Clinical trial NCT03049449
Conditions: Lymphoma, Large-Cell, Anaplastic Enteropathy-Associated T-Cell Lymphoma Lymphoma, Large B-Cell, Diffuse Lymphoma, Extranodal NK-T-Cell Lymphoma, T-Cell, Peripheral
Keywords: Gray Zone Lymphoma Immunotherapy Peripheral T-Cell Lymphoma Anaplastic Large Cell Lymphoma Angioimmunoblastic T-cell lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-03-17; Completion date: 2022-01-26
Enrollment: 26 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Background:

* Improved treatments for a variety of treatment-resistant, TNFRSF8 (CD30)-expressing malignancies including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30- expressing lymphomas are needed.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen B-lymphocyte antigen CD19 (CD19) have caused complete remissions in a small number of patients with lymphoma. These results demonstrate that CAR-expressing T cells can have anti-lymphoma activity in humans.
* CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which allows selection of CD30-expressing malignancies for treatment.
* CD30 is not known to be expressed by normal cells except for a small number of activated lymphocytes.
* We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.
* This particular CAR has not been tested before in humans.
* Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of a small number of normal activated lymphocytes is possible, and unknown toxicities are also possible.

Objectives:

Primary

-Determine the safety and feasibility of administering T-cells expressing a novel fully human anti-CD30 CAR to patients with advanced CD30-expressing lymphomas.

Eligibility:

* Patients must have anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma, enteropathy associated T-cell lymphoma, or extranodal natural killer (NK)/T-cell lymphoma, nasal type
* Patients must have malignancy that is both measurable on a computed tomography (CT) scan with a largest diameter of at least 1.5 cm and possessing increased metabolic activity detectable by positron emission tomography (PET) scan. Alternatively, patients with lymphoma detected by flow cytometry of bone marrow are eligible.
* Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 is required.
* No active infections are allowed including evidence of active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. At the time of protocol enrollment patients must be seronegative for cytomegalovirus (CMV) by antibody testing or must have a negative blood CMV polymerase chain reaction (PCR).
* Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater than or equal to 55,000/micro L, hemoglobin greater than or equal to 8g/dL
* Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids above 5 mg/day of prednisone or equivalent corticosteroid dose) and initiation of required leukapheresis.
* Clear CD30 expression must be detected on 75% or more of malignant cells from either bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s malignancy will need to be assessed for CD30 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffin-embedded bone marrow or lymphoma sections are available from prior biopsies, these can be used to determine CD30 expression by immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come from a biopsy obtained at any time before enrollment, unless the patient has received a prior anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy following completion of the most recent anti-CD30 monoclonal antibody treatment.
* Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma must have received 2 prior treatment regimens at least 1 of which included an anthracycline and an anti-CD20 monoclonal antibody.
* Patients who have never had an allogeneic hematopoietic stem cell transplant as well as patients who have had a 9/10 or 10/10 human leukocyte antigen (HLA)-matched sibling or a 9/10 or 10/10 HLA- matched unrelated donor hematopoietic stem cell transplant are potentially eligible.
* Women who are pregnant or plan to become pregnant will be excluded.

Detailed description:
Background:

* Improved treatments for a variety of treatment-resistant, TNFRSF8 (CD30)-expressing malignancies including Hodgkin lymphoma, anaplastic large cell lymphoma, and other CD30- expressing lymphomas are needed.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen B-lymphocyte antigen CD19 (CD19) have caused complete remissions in a small number of patients with lymphoma. These results demonstrate that CAR-expressing T cells can have anti-lymphoma activity in humans.
* CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, which allows selection of CD30-expressing malignancies for treatment.
* CD30 is not known to be expressed by normal cells except for a small number of activated lymphocytes.
* We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice.
* This particular CAR has not been tested before in humans.
* Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of a small number of normal activated lymphocytes is possible, and unknown toxicities are also possible.

Objectives:

Primary

-Determine the safety and feasibility of administering T-cells expressing a novel fully-human anti-CD30 CAR to patients with advanced CD30-expressing lymphomas.

Eligibility:

* Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma, enteropathy-associated T-cell lymphoma, or extranodal natural killer (NK)//T-cell lymphoma, nasal type
* Patients must have malignancy that is both measurable on a computed tomography (CT) scan with a largest diameter of at least 1.5 cm and possessing increased metabolic activity detectable by positron emission tomography (PET) scan. Alternatively, patients with lymphoma detected by flow cytometry of bone marrow are eligible.
* Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 is required.
* No active infections are allowed including evidence of active human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. At the time of protocol enrollment, patients must be seronegative for cytomegalovirus (CMV) by antibody testing or must have a negative blood CMV polymerase chain reaction (PCR).
* Absolute neutrophil count greater than or equal to 1000/micro L, platelet count greater than or equal to 55,000/micro L, hemoglobin greater than or equal to 8g/dL
* Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal to 3 times the upper limit of the institutional normal unless liver involvement by malignancy is demonstrated.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids above 5 mg/day of prednisone or equivalent corticosteroid dose) and initiation of required leukapheresis.
* Clear CD30 expression must be detected on 75% or more of malignant cells from either bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The patient s malignancy will need to be assessed for CD30 expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffin-embedded bone marrow or lymphoma sections are available from prior biopsies, these can be used to determine CD30 expression by immunohistochemistry; otherwise, patients will need to come to the NIH for a biopsy to determine CD30 expression. The sample for CD30 expression can come from a biopsy obtained at any time before enrollment, unless the patient has received a prior anti-CD30 monoclonal antibody, in which case the sample must come from a biopsy following completion of the most recent anti-CD30 monoclonal antibody treatment.
* Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma must have received 2 prior treatment regimens at least 1 of which included an anthracycline and an anti-CD20 monoclonal antibody.
* Patients who have never had an allogeneic hematopoietic stem cell transplant as well as patients who have had a 9/10 or 10/10 human leukocyte antigen (HLA)-matched sibling or a 9/10 or 10/10 HLA- matched unrelated donor hematopoietic stem cell transplant are potentially eligible.
* Women who are pregnant or plan to become pregnant will be excluded.

Design:

* This is a phase I dose-escalation trial.
* Patients will undergo leukapheresis.
* T cells obtained by leukapheresis will be genetically modified to express an anti-CD30 CAR.
* Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused anti-CD30 CAR-expressing T cells.
* A chemotherapy conditioning regimen of cyclophosphamide and fludarabine will be administered prior to all CAR T-Cell infusions. Fludarabine will be given on the same days as the cyclophosphamide.
* Two days after the chemotherapy ends, patients will receive an infusion of anti-CD30-CAR-expressing T cells.
* The initial dose level of this dose-escalation trial will be 0.3x10(6) CAR+ T cells/kg of recipient bodyweight for Cohort 1. The initial dose level will be 1 x 10 (6) CAR+T cells/kg for Cohort 2.
* The cell dose administered will be escalated until a maximum tolerated dose is determined.
* Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.
* Outpatient follow-up is planned for 2 weeks and 1, 2, 3, 4, 6, 9, and 12 months after the CAR T-cell infusion. Long-term gene-therapy follow-up consisting of yearly visits to a doctor near the patients home for 4 more years and then yearly telephone contact for 10 additional years will be required.
* As of Amendment E (Protocol version: 08/03/2018), repeat treatments consisting of the conditioning chemotherapy followed by a CAR T-cell infusion at the maximum tolerated dose (MTD) for the patients cohort are allowed for eligible patients with any best responses except continuing complete remission or progressive malignancy.
* Re-enrollment will be allowed for a small number of subjects.

Arms: arm 1: All patients will be receiving starting dose: 0.3x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) (up to a maximum dose of 18x10\^6 CAR+ T cells/kg) infuse on day 0 and Cyclophosphamide: 300 or 500 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 and Fludarabine: 30 mg/m\^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3
Interventions: intervention 1: Anti-Tumor Necrosis Factor (TNF) Receptor Superfamily Member 8 (CD30) Chimeric Antigen Receptor (CAR) T cells intervention 2: Cyclophosphamide intervention 3: Fludarabine
Intervention descriptions: intervention 1: Dose-escalation trial starting dose: 0.3x10\^6 Chimeric Antigen Receptor (CAR)+ T cells/kg (weight based dosing) (up to a maximum dose of 18x10\^6 CAR+ T cells/kg) infuse on day 0 intervention 2: 300 or 500 mg/m\^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3 intervention 3: 30 mg/m\^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Protocol documents:
Prot_SAP_000.pdf: 
1 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
Abbreviated Title: Anti-CD30-CAR T cells  
NIH Protocol #: 17-C-0048 
IBC#: RD-16-V-05 
OSP#: 1703-1581 
NCT#: NCT03049449 
Version Date:  October 19, 2020 
Amendment: J 
Title:  Anti-CD30 CAR T Cells with Fully-human Binding Domains for Treating CD30-
expressing Lymphomas including Anaplastic Large Cell Lymphomas 
NCI Principal Investigator: James N. Kochenderfer, M.D.  
Surgery Branch 
Center for Cancer Research, 
National Cancer Institute, National Institutes of Health 
10 Center Drive, Rm. 6B17, MSC 1203 
Telephone:  240-760-6062 
Email:  kochendj@mail.nih.gov 
 
Investigational Agents:     
Drug Name: 
Anti-CD30-CAR T cells 
IND Number: 
17150 
Sponsor: 
Center for Cancer Research 
 
Commercial Agents: Cyclophosphamide, Fludarabine   
 
 
 


2 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
TABLE OF ABBREVIATIONS 
Abbreviation 
Full Terminology 
ABVD 
Doxorubicin-bleomycin-vinblastine-dacarbazine 
AE 
Adverse event 
ALCL 
Anaplastic large cell lymphoma 
ALK- ALCL 
Anaplastic lymphoma kinase negative anaplastic large cell lymphoma 
ALL 
Acute lymphocytic leukemia 
alloHSCT 
Allogeneic hematopoietic stem cell transplant 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
autoHSCT 
Autologous hematopoietic stem cell transplant 
AVD 
Doxorubicin-vinblastine-dacarbazine 
β-HCG 
Beta-human chorionic gonadotropin 
BEACOPP 
Bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-
procarbazine-prednisone 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
C3D 
Cancer Center Clinical Data System 
CAR 
Chimeric antigen receptor 
CBC 
Complete Blood Count 
CCR 
Center for Cancer Research 
cDNA 
Complementary Deoxyribonucleic acid 


3 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
Abbreviation 
Full Terminology 
CFSE 
carboxyfluorescein diacetate,succinimidyl ester proliferation assay 
CHOEP 
Cyclophosphamide-doxorubicin-vincristine-etoposide-prednisone 
CHOP 
Cyclophosphamide-doxorubicin-vincristine-prednisone 
CIT 
Center for Information Technology 
CK 
Creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration formula 
Cl 
Chloride 
CLL 
Chronic lymphocytic leukemia 
CML 
Chronic myeloid leukemia 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CO2 
Bicarbonate 
CPT 
Cell preparation tube 
CR 
Complete remission 
CRIS 
Clinical Research Information System 
CRO 
Central Registration Office 
CRP 
C-reactive peptide 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse events 
DA-EPOCH-R 
Dose 
adjusted 
etoposide-prednisone-doxorubicin-vincristine-
doxorubicin-rituximab 
DLBCL 
Diffuse large B cell lymphoma 
DLI 
Donor lymphocyte infusion 


4 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
Abbreviation 
Full Terminology 
DLT 
Dose limiting toxicity 
DTM 
Department of Transfusion Medicine 
EATL 
Enteropathy-associated T-cell lymphoma 
EBV 
Epstein-Barr Virus  
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-free survival 
EKG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
ENKTL 
Extranodal natural killer/T-cell lymphoma 
SB 
Surgery Branch 
FDA 
Food and Drug Adminstration 
FDG 
Fludeoxyglucose 
FSH 
Follicle stimulating hormone  
G6PD 
Glucose-6-phosphate dehydrogenase 
GnRH 
Gonadotropin-releasing hormone 
GVHD 
Graft versus host disease 
GVL 
Graft versus lymphoma effect 
GVM 
Graft versus malignancy 
Hb 
Hemoglobin 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus  
HL 
Hodgkin lymphoma 
HLA 
Human leukocyte antigen 


5 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
Abbreviation 
Full Terminology 
HRPP 
Human Research Protections Program 
HSV 
Herpes simplex virus 
HTLV-1 
Human T-cell Lymphotropic virus 1 
IBC 
Institutional Biosafety Committee 
IFNγ 
Interferon gamma 
IL 
Interleukin 
IND 
Investigational new drug 
IRB 
Institutional review board 
iRIS 
Integrated Research Information System 
K 
Potassium 
LAM-PCR 
Linear amplification mediated polymerase chain reaction 
LDH 
Lactate dehydrogenase 
Mg 
Magnesium 
MTD 
Maximum tolerated dose 
MRI 
Magnetic resonance imaging 
Na 
Sodium 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OSP 
Office of Science Policy 
ORR 
Overall response rate 
OS 
Overall survival 
OHSRP 
Office for Human Subjects Research Protections 
PBMC 
Peripheral blood mononuclear cells 


6 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
Abbreviation 
Full Terminology 
PD 
Progressive disease 
PE 
Physical Exam 
PET 
Positron emission tomography 
PI 
Principal Investigator 
PICC 
Peripherally inserted central catheter 
PMBL 
Primary mediastinal B cell lymphoma 
PR 
Partial remission 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PTCL NOS 
Peripheral T cell lymphoma not otherwise specified 
qPCR 
Quantitative polymerase chain reaction 
R-CHOP 
Rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone 
RCL 
Replication competent lentivirus 
RNA 
Ribonucleic acid 
RPR 
Rapid plasma reagin 
RT-PCR 
Real-time polymerase chain reaction 
SPD 
Sum of the product of diameters 
scFv 
Single chain variable fragment 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SOP 
Standard operating procedure 
SST 
Serum separator tube 
TBI 
Total body irradiation 


7 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
Abbreviation 
Full Terminology 
TBNK 
Refers to peripheral blood lymphocyte phenotyping as T, B, or NK 
cells.  
TCRs 
T cell receptors 
TNFR 
Tumor necrosis factor receptor 
TRAF 
Tumor necrosis factor receptor associated factors 
 
 
 


8 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
PRÉCIS  
Background: 
• Improved treatments for a variety of treatment-resistant, CD30-expressing malignancies 
including anaplastic large cell lymphoma, and other CD30-expressing lymphomas are 
needed.  
• T cells can be genetically modified to express chimeric antigen receptors (CARs) that 
specifically target malignancy-associated antigens. 
• Autologous T cells genetically modified to express CARs targeting the B-cell antigen 
CD19 have caused complete remissions in a small number of patients with lymphoma.  
These results demonstrate that CAR-expressing T cells can have anti-lymphoma activity 
in humans. 
• CD30 expression can be easily detected by immunohistochemistry on lymphoma cells, 
which allows selection of CD30-expressing malignancies for treatment. 
• CD30 is not known to be expressed by normal cells except for a small number of activated 
lymphocytes. 
• We have constructed a novel fully-human anti-CD30 CAR that can specifically recognize 
CD30-expressing target cells in vitro and eradicate CD30-expressing tumors in mice. 
• This particular CAR has not been tested before in humans. 
• Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and 
neurological toxicities.  Elimination of a small number of normal activated lymphocytes is 
possible, and unknown toxicities are also possible. 
Objectives: 
Primary 
• Determine the safety and feasibility of administering T cells expressing a novel fully-
human anti-CD30 CAR to patients with advanced CD30-expresssing lymphomas. 
 
Eligibility: 
• Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, 
peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not 
otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma, 
enteropathy-associated T-cell lymphoma, or extranodal NK/T-cell lymphoma, nasal type 
• Patients must have malignancy that is both measurable on a CT scan with a largest diameter 
of at least 1.5 cm and possessing increased metabolic activity detectable by PET scan.  
Alternatively patients with lymphoma detected by flow cytometry of bone marrow are 
eligible. 
• Patients must have a creatinine of 1.6 mg/dL or less and a normal cardiac ejection fraction. 
• An ECOG performance status of 0-2 is required. 


9 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
• No active infections are allowed including evidence of active HIV, hepatitis B, or hepatitis 
C. At the time of protocol enrollment, patients must be seronegative for CMV by antibody 
testing or must have a  negative blood CMV PCR.  
• Absolute neutrophil count≥1000/µL, platelet count≥55,000/µL, hemoglobin ≥ 8g/dL  
• Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal 
unless liver involvement by malignancy is demonstrated. 
• At least 14 days must elapse between the time of any prior systemic treatment (including 
corticosteroids above 5 mg/day of prednisone or equivalent corticosteroid dose) and 
initiation of required leukapheresis. 
• Clear CD30 expression must be detected on 75% or more of malignant cells from either 
bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The 
patient’s malignancy will need to be assessed for CD30 expression by flow cytometry or 
immunohistochemistry performed at the NIH.  If unstained, paraffin-embedded bone 
marrow or lymphoma sections are available from prior biopsies, these can be used to 
determine CD30 expression by immunohistochemistry; otherwise, patients will need to 
come to the NIH for a biopsy to determine CD30 expression.  The sample for CD30 
expression can come from a biopsy obtained at any time before enrollment, unless the 
patient has received a prior anti-CD30 monoclonal antibody, in which case the sample must 
come from a biopsy following completion of the most recent anti-CD30 monoclonal 
antibody treatment. 
• Eligible patients with diffuse large B-cell lymphoma or primary mediastinal B-cell 
lymphoma must have received 2 prior treatment regimens at least 1 of which included an 
anthracycline and an anti-CD20 monoclonal antibody.  
• Patients who have never had an allogeneic hematopoietic stem cell transplant as well as 
patients who have had a 9/10 or 10/10 HLA-matched sibling or a 9/10 or 10/10 HLA-
matched unrelated donor hematopoietic stem cell transplant are potentially eligible. 
• Women who are pregnant or plan to become pregnant will be excluded.  
Design: 
• This is a phase I dose-escalation trial. 
• Patients will undergo leukapheresis. 
• T cells obtained by leukapheresis will be genetically modified to express an anti-CD30 
CAR. 
• Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with 
the intent of enhancing the activity of the infused anti-CD30 CAR-expressing T cells. 
• A chemotherapy conditioning regimen of cyclophosphamide and fludarabine will be 
administered prior to all CAR T-cell infusions Fludarabine will be given on the same 
days as the cyclophosphamide. 
• Two days after the chemotherapy ends, patients will receive an infusion of anti-CD30-
CAR-expressing T cells. 


10 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
• The initial dose level of this dose-escalation trial will be 0.3x106 CAR+ T cells/kg of 
recipient bodyweigh for Cohort 1. The initial dose level will be 1 x 106 CAR+ T cells/kg 
for Cohort 2. 
• The cell dose administered will be escalated until a maximum tolerated dose is 
determined. 
• Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to 
monitor for toxicity. 
• Outpatient follow-up is planned for 2 weeks and 1, 2, 3, 4, 6, 9, and 12 months after 
the CAR T-cell infusion.  Long-term gene-therapy follow-up consisting of yearly visits 
to a doctor near the patient’s home for 4 more years and then yearly telephone contact 
for 10 additional years will be required.  
• As of Amendment E (Protocol version: 08/03/2018), repeat treatments consisting of 
the conditioning chemotherapy followed by a CAR T-cell infusion at the MTD for the 
patient’s cohort are allowed for eligible patients with any best responses except 
continuing complete remission or progressive malignancy.  
• Re-enrollment will be allowed for a small number of subjects. 


11 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
TABLE OF CONTENTS  
TABLE OF ABBREVIATIONS .............................................................................................. 2 
PRÉCIS .................................................................................................................................. 8 
1 
INTRODUCTION ......................................................................................................... 16 
1.1 
Study Objectives...................................................................................................... 16 
1.1.1 
Primary Objective ............................................................................................. 16 
1.1.2 
Secondary Objectives........................................................................................ 16 
1.2 
Background and Rationale ....................................................................................... 16 
1.2.1 
Introduction ...................................................................................................... 16 
1.2.2 
Biology of CD30 .............................................................................................. 16 
1.2.3 
Clinical background of CD30+ lymphomas ........................................................ 19 
1.2.4 
Proof of concept of CD30 as a therapeutic target: Brentuximab and MDX-060 ... 20 
1.2.5 
Role of allogeneic hematopoietic stem cell transplant in CD30+ lymphomas ....... 21 
1.2.6 
Donor Lymphocyte Infusion (DLI) .................................................................... 21 
1.2.7 
Mechanism of the graft-versus-malignancy (GVM) effect .................................. 22 
1.2.8 
Definition and Assessment of Graft-versus-host Disease .................................... 23 
1.2.9 
T-cell gene therapy ........................................................................................... 23 
1.2.10 Chimeric antigen receptors preclinical background ............................................ 24 
1.2.11 Clinical results with anti-CD19 CAR T cells...................................................... 25 
1.2.12 Anti-CD30 CAR development and preclinical testing ........................................ 27 
1.2.13 Rationale for immunosuppressive chemotherapy and selection of lymphocyte-
depleting chemotherapy regimen. ................................................................................... 34 
1.2.14 Rationale for dose-escalation............................................................................. 35 
1.2.15 Rationale for a fully-human CAR ...................................................................... 36 
1.2.16 Summary of risks and potential benefits ............................................................ 36 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ................................................... 38 
2.1 
Eligibility Criteria .................................................................................................... 38 
2.1.1 
Inclusion Criteria .............................................................................................. 38 
2.1.2 
Exclusion criteria .............................................................................................. 41 
2.1.3 
Recruitment Strategies ...................................................................................... 42 
2.2 
Screening Evaluation ............................................................................................... 42 
2.2.1 
Screening activities performed after a consent for screening has been signed ...... 42 


12 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
2.3 
Participant Registration and Status Update Procedures .............................................. 43 
2.3.1 
Treatment Assignment Procedures for Registration Purposes Only: .................... 43 
3 
STUDY IMPLEMENTATION....................................................................................... 44 
3.1 
Study Design ........................................................................................................... 44 
3.1.1 
General study plan ............................................................................................ 44 
3.1.2 
Planned repeat treatments.................................................................................. 44 
3.1.3 
Inclusion of patients who have had allogeneic hematopoietic stem cell 
transplantation (allo-HSCT) ........................................................................................... 45 
3.1.4 
Protocol schema ............................................................................................... 46 
3.1.5 
Dose Limiting Toxicity ..................................................................................... 47 
3.1.6 
Dose Escalation ................................................................................................ 47 
3.2 
Dose Modifications/Delay........................................................................................ 51 
3.3 
Stopping Criteria ..................................................................................................... 51 
3.4 
Drug Administration ................................................................................................ 52 
3.4.1 
Leukapheresis................................................................................................... 52 
3.4.2 
Anti-CD30-CAR-expressing T-cell preparation ................................................. 52 
3.4.3 
Conditioning chemotherapy and anti-CD30 CAR T-cell administration .............. 53 
3.4.4 
Overall summary of the treatment plan .............................................................. 53 
3.5 
Protocol Evaluation ................................................................................................. 54 
3.5.1 
Baseline evaluations and interventions............................................................... 54 
3.5.2 
Studies to be performed on Day 0 and during the mandatory 9-day inpatient 
admission after cell infusion ........................................................................................... 56 
3.5.3 
Post-infusion outpatient evaluation .................................................................... 56 
3.6 
Study Calendar ........................................................................................................ 58 
3.7 
Gene-therapy-specific follow-up .............................................................................. 62 
3.7.1 
Clinical Evaluation ........................................................................................... 62 
3.7.2 
Replication competent lentivirus (RCL) testing .................................................. 62 
3.8 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................... 63 
3.8.1 
Criteria for removal from protocol therapy......................................................... 63 
3.8.2 
Off-study Criteria ............................................................................................. 63 
4 
CONCOMITANT MEDICATIONS/MEASURES .......................................................... 64 
4.1 
Antibiotic prophylaxis.............................................................................................. 64 
4.2 
Blood product support.............................................................................................. 65 


