hodgkin disease and why some people respond to treatment better than other people. The blood 
draws would be taken when other standard blood tests are being performed.  
 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY (Part B only) 
(for teens from 13 through 17 years of age) 
 
A Study of Brentuximab Vedotin and Gemcitabine for Children with Hodgkin Disease  
 
1. We are asking you to take part in a research study because you have Hodgkin disease that either 
didn’t get better with your treatment or came back after the end of treatment. Hodgkin disease is a 
type of cancer that grows in the tissues in your body that make and store white blood cells. White 
blood cells help protect your body against infections. A research study is when doctors work 
together to try out new ways to help people who are sick. 
 
2. Children and teens who are part of this study will be will be treated with chemotherapy. Everyone 
in this study will be treated with two chemotherapy drugs used to treat Hodgkin disease. These 
drugs are: brentuximab vedotin and gemcitabine. After every 2 cycles of treatment, we will look at 
changes on scans (called CT and PET scans) to measure how the cancer is responding to therapy.   
 
3. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is to get rid of the 
cancer for as long as possible.  
 
4. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may not get rid of 
your cancer as well as a non-study treatment. This could increase the chance of the cancer returning. 
Also, the use of brentuximab vedotin and gemcitabine may cause complications. Other things may 
happen to you that we don’t yet know about. 
 
5. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
6. As part of this study, we will collect additional blood. These studies will help us better understand 
Hodgkin disease and why some people respond to treatment better than other people. The blood 
draws would be taken when other standard blood tests are being performed.