13 
Abbreviated Title: Anti- CD30 CAR T-cells   
Version Date: October 19, 2020 
 
4.3 
Anti-emetics ............................................................................................................ 65 
4.4 
Granulocyte colony-stimulating factor ...................................................................... 65 
4.5 
Avoidance of corticosteroids .................................................................................... 65 
4.6 
Guidelines for management of common acute toxicities that occur after CAR T cell 
infusions............................................................................................................................ 65 
4.7 
Emergency treatment for patients not eligible for the protocol ................................... 65 
5 
BIOSPECIMEN COLLECTION .................................................................................... 65 
5.1 
CORRELATIVE STUDIES FOR RESEARCH ........................................................ 66 
5.1.1 
Biospecimen collection before the start of the conditioning chemotherapy: ......... 66 
5.1.2 
Biospecimen collection on Day 0 and after CAR T-cell infusion during the required 
hospitalization................................................................................................................ 66 
5.1.3 
Biospecimen collection during outpatient follow-up........................................... 66 
5.1.4 
Immunological Testing ..................................................................................... 66 
5.1.5 
Additional biopsies and additional blood draws ................................................. 67 
5.1.6 
Future studies ................................................................................................... 68 
5.2 
Sample Storage, Tracking and Disposition................................................................ 68 
5.2.1 
Samples Sent to Figg Lab.................................................................................. 68 
5.2.2 
Sample Storage, Tracking and Disposition......................................................... 69 
5.2.3 
Sample Storage, Tracking, and Disposition for Surgery Branch .......................... 70 
5.2.4 
Protocol Completion/Sample Destruction .......................................................... 70 
6 
DATA COLLECTION AND EVALUATION ................................................................ 71 
6.1 
Data Collection........................................................................................................ 71 
6.1.1 
Adverse event recording: .................................................................................. 71 
6.2 
Data Sharing Plans................................................................................................... 72 
6.2.1 
Human Data Sharing Plan ................................................................................. 72 
6.3 
Response Criteria..................................................................................................... 72 
6.3.1 
Response Criteria for Lymphoma ...................................................................... 72 
6.4 
Toxicity Criteria ...................................................................................................... 74 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.... 74 
7.1 
Definitions............................................................................................................... 74 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting .................................... 74 
7.2.1 
Expedited Reporting ......................................................................................... 74 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................. 74 


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7.3 
NCI Clinical Director (CD) Reporting ...................................................................... 75 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ...................................... 75 
7.4.1 
Serious Adverse Event Reports to IBC .............................................................. 75 
7.4.2 
Annual Reports to IBC...................................................................................... 75 
7.5 
NIH Required Data and Safety Monitoring Plan........................................................ 76 
7.5.1 
Principal Investigator/Research Team................................................................ 76 
7.5.2 
Safety Monitoring Committee (SMC) ................................................................ 76 
8 
Sponsor Protocol/ Safety Reporting ................................................................................ 77 
8.1 
Definitions............................................................................................................... 77 
8.1.1 
Adverse Event .................................................................................................. 77 
8.1.2 
Serious Adverse Event (SAE) ........................................................................... 77 
8.1.3 
Life-threatening ................................................................................................ 77 
8.1.4 
Severity ............................................................................................................ 78 
8.1.5 
Relationship to Study Product ........................................................................... 78 
8.2 
Assessment of Safety Events .................................................................................... 78 
8.3 
Reporting of Serious Adverse Events........................................................................ 78 
8.4 
Reporting Pregnancy................................................................................................ 79 
8.4.1 
Maternal exposure ........................................................................................... 79 
8.4.2 
Paternal exposure.............................................................................................. 79 
8.5 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
 
79 
9 
CLINICAL MONITORING ........................................................................................... 79 
10 STATISTICAL CONSIDERATIONS ............................................................................ 80 
11 HUMAN SUBJECTS PROTECTIONS .......................................................................... 81 
11.1 
Rationale For Subject Selection ............................................................................ 81 
11.2 
Participation/selection rationale ............................................................................ 81 
11.3 
Participation of Children....................................................................................... 81 
11.4 
Participation of Subjects Unable to Give Consent .................................................. 82 
11.5 
Evaluation of Benefits and Risks/Discomforts ....................................................... 82 
11.5.1 Risks of exposure to Ionizing Radiation............................................................. 83 
11.5.2 Risks of Scans and Contrast ........................................................................... 83 
11.5.3 Risks of blood Sampling ................................................................................... 83 


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11.5.4 Risks of Bone marrow aspiration and biopsy ................................................. 83 
11.5.5 Risks of Intravenous Catheter ........................................................................ 83 
11.5.6 Risks of Lumbar Puncture.............................................................................. 83 
11.5.7 Risks of Apheresis ........................................................................................... 83 
11.6 
Consent Process and Documentation ..................................................................... 84 
12 PHARMACEUTICAL INFORMATION ........................................................................ 84 
12.1 
Lentiviral Vector Containing the anti-CD30 CAR Gene......................................... 84 
12.1.1 Cells manufacturing .......................................................................................... 84 
12.1.2 Toxicities ......................................................................................................... 85 
12.1.3 Administration procedures: ............................................................................... 85 
12.2 
Commercial Agents:............................................................................................. 85 
12.2.1 Cyclophosphamide ........................................................................................... 85 
12.2.2 FLUDARABINE .............................................................................................. 85 
13 REFERENCES .............................................................................................................. 86 
14 APPENDICES ............................................................................................................. 100 
14.1 
Appendix A: Performance Status Criteria ............................................................ 100 
14.2 
Appendix B: Data Collection Elements Required By Protocol ............................. 101 
14.3 
Appendix C:  Guidelines for management of common toxicities that occur after CAR 
T-cell infusions................................................................................................................ 103 
14.4 
Appendix D: Clinical Staging and treatment of Acute GVHD 108,109 ..................... 108 
14.5 
Appendix E:  Infusion Instructions ...................................................................... 111 
 
 


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1 
 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
Determine the safety and feasibility of administering T cells expressing a novel fully-human anti-
CD30 chimeric antigen receptor (CAR) to patients with advanced CD30-expressing hematologic 
malignancies. 
1.1.2 Secondary Objectives 
• Evaluate the in vivo persistence and peak blood levels of anti-CD30 CAR T cells after 
CAR T-cell infusions.   
• Assess for evidence of anti-lymphoma activity by anti-CD30 CAR T cells. 
• Assess the immunogenicity of the CAR used in this protocol. 
 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Introduction 
We have developed a fully-human anti-CD30 CAR, and we have demonstrated that T cells 
expressing this CAR have CD30-specific activity in vitro and in vivo.  Anti-CD30-CAR-
expressing T cells expressing this CAR can eradicate tumors in mice.  We propose to conduct a 
phase I clinical trial of anti-CD30-CAR-expressing T cells.  This clinical trial will enroll patients 
with advanced CD30-expressing malignancies.  Patients enrolled on the trial will receive a single 
cycle of chemotherapy that is designed to decrease endogenous lymphocyte counts because 
extensive evidence demonstrates that depleting endogenous lymphocytes, and possibly other cells, 
with chemotherapy or total body irradiation dramatically increases the anti-tumor activity of 
adoptively transferred T cells.1-3  After the lymphocyte-depleting chemotherapy, patients will 
receive an infusion of autologous anti-CD30-CAR T cells.  The T-cell dose will escalate with 
sequential cohorts of patients until a maximum tolerated dose is determined.   
1.2.2 Biology of CD30 
CD30 (TNFRSF8) is a type I transmembrane receptor that belongs to the TNF receptor (TNFR) 
superfamily.  CD30 is strongly expressed by neoplastic cells of Hodgkin lymphoma (HL) and 
anaplastic large cell lymphoma (ALCL)4. Further studies described expression of CD30 in several 
types of non-Hodgkin lymphoma, embryonal cell carcinoma, and some mesenchymal cell tumors.5 
Expression of CD30 in T-cell lymphomas is heterogenous, but has been reported in up 57% of 
patients with these types of tumors.6-8 In addition, studies have shown that 14-21% of diffuse large 
B cell lymphomas can express CD30. 9,10 CD30 expression was found to be largely absent from 
non-lymphoid tissues.5,6 However, expression of the receptor has been reported in human decidual 
cells, the endometrial cells that form the uterine lining during pregnancy.11 Positive staining of 
Ganglion and Purkinje cells of the brain and exocrine pancreatic cells were later excluded as an 
artifact of paraffin embedded tissues.5,6 Although expression is very low during resting conditions, 
CD30 can be upregulated by activated B cells and CD4+ and CD8+ T cells in a variety of settings 
including viral infections, such as Epstein Barr Virus and HIV-1, as well as during some 


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autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus.5,12 CD30 
can also be released as a soluble receptor (sCD30), and serum levels of sCD30 have correlated 
with worsened outcomes of HL and ALCL.13,14 However, serum levels of sCD30 increase during 
some viral diseases, so it is unlikely to be a good diagnostic marker.5,15,16 Because of its high 
expression on some lymphoid malignancies and limited expression on non-hematopoietic tissues, 
CD30 is an excellent candidate for the development of targeted therapeutics.  
The ligand for CD30 is CD30 ligand (CD30L), which is expressed on numerous cell types 
including T cells, B cells, monocytes, neutrophils, and eosinophils.12 Like many members of the 
TNFR superfamily, the cytoplasmic portion of CD30 contains binding sites for several TNF 
receptor associated factors (TRAF), adaptor proteins involved in the signaling cascade. CD30 has 
been shown to interact with TRAF-1,2,3 and 5, and these signaling molecules can then lead to the 
activation of the transcription factor NF-κB.17-20 CD30 has co-stimulatory functions that can alter 
T-cell effector functions through several actions ranging from inducing cellular proliferation to 
pro-apoptotic activity to lymphocyte trafficking. Studies using CD30 deficient (CD30-/-) mice have 
suggested that CD30 may have roles in regulating T-cell responses. In a model of graft versus host 
disease, blocking CD30/CD30L interactions reduced migration of CD4+ T cells to the 
gastrointestinal track but did not affect proliferation or apoptosis.21 However, another study 
showed that CD30 signaling limits the expansion of autoreactive CD8+ T cells in a mouse model 
of autoimmune diabetes.22 Furthermore, there is some controversy over the role of CD30 in 
negative selection of T cells in the thymus.23,24 It has also been suggested that CD30 could function 
in memory CD8+ T cell production.25 In ALCL cells, CD30 activation induces apoptosis, but HL 
cells were insensitive to CD30 activation.26 These pleotropic effects of CD30 signaling are likely 
context-dependent and are determined by the availability of secondary signaling molecules.  
Brentuximab vedotin is an antibody drug conjugate that consists of the monoclonal anti-CD30 
antibody, cAC10, conjugated to the antimitotic chemotherapeutic, monomethyl auristatin E.27,28 
The success of Brentuximab vedotin in the treatment of HL and ALCL further supports the notion 
that therapies targeting CD30 could improve disease outcomes for CD30+ malignancies, and there 
has been great interest in developing new therapeutics.29 Previous work has shown progress 
towards development of a fully human anti-CD30 monoclonal antibody, clone 5F11(MDX-060), 
that improved survival in a mouse model of HL likely through antibody-dependent cellular 
cytotoxicity.30 In a clinical trial of 72 patients treated with MDX-060 objective clinical responses 
were seen in 6 patients, and importantly toxicity was rare.31  
Figure 1 shows that CD30 had a restricted pattern of expression.  CD30 cDNA copies were 
measured in samples of the indicated normal tissues by a very sensitive qPCR assay that was 
capable of detecting CD30 cDNA levels as low as 10 copies per 105 actin cDNA copies.  In 
addition, qPCR was performed on cDNA from HH, a CD30+ lymphoma cell line as a positive 
control.  Actin copies were also measured by qPCR in all of the samples, and the results were 
expressed as the number of CD30 cDNA copies per 105 actin cDNA copies.  Extensive 
immunohistochemistry studies of CD30 expression on normal tissues have shown that the only 
normal tissues that express CD30 are activated lymphocytes and, according to 1 report, 
endometrial decidual cells of the lining of the pregnant uterus and some deciduoid cells of the 
lining of the endometrium during the secretory phase of the menstrual cycle.6,11,15   In experiments 
performed in the NCI Laboratory of Pathology for this protocol, CD30 was carefully assessed by 
immunohistochemistry on a large panel of endometrial samples.  The proliferative phase 


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endometrium was completely negative for CD30 expression in agreement with other reports.  The 
secretory phase of the endometrium was assessed at the following time-points of the menstrual 
cycle, day 16-18, day 19-20, day 21-22, day 23-24, day 25-26, and day 27-28.  All samples were 
negative for CD30 except for dim and very rare CD30 expression (<1% of total cells) at the day 
27-28 time point in 2/14 patients.  Because the endometrium is shed at or shortly after day 28 and 
because of the extremely rare and weak CD30 expression in only 2/14 patients, we do not 
anticipate any significant toxicity will be caused by anti-CD30 CAR T cells.  Importantly, CD30 
expression was assessed for and found to be absent in all major organs including brain, heart, 
lungs, kidney, skin, liver, intestines (large and small), blood vessels, skin, and testes.6,11,15 
Figure 1CD30 RNA expression in normal tissues 
       A. 
B. 
 
 
 
 
 
C D 3 0 +  H H  c e lls
A d re n a l
B o n e  m a rro w
B ra in
C e rv ix
C o lo n
D u o d e n u m
E p id id y m u s
E s o p h a g u s
F a t
H e a rt
H e a rt L e ft V e n tric le
H e a rt R ig h t V e n tric le
K id n e y
L iv e r
L u n g
L y m p h  N o d e
B lo o d  ly m p h o c y te s
M a m m a ry  g la n d
M u s c le
N a s a l M u c o s a
O p tic  N e rv e
O v a ry
O v id u c t
P a n c re a s
0
2 0 0
4 0 0
6 0 0
C D 3 0  c o p ie s /1 0
5  a c tin  c o p ie s
C D 3 0  c o p ie s /1 0
5  a c tin  c o p ie s
C D 3 0 +  H H  c e lls
P e n is
P e ric a rd iu m
P itu ita ry
P la c e n ta
P ro s ta te
R e c tu m
R e tin a
S e m in a l v e s ic le s
S k in
S m a ll In te s tin e
S p in a l c o rd
S p le e n
S to m a c h
T e s tis
T h y m u s
T h y ro id
T o n g u e
T o n s il
T ra c h e a
U re te r
U rin a ry  B la d d e r
U te ru s
U v u la
V a g in a
0
2 0 0
4 0 0
6 0 0


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Immunohistochemical staining of normal human tissues for CD30 performed at the Laboratory of 
Pathology at the NIH shows that all normal tissues tested; uterus, left atrium, left ventricle, skeletal 
muscle, tail of the pancreas, and lung; did not express CD30 by immunohistochemistry. A 
concurrently tested positive control, splenic tissue involved by Hodgkin lymphoma in an HIV 
positive patient, consistently expressed CD30 by immunohistochemistry (Dr. Stefania Pittaluga, 
unpublished data).  
1.2.3 Clinical background of CD30+ lymphomas  
 Hodgkin lymphoma (HL) is an aggressive malignancy that is curable with anthracycline-based 
regimens, such as ABVD or BEACOPP, and with radiation therapy in cases of localized disease. 
Yet 15-27% of patients with advanced or unfavorable HL are not cured with first-line therapy and 
develop relapsed or refractory disease.32 Of that subset of patients, only approximately 40% 
achieve sustained remissions with standard salvage chemotherapy followed by autologous 
hematopoietic stem cell transplantation (autoHSCT).33-35 Those who have relapsed disease 
following autoHSCT have a 5-year overall survival (OS) of only 32%.36 Overall, about 20% of 
patients with HL will not be cured with current therapies.37  To investigate non-cytotoxic 
approaches in this chemotherapy-refractory group, a phase I trial was conducted in a heavily pre-
treated group of patients with HL, 78% of whom had relapsed following autoHSCT.  The anti-PD-
1 antibody nivolumab resulted in an 87% response rate, though follow-up was short and most 
responses were only partial responses.38  
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin 
lymphoma.39 DLBCL is often curable by anthracycline-based chemotherapy combined with 
rituximab (R-CHOP or DA-EPOCH-R) in the first-line setting, but at least 40% of patients have 
relapsed or refractory disease.40 Patients with DLBCL that is refractory to first salvage 
chemotherapy have response rates to second salvage therapy of only 14-43%.41-45 Patients with 
DLBCL refractory to second line chemotherapy have very poor prognoses with a reported median 
survival of only 4 months and a one year survival rate of only 4%.45 Primary mediastinal B-cell 
lymphoma (PMBL) is a subtype of DLBCL that is closely related to nodular sclerosis HL. In one 
report, PMBL was shown to be highly responsive to the DA-EPOCH-R regimen, with a 5-year 
event-free survival (EFS) of 93%, with report of successful salvage radiotherapy in patients with 
refractory localized disease.46 Conversely, mediastinal grey zone lymphoma is a rare disease with 
pathologic features intermediate between nodular sclerosis HL and PMBL, with reported 5-year 
EFS of only 62% with DA-EPOCH-R.47 Yet there is no agreed upon standard therapy for non-
localized relapsed or refractory PMBL or grey zone lymphoma, and novel approaches are 
needed.48 
Peripheral T-cell lymphomas are a heterogeneous group of T-cell malignancies, including 
anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma not otherwise specified 
(PTCL-NOS), enteropathy-associated T-cell lymphoma (EATL), and extranodal natural killer/T-
cell lymphoma (ENKT). Standard first-line therapy for the most common PTCL subtypes, ALCL, 
PTCL-NOS, EATL, and advanced ENKTL, consists of anthracycline-based regimens, such as 
CHOP, CHOEP, or DA-EPOCH. Unfortunately the response to first-line therapy is not as robust 
as in B-cell malignancies. The 3-year EFS estimates for patients with anaplastic lymphoma kinase 
negative anaplastic large cell lymphoma (ALK- ALCL) and PTCL-NOS are 46% and 41%, 
respectively.49 Five year overall survival for EATL has been estimated at 10-20%,50,51 and median 
survival for advanced ENKTL with anthracycline based regimens is less than a year.52 The role of 


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auto-HSCT following first remission in peripheral T-cell lymphomas remains controversial, with 
the best single arm data supporting the practice in ALK- ALCL, in which five-year OS was 70%.53 
A minority of patients with relapsed or refractory PTCL following first-line systemic therapy 
achieves responses with histone deacetylase inhibitors or the antifolate pralatrexate. PTCL overall 
response rates (ORR) have been reported as 25% with romidepsin,54 31% with belinostat,55 and 
29% with pralatrexate.56  
1.2.4 Proof of concept of CD30 as a therapeutic target: Brentuximab and MDX-060 
Brentuximab vedotin is an antibody-drug conjugate, consisting of an anti-CD30 antibody 
conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-
disrupting agent.57 In a phase I trial of brentuximab in relapsed and refractory histologically CD30+ 
HL, ALCL, and AITL, the ORR was 38% with median duration of response being 9.7 months.58  
In a phase II trial of brentuximab in patients with CD30+ HL relapsed or refractory following auto-
HSCT, the ORR was 75% with a CR rate of 34%,59 and long term follow-up showed a median 
PFS of only 9.3 months.60  Brentuximab has been further shown to produce responses in HL both 
prior to auto-ASCT61 and following autoHSCT as consolidation therapy,57 as well as in the up-
front setting in combination with AVD.62 Robust responses were also seen in relapsed and 
refractory ALCL in the phase 2 setting, with 86% objective response and median duration of 
response 13 months.63 Responses in relapsed and refractory PTCL-NOS have been less impressive, 
with ORR of 33%,64 though the ORR was 85% in the front-line setting when brentuximab was 
given sequentially with CHOP.65 Activity of brentuximab has also been demonstrated in CD30+ 
DLBCL, with ORR of 44% in a mostly chemotherapy refractory population.66 Reported grade 3-
4 toxicities of brentuximab include peripheral neuropathy (likely due to the MMAE), neutropenia, 
thrombocytopenia, anemia, tumor lysis syndrome, progressive multifocal leukoencephalopathy, 
pancreatitis, acute renal failure, pyrexia, dyspnea, arthralgia, nausea, diarrhea, and fatigue.57-
59,61,63,64,67,68 In the setting of combination therapy with ABVD, but not in combination with AVD, 
brentuximab was associated with grade 3-4 pulmonary toxic effects and resulted in two deaths 
related to pulmonary toxicity.62 Loss of CD30 expression has not been shown in tissue biopsy 
samples from patients with HL or ALCL who had progressive disease despite prior brentuximab, 
in which cases CD30 continues to be expressed.69 This suggests that novel approaches to CD30 
targeted therapy could benefit patients with relapsed disease following brentuximab therapy.  
MDX-060 is a fully human anti-CD30 monoclonal antibody that, in a trial of 72 patients with 
relapsed or refractory histologically CD30+ lymphomas, resulted in 2 partial and 4 complete 
responses, with median duration of CR being 5 months.31 MDX-060 is also known as 5F11. Grade 
3-4 toxicities included dyspnea, acute respiratory distress syndrome, anemia, tamponade, 
epistaxis, increased liver transaminases, and psoriasis. These toxicities are quite rare, and in 
patients with very advanced Hodgkin disease, it is unclear if they are truly related to the anti-CD30 
monoclonal antibodies administered.  
1.2.5 Clinical results with anti-CD30 CAR T cells  
Limited results of use of anti-CD30 CAR T cells in humans are available. In recent data presented 
at the 2015 annual meeting of the American Society for Hematology, results from nine patients (7 
with HL and 2 with ALCL) receiving anti-CD30 CAR T cells were reported. One patient achieved 
a CR and one patient achieved a PR. No cytokine-storm related toxicities were observed.70 In 
another study, a partial response was reported in a single patient with relapsed HL who received 


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three daily doses of fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 followed by an 
infusion of 3.2 x 108 anti-CD30 CAR cells, which were 5% CAR positive.71 This patient did not 
experience any infusion related toxicities.  
1.2.5 Role of allogeneic hematopoietic stem cell transplant in CD30+ lymphomas 
Allogeneic hematopoietic stem cell transplant (alloHSCT) has been shown to result in a graft 
versus lymphoma (GVL) effect in a select group of patients with HL with second relapse, 
following autoHSCT in most patients, with 3-year OS of 63% in one retrospective series.72 GVL 
effect in relapsed and refractory DLBCL has resulted in a 5-year OS of 18-26% with alloHSCT in 
a large retrospective series73 and in a 3-year OS of 45-54% in two other reports,74,75 again 
demonstrating that sustained remissions are possible in a small subset of patients. Results of 
alloHSCT in PTCL subtypes show that in a relatively young, fit group, 5-year OS was 50-57%.76,77 
The GVL effect of allo-HSCT in each of these lymphoid malignancies suggests that T-cell 
mediated immunotherapy can result in sustained remissions in a minority of cases.   
1.2.6 Donor Lymphocyte Infusion (DLI) 
Donor lymphocyte infusions (DLI) are infusions of unmanipulated lymphocytes used to treat 
malignancy after allo-HSCT.  DLI can induce remissions in 70-80% of patients with chronic 
myeloid leukemia (CML) that relapses into chronic phase after alloHSCT.78-80  Susceptibility of 
hematologic malignancies to DLI after alloHSCT varies depending on disease histology.81  
The most important toxicity of DLI is GVHD. Grade II-IV acute GVHD has been estimated to 
occur in 28% to 44% of patients.82-84  A recent review of DLI found that grade II-IV acute GVHD 
occurred after DLI in 34% to 48% of patients receiving DLI for various diseases and grade III-IV 
acute GVHD occurred after DLI in 20-35% of patients.85 Chronic GVHD occurs commonly after 
DLI with an incidence of 33% to 83% and highly variable severity.82-85  When DLI is used to treat 
CML, the incidence of GVHD increases as the number of T cells contained in the DLI 
increases.86,87  For CML, DLIs with higher numbers of T cells had an equivalent anti-leukemia 
effect as DLIs containing lower numbers of T cells.86  In another study, DLIs that contained greater 
than or equal to 1x107 T cells/kg of recipient bodyweight were associated with an increased 
incidence of GVHD compared to DLIs containing lower doses of T cells.88  Miller and coworkers 
induced profound lymphodepletion with fludarabine and cyclophosphamide chemotherapy before 
DLI in an attempt to increase GVM. 89  This therapy was associated with high levels of severe 
acute GVHD.89  Forty-seven percent of patients treated with fludarabine and cyclophosphamide 
prior to a DLI of 1x108 T cells/kg of recipient bodyweight developed grade III-IV acute GVHD, 
and 5 of 15 patients suffered fatal outcomes directly attributable to GVHD.89  Because many 
patients with relapsed malignancy after alloHSCT require urgent treatment for rapidly progressive 
disease, many patients receive chemotherapy prior to DLI.82,83,90  The chemotherapy regimens that 
are administered to patients for disease control prior to DLI are generally not as 
immunosuppressive as the fludarabine plus cyclophosphamide regimen administered by Miller 
and coworkers.  Patients with relapsed myeloid malignancy after alloHSCT were treated with the 
combination of chemotherapy and DLI.  These patients received DLIs with a median T cell dose 
of 1x108 T cells/kg of recipient bodyweight, and 44% of patients developed grade II-IV acute 
GVHD.91 The anti-leukemia activity of chemotherapy plus DLI appeared to be greater than the 
anti-leukemia activity achieved in historical control patients that were treated with DLI alone.91  
Porter and coworkers treated patients with a conventional DLI followed by an infusion of T cells 


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that had been activated ex vivo with beads that were conjugated to anti-CD3 and anti-CD28 
antibodies.92  The number of ex vivo activated T cells that was administered to each patient was 
escalated from 1x106 to 1x108 T cells per kg of recipient bodyweight. The rate of GVHD observed 
after this therapy was not different from the rate that would be expected with conventional DLI 
alone.92 
1.2.7   Mechanism of the graft-versus-malignancy (GVM) effect 
The prolonged remissions of advanced B-cell malignancies that have often occurred after non-
myeloablative allo-HSCT demonstrate that there is an immunologic GVM effect against these 
diseases.93-96  The GVM effect against B-cell malignancies is clearly demonstrated by the 
remissions that have sometimes occurred when these diseases were treated with DLI in the absence 
of other therapies after allo-HSCT.78-80,82,83,97  For CML, acute myeloid leukemia (AML) and ALL, 
the GVM effect is closely associated with GVHD.  When relapse rates of leukemia patients with 
and without GVHD were compared, relapse rates were lower for patients with GVHD than for 
patients without GVHD.98 99   Comparisons of relapse rates of T cell-depleted allo-HSCT and T-
replete allo-HSCT indicated that transplantation of donor T cells prevented relapse after allo-
HSCT for ALL, AML and CML.98,100  There was also a decreased rate of relapse for patients with 
AML and CML that received transplants from allogeneic donors compared to patients that received 
transplants from syngeneic (identical twin) donors,98 indicating an important role for allogeneic 
immunity in the GVM effect against these leukemias.  In contrast, no differences in relapse rates 
for lymphoma were detected when allogeneic T-cell replete, allogeneic T-cell-depleted, and 
syngeneic transplants were compared.101  However, this study only assessed patients that were 
treated with myeloablative transplants between the years 1985 and 1998.  Nonmyeloablative 
transplants were excluded.101  Because of these limitations it is possible that this study missed a 
subtle yet important GVM effect. 
Although the cellular mechanism of the GVM effect has not been defined and may be quite 
heterogeneous, substantial clinical evidence points to an important role for T cells and minor 
histocompatibility antigens.102  Most importantly, when T cell-replete alloHSCT and T cell-
depleted allo-HSCT were compared, there was an increased relapse risk in ALL, AML and CML 
patients that received T cell-depleted allo-HSCT.98,100  In addition, a patient with CML that had 
relapsed after standard DLI was treated with T cells that specifically recognized the patient’s CML 
cells.103  The CML-specific T cells were derived by culturing T cells from the patient’s allogeneic 
donor with CML cells from the patient.  The patient entered a CR that lasted two years after 
treatment with these CML-specific T cells.103  An important role for minor histocompatibility 
antigens in GVM was suggested by a study that showed a decreased rate of relapse among male 
patients with CML who received allogeneic transplants from female donors compared to all other 
donor/recipient sex combinations.104  The transplant combination consisting of a female donor 
with a male recipient is the only transplant combination in which female donor T cells that are 
specific for minor histocompatibility antigens encoded by the Y-chromosome might make a 
contribution to GVM.104 
CML is clearly very susceptible to an immunologic GVM effect.78-80,97 The results obtained when 
acute leukemia and lymphoma are treated with DLI demonstrate that a weaker GVM effect is 
active against these diseases.78-80,82,83,105  The strong GVM effect that is present when CML is 
treated with T-cell-replete allo-HSCT demonstrates that T cells can play an important role in 
mediating a clinically significant GVM effect.  Augmentation of the less powerful GVM effect 


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associated with allo-HSCT for lymphomas might improve the outcomes of patients with these 
diseases.  One possible way to augment the GVM effect against lymphomas is to genetically 
engineer donor T cells to express receptors that specifically recognize antigens expressed by 
malignant  cells.  
 
1.2.8 Definition and Assessment of Graft-versus-host Disease  
Graft-versus-host disease (GVHD) is an attack against normal recipient tissues that is mediated by 
the cells transferred with the transplant graft.106  For GVHD to occur, there must be antigenic 
differences between the recipient and the allograft donor.106  GVHD is divided into two broad 
categories, acute GVHD and chronic GVHD.  Characteristic features of acute GVHD include 
maculopapular rash, gastrointestinal disorders (nausea, diarrhea, or ileus), and cholestatic liver 
disease.107  Chronic GVHD can manifest with a wide variety of signs and symptoms.107  Formal 
definitions of four subsets of GVHD have been published.107 
1. 
Classic acute GVHD: GVHD occurring less than or equal to 100 days after transplantation 
or DLI with characteristic features of acute GVHD and without characteristic features of 
chronic GVHD.  
2. 
Persistent, recurrent, or late-onset acute GVHD:  GVHD occurring greater than 100 days 
after transplantation or DLI with characteristic features of acute GVHD and without 
characteristic features of chronic GVHD. 
3. 
Classic chronic GVHD:  GVHD occurring at any time that has characteristic features of 
chronic GVHD but that does not have characteristic features of acute GVHD. 
4. 
Overlap syndrome:  GVHD occurring at any time that has characteristic features of both 
acute and chronic GVHD.  
Acute GVHD is graded according to standard grading systems as grades I through IV with grade 
IV being the most severe (see Section 1.1).108,109   Chronic GVHD is given a global score of mild, 
moderate, or severe according to the report of the NIH Consensus Development Project on Criteria 
for Clinical Trials in Chronic GVHD.110  Based on organ scores detailed in Jagasia et al.  Chronic 
GVHD can be staged as described here.  Mild chronic GVHD involves only 1 or 2 organs or sites 
(except the lung), with no clinically significant functional impairment (maximum of score 1 in all 
affected organs or sites). Moderate chronic GVHD involves (1) at least 1 organ or site with 
clinically significant but no major disability (maximum score of 2 in any affected organ or site) or 
(2) 3 or more organs or sites with no clinically significant functional impairment (maximum score 
of 1 in all affected organs or sites). A lung score of 1 will also be considered moderate chronic 
GVHD. Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in 
any organ or site). A lung score of 2 or greater will also be considered severe chronic GVHD. 
 
1.2.9 T-cell gene therapy 
In an attempt to develop effective immunotherapies for cancer that are less toxic than allogeneic 
stem cell transplantation, many investigators have developed T-cell gene therapy approaches to 
specifically target T cells to tumor-associated antigens.111  T cells can be prepared for adoptive 
transfer by genetically modifying the T cells to express receptors that specifically recognize tumor-
associated antigens.111-118  Genetic modification of T cells is a quick and reliable process, and 


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clinical trials of genetically modified T cells targeting a variety of malignancies have been carried 
out.111,119-122  Genetically modified antigen-specific T cells can be generated from peripheral blood 
mononuclear cells (PBMC) in sufficient numbers for clinical treatment within 10 days.120  
Genetically modifying T cells with gammaretroviruses consistently causes high and sustained 
levels of expression of introduced genes without in vitro selection,119,122-124 and genetic 
modification of mature T cells with gammaretroviruses has a long history of safety in humans.125-
127  There are two general approaches for generating antigen-specific T cells by genetic 
modification:  introducing genes encoding natural αβ T cell receptors (TCRs) or introducing genes 
encoding chimeric antigen receptors (CARs).111,113,115,117  CARs are fusion proteins incorporating 
antigen recognition moieties and T cell activation domains.116,128-130  The antigen-binding domains 
of most CARs currently undergoing clinical and preclinical development are antibody variable 
regions.113,116,128,130  TCRs recognize peptides presented by human leukocyte antigen (HLA) 
molecules; therefore, TCRs are HLA-restricted, and a particular TCR will only be useful in 
patients expressing certain HLA molecules,111,113,115,128 which limits the number of patients who 
could be treated with T cells genetically modified to express a TCR.  In contrast, CARs recognize 
intact cell-surface proteins and glycolipids, so CARs are not HLA-restricted, and CARs can be 
used to treat patients regardless of their HLA types.111,113,131-133 
 
1.2.10 Chimeric antigen receptors preclinical background 
Preclinical experiments evaluating CAR-expressing T cells as cancer therapy were initiated in 
1993.134,135  These experiments led to a clinical trial of CAR-transduced T cells targeting the α-
folate receptor on ovarian cancer cells; no tumor regressions were observed during this clinical 
trial.136  Preclinical studies have assessed a wide variety of factors that could affect in vivo function 
of CAR-expressing T cells.  Multiple approaches for inserting CAR genes into T cells by using 
gammaretroviruses,119,122-125,137-139 lentiviruses,120,140-143 or transposon systems144,145 have been 
assessed.  Because all methods of T-cell genetic modification require a period of in vitro culture, 
various T-cell culture techniques have been evaluated.120,137,146  Different portions of CARs 
including antigen-recognition moieties, extracellular structural components, costimulatory 
domains such as the cytoplasmic portion of the CD28 protein, and T-cell-activation moieties such 
as the signaling domains of the CD3ζ protein can all be important to the in vivo function of CAR-
expressing T cells, and all of these portions of CARs remain the subject of intensive 
investigation.128,137,141,147-149   
Much of the preclinical work evaluating CARs has been performed with CARs targeting the B-
cell antigen CD19.137-139,144,150-152 Data suggesting that T-cell costimulation played an important 
role in the activity of CAR-expressing T cells in vivo led investigators to add signaling moieties 
from the costimulatory molecule CD28 to CARs.139,148  These studies showed that adding CD28 
moieties to CARs enhanced antigen-specific cytokine production and proliferation by anti-CD19 
CAR T cells.148,153,154  T cells expressing CARs with CD28 signaling moieties and CD3ζ signaling 
domains were more effective than T cells expressing CARs without CD28 moieties at eradicating 
human leukemia cells from mice.153,154  Subsequently, CARs incorporating other signaling 
domains from costimulatory molecules such as 4-1BB (CD137) were developed.140  Anti-CD19 
CARs containing the signaling domains of both 4-1BB and CD3ζ were superior to CARs 
containing the signaling domains of CD3ζ without any costimulatory domains at eradicating 


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human malignant cells from mice.141,147   Similar to CD28, including 4-1BB signaling moieties in 
CARs led to increased CD19-specific proliferation and enhanced in vivo persistence.141  In contrast 
to T cells expressing a CAR with a CD28 moiety, the increased in vitro proliferation and prolonged 
in vivo persistence of T cells expressing a 4-1BB-containing CAR occurred whether or not the T 
cells were exposed to the antigen that the CAR recognized.141,147   
1.2.11 Clinical results with anti-CD19 CAR T cells 
Because the vast majority of clinical results with CAR T-cell therapies are with anti-CD19 CARs 
a summary of clinical results with anti-CD19 CARs is included here.  Of course, clinical results 
with anti-CD30 CARs might be better or worse than the results obtained with anti-CD19 CARs. 
Results from several clinical trials of anti-CD19 CAR T cells have been reported to date in peer-
reviewed papers.119,120,122-124,155-159  The first evidence of antigen-specific activity of anti-CD19 
CAR T cells in humans was generated during a clinical trial at the National Cancer Institute in a 
patient who experienced a dramatic regression of advanced follicular lymphoma.123  This clinical 
trial utilized a gammaretroviral vector to introduce an anti-CD19 CAR containing the signaling 
domains of the CD28 and CD3ζ molecules.123 The anti-CD19 CAR-transduced T cells were 
prepared by using a 24-day in vitro culture process.  The clinical treatment regimen consisted of 
lymphocyte-depleting chemotherapy followed by an infusion of anti-CD19 CAR T cells and a 
course of high-dose interleukin-2 (IL-2).  The first patient treated on this protocol had a large 
disease burden of follicular lymphoma.  This first patient experienced no acute toxicities except 
for a low grade fever that lasted for 2 days, and he obtained a partial remission (PR) that lasted for 
32 weeks after treatment.123  Bone marrow biopsies revealed a complete elimination of extensive 
bone marrow lymphoma that was present before treatment; in addition, normal B-lineage cells 
were completely eradicated from the bone marrow.123  The bone marrow B-cell eradication was 
confirmed by flow cytometry, and it persisted for over 36 weeks.123  B cells were also completely 
absent from the blood during this time, while T cells and other blood cells recovered rapidly.123  
Seven months after the anti-CD19 CAR T cell infusion, progressive lymphoma was detected in 
the patient’s cervical lymph nodes.  The lymphoma remained CD19+, so the patient was treated a 
second time with anti-CD19 CAR T cells.  The first and second treatment regimens were the same 
except the patient received a higher dose of cells with the second treatment.  After the second 
treatment, the patient obtained a second partial remission that is ongoing over 5 years post-
treatment.122    
Seven more patients were subsequently treated with the same regimen of chemotherapy, anti-
CD19 CAR T cells, and high-dose IL-2.122  In 4 of 7 evaluable patients on the trial, administration 
of anti-CD19 CAR T cells was associated with a profound and prolonged B-cell depletion.122,123  
In all 4 patients with B-cell depletion, the depletion lasted for over 36 weeks. The B-cell depletion 
could not be attributed to the chemotherapy that was administered because blood B-cells recovered 
to normal levels in 8 to 19 weeks in patients receiving the same chemotherapy plus infusions of T 
cells targeting NY-ESO or gp100, which are antigens that are not expressed by B cells.123  Because 
normal B cells express CD19, prolonged normal B-cell depletion after anti-CD19 CAR T-cell 
infusions demonstrated that CAR-expressing T cells had a powerful ability to eradicate CD19+ 
cells in humans.  All of the patients with long-term B-cell depletion obtained either complete or 
partial remissions of their malignancies, and the 4 patients with long-term B cell depletion also 
developed hypogammaglobulinemia.  Hypogammaglobulinemia in these patients was routinely 
treated with infusions of intravenous immunoglobulins.  Of the eight patients treated, seven 


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patients were evaluable for malignancy response; the one patient who was not evaluable died with 
pneumonia caused by influenza A.122  Six of the seven evaluable patients had remissions of their 
malignancies.  Two of the remissions were complete remissions (CRs) of CLL.122  Both of these 
CRs were confirmed by multicolor flow cytometry of bone marrow cells.122  One of these CRs 
lasted 24 months, and the other is ongoing at 48 months.122  Most patients treated with this regimen 
of chemotherapy, anti-CD19 CAR T cells, and IL-2 experienced significant acute toxicities 
including fever, hypotension, and neurological toxicities such as delirium and obtundation.122  All 
of these toxicities peaked within 10 days after the cell infusion and resolved less than 3 weeks after 
the cell infusion.122  These acute toxicities correlated with serum levels of the inflammatory 
cytokines tumor necrosis factor and interferon-γ, and T cells producing these inflammatory 
cytokines in a CD19-specific manner were detected in the blood of patients after the anti-CD19 
CAR T cell infusions.122  In our experience, patients with CLL and ALL tended to have more 
violent cytokine release syndromes than did patients with lymphoma.  The severity of cytokine-
release syndrome in patients’ leukemia tends to correlate with disease burden in our experience.  
Patients with lymphoma tend to have a more varied clinical course with some patients experiencing 
hypotension and tachycardia, while others had isolated neurological toxicity.  
 We continued studies using the same CAR as in our previously reported anti-CD19 CAR T-cell 
reports.  In these more recent studies, IL-2 was not administered to patients and the T-cell 
production process was shortened from 24 days to 10 days.  The elimination of IL-2 administration 
was done in an attempt to lessen toxicity, and the shortening of the cell production process was 
done in an attempt to both simplify the cell production and to increase in vivo T-cell persistence 
and proliferation.  We reported the results of this modified clinical protocol in a very recent 
paper.160  In summary this paper reported treatment of 15 patients with advanced B-cell 
malignancies.  Nine patients had diffuse large B-cell lymphoma (DLBCL), 2 patients had indolent 
lymphomas, and 4 patients had chronic lymphocytic leukemia (CLL).  Patients received a 
conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single 
infusion of anti-CD19-CAR T cells.  Of 15 patients, 8 obtained complete remissions (CRs), 4 
patients obtained partial remissions, 1 patient had stable lymphoma, and 2 patients were not 
evaluable for response.  CRs were obtained by 4 of 7 evaluable patients with chemotherapy-
refractory DLBCL; 3 of these 4 CRs are ongoing with durations ranging from 9 to 22 months.  
Acute toxicities including fever, hypotension, delirium, and other neurological toxicities occurred 
in some patients after infusion of anti-CD19-CAR T cells; these toxicities resolved within 3 weeks 
after cell infusion.  One patient died suddenly of an unknown cause 16 days after cell infusion.  
CAR T cells were detected in the blood of patients at peak levels ranging from 9 to 777 CAR+ T 
cells/µL.  Elimination of exogenous IL-2 from our protocol did eliminate the toxicity that is known 
to occur with administration of high-dose IL-2, but cytokine-release type toxicity attributable to 
the CAR T cells still remained. 
In an attempt to further reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we 
substantially reduced the dose of the chemotherapy regimen administered before CAR T-cell 
infusions.  We treated 9 patients with B-cell lymphoma who received a single infusion of 1x106 
anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a low-dose chemotherapy 
regimen of 3 daily doses of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 administered 
on the same days.  Eight of the 9 patients had DLBCL that was refractory to chemotherapy (chemo-


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refractory) or had relapsed less than 1 year after autologous stem cell transplantation.  Both of 
these clinical situations carry a grim prognosis, with median survivals of only a few months.  
Despite the very poor prognosis of our patients, one patient with DLBCL obtained a CR and 4 
DLBCL patients obtained PRs.  The PRs included complete resolution of large lymphoma masses.  
Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose 
chemotherapy, toxicity was reduced when CAR T cells were infused after low-dose chemotherapy.  
None of the 9 patients treated with low-dose chemotherapy and CAR T cells required vasopressor 
drugs or mechanical ventilation, although some patients did experience short-term neurological 
toxicity.  As expected, the severity of neutropenia and thrombocytopenia was reduced with the low 
dose chemotherapy compared to high-dose chemotherapy.  Blood anti-CD19 CAR T cell levels 
have been assessed in 6 patients with a quantitative PCR assay that can detect cells containing the 
CAR gene; we detected CAR+ cells in the blood of all 6 patients.  These results demonstrate that 
anti-CD19 CAR T cells administered after low-dose chemotherapy have significant activity 
against chemo-refractory DLBCL and could potentially become a standard treatment for patients 
with lymphoma.  
The effectiveness of anti-CD19 CAR T cells against advanced B-cell malignancies, particularly 
CLL and ALL has been reported by multiple groups.142,157-159,161  Multiple groups have recently 
demonstrated the 70% to 90% complete remission rates when anti-CD19 CAR T cells are used to 
treat ALL.157,159,161  These impressive response rates have been associated with significant toxicity 
that can be divided into 2 main categories.   The first category is “cytokine-release syndrome” that 
consists mainly of fever, tachycardia, hypotension, fatigue, and in some cases myocardial 
dysfunction; these toxicities typically last for a few days to approximately 2 weeks before 
resolving.157,159,161  The second main category is neurological toxicity that sometimes occurs in 
patients not suffering from the typical cytokine-release syndrome toxicities.  Commonly observed 
neurological toxicities include aphasia, tremor, seizures, and ataxia; similar to other toxicities, the 
neurological toxicities typically last from 1 or two days to 3 weeks before resolving.159,161   
This clinical trial will also enroll patients who have had allogeneic hematopoietic stem cell 
transplants alloHSCT in the past.  The cells for producing anti-CD30 CAR T cells will be obtained 
from the transplant recipients (patients with malignancy) rather than the transplant donors.   In 
prior experience, administration of anti-CD19 CAR T cells, either T cells derived from normal 
transplant donors or from transplant recipients, graft-versus-host disease incidence has been 
extremely low.157,162,163   In our own experience with donor-derived allogeneic anti-CD19 CAR T 
cells, no patient has developed acute GVHD out of a total of 19 patients treated (unpublished data 
and 162).  Despite the low GVHD rate, many alloHSCT patients with persisting B-cell malignancies 
have obtained remissions on clinical trials of anti-CD19 CAR T cells. 157,161-163 
1.2.12 Anti-CD30 CAR development and preclinical testing 
We designed a CAR that incorporated a single chain variable fragment (scFv) from the fully-
human anti-CD30 antibody 5F11.  The 5F11 antibody was derived by immunizing mice transgenic 
for human immunoglobulin genes.  This CAR also contained the hinge,  transmembrane, and 
cytoplasmic regions of the human CD28 molecule, and the cytoplasmic region of the CD3-zeta 
molecule.  The CAR gene is encoded by a self-inactivating lentiviral vector.  The CAR was 
designated LSIN-5F11-28Z.  LSIN stands for self-inactivating lentivirus.  A diagram of the CAR 


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is shown in Figure 2.  After transductions, we found high levels of cell surface expression of the 
anti-CD30 CAR on the transduced T cells (Figure 3). 
 
Figure 2 
 
 
 
Figure 3 
 
             
Figure 3 shows anti-CD30 CAR expression on T cells from Donor 1 six days after transduction 
with lentiviruses encoding the LSIN-5F11-28Z CAR.  Transductions were carried out 1 day after 
the cultures were started, so the T cells had been in culture for a total of 7 days at the time of this 
analysis.  The plots are gated on live, CD3+ lymphocytes. 
We also performed a series of in vitro assays to assess the function of anti-CD30-CAR-expressing 
T cells, and we found that CD30-CAR-expressing T cells exhibit CD30-specific activities 
including CD107a upregulation and cytokine production in vitro.  These experiments showed that 
anti-CD30-CAR-expressing T cells are activated in an antigen-specific manner. 
 
 
 
 
 
 
CD28 hinge, transmembrane 
and intracellular
CD3ζ 
Anti-CD30 scFv   
3’SIN LTR   
MSCV promoter 
5’SIN LTR   


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Abbreviated Title: Anti- CD30 CAR T-cells   
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Figure 4 
         
 
 
Because activated T cells express CD30, we hypothesized that the 5F11-28Z CAR T cells might 
eliminate CD30+ activated T cells from cultures of anti-CD30 CAR-transduced T cells.  In multiple 
experiments we found that cultures of 5F11-28Z-transduced T cells had only residual CD30+ T 
cells that usually expressed low levels of CD30.  In contrast, untransduced T-cell cultures 
contained sizable populations of CD30+ T cells, some of which had high levels of CD30 
expression.  For the same cultures of Patient 1’s T cells shown in Figure 3, Figure 4shows CD30 
staining of T cells.  The plots in Figure 4 are gated on live CD3+ lymphocytes. 
Figure 5 
 
 
Figure 5 shows upregulation of CD107a, which indicates degranulation and correlates with 
cytotoxicity,164 when anti-CD30 CAR-expressing T cells from Donor 2 were cultured with the 
CD30-expressing cell line SUDHL-1.  CD107a was not upregulated when anti-CD30-CAR-
expressing T cells from Donor 2 were cultured for 4 hours with the negative control cell line ngfr-


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bv173, which does not express CD30.  The plots show that the 5F11-28Z CAR T cells recognize 
CD30 in an antigen-specific manner. 
It is critical to test any new CAR for specificity.  To test for specificity, we cultured CAR-
expressing T cells or untransduced T cells from the same patient with target cells overnight, and 
then performed a standard IFNγ (enzyme-linked immunosorbent assay) ELISA to see if T cells are 
activated, as indicated by IFNγ release, when the T cells are cultured with particular target cells 
(Table 1).  Ideally, the anti-CD30 CAR T cells should only react with CD30+ target cells.  We 
performed ELISA assays on culture supernatant from overnight co-cultures of T cells plus either 
CD30+ or CD30-negative target cells.   T cells transduced with the anti-CD30 CAR produced large 
amounts of IFNγ when they were cultured overnight with the CD30-expressing cell lines but only 
small amounts of IFNγ when cultured with CD30-negative cell lines or CD30-negative primary 
human CD34+ hematopoietic stem cells (Table 1).    In all of the experiments reported in Table 1, 
effector T cells from a patient were either transduced with 5F11-28Z or left untransduced (UT).  
All numbers in the table are IFNγ levels in picograms/mL.  The CD30+ target cells used in these 
experiments were the CD30+ lymphoma cell lines SU-DHL-1, HH, and HDLM-2.  A chronic 
myeloid leukemia cell line called bv173 was transduced with the gene for CD30 to provide another 
CD30+ target.  These CD30-negative cell lines were used:  the leukemia cell line ngfr-bv173 
(bv173 transduced with the low-affinity nerve growth factor gene); the T-cell leukemia cell line 
CCRF-CEM, Saos-2 (a bone sarcoma cell line); A549 (a lung carcinoma cell line); MDA-231 (a 
breast cancer cell line); 293GP (a human embryonic kidney cell line); TC71 (a Ewings sarcoma 
cell line); COLO205 (a colon carcinoma cell line); U251 (a glioblastoma cell line) and Panc10.05 
(a pancreatic carcinoma cell line).  Primary human CD34+ hematopoietic stem cells were also used 
as targets.  In each experiment, the result for effector T cell cultured alone was also given.   
Experiment 3 in Table 1 makes the important point that soluble CD30 protein added to ELISA co-
cultures along with 5F11-28Z T cells and target cells only slightly reduced the amount of IFNγ 
produced by the CAR T cells.  This indicates that CD30 protein does not block CAR recognition 
of target cells.  This is important because CD30 can be shed by lymphomas, and some patients 
with CD30+ lymphomas have soluble CD30 in their serum and presumably in their lymphoma 
masses. 
Table 1 Specificity of 5F11-28Z-transduced T cells 
Experiment 1 
                                                                       Targets 
CAR 
expressed by T 
cells 
SUDHL-1 HH 
CD30-bv173 
NGFR-
bv173 
CCRF-
CEM 
T 
cells 
alone 
% T cells 
expressing 
CAR 
5F11-28Z 
25468 
78624 
3781 
33 
31 
13 
93.6 
Un-
transduced 
17 
29 
39 
26 
16 
<12 
0 
 
T cells expressing the indicated CARs in the far left column were cultured with the indicated target 
cells overnight, and then a standard IFNγ ELISA was performed.  SUDHL-1, HH, and CD30-
bv173 are CD30+ cell lines.  NGFR-bv173 and CCRF-CEM are CD30-negative cell lines.   The 


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numbers are pg/mL of IFNγ released at the end of the culture period.  The percent of T cells 
expressing each CAR was determined by staining CAR-transduced and Untransduced T cells with 
Protein L and subtracting the % protein L staining of untransduced T cells from the % protein L 
staining of each CAR-transduced T-cell population. 
  
Experiment 2 
 
T cells expressing the indicated CARs in the far left column were cultured with the indicated target 
cells overnight, and then a standard IFNγ ELISA was performed.  SUDHL-1, and HDLM-2 are 
CD30+ cell lines.  NGFR-bv173, CCRF-CEM, and 293GP are CD30-negative cell lines.   The 
numbers are pg/mL of IFNγ released at the end of the culture period.   The percent of T cells 
expressing each CAR was determined by staining CAR-transduced and untransduced T cells with 
Protein L and subtracting the % protein L staining of untransduced T cells from the % protein L 
staining of each CAR-transduced T-cell population. 
Experiment 3 
 
T cells expressing the 5F11-28 CAR or left un-transduced as indicated in the far left column were 
cultured with the indicated target cells overnight, and then a standard IFNγ ELISA was performed.  
HH are CD30+ cell lines.  The numbers followed by pg/mL refers to the concentration of human 
CD30 protein added to the media during the entire time that the T cells and target cells were 
cultured together.  U251 and Colo-2015 are CD30-negative cell lines. The numbers are pg/mL of 
IFNγ released at the end of the culture period.  94.8% of the 5F11-28Z T cells expressed the CAR 
as measured by flow cytometry. 
Targets 
CAR 
expressed by 
T cells 
SUD
HL-1 
HDLM-2 
NGFR-
bv173 
CCRF-
CEM 
293GP 
T cells 
alone 
% 
of 
T 
cells 
expressing 
CAR 
5F11-28Z 
3489 
3534 
14 
23 
176 
<12 
95.8 
Un-
transduced 
13 
20 
30 
<12 
137 
<12 
0 
                                                                       Targets 
CAR 
expressed 
by T cells 
HH0µg/
mL 
CD30 
HH 
5 µg/mL 
CD30 
HH 
1 
µg/mL 
CD30 
HH 
0.2 
µg/mL 
CD30 
U25
1 
Colo-
205 
T 
cells 
with no 
target 
Tcells 
with no 
target 
5 µg/mL 
CD30 
5F11-28Z 
23021 
18690 
19920 
18403 
15 
<12 
<12 
278 
Un-
transduced 
 
 
 
 
 
 
143 
123 


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Experiment 4 
Targets 
CAR 
expressed by T 
cells 
HH 
A549 
TC71 
Sol8 
Panc10.05 
MDA231 
Primary 
CD34+ 
T cells 
alone 
5F11-28Z 
12669
2 
107 
773 
92 
48 
354 
153 
26 
Un-
transduced 
508 
20 
28 
33 
12 
163 
71 
<12 
 
T-cells expressing the 5F11-28 CAR or left un-transduced as indicated in the far left column were 
cultured with the indicated target cells overnight, and then a standard IFNγ ELISA was performed.  
HH is a CD30+ lymphoma cell line.  A549, TC71, Sol8, Panc10.05, and MDA231 are CD30-
negtive cells lines.  Primary CD34+ hematopoietic stem cells were also included.  95.8% of the 
5F11-28Z T cells expressed the CAR as measured by flow cytometry. 5F11-28Z-transduced T 
cells also proliferated in a CD30-specific manner. 
Figure 6 
 
Figure 6shows a carboxyfluorescein diacetate,succinimidyl ester (CFSE) proliferation assay in 
which anti-CD30-CAR-transduced T cells were cultured for 4 days with either CD30-bv173 cells 
or CD30-negative ngfr-bv173 cells.  CFSE was diluted to a greater degree, indicating more 
proliferation, compared to when 5F11-28Z-transduced T cells were cultured with CD30-negative 
ngfr-bv173target cells.  The assay was conducted as described previously.165 
 
 
Figure 7 


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Figure 7 shows an experiment in which immunocompromised NSG mice were engrafted with HH 
lymphoma cells.  The cells grow rapidly, and after 4 days, solid masses were present.  Mice were 
then either left untreated or treated with a single infusion of 8 million T cells that were transduced 
with either 5F11-CD28Z or 5F11-CD828Z or the negative-control CAR SP6-CD828Z.  T cells 
expressing either 5F11CAR were able to eliminate tumors in the mice, and clear superiority of one 
CAR over the other has not been established in this model. 
Figure 8 
 
 
The overall survival of mice in the same experiment from Figure 7is shown in Figure 8.  None of 
the mice treated with either 5F11-28Z or 5F11-CD828Z had a recurrence of their tumors.  Of note, 
the HH cell line sheds substantial amounts or soluble CD30, and mice with HH tumors have CD30 
detectable in their serum by ELISA.  This shows that anti-CD30 CARs can be effective even in 
the presence of soluble CD30.    
In the experiments depicted in Figure 7 and Figure 8, CAR T cells were infused on Day 0, and 
no other treatments were administered.  In the experiments reported in Figure 7 and Figure 8, 


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there were 10 mice in each group except the untreated group, which had 9 mice.   The experiment 
was terminated at day 40 because NSG mice receiving infusions of human T cells eventually 
develop graft-versus-host disease, which confounds experimental results. 
As shown in Figure 4, CD30+ T cells are eliminated from cultures of 5F11-28Z-transduced T cells.   
This raises the concern that T-cell cultures of anti-CD30 CAR-expressing T cells might not yield 
enough T cells to conduct a clinical treatment.  We have performed multiple experiments in which 
the proliferation and overall increase in T-cell number were assessed in cultures of anti-CD30 
CAR-transduced T cells.  Results of one of 4 experiments with similar results are shown in Figure 
9.  5F11-containing CARs did proliferate well with an increase in T-cell number compatible with 
obtaining enough cells for a clinical treatment in cultures of 3 different anti-CD30 CARs including 
5F11-28Z, 5F11-CD828Z, and 5F11-CD8BBZ (which has a 4-1BB costimulatory domain).  We 
conclude from this that fratricide of CD30+ T cells by anti-CD30 CAR-containing T cells will not 
preclude generation of a clinical anti-CD30 CAR T-cell product. 
Figure 9 
 
 
1.2.13 Rationale for immunosuppressive chemotherapy and selection of lymphocyte-
depleting chemotherapy regimen.  
We plan to administer a conditioning chemotherapy regimen of cyclophosphamide and fludarabine 
before infusions of CAR-expressing T cells because substantial evidence demonstrates an 
enhancement of the anti-malignancy activity of adoptively-transferred T cells when chemotherapy 
or radiotherapy are administered before the T cell infusions.1,2,166  In mice, administering 
chemotherapy or radiotherapy prior to infusions of tumor-antigen-specific T cells dramatically 
enhanced the anti-tumor efficacy of the transferred T cells.1-3,111,115,166  Administering 
chemotherapy or radiotherapy enhances adoptive T-cell therapy by multiple mechanisms including 
depletion of regulatory T cells and elevation of T-cell stimulating serum cytokines including 
interleukin-15 (IL-15) and interleukin-7 (IL-7), and possibly depletion of myeloid suppressor cells 
and other mechanisms.1-3,167  Removal of endogenous “cytokine sinks” by depleting endogenous 
T cells and natural killer cells caused serum levels of important T-cell stimulating cytokines such 
as IL-15 and IL-7 to increase, and increases in T-cell function and anti-tumor activity were 
dependent on IL-15 and IL-7.1  Experiments in a murine xenograft model showed that regulatory 


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T cells could impair the anti-tumor efficacy of anti-CD19 CAR T cells.168  Myeloid suppressor 
cells have been shown to inhibit anti-tumor responses.167  Experiments with a syngeneic murine 
model showed that lymphocyte-depleting total body irradiation (TBI) administered prior to 
infusions of anti-CD19-CAR-transduced T cells was required for the T cells to cure lymphoma.152   
In these experiments, some mice received TBI, and other mice did not receive TBI.  All mice were 
then challenged with lymphoma and treated with syngeneic anti-CD19-CAR T cells.  Mice 
receiving TBI had a 100% cure rate and mice not receiving TBI had a 0% cure rate.152  
Strong suggestive evidence of enhancement of the activity of adoptively-transferred T cells has 
been generated in humans.119,169,170  Very few clinical responses have occurred and very little 
evidence of in vivo activity has been generated in clinical trials of autologous anti-CD19-CAR T 
cells administered without lymphocyte-depleting chemotherapy.119,124  In contrast, many 
regressions and evidence of long-term B-cell depletion have occurred in clinical trials in which 
patients received anti-CD19-CAR T cells after lymphocyte-depleting chemotherapy.120,122,123,142   
The chemotherapy regimen that best increases the anti-malignancy efficacy of CAR-expressing T 
cells is not known, but the most commonly used chemotherapy regimens that have been used in 
clinical trials and that convincingly demonstrate persistence and in vivo activity of adoptively 
transferred T cells have included cyclophosphamide and/or fludarabine.120-123,169,170  Both 
cyclophosphamide and fludarabine are highly effective at depleting lymphocytes.169,170  One well-
characterized and commonly used regimen is the combination of 300 mg/m2 of cyclophosphamide 
administered daily for 3 days and fludarabine 30 mg/m2 administered daily for three days on the  
same days as the cyclophosphamide.171  Multiple cycles of this regimen can be tolerated by heavily 
pretreated leukemia and lymphoma patients.171  As of amendment E (protocol version: 
08/03/2018), the chemotherapy regimen is changed to cyclophosphamide 500 mg/m2 and 
fludarabine 30 mg/m2 daily for three days starting with Cohort 1 Dose Level 3 and Cohort 2 Dose 
Level 2 as described in Section 3.1.6 and Section 3.4.4.1. This is based on suboptimal lymphocyte 
depletion seen in 7 of the first 8 patients treated. This regimen was used successfully in a report of 
anti-CD19 CAR T-cell therapy  172.  
1.2.14 Rationale for dose-escalation  
The clinical trial described in this protocol is planned as a dose escalation in which the number of 
anti-CD30-CAR T cells administered to patients will be increased with sequential dose levels.  The 
rationale for conducting a dose-escalation trial of a cellular therapy is based on two main sources 
of evidence.  First, the anti-tumor efficacy of adoptively-transferred T cell treatments increases as 
the dose of T cells administered to mice increases.173-175  Second, in the setting of allogeneic 
transplantation, relapsed malignancy is often treated with infusions of allogeneic donor 
lymphocytes (DLIs).176,177  The incidence of graft-versus-host disease, which is caused by T cells 
attacking allogeneic antigens on host tissues, increases as the dose of T cells administered in DLIs 
increases.176,177 Previous experience with autologous anti-CD19 CAR T cells has shown that a cell 
dose of 5 x 106 cells/kg may be too toxic, but a dose of 1 x 106 cells/kg is tolerable.160 In this trial, 
the first dose level for patients in Cohort 1 has been set at less than a third of this tolerable dose, 
at 0.3 x 106 cells/kg. Based on the favorable safety profile found at the 0.3 x 106 cells/kg and at 
the 1 x 106 cells/kg doses for patients in Cohort 1, this protocol was amended  to allow 1 x 106 
cells/kg to be the starting dose for patients in Cohort 2 with amendment D (Protocol version: 
05/03/2018).  


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1.2.15 Rationale for a fully-human CAR 
Immune responses against genetically-modified T cells have previously been reported.156,178,179  
Cytotoxic T-cell responses against suicide-gene-modified T cells have previously been 
documented.178  The CARs used in all published CAR studies to date used antibody components 
that were derived from murine antibodies.  It would be expected that in at least some patients these 
murine components would be immunogenic.  As with other aspects of the CAR field, most work 
concerning CAR immunogenicity has been conducted with anti-CD19 CARs.  Supporting this 
belief are data from a small number of patients that indicate that T-cell responses can develop 
against the FMC63 single chain variable fragment (scFv) that is a part of most anti-CD19 CARs 
that are currently being tested.  Jensen and coworkers and Lee and coworkers have reported T-cell 
responses against the FMC63 murine scFv.156,179  Riddell and coworkers have reported cytotoxic 
T-cell responses against the FMC63 scFv (Riddell, Presentation at the American Society of 
Hematology Annual Meeting, 2013).  Because this protocol intends to give patients multiple doses 
of CAR-modified T cells, the risk of developing anti-CAR immune responses is possibly even 
higher than in most previous clinical trials that only administered a single infusion of CAR T cells.  
All in all, use of a fully-human CAR will decrease the risk of anti-CAR T-cell responses that we 
hypothesize could interfere with CAR T-cell efficacy especially when multiple infusions of T cells 
are given.   
The use of a fully-human CAR might increase persistence of CARs after a first dose of CAR T 
cells.  In our ongoing trials of  murine anti-CD19 CARs, persistence of CAR T cells in the blood 
has been limited.160 We hope that the fully-human anti-CD30 CAR will have longer persistence.   
1.2.16 Summary of risks and potential benefits 
This clinical trial is being performed to evaluate a genetically-modified T-cell therapy for 
advanced CD30+ lymphomas, which are often incurable diseases.  Only patients with malignancies 
persisting despite at least 2 prior lines of therapy will be enrolled. The risks of the study fall into 
6 general categories.  First, chemotherapy that is part of the protocol treatment could cause 
cytopenias.  As with any chemotherapy that causes neutropenia and thrombocytopenia, this 
chemotherapy could cause toxicities such as infections and bleeding. The second category of 
toxicity is cytokine-release-type toxicities such as high fevers, tachycardia, transient abnormalities 
of liver function, and hypotension.  These cytokine-release-type toxicities have been detected in 
other clinical trials of CAR T cells during the first 2 weeks after anti-CD19 CAR T cells were 
infused.122,158   A third category of potential toxicities are neurological toxicities such as delirium, 
obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities including 
aphasia and focal paresis.  In previous anti-CD19 CAR trials, cytokine-release toxicities and 
neurological toxicities have been limited in duration with toxicities generally resolving within 2 
days to 3 weeks.  Of course, with anti-CD30 CAR T cells, toxicity could be more or less severe 
than the toxicity that occurs after infusion of anti-CD19 CAR T cells.   
The fourth possible category of toxicity is direct damage to normal tissues by the CAR T cells.  
This could happen because of unexpected cross-reactivity of the anti-CD30 CAR with proteins 
other than CD30 in vivo.  This trial will be the first of a CAR containing the fully-human 5F11 
variable regions, so cross-reactivity with normal proteins is not inconceivable.  We have performed 
extensive testing of 5F11 CARs by culturing 5F11-CD28Z CAR T cells with a variety of human 
cell lines, and we have not seen recognition of cell lines that did not express CD30.  While we did 


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not witness this in our cell line data or immunohistochemistry data from the NIH Department of 
Pathology, CD30 has been reported to be expressed on the deciduoid cells of the uterine lining of 
the pregnant uterus and in the uterus in the secretory phase.11 Therefore for safety reasons women 
having had menses in the last six months prior to enrollment will be excluded. Participating women 
must have a serum FSH in the post-menopausal range, greater than 22 units/Liter. The occurrence 
of post-autologous stem cell transplant amenorrhea in women under the age of 40 is substantial, 
with resumption of normal menses in only 45% of patients having received 2 or more lines of 
salvage therapy,180 meaning a large portion of the population of pre-menopausal women eligible 
for this protocol will likely already have baseline amenorrhea. Participating women will also have 
to agree to continue appropriate contraception and not become pregnant for one year following the 
last CAR T cell infusion, as per the hypothetical risk of toxicity to the endometrium of the pregnant 
uterus. Additional possible toxicities are those reported with anti-CD30 monoclonal antibodies, as 
described in section 1.2.4.  
A fifth category of toxicity caused by anti-CD30 CAR T cells is impairment of normal immunity 
because CD30 is expressed on activated T cells and activated B cells.   A 6th potential type of 
toxicity that has never actually occurred in a clinical trial of T-cell gene therapies is a gene therapy-
specific toxicity such as occurrence of a replication-competent lentivirus or transformation of T 
cells caused by insertional mutagenesis.125    
The potential benefits to subjects enrolling on this trial include the possibility that the anti-CD30-
CAR T cells can cause a significant anti-malignancy effect.  Many patients enrolled on trials of 
anti-CD19 CAR 
T 
cells 
obtained prolonged complete remissions of advanced 
malignancies,120,122,181 so there is a chance that recipients of the anti-CD30 CAR T cells that are 
being evaluated in this protocol could derive a direct benefit from participation in this trial.  In 
contrast, some patients did not obtain remissions on prior anti-CD19 CAR trials and in some 
patients the remissions were not lasting.  Of course clinical results with anti-CD30 CAR T cells 
could be either better or worse than results with anti-CD19 CAR T cells.  A small number of 
patients may have lymphomas that express both CD19 and CD30, specifically patients with 
DLBCL, PMBL, or grey zone lymphomas, and may be eligible for both the NCI SB autologous 
fully human anti-CD19 CAR T cell protocol and this protocol. In these cases, the patients would 
be referred first to the anti-CD19 CAR T cell protocol, as extensive data from multiple centers 
have already shown anti-CD19 CAR T cells to be active in chemorefractory DLBCL with expected 
cytokine release toxicities. Patients might also derive a benefit from knowing that they are 
contributing to the development of new cellular therapies for cancer.  Aiding in the development 
of new therapies might help future patients. 
As of amendment G (Protocol version: 08/12/2019) we are no longer enrolling Hodgkin 
lymphoma patients due to a lack of efficacy against Hodgkin lymphoma patients.  This anti-CD30 
CAR T-cell product appears to have modest activity in patients with Hodgkin lymphoma. Possible 
reasons for limited anti-malignancy efficacy in Hodgkin lymphoma include inhibition of the CAR 
T cells by the tumor microenvironment. Additionally, malignant Reed Sternberg cells, which 
express CD30, make up a minority of the cells in a Hodgkin lymphoma tumor mass; therefore, 
even in patients with significant burdens of lymphoma, the antigen stimulation of the CAR T cells 
by CD30 may be limited.   
 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
Note: if a patient meets an eligibility requirement as outlined below, and is enrolled on the protocol 
but then is found to no longer meet the eligibility requirement after enrollment but before the start 
of protocol treatment, the treatment will be aborted or delayed. 
2.1.1 Inclusion Criteria 
2.1.1.1 Malignancy criteria 
• Patients must have anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, 
peripheral T-cell lymphoma not otherwise specified, diffuse large B-cell lymphoma not 
otherwise specified, primary mediastinal B-cell lymphoma, grey zone lymphoma, 
enteropathy-associated T-cell lymphoma, or extranodal NK/T-cell lymphoma, nasal type 
• Clear CD30 expression must be detected on 75% or more of malignant cells from either 
bone marrow or lymphoma mass by flow cytometry or immunohistochemistry. The 
patient’s malignancy will need to be assessed for CD30 expression by flow cytometry or 
immunohistochemistry performed at the NIH.  If unstained, paraffin-embedded bone 
marrow or lymphoma sections are available from prior biopsies, these can be used to 
determine CD30 expression by immunohistochemistry; otherwise, patients will need to 
come to the NIH for a biopsy to determine CD30 expression.  The sample for CD30 
expression can come from a biopsy obtained at any time before enrollment, unless the 
patient has received a prior anti-CD30 monoclonal antibody, in which case the sample must 
come from a biopsy following completion of the most recent anti-CD30 monoclonal 
antibody treatment. 
• Eligible patients with with diffuse large B-cell lymphoma or primary mediastinal B-cell 
lymphoma must have received 2 prior treatment regimens at least 1 of which included an 
anthracycline and an anti-CD20 monoclonal antibody  
• Patients must have measurable malignancy as defined by at least one of the criteria below. 
 Lymphoma mass that is measurable (minimum 1.5 cm in largest diameter) by CT 
scan is required unless bone marrow lymphoma is detectable.  
 
 For a lymphoma mass to count as measurable malignancy, it must have abnormally 
increased metabolic activity when assessed by positron emission tomography (PET) 
scan. 
 For lymphoma with only bone marrow involvement, no mass is necessary, but if a 
mass is not present, bone marrow malignancy must be detectable by flow cytometry. 
 
2.1.1.2   Other inclusion criteria 
• Greater than or equal to 18 years of age and less than or equal to age 73.  
• Able to understand and sign the Informed Consent Document. 
• Clinical performance status of ECOG  0-2 


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• Room air oxygen saturation of 92% or greater 
• Male patients and must be willing to practice birth control from the time of enrollment on 
this study and for four months following the final CAR T cell infusion. Pre-menopausal 
patients (female patients who have had a menstrual period within the last year) must be 
willing to practice birth control from the time of enrollment and for one year following the 
final CAR T cell infusion.  
• Seronegative for HIV antibody.  (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who are HIV seropositive can have 
decreased immune -competence and thus are less responsive to the experimental treatment 
and more susceptible to its toxicities.)  
• Seronegative for HTLV-1.  
• Negative for hepatitis B surface antigen. Positive hepatitis B tests can be further evaluated 
by confirmatory tests; and if confirmatory tests are negative, the patient can be enrolled.  
• Seronegative for hepatitis C antibody unless antigen negative.  If hepatitis C antibody test 
is positive, then patients must be tested for the presence of RNA by RT-PCR and be HCV  
RNA negative to be enrolled.   
• A patient with a prior history of hepatits B or a prior history of hepatitis C may participate, 
as long as the patient’s viral hepatitis has been treated, and the patient has no detectable 
HBV DNA or HCV RNA.  
• At time of protocol enrollment, the patient should be negative for CMV by antibody testing 
or by PCR. In case of disagreement between these 2 CMV tests, the tests will be repeated 
and Dept. of Laboratory Medicine consulted. 
• Absolute neutrophil count greater than or equal to 1000/mm3 without the support of 
filgrastim or other growth factors 
• Platelet count greater than or equal to 55,000/mm3 
• Hemoglobin greater than 8.0 g/dl.  Transfusion support is allowed.  
• Less than 5% malignant cells in the peripheral blood leukocytes  
• Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal 
unless liver involvement by malignancy is demonstrated. 
• Serum creatinine less than or equal to 1.6 mg/dL. 
• Total bilirubin less than or equal to 2.0 mg/dl.  
• At least 14 days must have elapsed since any prior systemic therapy prior to apheresis and 
prior to the initiation of chemotherapy (including systemic corticosteroids at doses greater 
than  prednisone 5 mg/day or the equivalent corticosteroid doses). Because this protocol 
requires collection of autologous blood cells by leukapheresis in order to prepare CAR T 
cells, systemic anti-malignancy therapy including systemic corticosteroid therapy at doses 
greater than  prednisone 5 mg/day or the equivalent corticosteroid doses is not allowed 
within 14 days prior to the required leukapheresis. NOTE:  Because of the long half-life 
and potential to affect CAR T cells, 30 days must elapse from the time of administration 
of anti-PD-1 or anti-PD-L1 antibodies or other agents that in the opinion of the PI can 
stimulate immune activity and infusion of CAR T cells. 
• Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography) and 
no evidence of hemodynamically significant pericardial effusion as determined by an 
echocardiogram within 4 weeks of the start of the treatment protocol. 


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• Patients must not take corticosteroids at doses higher than 5 mg/day of prednisone or the 
equivalent for 14 days before apheresis, and for 14 days prior to the conditioning 
chemotherapy regimen.   
• Patients must be willing to undergo endotracheal intubation, mechanical ventilation, 
dialysis, CPR, and electrical defibrillation. Patients must be willing to receive vasopressor 
drugs and all other standard intensive care unit interventions. Any living will must be 
amended to allow these interventions or the patient will not eligible.  
• Patients who have been treated on other protocols of genetically-modified T cells at the 
NIH only are potentially eligible under these conditions: 
o At least 6 months have elapsed since the last genetically-modified T-cell therapy 
that the patient received and there is no evidence of replication-competent 
retroviruses (evidence must be provided from prior NIH gene-therapy protocol 
Principal Investigator) and persisting genetically-modified T cells are not 
detectable in the patient’s blood (evidence must be provided by prior NIH gene-
therapy protocol Principal Investigator). 
 
2.1.1.3 Additional inclusion criteria pertinent only for patients with prior allogeneic 
transplantation: 
 
• Recipients must have received an 9/10 or 10/10 HLA-matched sibling allogeneic 
hematopoietic stem cell transplant, or a 9/10 or 10/10 HLA-matched  unrelated donor 
(URD) allo-HSCT for an eligible CD30+ lymphoma.  
  
• Donor T cell engraftment after allo-HSCT (>90% donor chimerism of the T cell 
compartment). 
 
• Patients must be at least 90 days post-transplant. 
 
• Patients must be off all systemic immunosuppressive drugs including corticosteroids at 
doses of greater than 5 mg/day prednisone or equivalent, if given for treatment of graft 
versus host disease, for at least 28 days prior to protocol enrollment and must remain off 
immunosuppressive drugs while enrolled on the protocol.  Patients must not be taking any 
systemic steroids at doses greater than 5 mg/day prednisone or equivalent for 14 days prior 
to apheresis and initiation of chemotherapy. Topical corticosteroid preparations applied to 
the skin such as solutions, creams, and ointments are allowed.  Inhaled corticosteroids are 
allowed, and corticosteroid eye drops are allowed. 
 
• Prior DLIs are not necessary. 
 
• Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic 
GVHD while off of systemic immunosuppressive therapy for at least 28 days. Minimal 
clinical evidence of acute GVHD defined as grade 0 to I acute GVHD  (see Section 1.1 
).109  Minimal evidence of chronic GVHD is defined as mild global score chronic GVHD 
(as defined by the 2005 NIH consensus project) or no chronic GVHD (see Section 14.5).107   


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Subjects with disease that is controlled to stage I acute GVHD or to mild global score 
chronic GVHD with local topical cutaneous steroids will be eligible for enrollment. 
 
2.1.2 Exclusion criteria 
• 
Patients with Hodgkin lymphoma are no longer eligible for participation (as of amendment 
G, Protocol version: 08/12/2019). 
• 
Patients that require urgent therapy due to tumor mass effects or spinal cord compression. 
• 
Patients with lymphoma masses 10.0 cm or larger in longest diameter will not be eligible. 
• 
Patients that have active hemolytic anemia. 
• 
Patients who are currently taking any medications for systemic anticoagulation other than 
aspirin will not be eligible.  
• 
Patients with second malignancies in addition to their lymphoma are not eligible if the 
second malignancy has required treatment (including maintenance therapy) within the past 
4 years or is not in complete remission. There are two exceptions to this criterion:  
successfully treated non-metastatic basal cell or squamous cell skin carcinoma.    
• 
Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus or infant. 
Women of child-bearing potential are defined as all women except women who are post-
menopausal or who have had a hysterectomy.  Postmenopausal will be defined as women 
over the age of 55 who have not had a menstrual period in at least 1 year. 
• 
Active uncontrolled systemic infections (defined as infections causing fevers and 
infections requiring intravenous antibiotics when the intravenous antibiotics have been 
administered for less than 72 hours); active coagulation disorders or other major 
uncontrolled medical illnesses of the cardiovascular, respiratory, endocrine, renal, 
gastrointestinal, genitourinary or immune system; history of myocardial infarction; history 
of idiopathic ventricular tachycardia or ventricular fibrillation in the past 12 months or 
history of ventricular tachycardia or ventricular fibrillation (VT/VF) associated with 
VT/VF risk factors (e.g., QT prolongation and cardiomyopathy); active cardiac 
arrhythmias (Active atrial fibrillation is not allowed, but resolved atrial fibrillation is 
allowed.); active obstructive or restrictive pulmonary disease; or active autoimmune 
diseases such as rheumatoid arthritis. 
• 
Patients will not be seen for screening appointments or enrolled on the protocol if they have 
been hospitalized within the 7 days prior to the screening appointment or the date of 
protocol enrollment. 
• 
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease), unless the immunodeficiency has been cured by allogeneic stem cell transplant 
• 
Systemic corticosteroid therapy at doses greater than 5 mg/day of prednisone or the 
equivalentdose is not allowed within 14 days prior to the required leukapheresis, or the 
initiation of the conditioning chemotherapy regimen.  Corticosteroid creams, ointments, 
and eye drops are allowed. 
• 
History of severe immediate hypersensitivity reaction to any of the agents used in this 
study. 
• 
Patients with current CNS involvement by malignancy (either by imaging or cerebrospinal 
fluid involvement or biopsy-proven). 
• 
Patients currently taking anticoagulants 


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2.1.3 Recruitment Strategies 
This protocol may be abstracted into a plain language announcement posted on the NIH websites 
and on NIH social media platforms. Recruitment flyers will also be distributed to oncologists  who 
may refer patients. Recruitment flyers may also be emailed to individuals who have previously 
indicated their interest in being notified about NIH clinical trials through email. Participants will 
be recruited from the current patient population at NIH, and local community physicians. 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed after a consent for screening has been signed 
Note: Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01C0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research 
Program Clinical Protocols). 
The following assessments must be completed within 4 weeks prior to starting the 
chemotherapy conditioning regimen unless otherwise noted (if not, then the evaluation 
must be repeated):  
• 
Complete history and physical examination, including, weight, height, and vital signs. Note 
in detail the exact size and location of any lesions that exist.  
• 
Confirmation of diagnosis of lymphoma by the NCI Laboratory of Pathology and 
confirmation of clear CD30 expression on greater than 75% of the malignant cells from 
either bone marrow or a lymphoma mass by flow cytometry or immunohistochemistry.  
The sample used for this CD30 expression analysis can come from any time prior to 
enrollment on the protocol.  The sample can be a fresh biopsy or paraffin-fixed slides. 
• 
EKG  
• 
MRI of the brain 
• 
PET-CT if necessary to document measurable malignancy 
• 
CT scan of neck, chest, abdomen, and pelvis if necessary to document measurable 
malignancy. 
• 
Bone marrow biopsy with flow only if necessary to document measurable CD30+ 
malignancy for enrollment purposes.  If not necessary for enrollment and if not necessary 
clinically to investigate cytopenias, the bone marrow biopsy is not needed.   
• 
Donor venous assessment (If has been performed with-in six  months of apheresis,  it does 
not need to be repeated) 
• 
Antibody screen for Hepatitis B and C, HIV, HTLV-I/II, T. cruzi (Chagas agent), West 
Nile, CMV, and syphilis (RPR) 
• 
Blood PCR for EBV, CMV, BK virus, and JC virus.  
• 
Cardiac echocardiogram 
• 
Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, 
Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Phosphorus, 


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Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, 
Total CK, Uric Acid 
• 
CBC with differential  
• 
PT/PTT 
• 
Glucose-6-phosphate dehydrogenase (G6PD) deficiency screening 
• 
Thyroid Stimulating Hormone, T3 
• 
Serum cortisol  
• β-HCG pregnancy test (serum or urine) on all women of child-bearing potential. Women 
of child-bearing potential are defined as all women except women who are post-
menopausal or who have had a hysterectomy.  Postmenopausal will be defined as women 
over the age of 55 who have not had a menstrual period in at least 1 year. 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
2.3.1 Treatment Assignment Procedures for Registration Purposes Only: 
Cohorts:  
Number Name 
Description 
1 
Cohort 1 
Dose escalation for patients who never had 
an alloHSCT 
2 
Cohort 2 
Dose escalation for patients who have had 
an alloHSCT 
 
Arm:  
Number Name 
Description 
1 
CAR T-cells + Immuno 
therapy 
All patients will be receiving starting dose: 0.3 x106 or 1.0 x106 
CAR+ T cells/kg (weight based dosing)(up to a maximum dose of 
18x106 CAR+ T cells/kg) infuse on day 0 + Cyclophosphamide: 
300 or 500 mg/m2 IV infusion over 30 minutes on days -5, -4 and 
-3 + Fludarabine: 30 mg/m2 IV infusion over 30 minutes 
administered immediately following the cyclophosphamide on 
days -5, -4, and -3 
  
Arm Assignment:  
Patients in cohort 1 will be directly assigned to arm 1 


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Patients in cohort 2 will be directly assigned to arm 1 
 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
3.1.1 General study plan   
This protocol is a phase I dose-escalation study of autologous T cells that are genetically modified 
to express a fully-human anti-CD30 CAR.  The cell dose will be escalated unless occurrence of 
dose-limiting toxicities limits further escalation or until the maximum planned dose level is 
reached.  The protocol will enroll patients who have never had an allogeneic hematopoietic stem 
cell transplant (allo-HSCT) and patients who have had allo-HSCT.   
The protocol will enroll patients with malignancies that are resistant to standard therapies.   Patients 
will be evaluated for general health with an emphasis on detecting cardiac and neurological 
abnormalities.  An assessment of CD30 expression will be an important part of the eligibility 
screening.  Patients enrolled on the study will undergo leukapheresis, and anti-CD30-CAR-
expressing T cells will be generated by transducing the patient’s T cells with a lentivirus encoding 
the anti-CD30 CAR.  Patients will receive a conditioning chemotherapy regimen of 
cyclophosphamide 300 mg/m2 or 500 mg/m2 daily for 3 days and fludarabine 30 mg/m2 IV daily 
for 3 days on the same days.  This is an extensively-used chemotherapy regimen that can be easily 
administered on an outpatient basis.  Results using similar lymphodepletion regimens 
incorporating varying doses of fludarabine and cyclophosphamide have been previously reported 
in anti-CD19 CAR T cell clinical trials.157,160,161 Two days after the end of the conditioning 
chemotherapy, patients will receive a single infusion of anti-CD30-CAR-expressing T cells.  A 
minimum 9-day hospitalization will be required after the cell infusion to monitor closely for acute 
toxicities.  If acute toxicities occur or the patient remains at risk, it is anticipated that the patient 
will have a longer inpatient stay for medical management.   Patients are required to stay within 60 
minutes driving time from the Clinical Center until day 14 after the CAR T-cell infusion.  Patients 
will then be evaluated for toxicity, and malignancy will be staged at 1, 2, 3, 4, 6, 9, and 12 months 
after the infusion.   
A small number of subjects may be eligible for re-enrollment if a patient is removed from the 
protocol BEFORE completing protocol therapy, and would be required to meet all eligibility 
criteria at the time of re-enrollment.  Patients will be assigned a new sequential study number for 
the reenrollment study period. Any cryopreserved anti-CD30 CAR T cells produced from a patient 
who was removed from the study can be used to treat that patient after re-enrollment.  We do not 
anticipate changes in the risk profile for the initial versus re-enrollment 
3.1.2 Planned repeat treatments 
As of amendment E (Protocol version: 08/03/2018), patients will be allowed to receive multiple 
CAR T-cell infusions. Once the MTD has been determined for a cohort, patients in that cohort will 
be allowed to receive a second and potentially a third CAR T-cell treatment at the MTD for that 
patient’s cohort. A maximum of 3 total CAR T-cell infusions per patient are allowed. 
Administration of second and third treatments will follow the same treatment plan as first 
treatments including the cyclophosphamide and fludarabine chemotherapy. Second and third 


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treatments will only be administered if the patient has measurable residual malignancy at least 2 
months after the most recent prior treatment. Patients with a best response of progressive disease 
after a treatment are not eligible for re-treatment. Patient experiencing a DLT at any time are not 
eligible for retreatment. To be eligible for retreatment, a patient must have either cryopreserved 
CAR T cells or PBMC available that have never been exposed to a gene-therapy vector. If more 
than 1 of the first 3 patients, or 2 of the first 6 patients who are retreated have adverse events that 
meet criteria used to define DLTs, re-treatments will be stopped. 
3.1.3 Inclusion of patients who have had allogeneic hematopoietic stem cell transplantation 
(allo-HSCT) 
This trial will enroll patients with a history of allo-HSCT.  Because patients who have had an allo-
HSCT might be more prone to a variety of toxicities than patients who have not had a transplant 
and because the biology of adoptively-transferred T cells could be different in the allogeneic 
transplant setting, allo-HSCT patients will be enrolled on a separate cohort than patients who have 
not had an allo-HSCT.  Cohort 1 will enroll patients who have not had an allogeneic hematopoietic 
stem cell transplant, and Cohort 2 will enroll patients who have had an 9/10 or 10/10 HLA-(human 
leukocyte antigen)-matched sibling or an 9/10 or 10/10-HLA-matched unrelated donor transplant.   
 
 


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3.1.4 Protocol schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
In vitro generation of  
Anti-CD30-expressing 
T cells (7-9 days) 
Pretreatment staging 
Infusion of recipient with 
Anti-CD30-CAR-expressing T-Cells 
(Inpatient for 9-days minimum post 
infusion) 
Follow-up 2 weeks and 1, 2, 3, 4, 6, 9, and 12 
months post-infusion followed by continued 
long-term up follow-up. 
Outpatient or inpatient 
cyclophosphamide plus fludarabine 
conditioning chemotherapy 
Protocol enrollment screening 
Up to two re-
retreatments for 
eligible patients 


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3.1.5 Dose Limiting Toxicity  
Dose-limiting toxicities are defined as the following toxicities occurring within 30 days of CAR 
T-cell infusion (Note that DLTs will only be considered in patients who have received CAR T-cell 
infusions): 
• Grade 3 toxicities possibly, probably, or definitely related to either the anti-CD30 CAR 
T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 
days 
• Grade 4 toxicities possibly, probably, or definitely related to the anti-CD30 CAR T cells 
or the chemotherapy 
The following specific toxicities will not be dose-limiting toxicities: 
• Neutropenia (ANC<500/µL) lasting continuously  14 days or less 
• Anemia (Hgb <8 g/dL) lasting continuously 10 days or less 
• Transfusion-dependent thrombocytopenia lasting 25 days or less 
• Thrombocytopenia that does not require transfusion support 
• Asymptomatic hypophosphatemia of any grade 
• All cytopenias except neutropenia, anemia, or thrombocytopenia 
• Hypotension requiring treatment with vasopressors (norepinephrine dose of >2 
mcg/minute or equivalent, doses less than or equal to 2 mcg/minute are not a DLT)for 72 
hours or less.  The 72 hours is measured from the first institution of vasopressors even if 
vasopressors are temporarily discontinued and then re-started.  
• Fever 
• Grade 4 elevation in alanine aminotransferase, or aspartate aminotransferase, or  bilirubin 
that resolves to Grade 3 or less within 3 days or less  
• Grade 4 creatinine kinase elevation that resolves to Grade 3 or less within 3 days or less 
• Grade 4 prothrombin time (PT) or partial thromboplastin time (PTT) that resolves to Grade 
3 in 3 days or less with no evidence of clinically-significant bleeding or thrombosis 
• Asymptomatic electrolyte disturbances regardless of grade 
• Prolongation of the QTc interval of the ECG 
• Infections controlled by antibiotics 
For past recipients of allogeneic hematopoietic stem cell transplants only, the following will also 
be DLTs 
• Grade IV acute GVHD by 60 days after infusion of anti-CD30 T cells (see Section 1.1 ) 
• Grade III acute GVHD by 60 days after infusion of anti-CD30 T cells that does not 
resolve to a Grade 0-1 with corticosteroid therapy within 30 days of onset (see Section 
14.4) 
3.1.6 Dose Escalation 
The trial will be a dose-escalation with 5 dose levels based on the patient’s actual bodyweight. As 
noted above, there will be two separate cohorts of patients enrolled on the trial, Cohort 1:  Patients 
who have not had an allogeneic hematopoietic stem cell transplant (allo-HSCT) and Cohort 2:  
Patients who have had a 9/10 or 10/10 HLA-matched sibling or an 9/10 or 10/10-matched unrelated 


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donor transplant.  Each cohort will have a completely separate dose escalation, DLTs occurring in 
allo-HSCT recipients will not affect dose escalation on the cohort of patients who have not had an 
allo-HSCT.  Likewise, the dose escalation of the allo-HSCT patients will not be affected by the 
no-allo-HSCT patient dose escalation. A separate dose MTD will be established for each cohort. 
In this trial, the first dose level for patients in Cohort 1 has been set at 0.3 x 106 cells/kg. Based on 
the favorable safety profile found at the 0.3 x 106 cells/kg and at the 1 x 106 cells/kg doses for 
patients in Cohort 1, this protocol was amended to allow 1 x 106 cells/kg to be the starting dose 
for patients in Cohort 2. The dose escalation for Cohort 1 is depicted in Table 2, and the dose 
escalation for Cohort 2 is depicted in Table 3.  
As of implementation amendment E (Protocol version: 08/03/2018), the cyclophosphamide dose 
in the conditioning chemotherapy regimen will be increased to 500 mg/m2 daily. To allow a careful 
evaluation of this change, we will treat a minimum of 3 patients on cohort 1 dose level 3 with 500 
mg/m2 of cyclophosphamide daily before proceeding with the planned dose escalation, even 
though 3 patients have already been treated on cohort 1 dose level 3 with the prior 
cyclophosphamide dose of 300 mg/m2 daily.  
 
The following dose escalation plan refers to the first dose of CAR T cells received by patients on  
both cohorts of the protocol.  CAR+ T cells are defined as CD3+CAR+ cells as measured by flow 
cytometry according to Department of Transfusion Medicine (DTM) SOPs.  The number of anti-
CD30-CAR-expressing T cells transferred for each dose level will be as follows:  
 
Table 2: First-dose Escalation Plan for Cohort 1 
First-dose Escalation Plan for Cohort 1:  separate but identical dose escalation 
plans will be used for both Cohort 1 (patients who never had an allo-HSCT) and 
Cohort 2 (patients who have had an allo-HSCT).  Doses +/- 10% from the listed 
doses are acceptable. 
Dose Level 
Dose of anti-CD30 CAR T cells  
Level -1 
0.15x106 CAR+ T cells per kg of recipient bodyweight 
Level 1 
0.3x106 CAR+ T cells per kg of recipient bodyweight 
Level 2 
1.0x106 CAR+ T cells per kg of recipient bodyweight,   
 
Level 3 
3.0x106 CAR+ T cells per kg of recipient bodyweight with a 
maximum dose of 360 x106 CAR+ T cells 
 


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Table 3: First-dose Escalation Plan for Cohort 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Each dose level will include a minimum of 3 patients.  All cell doses will be cryopreserved cells  
thawed just before infusion. All infusions will be preceded by the fludarabine and 
cyclophosphamide conditioning regimen.  The percentage of CAR+ T cells and the number of total 
cells to infuse to obtain the indicated numbers of CAR+ T cells will be determined prior to 
cryopreservation.  There will be a minimum of 9 days between the CAR T-cell infusion of a patient 
and the start of the conditioning chemotherapy regimen for the next patient on the same cohort.  
Level 4 
9.0x106 CAR+ T cells per kg of recipient bodyweight with a 
maximum dose of 108 x107 CAR+ T cells 
 
Level 5 
18x106 CAR+ T cells per kg of recipient bodyweight with a 
maximum dose of 216 x107 CAR+ T cells 
 
First-dose Escalation Plan for Cohort 2:  separate but identical dose 
escalation plans will be used for both Cohort 1 (patients who never had an 
allo-HSCT) and Cohort 2 (patients who have had an allo-HSCT).  Doses +/- 
10% from the listed doses are acceptable. 
Dose Level 
Dose of anti-CD30 CAR T cells  
Level -1 
0.3x106 CAR+ T cells per kg of recipient bodyweight 
Level 1 
1.0x106 CAR+ T cells per kg of recipient bodyweight,   
 
Level 2 
3.0x106 CAR+ T cells per kg of recipient bodyweight with a 
maximum dose of 360 x106 CAR+ T cells 
 
Level 3 
9.0x106 CAR+ T cells per kg of recipient bodyweight with a 
maximum dose of 108 x107 CAR+ T cells 
 
Level 4 
18x106 CAR+ T cells per kg of recipient bodyweight with a 
maximum dose of 216 x107 CAR+ T cells 
 


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This will cause a 14 day delay between sequential CAR T-cell infusions on each cohort.  Twenty-
eight days must elapse between cell infusion to the last patient on a dose level and protocol 
enrollment of the first patient on the next highest dose level for each cohort.   
Patients will be enrolled sequentially; therefore, enrollment will not proceed to a higher dose level 
until all patients have been treated in the prior cohort.  If sufficient cells cannot be grown to meet 
the criteria for the first dose of cells for the assigned dose level, the treatment will be aborted.  A 
second attempt will be made to prepare cells for the patient if the patient agrees and if the patient 
still meets all eligibility criteria.  
Should none of the first 3 patients treated on a dose level experience a DLT enrollment can start 
on the next higher dose level.  Should 1 of 3 patients experience a dose limiting toxicity on a 
particular dose level,  three more patients would be treated at that dose level to confirm that no 
greater than 1/6 patients have a DLT prior to proceeding to the next higher level.  If 1/6 patients 
have a DLT at a particular dose level, accrual can proceed to the next higher dose level.  If a level 
with 2 or more DLTs in 3-6 patients has been identified, 3 additional patients will be accrued at 
the next-lowest dose for a total of 6, in order to further characterize the safety of the maximum 
tolerated dose.  The maximum tolerated dose is the dose at which a maximum of 1 of 6 patients 
has a DLT.  If 2 DLTs occur on dose level 1, accrual will proceed at dose level -1, as indicated in  
Table 2: First-dose Escalation Plan for Cohort 1 and Table 3.  
After a maximum tolerated dose is defined, additional patients can be treated on this trial.  Up to 
8 total additional recipients can be treated with the MTD after an MTD is established.  If cell 
growth limitations preclude administration of the maximum tolerated dose, the patient will receive 
as many cells as possible up to the maximum tolerated dose.  If it proves to be technically 
impossible or impractical to achieve the higher dose levels due to cell production constraints and 
a maximum tolerated dose has not been reached, the highest achievable dose level will be declared 
the maximum feasible dose. 
Dose escalations will follow the rules outlined in the Table 4 below. 
Table 4: Dose Escalations Rules 
Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Up to three (3) additional patients 
will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 


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Number of Patients with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
• If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  Up 
to three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended 
phase 2 dose.  
 
3.2 
DOSE MODIFICATIONS/DELAY 
       Other Toxicity: 
• Patients may be removed from further treatment if they have active infections defined as 
infections causing fevers or infections requiring intravenous anti-microbial therapy and 
intravenous anti-microbial therapy has been initiated less than 72 hours before the start 
of chemotherapy.  This means that patients are on-study but have not yet started treatment 
could have treatment cancelled or delayed; however such patients are eligible for 
treatment after the infection resolves.   
• If a patient experiences a grade 3 or greater toxicity (with the exception of cytopenias or 
nausea) while on-study before the CAR T-cell infusion, the CAR T-cell infusion must be 
delayed until the toxicity improves to a grade 2 or less or cancelled.  
3.3 
STOPPING CRITERIA 
• If no responses of PR or CR occur after 2 patients are treated on the highest dose level for 
both Cohort 1 and Cohort 2, the protocol will be stopped. 
• Instructions for how to proceed when toxicity occurs will be as instructed by the dose 
escalation section of the protocol (3.1.6). 
• A death on study not attributible to progressive malignancy within 30 days of a cell infusion 
for the initial 5 subjects in either cohort will be a cause for a pause to accrual to investigate 
the event followed by  an amendment submission to the FDA and NIH Intramural IRB if 
required. 
• If 3 or more of the first 9 patients on either cohort experience grade 4 toxicity possibly or 
probably attributable to CAR T cells within 30 days of cell infusion, this will be a cause 
for a pause to accrual to reassess the safety of the product followed by an amendment 
submission to the FDA and NIH Intramural IRB. 


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3.4 
DRUG ADMINISTRATION 
3.4.1 Leukapheresis 
The patient will undergo a 15 liter leukapheresis (generally, 15 liters will be processed to target a 
yield of 6-10 x109 mononuclear cells) in the Department of Transfusion Medicine (DTM) Dowling 
Apheresis Clinic according to DTM standard operating procedures.  The procedure requires dual 
venous access, and takes approximately 3-4 hours to complete.  A central line will be placed if 
peripheral venous access is not sufficient.  
3.4.2 Anti-CD30-CAR-expressing T-cell preparation 
After cells are obtained by apheresis, further cell processing to generate anti-CD30 CAR-
expressing T cells will occur in the DTM according to standard operating procedures (SOPs).  
Either freshly-collected cells or cryopreserved cells can be used to initiate the cell-preparation 
process.  Peripheral blood mononuclear cells will be isolated. Sufficient cells for the initial cell 
production and 1 complete back-up cell production will be retained in the Department of 
Transfusion Medicine.  The excess cells will be sent to the Surgery Branch Cell Production Facility 
SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-3755 for cryopreservation at 200 to 300 million 
PBMC per vial. .  The anti-CD3 monoclonal antibody OKT3 will be used to stimulate T-cell 
proliferation. The cells will be transduced by exposing them to replication-incompetent 
lentiviruses encoding the anti-CD30 CAR by using DTM SOPs.  The cells will continue to 
proliferate in culture.  Anti-CD30-CAR T cells will be cryopreserved between day 7 and day 9 of 
culture.  CAR+ T cells defined as cells staining for both CD3 and protein L in flow cytometry 
assays conducted in accordance with DTM SOPS will be quantitated by flow cytometry. Sufficient 
cells will be cryopreserved for a second dose that will be one dose-level higher (up to a maximum 
of 18x106 CAR+ T cells/kg) than the first dose.  Only for patients entering the study on the first 3 
dose levels, sufficient cells will also be cryopreserved for a third dose that will be the same as the 
second dose or one dose level higher than the second dose (up to a maximum of 18x106 CAR+ T 
cells/kg). For example for a patient receiving a first dose of 1x106 CAR+ T cells/kg, sufficient cells 
need to be produced and cryopreserved for a second dose of 3x106 CAR+ T cells/kg and a 3rd dose 
of 9x106 CAR+ T cells/kg.  Cryopreserved cells will be used for all infusions. 
Ten vials of the infused cells will be cryopreserved for research use and stored in the Surgery 
Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-3755.  Each vial 
will contain 10-20 million cells. 
Before cryopreservation, the percentage of T cells expressing the CAR will be determined by flow 
cytometry, and this percentage of CAR+ T cells will be used in calculating the total number of cells 
to be cryopreserved in a single-infusion bag to meet the dose requirements of the dose-escalation 
plan described in Table 1, Section 3.1.  As noted above, cells for potential 2nd doses will also be 
cryopreserved.   For the first 2 dose levels, third infusions will also be cryopreserved at this time.  
In addition to flow cytometry, further testing of the cells will take place prior to infusion to evaluate 
for microbial contamination, replication-competent lentiviruses, and viability.  Details of this 
testing can be found in the appropriate DTM SOPs. When a patient is no longer eligible on this 
protocol due to meetingany of the off-study criteria listed in section 3.8.2, any remaining 
cryopreserved cells from this protocol will be coded-linked and used for research or discarded after 
approval of the Principal Investigator of this protocol. 


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 Note: All cells sent to the Surgery Branch Cell Production facility will be transferred to NCI 
Frederick Biorepository. 
   
3.4.3 Conditioning chemotherapy and anti-CD30 CAR T-cell administration 
Table 5 
Drug 
Dose  
Days 
Cyclophosphamide  
300  mg/m2 IV infusion 
over 30 minutes (for the 
first 3 patients treated on 
Cohort 1 Dose Level 3, and 
for all patients on Cohort 1 
Dose Level 1 and 2, and 
Cohort 2 Dose Level 1) 
500  mg/m2 IV infusion 
over 30 minutes (For all 
subsequent patients in either 
cohort) 
Daily x 3 doses on days -5, 
-4, -3 
Fludarabine 
30 mg/m2 IV infusion over 
30 minutes administered 
immediately following the 
cyclophosphamide on day 
 -5, -4, -3 
Daily x 3 doses on days -5, 
-4, -3 
 
Anti-CD30 CAR T cells 
Variable.  
Infuse on day 0 
3.4.4 Overall summary of the treatment plan 
3.4.4.1 Detailed treatment plan 
Day -5, -4, and -3:  Patients will receive pre-hydration with 1000 mL 0.9% sodium chloride I.V. 
over 1 to 3 hours.  
Patients will receive anti-emetics following NIH Clinical Center guidelines, but dexamethasone 
will not be administered.  One suggested regimen is ondansetron 16 to 24 mg orally on days -5, 
-4, and -3 1 hour before chemotherapy (I.V. ondansetron can be substituted).    Patients should be 
provided with anti-emetics such as lorazepam and prochlorperazine to use at home.   
Next, for all patients treated on cohort 1, dose levels 1 and 2,  the first 3 patients treated on Cohort 
1 Dose Level 3, and for all patients on Cohort 2 Dose Level 1, on days -5, -4, and -3, 
cyclophosphamide at a dose of 300 mg/m2 I.V. will be diluted in 100 ml 5% dextrose solution and 
infused over 30 minutes. For all subsequent patients in either cohort, on days -5, -4, and -3, 
cyclophosphamide at a dose of 500 mg/m2 I.V. will be diluted in 100 ml 5% dextrose solution and 


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infused over 30 minutes. After the cyclophosphamide on days -5, -4, and -3, all patients will 
receive 30 mg/m2 I.V. fludarabine in 100 mL 0.9% sodium chloride over 30 minutes.  Note: in 
patients with a creatinine clearance calculated by the CKD-EPI equation less than 80 
ml/minute/1.73 m2of body surface area, the daily dose of fludarabine will be reduced by 20%.  
Following the fludarabine infusion, patients will receive 1000 mL 0.9% sodium chloride I.V. over 
1-2 hours.  Furosemide will be given if needed.   
Days -2 and -1:  No interventions except as needed for general supportive care such as anti-emetics.  
To minimize bladder toxicity, patients should increase normal oral fluid intake to at least 2 L/day. 
Day 0:  CAR T cells will be administered.  Premedication for the cell infusion will be given 
approximately 30 to 45 minutes prior to the infusion.  The premedications are acetaminophen 650 
mg orally and diphenhydramine 12.5 mg IV.  Cells will be delivered to the patient care unit from 
the Department of Transfusion Medicine.  Prior to infusion, the cell product identity label is 
double-checked by two authorized staff (MD or RN), and identification of the product and 
documentation of administration are entered in the patient’s chart as is done for blood banking 
protocols.  The cells are to be infused intravenously over 20-30 minutes.  Details of the 
infusion procedure are included in section 14.5, Appendix E . 
Days 1 to 9: Mandatory hospitalization for observation and treatment as necessary. Note:  
hospitalization for CAR T-cell patients is routinely extended; extension of hospitalization beyond 
the required 9 days is anticipated for CAR T cell toxicity management. In addition, patients are 
required to stay within 60 minutes driving time from the Clinical Center until day 14 after the CAR 
T-cell infusion.   
Guidelines for dealing with toxicities that often occur after CAR T cell infusions including 
hypotension, fever and tachycardia are given in Appendix C.   
A CBC with differential will be obtained daily.  If the absolute neutrophil count becomes less 
than 500/microliter, filgrastim will be initiated at a dose of 300 micrograms daily 
subcutaneously for patients under 70 kg in weight and at a dose of 480 micrograms daily for 
patients over 70 kg in weight.  Filgrastim will be given daily and then discontinued as soon as the 
absolute neutrophil count recovers to 1500/microliter. 
3.5 
PROTOCOL EVALUATION  
3.5.1 Baseline evaluations and interventions 
The following tests must be completed within 14 days of the start of the conditioning 
chemotherapy regimen: 
• Patients must have a central venous access before the time of cell infusion.  This might 
require placement of a non-valved P.I.C.C line or other device.  Non-valved PICC lines are 
greatly preferred over valved PICC lines for this protocol. 
• Physical exam with vital signs and oxygen saturation 
• CT scan of neck, chest, abdomen, and pelvis 
• PET-CT of the torso  
• Bone marrow aspirate and biopsy:  specifically ask for CD30 immunohistochemistry 
staining of the bone marrow biopsy.  Flow cytometry must be performed.  The bone 


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marrow biopsy must take place at some time after the patient’s most recent malignancy 
treatment.  If a bone marrow biopsy was performed at the NIH as part of protocol screening 
within 4 weeks of the start of treatment, it does not have to be repeated unless necessary 
for staging. 
• G-banding cytogenetics on the bone marrow if there is a suspicion of myelodysplastic 
syndrome. 
• 250 microgram cosyntropin stimulation test if suspicious for adrenal insufficiency based 
on low serum sodium, high serum potassium, hypotension, low serum cortisol, a history of 
adrenal insufficiency, or other clinical indication 
• Blood CMV PCR  
• Blood will be collected for research purposes.  Twelve CPT tubes (8 mL each) of blood 
will be collected within 3 days prior to initiation of the conditioning chemotherapy 
regimen. This is a total of 96 mL of blood.  Some of this blood will be used for immunology 
assays and some will be used for RCL assays. This blood can be collected on different days 
as long as a total of 12 CPT tubes are collected prior to initiation of the chemotherapy.  
Send to the Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 
240-858-3755. 
• In addition to the CPT tubes, draw 16 mL of blood to obtain serum for research purposes 
(2 SST tubes, 8 mL per tube) within 3 days prior to the start of the chemotherapy.  Send to 
the Figg lab; For sample pick-up, page 102-11964. 
3.4.2 The following tests must be completed within 7 days of the start of the conditioning 
chemotherapy regimen: 
• TBNK (T, B, and NK cell) 
• Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, 
Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Phosphorus, 
Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, 
Total CK, Uric Acid (to be repeated on the first day of the chemotherapy at the discretion 
of the PI)  
• Serum quantitative immunoglobulins 
• ABO typing 
• CBC with differential and platelet count(to be repeated on  the first day of the 
chemotherapy at the discretion of the PI)  
• PT/PTT 
• Urinalysis; if results are abnormal, send for urine culture 
• β-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
• C-reactive peptide (CRP) 
  


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3.5.2 Studies to be performed on Day 0 and during the mandatory 9-day inpatient 
admission after cell infusion 
• Vital signs including pulse oximetry will be monitored q1h x 4 hours after completion of 
the CAR T cell infusion and then every 4 hours otherwise unless otherwise clinically 
indicated. 
• Daily physical exam 
• CBC twice daily from day 0 until day 9 with differential once daily. After day 9 do a CBC 
with differential daily until discharge. (Note: In the case of a later day infusion or early 
discharge, this may be only once a day) 
• C-reactive peptide (CRP) within 7 days before the first dose of chemotherapy on day -5 
and daily while hospitalized. 
• TBNK(T, B, and NK cell) on the day of CAR T-cell infusion (day 0) and day 7 after 
infusion 
• Chemistries twice daily starting from day 0 to day 9.  After day 9, do chemistries once 
daily until discharge: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, 
LDH, Total Protein, Uric Acid. (Note: In the case of a later day infusion or early discharge, 
this may be only once a day) 
• PT/PTT  and fibrinogen daily after infusion  
• Other tests will be performed as clinically indicated. 
• Day 0 Research Blood: 1 SST tube will be drawn on the morning of CAR cell infusion 
prior to infusion of CAR T cells. Send to the Figg lab; for sample pick-up, page 102-
11964. 
• Post-infusion Research blood:  Every Monday, Wednesday, and Friday during 
hospitalization, starting on the first Monday, Wednesday, or Friday after the day of CAR 
T-cell infusion and lasting up to14 days after infusion, 56 mL of patient peripheral blood 
will be obtained (6 CPT tubes 8 mL each and 1 SST tube 8 mL). Send CPT tubes to the 
Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 240-858-
3755. Send SST tubes to the Figg lab; for sample pick-up, page 102-11964. 
• Additional Post-infusion research blood: 1 SST tube will be drawn on the first Sunday 
after CAR T-cell infusion.  This tube will be stored refrigerated on the nursing unit and 
processed first thing Monday morning at the latest. Send to the Figg lab; For sample pick-
up, page 102-11964.  
 
 
3.5.3 Post-infusion outpatient evaluation 
Patients will be seen at the NIH in follow-up to evaluate disease status and late problems related 
to CAR T-cell infusion at the following time-points:  +14 (+/- 1 day), +30 (+/- 5 days), +60 (+/- 7 
days), +90 (+/- 7 days), +120 (+/- 7 days) and at 180 (+/- 14 days), 270 (+/- 14 days), and 365 (+/- 
30 days) after CAR T-cell infusion. After 12 months, the patient will be seen approximately every 


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6 months (+/- 30 days) up to three years post-infusion; subsequently, patients will be seen annually 
(+/- 30 days) up to 5 years post infusion. At all outpatient follow-up visits unless otherwise noted, 
patients will have the following tests performed to determine clinical response: 
• 6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for 
immunological testing. Send to the Surgery Branch Cell Production Facility SB-CPF. Bldg. 
10 3W-3808.  Phone: 240-858-3755.  
• 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  Send to the 
Figg lab; For sample pick-up, page 102-11964 
Note: after the first year of follow-up, research blood will be reduced to 4 CPT tubes 
(32 mL total) during required protocol visits. 
• CT scans and PET scans (as needed for disease assessment) at outpatient follow-up 
appointments starting 1 month after infusion as described in section 3.6 
• Patients may need 1 biopsy to confirm lymphoma progression. Patients may also undergo 
a maximum of 2 biopsy after CAR T-cell infusion to obtain material to study interactions 
between CAR T cell and the lymphoma microenvironment. These biopsies could occur 
either during the inpatient stay or during the outpatient phase. CT-guidance might be 
needed for these biopsies. 
• Post-treatment bone marrow biopsies are needed only to document CR in patients in CR at 
all other sites and with pre-treatment bone marrow lymphoma involvement.   Aspirate may 
be sent for flow cytometry to the lab of Dr. Maryalice Stetler-Stevenson.  CD30 staining 
must be requested for the flow cytometry.  CD30 immunohistochemistry should also be 
requested on the bone marrow biopsies.   
• Post-CAR T-cell infusion research bone marrow samples will not be collected unless a 
sample is needed to investigate bone marrow toxicities such as prolonged cytopenia or 
second malignancies. In these cases, , send one tube of bone marrow aspirate for research 
purposes to Surgery Branch Cell Production Facility SB-CPF. Bldg. 10 3W-3808.  Phone: 
240-858-3755. 
• Physical exam with vital signs and oxygen saturation 
• Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, 
Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Phosphorus, 
Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, 
Total CK, Uric Acid 
• 
TBNK 
• 
Blood for serum quantitative immunoglobulins 
• 
CBC with differential 
• 
Blood PCR for CMV, EBV, BK virus, and JC virus at all follow-up visits until six months 
have elapsed after the final cell infusion.  
• 
Patients only need lumbar punctures if necessary to stage malignancy or to investigate 
toxicity. 
• Gene-therapy-specific follow-up must be carried out as described in section 3.7. 


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3.6 
STUDY CALENDAR  
Procedures a 
Screening/ 
Baseline 
 
Pre-cell 
infusion
/ Day 0 
Day 
+7b 
Day+14 
(+/- 
1 
day) and  
Day+30 
(+/- 
5 
days) 
Dayq 
+60 
(+/- 
7 
days) 
Day 
+90 
(+/- 
7 
days) 
Day 
+120 
(+/- 
7 
days) 
Day 
+180 
(+/- 14 
days) 
Day 
+270 
(+/- 14 
days) 
Day 
+365 
(+/- 30 
days) 
Every 
6 
month after 
day 365 up 
to 3 years 
then 
annually(+
/- 30 days)  
Clinical Assessments 
 
 
 
History and PE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, O2 saturation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
 
Xj 
 
 
 
 
 
 
 
 
 
Performance Score 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
CBC with differential  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sodium, Potassium 
Chloride, CO2, Creatinine, 
Glucose, BUN, Albumin, 
Calcium, Magnesium, 
Phosphorus, Alkaline 
Phosphatase, ALT, AST, T. 
Bilirubin, D. Bilirubin, 
LDH, Total Protein, CK, 
Uric Acid 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Blood Beta HCG pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT and Fibrinogen 
X 
 
X b 
X b 
 
 
 
 
 
 
 
 
 
Thyroid Stimulating 
Hormone, T3 
X 
 
 
 
 
 
 
 
 
 
 
 


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Procedures a 
Screening/ 
Baseline 
 
Pre-cell 
infusion
/ Day 0 
Day 
+7b 
Day+14 
(+/- 
1 
day) and  
Day+30 
(+/- 
5 
days) 
Dayq 
+60 
(+/- 
7 
days) 
Day 
+90 
(+/- 
7 
days) 
Day 
+120 
(+/- 
7 
days) 
Day 
+180 
(+/- 14 
days) 
Day 
+270 
(+/- 14 
days) 
Day 
+365 
(+/- 30 
days) 
Every 
6 
month after 
day 365 up 
to 3 years 
then 
annually(+
/- 30 days)  
Quantitative 
immunoglobulins  
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Antibody screen for 
Hepatitis B and C; CMV, 
HIV, HTLV-I/II, T. cruzi 
(Chagas agent), West Nile, 
and syphilis (RPR) 
Xh 
 
 
 
 
 
 
 
 
 
 
 
Blood PCR for CMV, EBV, 
BK virus and JC virus 
Xc 
 
 
 
X 
X 
X 
X 
X 
 
 
 
TBNK  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
G6PD 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (culture prn) 
X 
 
 
 
 
 
 
 
 
 
 
 
ABO typing 
X 
 
 
 
 
 
 
 
 
 
 
 
CT neck, chest, abdomen, 
pelvis 
X 
 
 
 
Xl 
X 
X 
X 
X 
X 
X 
X 
PET  
X 
 
 
 
Xl 
X 
X 
X 
X 
X 
X 
X 
Brain MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
Other Specific Assessments 
 
 
 
Documentation of CD30 
expression by malignancy 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum cortisol 
X 
 
 
 
 
 
 
 
 
 
 
 
250 microgram 
cosyntropin teste 
Xr 
 
 
 
 
 
 
 
 
 
 
 


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Procedures a 
Screening/ 
Baseline 
 
Pre-cell 
infusion
/ Day 0 
Day 
+7b 
Day+14 
(+/- 
1 
day) and  
Day+30 
(+/- 
5 
days) 
Dayq 
+60 
(+/- 
7 
days) 
Day 
+90 
(+/- 
7 
days) 
Day 
+120 
(+/- 
7 
days) 
Day 
+180 
(+/- 14 
days) 
Day 
+270 
(+/- 14 
days) 
Day 
+365 
(+/- 30 
days) 
Every 
6 
month after 
day 365 up 
to 3 years 
then 
annually(+
/- 30 days)  
EKG, echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
RCL (replication 
competent lentivirus) 
X 
 
 
 
 
 
X 
X 
X 
 
X 
Xi 
Central Venous catheter 
placement 
 
 
X 
 
 
 
 
 
 
 
 
 
Donor Venous Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biopsy with flow 
X f 
 
 
 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
Research Blood 
Xp 
 
Xm, n, o 
Xm, n, o 
X 
X 
X 
X 
X 
X 
X 
Xk 
Adverse Event 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a see section 2.2 and section 3.5 for details 
 
b see section 3.4 or details of testing during hospitalization 
 
c CMV PCR also performed at baseline, all others only during screening are required 
 
e only  if cortisol<18 mg/dL or clinical suspicion of adrenal insufficiency  
f All patients need a pre-treatment bone marrow biopsies.   Patients only need bone marrow biopsies post-treatment if the pre-treatment 
bone marrow was positive and the patient is in CR at all other sites. 
g only at 2, 3, 4, 5 year post-infusion time points, see section 3.6 for details 


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h  During screening only. 
 
i Annually RCL blood collection will only continue after the 1 year time-point if a previous RCL test has been positiveJ Height and 
weight at admission is adequate even if not D0 
 
kUntil 5 years follow-up period 
 
l CT and PET will be performed only at day 30 
mDraw 1 SST tube on the first Sunday after CAR T-cell infusion.  This SST tube should be stored refrigerated on the nursing unit until 
Monday morning when it should be processed first thing Monday morning at the latest. 
nDraw 1 SST tube on the morning of CAR T-cell infusion (Day 0). 
oIn addition to the day 0 and 1st Sunday research blood mentioned above, research blood is drawn every Mon-Wed-Fri while the patient 
is inpatient. 
pBaseline Only 
Q Assessment may be performed remotely per PI discretion (outside labs will be accepted and symptoms assessment may be performed 
via telephone)  
r required at baseline, only needed at screening if needed to evaluate disease. 
 
 
 
 


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3.7 
GENE-THERAPY-SPECIFIC FOLLOW-UP 
3.7.1 Clinical Evaluation 
Long-term follow up of patients receiving gene transfer is required by the FDA and must continue 
even after the patient comes off the study. Long-term follow-up for patients who are no longer 
enrolled on this study will be done under a different protocol, 15-C-0141.  Physical examinations 
will be performed and documented annually for 5 years following cell infusion to evaluate long-
term safety.  Physical exams can be performed by other physicians if clinic notes are obtained and 
retained in SB.  A complete blood count should be done at these physician visits for the first 5 
years after infusion.  After 5 years, health status data will be obtained from surviving patients via 
telephone contact or mailed questionnaires for 10 additional years for a total of 15 years after cell 
infusion.  
Testing for persistence of CAR transduced cells 
Persistence of CAR transduced cells will be assessed by quantitative PCR and/or flow cytometry 
at 1, 2, 3, 6 and 12 months after cell infusion or until they are no longer detectable or until a stable 
or decreasing level of CAR T cells is present at least 3 years after infusion.  If any patient shows a 
high level of persistence of CAR gene transduced cells or an increasing population of CAR gene 
transduced T cells at month 6 or later (by FACS staining or qPCR), the previously archived 
samples will be subjected to techniques that would allow the identification of predominant clonal 
populations of transduced cells. 
3.7.2 Replication competent lentivirus (RCL) testing 
Patients’ blood samples will be obtained for analysis for detection of replication competent 
lentiviruses (RCL) by VSV-G-specific PCR prior to cell infusion and at 3, 6, and 12 months post 
cell administration.  If all of these samples are negative for RCL, blood collection for RCL will be 
discontinued after the 12 month time-point.  
In case of detection of replication-competent lentivirus, the following actions will be taken: 
a. Immediately report the finding of RCL to the FDA, the NIH Intramural IRB, the NIH 
Institutional Biosafety Committee, the OSP, and the Indiana University Vector Production 
Facility (where the vector was made). 
b. Repeat the culture-based RCL testing and RCL PCR on the infused cells for the patient 
in question.  Repeat the RCL PCR on the sample that was found to be positive.   
c. Have the patient come to the NIH for a clinic visit.  Perform a complete history and 
physical exam.  Draw blood for a complete blood count with differential, flow cytometry to 
assess T, B, and NK cell numbers in the blood, repeat RCL PCR, perform standard HIV 
screening, repeat PCR to assess for the presence of CAR-expressing T cells in the blood.  
Perform a bone marrow biopsy with flow cytometry, and assess the bone marrow for the 
presence of CAR-expressing T cells. 
d. If no abnormalities requiring intervention are found after evaluating the patient, the 
patient should return monthly for a history, physical, CBC, and repeat RCL PCR tests on 
the blood. 


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3.8 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit:  
• If no CAR-T cells administered at least 30 days after removal from study chemotherapy 
treatment. 
• If CAR-T cells given, the first 60 days after the subject receives the last admistration of 
CAR-T-cells..   
 
3.8.1 Criteria for removal from protocol therapy 
Note that the treatment consists of a conditioning chemotherapy regimen followed by a T-cell 
infusion, so off-treatment criteria mainly apply to eligibility for cancellation of cell infusion for 
toxicity arising during the conditioning chemotherapy.  
Patients will be taken off treatment for the following: 
• The patient no longer meets the eligibility criteria for the protocol after enrolling but before 
start of the chemotherapy conditioning regimen.  If the reason that the patient is not eligible 
can be rapidly resolved within 2 weeks, the patient can proceed on treatment for up to two 
weeks, otherwise the patient must come off treatment and then off study as appropriate.  
An exception to this is that a platelet count of 50,000 or more is considered adequate to 
start chemotherapy.The patient started chemotherapy but cannot complete the entire 
treatment (ending with completed cell infusion) for any reason specified in the protocol or 
PI discretion.  If the reason that the patient is not able to complete treatment can be rapidly 
resolved, the patient can proceed on treatment, otherwise the patient must come off 
treatment and then off study as appropriate. 
• The patient receives any other treatment for their malignancy (including corticosteroids at 
a dose higher than 5 mg/day of prednisone or equivalent) except the planned protocol 
treatment within 3 weeks of the start of the initial protocol treatment or if the patient 
receives any treatment for their malignancy at any time after their initial CAR T-cell 
infusion.  If a patient receives corticosteroids in doses greater than 5 mg/day of prednisone 
or an equivalent dose of another corticosteroid within 2 weeks of the start of chemotherapy 
the treatment will need to be delayed or cancelled. 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment on this study in the judgment of the Principal Investigator. 
• Participant requests to be withdrawn from active therapy 
• Positive pregnancy test 
• Investigator discretion 
 
3.8.2 Off-study Criteria 
• The patient completes the study 
• The patient completes post treatment follow-up 
• The patient voluntarily withdraws 
• There is significant patient noncompliance 
• PI discretion 


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• Death 
• Development of progressive or relapsed malignancy after the CAR T cell infusion in 
patients not desiring or not eligible for re-treatment on this protocol. 
• The patient receives any anti-malignancy therapy after the CAR T-cell infusion. 
• Taking corticosteroids for any reason after CAR T-cell infusion at a dose higher than 5 
mg/day of prednisone or equivalent dose of another corticosteroid ( except to treat CAR T-
cell toxicity). 
• PI decision to end this study  
Note:Patients must be followed until all adverse events possibly, probably or definitely attributable 
to protocol treatment have resolved to grade 2 or less with the exception of lymphopenia and 
alopecia. If an adverse event is not expected to resolve to grade 2 or less this will be noted in the 
patient medical record and the patient will be taken off study. In addition, all patients must be 
followed for the gene therapy specific follow up as outlined in section 3.7 even after being taken 
off-study.  Patients taken off-study will be enrolled on a different protocol specifically to continue 
the FDA-required gene-therapy follow-up (NCI protocol 15-C-0141). 
     
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
ANTIBIOTIC PROPHYLAXIS 
• Patients with a CD4 T-cell count less than 200/µL will be maintained on pneumocystis 
prophylaxis with trimethoprim-sulfamethoxazole 1 double-strength tablet every Monday-
Wednesday-Friday. If patients cannot tolerate trimethoprim sulfamethoxazole, an 
alternative pneumocystis prophylaxis will be used.   PCP prophylaxis will be stopped after 
2 consecutive CD4 counts greater than 200/µL are documented. If ganciclovir, 
valganciclovir, or foscarnet are started, val- acyclovir or acyclovir will generally be 
discontinued. 
• Patients with a CD4 T-cell count less than 200/µL will be maintained on valacyclovir or 
acyclovir.  This prophylaxis will be stopped after 2 consecutive CD4 counts greater than 
200/µL are documented. If ganciclovir, valganciclovir, or foscarnet are started, 
valacyclovir or acyclovir will generally be discontinued. 
• Patients with serum IgG level less than 400 mg/dL will receive intravenous 
immunoglobulin replacement as needed to maintain an IgG level above 400 mg/dL.  An 
example of an intravenous immunoglobulin infusion to be used for this purpose would be 
Gammunex 500 mg/kg given as a single dose.  Intravenous immunoglobulin infusions 
should be preceded by premedication with diphenhydramine and acetaminophen, and rate 
of infusion should be started at low rates and escalated in a step-wise manner. 
• Neutropenic patients will start on broad spectrum antibiotics with a first fever of 38.30 C 
or greater or two fevers of 38.0 separated by at least 1 hour and concomitant ANC < 500/ml.  
• Aminoglycosides will be avoided unless there is clear evidence of sepsis. 
• A CBC with differential will be obtained daily.  If the absolute neutrophil count becomes 
less than 500/microliter, filgrastim will be initiated at a dose of 300 micrograms daily 
subcutaneously for patients under 70 kg in weight and at a dose of 480 micrograms daily 


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for patients over 70 kg and over in weight.  Filgrastim will be given daily and then 
discontinued as soon as the absolute neutrophil count recovers to 1500/microliter. 
4.2 
BLOOD PRODUCT SUPPORT 
• Leukocyte filters will be utilized for all blood and platelet transfusions with the exception 
of the CAR-transduced T cell infusions to decrease sensitization to transfused WBC and 
decrease the risk of CMV infection. 
• Patients who are seronegative for CMV should receive CMV-negative blood products 
whenever possible. 
• Using daily CBC’s as a guide, the patient will receive platelets and packed red blood cells 
(PRBC’s) as needed.  Attempts will be made to keep Hgb >8.0 gm/dl, and platelets 
>12,000/µL.   
• All blood products with the exception of the CAR-transduced T cells will be irradiated.  
4.3 
ANTI-EMETICS 
Anti-emetics will follow NIH Clinical Center Guidelines (except that corticosteroids will be 
avoided).  
4.4 
GRANULOCYTE COLONY-STIMULATING FACTOR 
If the absolute neutrophil count becomes less than 500/microliter, filgrastim will be initiated at a 
dose of 300 micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms 
daily for patients over 70 kg in weight.  Filgrastim will be discontinued as soon as the absolute 
neutrophil count recovers to 1500/microliter. 
4.5 
AVOIDANCE OF CORTICOSTEROIDS 
Patients should not take systemic corticosteroids including prednisone, dexamethasone or any 
other corticosteroid at any dose for any purpose without approval of the Principal Investigator. 
4.6 
GUIDELINES FOR MANAGEMENT OF COMMON ACUTE TOXICITIES THAT OCCUR AFTER 
CAR T CELL INFUSIONS 
Please see section 14.3, Appendix C.  These are guidelines only.  It is understood that treatment 
of these toxicities must be individualized for each patient.  Not following the exact 
recommendations in Section 14.3 is not a protocol deviation. 
4.7 
EMERGENCY TREATMENT FOR PATIENTS NOT ELIGIBLE FOR THE PROTOCOL 
It is allowed to give emergency standard of care anti-malignancy therapy to facilitate transfer of 
patients who become ineligible for the protocol treatment to another medical institution. 
5 
BIOSPECIMEN COLLECTION 
Biospecimen collection on this protocol will consist of blood draws and acquisition of bone 
marrow aspirates and possible biopsies of tumors for research purposes. The amount of blood that 
may be drawn from adult patients for research purposes shall not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight-week period. 


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5.1 
CORRELATIVE STUDIES FOR RESEARCH  
5.1.1 Biospecimen collection before the start of the conditioning chemotherapy: 
• 
Blood will be collected for research purposes.  A total of 12 CPT tubes (8 mL each of 
blood) will be collected prior to initiation of the conditioning chemotherapy regimen. This 
is a total of 96 mL of blood.  This blood can be collected on different days as long as a total 
of 12 CPT tubes are collected prior to the start of the chemotherapy and within 7 days of 
the start of the chemotherapy.  Send to the Surgery Branch Cell Production Facility SB-
CPF, Bldg. 10 3W-3808, Phone: 240-858-3755. 
• 
16 mL of blood will be drawn to obtain serum for research purposes (2 SST tubes, 8 mL 
per tube) within 14 days prior to the start of the chemotherapy.  Send to the Figg lab. 
• 
Specimens will be cryopreserved and assays will be performed retrospectively. 
5.1.2 Biospecimen collection on Day 0 and after CAR T-cell infusion during the required 
hospitalization 
Every Monday, Wednesday, and Friday during hospitalization, starting on the first Monday, 
Wednesday, or Friday after the CAR T-cell infusion and lasting up until 14 days after infusion of 
anti-CD30-CAR-transduced T cells, 56 mL of patient peripheral blood will be obtained (6 CPT 
tubes 8 mL each and 1 SST tube 8 mL).  Also, 1 SST tube (8 mL) will be drawn on the morning 
of CAR cell infusion prior to infusion of CAR T cells. 1 SST tube (8 mL) will be drawn on the 
first Sunday after CAR T-cell infusion.  The 1 SST tube will be sent to Figg lab. The 6 CPT tubes 
sent to Surgery Branch Cell Production Facility SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-
3755. 
5.1.3 Biospecimen collection during outpatient follow-up 
• Patients will return for outpatient follow-up clinic visits 2 weeks, 1 month, 2 months, 3 
months, 4 months, 6 months, 9 months and 12 months after the CAR T-cell infusion. After 
the 12-month follow-up appointment patients will return for follow-up every 6 months up 
until 3 years after treatment.  After 3 years, follow-up will be annual.  The specimens listed 
below will be performed at each outpatient clinic visit during the first year of follow up. 
 6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for 
immunological testing. Send CPT tubes to Surgery Branch Cell Production Facility 
SB-CPF, Bldg. 10 3W-3808, Phone: 240-858-3755.  
 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  The 
SST tubes will be sent to Figg lab. 
NOTE: After 1 year, research blood collected will be reduced to 4 CPT tubes at each visit. 
5.1.4 Immunological Testing 
• T-cell assays: Direct immunological monitoring will consist of quantifying CD3+ T cells 
that express the CAR by quantitative PCR, and/or by flow cytometry.  These assays will 
be performed to measure the persistence and estimate the proliferation of the infused CAR+ 
T cells.  A quantitative PCR assay or a flow cytometry assay will be used to quantitate 
CAR+ T cells at all post-infusion time-points up to at least 2 months after infusion, and 
CAR+ T cell analysis will continue until the CAR+ T cell level drops to undetectable levels 
unless a stable low level of CAR+ T cells is present at more than 3 years after infusion.  


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The absolute number of CAR+ PBMC will be estimated by multiplying the percentage of 
CAR+ PBMC by the absolute number of lymphocytes plus monocytes per microliter of 
blood.  Ex vivo immunological assays might be used to measure the antigen-specific 
functional activity of the CAR+ T cells and will consist of assays such as enzyme-linked 
immunosorbent assays (ELISAs), intracellular cytokine staining, and anti-CD107a 
degranulation assays. Immunological assays will be standardized by the inclusion of pre-
infusion recipient PBMC and in some cases an aliquot of the engineered T cells 
cryopreserved at the time of infusion.  
• Serum cytokine levels will also be measured by enzyme-linked immunosorbent assays 
(ELISAs) or similar assays.              
• Patients’ blood samples will be obtained and saved for analysis for detection of replication 
competent lentiviruses (RCL) by PCR at 3 months, 6 months, and 12 months after cell 
administration.  Infusion cells will be tested for RCL prior to infusion by PCR targeting 
the VSV-G gene. Blood collection for RCL monitoring will be discontinued if all patient 
samples have been negative for RCL at the 12 month time-point . If any post-treatment 
samples are positive, further analysis of the RCL and more extensive patient follow-up will 
be undertaken, in consultation with the FDA. RCL PCR assays are performed by the 
National Gene Vector Laboratory at Indiana University.  The results of these tests are 
maintained by the National Gene Vector Laboratory at Indiana University  and by the 
Surgery Branch (SB) research team. 
• Due to nature of these studies, it is expected that expansion of specific T-cell clones will 
be observed as T-cell proliferate in response to the targeted antigen.  Therefore, care will 
be taken to track T-cell persistence, but presence of an oligoclonal T cell population does 
not indicate an insertional mutagenesis event.    If any patient shows an increasing 
population of CAR gene transduced T cells at month 6 or later (by FACS staining or 
qPCR), the previously archived samples will be subjected to techniques that would allow 
the identification of predominant clonal populations of transduced cells.  Such techniques 
may include T cell cloning or LAM-PCR.  If a predominant or monoclonal T cell clone 
derived from CAR gene transduced cells is identified during the follow-up, the integration 
site and sequence will be identified and subsequently analyzed against human genome 
database to determine whether the sequences are associated with any known human 
cancers.  If a predominant integration site is observed, the T cell cloning or LAM-PCR test 
will be used at an interval of no more than three months after the first observation to see if 
the clone persists or is transient.  In all instances where monoclonality is persistent and 
particularly in instances where there is expansion of the clone, regardless of whether or not 
the sequence is known to be associated with a known human cancer, the subject should be 
monitored closely for signs of malignancy, so that treatment, if available, may be initiated 
early. 
5.1.5 Additional biopsies and additional blood draws 
Patients might be asked to undergo biopsies (up to 3) or additional blood draws for research 
purposes. Additional blood draws might be necessary to investigate T cell responses and serum 
cytokine levels in cases of clinical events such as rapid regressions of malignancy or toxicity. 
Biopsies including open surgical biopsies, fine needle aspirations, and core needle biopsies could 
be used to investigate CAR T-cell persistence or function at tumor sites. Open surgical, fine needle, 
or core needle biopsies might also be needed in some but not all patients to confirm continued 


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antigen expression by tumor cells in order to meet protocol eligibility requirements for antigen 
expression on the tumor cells before any CAR T-cell infusion.  For core needle biopsies 2 to 4 
cores will be obtained. For fine needle aspirations, 1 to 3 aspirations will be performed.  Standard 
techniques will be used for biopsies which may include CT and/or ultrasound guided 
biopsy.  These research biopsies or blood draws are optional and patients can participate in this 
trial whether or not they agree to undergo biopsies for research purposes unless the biopsies are 
needed to prove that the target antigen is expressed on the tumor for protocol eligibility..  These 
biopsies will only be performed if minimal morbidity is expected based on the procedure 
performed and the granulocyte and platelet count.  Biopsy tissue will be processed in the NCI 
Laboratory of Pathology. Studies will be performed to evaluate the antigen expression by the tumor 
and to evaluate the presence of transduced cells. Remainder material from any clinical biopsies 
obtained may also be utilized for research purposes. 
5.1.6 Future studies  
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study. However, this 
research may only be done if prospective IRB approval is obtained or the project is determined to 
not be human subjects research.  Patient PBMC not needed for future clinical use can be used for 
experiments aimed at developing new T-cell therapies not directly related to individual patients 
with permission of the PI.  If new risks are associated with the research (e.g. analysis of germ line 
genetic mutations) a protocol amendment will be required and informed consent will be obtained 
from all research subjects to whom these new studies and risks pertain.  
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.2.1 Samples Sent to Figg Lab 
• Venous blood samples will be collected in either a 4-mL or an 8-mL SST tube to be 
processed for serum and stored for future research. 
o Record the date and exact time of draw on the tube. Blood tubes may be kept in the 
refrigerator until pick-up.  
o For sample pick-up, page 102-11964. 
o For immediate help, call 240-760-6180 (main Blood Processing Core number) or, if 
no answer, 240-760-6190 (main clinical pharmacology lab number). 
o For questions regarding sample processing, contact the Blood Processing Core 
(BPC) at NCIBloodcore@mail.nih.gov or 240-760-6180. 
o The samples will be processed, barcoded, and stored in the Figg lab until requested 
by the investigator. 
After delivery to the SB-CPF, peripheral blood mononuclear cell samples will be sent to the 
Head, Clinical Support Laboratory Clinical Services Program, Applied/Developmental 


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Directorate Frederick National Laboratory for Cancer Research for processing and 
cryopreservation. They will be stored long-term at the NCI Frederick Repository. 
5.2.2 Sample Storage, Tracking and Disposition 
 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All 
samples will be sent to Blood Processing Core (BPC) and/or SB-CPF for processing and/or and 
storage until they are distributed to the designated place of analysis as described in the protocol. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required.  
5.2.2.1 Samples Managed by Dr. Figg’s Blood Processing Core (BPC)  
5.2.2.1.1 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) (Dr. Figg’s lab) will be barcoded, with data 
entered and stored in the Labmatrix utilized by the BPC. This is a secure program, with access to 
Labmatrix  limited to defined Figg lab personnel, who are issued individual user accounts. 
Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).  
5.2.2.1.2 Sample Storage and Destruction  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB-approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.  


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Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed or returned to the patient, if so requested. The PI will record any loss or 
unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 7.2. 
Sample bar-codes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrixr. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.  
5.2.3 Sample Storage, Tracking, and Disposition for Surgery Branch 
Samples received by the Surgery Branch research lab will be tracked using password protected 
web-based NCI database Labmatrix. All specimens will be tracked for date of receipt in the 
Surgery Branch lab, date analyzed, date returned to the originating hospital and/or date 
destroyed. Specimens will be stored in a locked laboratory cabinet or refrigerators in a locked 
research lab. All specimens will be entered into Labmatrix with identification and storage 
location. Access to the stored specimens will be restricted. Access to Labmatrix will be granted 
upon PI approval only. It is the responsibility of the NCI PI to ensure that the specimens are 
being used and stored in a manner consistent with IRB approval. All samples are stored in 
monitored freezers/refrigerators in 3NW NCI-SB laboratories at specified temperatures with 
alarm systems in place. 
5.2.4 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol.  
If the patient withdraws consent, the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2. 


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6 
DATA COLLECTION AND EVALUATION 
6.1 
DATA COLLECTION 
Data obtained on the study will be stored in real time into the Cancer Center Clinical Data System 
database (NCI C3D database) .It is expected that clinical data be entered into C3D no later than 
after 10 business days of the occurrence. The medical record will maintain complete records on 
each patient including any pertinent supplementary information obtained from outside 
laboratories, outside hospitals, radiology reports, laboratory reports, or other patient records. The 
medical record will serve as the primary source from which all research analyses will be 
performed.  Data collection will include the eligibility criteria checklist, patient history, specialty 
forms for pathology, radiology, toxicity monitoring, and relapse data and an off-study summary 
sheet, including a final assessment by the treating physician. After patients are seen in clinic at 
each scheduled follow up, the database will be updated in real-time. 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be kept 
in secure network drives or in approved alternative sites that comply with NIH security standards. 
Primary and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant. 
6.1.1 Adverse event recording: 
• Grade 1 adverse events will not be captured in the database. 
• All grade 2, 3, 4, and 5 adverse events will be recorded regardless of attribution. 
• All adverse events are recorded in the medical record.  
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for: 
• If no CAR-T cells administered, document AEs from the first study intervention, Study 
Day 1, through the end of treatment. Beyond 30 days after the last intervention, only 
adverse events which are serious and related to the study intervention need to be recorded  
• If CAR-T cells given, document AEs from the first study intervention, Study Day 1, 
through the end of treatment. Beyond 60 days after the last intervention, only adverse 
events which are serious and related to the study intervention need to be recorded.   
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
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• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
 
End of study procedures: Data will be stored according to HHS, FDA and NIH Intramural 
Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked data in an NIH-funded or approved public repository.   
_X_ Coded, linked data in BTRIS  
 
How and where will the data be shared?  
Data will be shared through: 
_X_ An NIH-funded or approved public repository.  Insert name or names:_clinical trials.gov. 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_X_ Publication and/or public presentations. 
When will the data be shared? 
_X_ Before publication. 
_X_ At the time of publication or shortly thereafter. 
6.3 
RESPONSE CRITERIA 
6.3.1 Response Criteria for Lymphoma 
Note: Do not evaluate for response until at least 4 weeks after cell infusion  
(Cheson et al. Revised Response Criteria for Malignant Lymphoma, Journal of Clinical Oncology 
2007 182 and Recommendations for Initial Evaluation, Staging, and Response Assessment of Non-
Hodgkin Lymphoma: The Lugano Classification Journal of Clinical Oncology, 2014183) 
 
6.3.1.1 Complete Remission (CR):  
CR requires all of the following:   Complete disappearance of all detectable clinical          evidence 
of disease and disease-related symptoms if present before therapy.  Regardless of FDG-avidity, if 


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all extranodal masses and lymph nodes are less than 1.0 cm or less in longest diameter, the patient 
is considered to be in CR.  
 
1. In typically FDG-avid lymphoma (diffuse large B cell lymphoma, and T cell lymphomas): 
in patients with no pretreatment PET scan or when the PET scan was positive before 
therapy, a post-treatment residual mass of  any size is permitted as long as it is PET 
negative. 
   
2. Variably FDG-avid lymphomas/FDG avidity unknown:  in patients without a pretreatment   
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed to normal size (≤ 1.5 cm in greatest diameter if > 1.5 cm before 
therapy).  Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more 
than 1 cm in their short axis before treatment must have decreased to ≤ 1.0 cm in their 
short axis after treatment.  
 
3. The spleen and/or liver, if considered to be enlarged before therapy on basis of            
Physical exam or CT scan must be normal size on CT scan for FDG-negative lymphoma.If 
FDG-avid lesions were present in the spleen or liver before treatment, these FDG-avid 
Lesions must have resolved. 
 
4. A bone marrow aspirate and biopsy is performed only when the patient had bone marrow 
involvement with lymphoma prior to therapy or if new abnormalities in the peripheral 
blood counts or blood smear cause clinical suspicion of bone marrow  involvement with 
lymphoma after treatment.  The bone marrow aspirate and biopsy must show no evidence 
of disease by morphology or if indeterminate by morphology it must be negative by 
immunohistochemistry.   
  
6.3.1.2 Partial Remission (PR): PR requires all of the following: 
1. ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses.  Dominant nodes or nodal masses should be clearly 
measurable in at least 2 perpendicular dimensions, should be from different regions of the 
body if possible and should include mediastinal and retroperitoneal nodes if possible.   
2. No increase in size of nodes, liver or spleen and no new sites of disease.   
3. If multiple splenic and hepatic nodules are present, they must regress by ≥ 50% in the 
SPD.  There must be a > 50% decrease in the greatest transverse diameter for single 
nodules.    
4. Bone marrow is irrelevant for determination of a PR.  If patient has persistent bone marrow 
involvement and otherwise meets criteria for CR the patient will be considered a PR. 
5. Typically FDG-avid lymphoma:  for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET scan should be positive in at 
least one previously involved site.   
 


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6.3.1.3 Progressive Disease (PD):  Defined by at least one of the following:   
1. ≥ 50% increase from nadir in the sum of the products of at least two lymph nodes, or if a 
single node is involved at least a 50% increase in the product of the diameters of this one 
node.   
2. Appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are 
decreasing in size 
3. Greater than or equal to a 50% increase in size of splenic or hepatic nodules  
4. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis.  
5. Lesions should be PET positive in typically FDG-avid lymphomas unless the lesion is too 
small to be detected by PET (<1.5 cm in its long axis by CT) 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.  PET should be positive in typically FDG-avid 
lymphomas. 
1. Flow cytometric, molecular or cytogenetic studies will not be used to determine 
response. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting 
with the exception of cytokine release syndrome (CRS), which will be graded according to the 
CRS grading scale of Lee et al.184.  All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
web site (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50).  
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  


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7.3 
NCI CLINICAL DIRECTOR (CD) REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.   
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify  IBC of any unexpected fatal or life-threatening 
experience associated with the use of the study agent as soon as possible but in no event later than 
7 calendar days of initial receipt of the information.  Serious adverse  events that are unexpected 
and associated with the use of the study agent, but are not fatal or life-threatening, must be reported 
to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator’s 
initial receipt of the information.  Adverse events may be reported by using the FDA Form 3500a. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below.  Alternatively, the IRB 
continuing review report can be sent to IBC in lieu of a separate report.  Please include the IBC 
protocol number on the report. 
7.4.2.1 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information:  
• the title and purpose of the trial  
• clinical site 
• the Principal Investigator 
• clinical protocol identifiers  
• participant population (such as disease indication and general age group, e.g., adult or 
pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  


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• if the trial has been completed, a brief description of any study results.  
7.4.2.2 Progress Report and Data Analysis  
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• a summary of all serious adverse events submitted during the past year 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
• if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death 
• a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability.  
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet weekly on a regular basis when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator. Events 
meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within 
the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 Safety Monitoring Committee (SMC) 
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial review 
will occur as soon as possible after the annual IRB continuing review date.   Subsequently, each 
protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more 
frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not 
be reviewed if there is no accrual within the review period. Written outcome letters will be 
generated in response to the monitoring activities and submitted to the Principal investigator and 
Clinical Director or Deputy Clinical Director, CCR, NCI. 


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8 
SPONSOR PROTOCOL/ SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 


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8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All  serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets a protocol-defined serious criterion or meets the definition of Adverse Event 
of Special Interest that require expedited reporting must be submitted immediately (within 24 
hours of awareness) to OSRO Safety using the CCR SAE report form. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 


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instructions 
can 
be 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842  
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
REPORTING PREGNANCY  
8.4.1 Maternal exposure 
If a patient becomes pregnant during the study, the study treatment should be discontinued 
immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the 
Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours 
of when the outcome of the Pregnancy become known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
8.4.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 4 
months after the last dose of receiving protocol treatment. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until (120 days) after the last dose 
should, if possible, be followed up and documented. 
8.5 REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 


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• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
10 STATISTICAL CONSIDERATIONS   
The primary endpoint of this trial is to determine the safety of administering CAR-expressing T 
cells to patients with malignancies.  Secondary objectives of this trial are to measure any anti-
malignancy effect that might occur, to assess the feasibility of administering CAR-expressing T 
cells,  and to measure persistence and function of CAR-expressing T cells.  The study will be 
conducted using a standard 3+3 approach as defined in section 3.1. 
Patients will be enrolled on a 2 different cohorts:  Cohort 1:  Patients who have not had an 
allogeneic hematopoietic stem cell transplant (allo HSCT) and Cohort 2:  Patients who have had 
a 9/10 or 10/10 HLA-matched sibling or an 9/10 or 10/10-matched unrelated donor transplant.  
Each cohort will have a separate but identical dose-escalation scheme.  The dose escalation 
schemes are separate because of the possibility of greater toxicity in the patients who have 
undergone prior alloHSCT.  DLTs occurring on one cohort’s dose escalation will not affect dose 
escalation of the other cohort.   
The trial will be conducted as 2 different dose escalation schemes, one for Cohort 1 (non-
alloHSCT) and Cohort 2 (alloHSCT recipients).  For each cohort, a dose escalation scheme with 
up to 5 dose levels and up to 6 patients per dose level will be carried out. (There will be an 
additional 3 patients in Cohort 1 Dose Level 3 who received the lower chemotherapy dose before 
Amendment E, Protocol version: 08/03/2018) In addition, up to 8 additional patients can be treated 
at the MTD for each cohort to establish additional safety and toxicity data at that level. Thus, up 
to 79 patients may be enrolled onto the trial. 
The fraction of post-allogeneic transplant patients experiencing Grade 3 or 4 toxicities will be 
compared to the fraction of patients who never had an allogeneic transplant experiencing Grade 3 
or 4 toxicities by using a Fisher’s exact test. 
The degree of persistence of CAR-transduced T cells will be evaluated by a quantitative measure 
(flow cytometry or quantitative PCR) in all patients.  Anti-malignancy effects will be measured by 
clinical response and categorized according to Section 6.3. The clinical responses will be 
interpreted cautiously in the context of a pilot study which may be used to guide parameters for 
study in future protocols if warranted. 
All other evaluations of secondary objectives will be performed using exploratory techniques. No 
formal adjustment for multiple comparisons will be used since the evaluations are being done to 
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It is anticipated that 5 years will be required to enroll up to a maximum of 79 patients onto this 
trial. 
11 HUMAN SUBJECTS PROTECTIONS  
11.1 RATIONALE FOR SUBJECT SELECTION 
The patients to be entered in this protocol have advanced hematologic malignancies that are almost 
always incurable diseases.  These patients have limited life expectancies.  Subjects from both 
genders and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria.  
To date, there is no information that suggests that differences in disease response would be 
expected in one group compared to another.  Efforts will be made to extend accrual to a 
representative population, but in this preliminary study, a balance must be struck between patient 
safety considerations and limitations on the number of individuals exposed to potentially toxic 
and/or ineffective treatments on the one hand and the need to explore gender and ethnic aspects of 
clinical research on the other hand.  If differences in outcome that correlate to gender or to ethnic 
identity are noted, accrual may be expanded or a follow-up study may be written to investigate 
those differences more fully. 
11.2 PARTICIPATION/SELECTION RATIONALE 
• The eligibility criteria for this protocol only allow enrollment of patients with advanced 
malignancies that are usually incurable despite recent advances in standard therapies. 
• Patients with treatment options with proven efficacy and limited toxicity will not be 
enrolled. 
• Improving the treatment of advanced hematologic malignancies is an important area of 
clinical research. 
• In previous studies, anti-CD19 CAR T cells have demonstrated dramatic activity against 
B-cell lymphoma and B-cell leukemia. Many patients have obtained remissions lasting 
more than 2 years on multiple clinical trials of anti-CD19 CAR T cells.  Some of these 
studies were clinical trials conducted by the Principal Investigator of this trial, and some 
patients treated on the Principal Investigator’s prior trials have been in complete remission 
for over 3 years.  The success of anti-CD19 CAR T cells against B-cell lymphomas 
provides a rationale for developing an anti-CD30 CAR for treating CD30+ lymphomas. 
• Because patients on previous trials of CAR T cells have experienced hypotension, 
tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function, 
participation in this trial clearly carries significant risk.  In many patients on prior CAR 
trials, toxicities were severe enough to require intensive care unit admission. We will limit 
enrollment to patients 73 years of age or less because based on our admittedly limited 
experience with prior CAR-T cell clinical trials, younger patients tolerate and recover from 
these toxicities better than elderly patients. 
11.3 PARTICIPATION OF CHILDREN 
Children will not be enrolled on this study, since the efficacy of this experimental procedure is 
unknown, it does not seem reasonable to expose children to this risk without further evidence of 
benefit.   


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11.4 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 11.5), all patients subjects ≥ age 18 will be offered the opportunity 
to fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability 
to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent 
assessment of whether an individual has the capacity to provide consent; assistance in identifying 
and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to 
appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed.  
11.5 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The experimental treatment has a chance to provide clinical benefit although it is quite possible 
that patients will obtain no clinical benefit.  A goal of this study is to improve upon the number of 
patients who may benefit from adoptive cell therapy by using genetically-modified T-cells, 
specifically CAR T cells.  The risks of the study fall into 6 general categories (see section 12 for 
details).  First, chemotherapy that could cause cytopenias is part of the protocol.  As with any 
chemotherapy that causes neutropenia and thrombocytopenia, this chemotherapy could cause 
toxicities such as infections and bleeding. The second category of toxicity is cytokine-release type 
toxicities such as high fevers, hypotension, and fever.  A third area of toxicity is neurological 
toxicity such as delirium, obtundation, myoclonus, seizures, headache, and transient focal 
neurological toxicities including aphasia and focal paresis.  Cytokine-release-type toxicities and 
neurological toxicities have appeared in other clinical trials of CAR T cells during the first 2 weeks 
after CAR T cells were infused.122,158  The 4th main category of toxicity is direct damage to normal 
tissues by the CAR T cells.  This could happen because of unexpected cross-reactivity of the anti-
CD30 CAR with proteins other than CD30 in vivo. A 5th category of toxicity caused by anti-CD30 
CAR T cells is impairment of normal immunity because CD30 is expressed on activated T cells 
and activated B cells. A 6th possible toxicity is gene-therapy-related toxicity caused by the 
lentiviral vector.  The lentiviral vector used in this trial inserts into the T-cell DNA of patients, so 
in theory, insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any 
of the hundreds of patients treated with mature T cells that were genetically modified by 
gammaretroviral or lentiviral vectors.125-127 
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site.  
The success of this clinical trial cannot be predicted at this time.  Because all patients in this 
protocol have advanced hematologic malignancies and limited life expectancies, the potential 
benefit is thought to outweigh the potential risks.  It is also anticipated that this study will provide 
scientific information relevant to tumor immunotherapy.  


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11.5.1 Risks of exposure to Ionizing Radiation 
The procedures for performing the CT scans will follow clinical policies, no special procedures 
apply to these additional assessments for research purposes.  In summary, subjects may receive 
additional radiation exposure from up to eight (8) CT neck +CAP , three (3) CT-Guided biopsies 
and eight (8)18FDG-PET/CT scans in the first year of the study. 
The total additional radiation dose for research purposes will be approximately 22.4 rem in the 
first year of the study. This amount is more than would be expected from everyday background 
radiation. Being exposed to too much radiation can cause harmful side effects such as an increase 
in the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 2.2 out 
of 100 (2.2%) and of getting a fatal cancer is 1.1 out of 100 (1.1%). 
11.5.2 Risks of Scans and Contrast 
If contrast dye is used, there is a small chance of developing an allergic reaction from the contrast 
material, which may cause symptoms ranging from mild itching or a rash to severe difficulty 
breathing, shock or rarely, death.  The contrast material may also cause kidney problems. Common 
reactions include pain in the vein where the contrast was given, a metallic or bitter taste in the 
mouth , headache, nausea and a warm or flushing feeling that lasts from 1-3 minutes.  
An IV line may need to be inserted for administration of the contrast agent or anesthetic, which 
may cause pain at the site where the IV is placed and there is a small risk of bruising or infection 
11.5.3 Risks of blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
11.5.4 Risks of Bone marrow aspiration and biopsy 
Side effect of  bone marrow aspiration and biopsy may feel a pressure sensation when the needle 
is being inserted and a pulling sensation and brief pain as the marrow is withdrawn. Potential 
complications of this procedure are local bleeding, pain at the site, and infection. Both of these 
are very rare. Bleeding can be stopped by applying local pressure and an infection can be treated 
with antibiotics. 
11.5.5 Risks of Intravenous Catheter 
Side effect of placing some catheters include pain, bleeding, infection and rarely, collapsed lung.  
The long- term risks of the catheter rarely include infection and clotting of veins.   
11.5.6 Risks of Lumbar Puncture 
Side effect of lumbar puncture may cause pain at the site where the needle goes in and the spinal 
fluid is taken.  There is a small risk of infection or bleeding. A third or fewer patients may 
experience some headache while the body replaces the fluid that is removed. 
11.5.7 Risks of Apheresis 
The risks of apheresis are similar to whole blood donation and include pain and bruising at the 
needle insertion site in the arms, lightheadedness, dizziness, nausea, and rarely fainting due to a 
rare reflex reaction to needle placement and to the temporary decrease in blood volume during 
apheresis.  It may also feel tingling around your mouth or in your fingers caused by a blood 
thinner given during the procedure.  The tingling may reduce by giving calcium containing 


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chewable antacid.  All the symptoms usually go away within a few minutes of stopping the 
procedure.    
11.6 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] if participant is an adult unable to consent) for review 
prior to consenting.  A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior 
to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed. 
Consent for the optional biopsies performed on this study will be obtained at the time of the 
procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented in 
the medical record and in the research record 
12 PHARMACEUTICAL INFORMATION   
Note: The commercial drugs used in this study will not alter labelling of the FDA approved drugs 
and nor does the investigation involve a route of administration or dosage level in use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of the drug product. 
12.1 LENTIVIRAL VECTOR CONTAINING THE ANTI-CD30 CAR GENE  
12.1.1 Cells manufacturing 
The lentiviral vector (LSIN-5F11-28Z) encoding a chimeric antigen receptor (CAR) directed 
against CD30 was prepared and preserved following cGMP conditions in the Indiana University 
Vector Production Facility. This self-inactivating 3rd generation lentiviral vector includes the 
murine stem cell virus promoter, and a truncated version of the woodchuck post-transcriptional 
regulatory element (WPRE) designated oPRE.185  The anti-CD30 CAR protein encoded by this 
vector contains a signal peptide from human CD8-alpha, 5F11 fully-human antibody light chain 
variable region (5F11 VL), linker peptide, 5F11 fully-human antibody heavy chain variable region 
(5F11 VH), human CD28 hinge, transmembrane, and cytoplasmic regions and the CD3-zeta 
(cytoplasmic region) T-cell activation domain.    
The vector will be stored at –80° C in the Dept. of Transfusion Medicine, Clinical Center NIH.  
Both storage facilities are equipped with around-the-clock temperature monitoring. Vector will be 


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used in in vitro transductions of T cells. There will be no re-use of the same unit of supernatant for 
different patients.  Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-
2).   The specific guidelines for Biosafety Level-2 (BSL-2) 
can be viewed at 
http://bmbl.od.nih.gov/sect3bsl2.htm  
12.1.2 Toxicities 
Please refer to section 1.2.16 
12.1.3 Administration procedures:  
Please see section 3.4.4 
12.2 COMMERCIAL AGENTS: 
Please refer to the US approved package insert for the full prescribing information here: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails 
12.2.1 Cyclophosphamide 
12.2.1.1 Source 
Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from 
commercial sources. 
12.2.1.2 Administration procedures 
The cyclophosphamide used in this regimen will be given as Intravenous infusion over 60 minutes.  
12.2.2 FLUDARABINE 
12.2.2.1 Source  
Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department 
from commercial sources. 
12.2.2.2 Administration procedures 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration. Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium chloride, 
USP over 15 to 30 minutes.  The doses will be based on body surface area (BSA).    
 
 


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14 APPENDICES 
14.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale* 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 


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14.2 APPENDIX B: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL  
All of the following elements will be recorded in the C3D database: 
 
A. Patient Enrollment 
 
• Date of birth, age, gender, race, ethnicity 
• Height 
• Weight 
• Performance Status 
• Date of original diagnosis 
• Stage at diagnosis 
 
• Tumor Histology and date of confirmation 
• CD30 expression by tumor type of tissue studied and date of confirmation 
• Date of Informed Consent signature, consent version and date of registration 
• Baseline History/Physical 
• Baseline Symptoms  
• Number of prior lines of therapy 
• Findings of consultations done at screening 
 
B. Study Drug administration and response for each course of therapy given 
• Dates anti-CD30-CAR-transduced T cells given 
• Dose level, actual dose, schedule and route given 
• Height, weight, and body surface area at start of each course (a course is defined as 
chemotherapy followed by a CAR T-cell infusion) 
• Response assessment for each restaging performed 
• Concomitant medications will not be collected in C3D 
         
C. Laboratory and Diagnostic Test Data 
 
•  All Clinical laboratory and diagnostic test results done at screening and until day 30 
post infusion with the following exceptions:Diagnostic tests which are not specified in 
the protocol, and if the results are not needed to document the start or end of an adverse 
event that requires reporting. Serologies-CMV, HSV, EBV, toxoplasmosis, adenovirus 
(patient and donor)TTV data  
• All staging studies including CT scan, PET scan results and bone marrow biopsy and 
peripheral blood flow cytometry results will be reported at the scheduled follow-up 
points at 1 months and 2 months after infusion; after 2 months only the overall 
malignancy status (CR, PR, stable disease, progression) will be reported.   
D. Adverse Events 
Please see section 6.1.1 Adverse Event Reporting 
E.  Tumor response and measurements 


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• Restaging studies performed at protocol specified time points and as clinically 
indicated. 
• Any physical exam finding before 1 month after the infusion will not be collected in 
C3D, only labs and Adverse Events. 
• Years 5-15 follow-up is only for survival. 
 
F.   Off study 
• Date and reason for off study 
• Date and cause of death 
• Autopsy findings 
 
 
 
 
 


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14.3 APPENDIX C:  GUIDELINES FOR MANAGEMENT OF COMMON TOXICITIES THAT OCCUR 
AFTER CAR T-CELL INFUSIONS 
 
Infusions of CAR T cells are often complicated by significant acute toxicities in the first 2 to 3 
weeks after the infusion.  In many cases the toxicities correlate with serum inflammatory cytokine 
levels.122 
The toxicities most often experienced by patients receiving infusions of CAR T cells include, but 
are not limited to, tumor lysis syndrome, fever, fatigue, hypotension, tachycardia, acute renal 
failure, and neurological toxicities such as aphasia, ataxia, headache, somnolence, and coma.  
Fever is usually the first toxicity to occur.   
Note these are guidelines that might require modification based on clinical circumstances of each 
patient, and failure to exactly follow these guidelines is not a protocol deviation or violation. 
Administration of corticosteroids should be avoided if at all possible to avoid killing or impairing 
the function of the CAR T cells. 
General Supportive Care Guidelines: 
1. All patients with significant malignancy burdens and without a contradiction such as 
allergy should be started on allopurinol at the time of the start of the chemotherapy 
conditioning regimen or 1 day before the CAR T cell infusion.  The suggested allopurinol 
dose is 200 to 300 mg/day with a possible loading dose of 300 to 400 mg.  
2. Vital signs should be checked a minimum of every 4 hours during hospitalization.  
Increasing the time interval between vital sign checks for patient convenience or other 
reasons should be avoided. 
3. Strict ins and outs should be recorded on all patients. 
4. As a minimum, keep hemoglobin greater than 8.0 g/dL and platelets greater than 
20K/microliter. 
5. Administer fresh frozen plasma (FFP) for a PTT 1.5-fold or more above the upper limit of 
normal. 
6. For patients with an increased PTT, check the fibrinogen level and keep the fibrinogen 
level above 100 mg/dL with cryoprecipitate. 
7. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and 
corticosteroids should be avoided. 
8. Patients with a heart rate persistently higher than 115/minute and fever should have vital 
signs checked every 2 hours. 
9. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics. 
10. Avoid meperidine due to seizure risk. 
11. Minimize benzodiazepine use to avoid aggravating delirium. 
12. Patients on this protocol will be placed on strict fall precautions including instructions to 
get out of bed only with assistance under the following conditions: 
1) Any history of syncope or near-syncope within 1 month before CAR T-cell infusion 
or any time after CAR T-cell infusion. 


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2) Any blood pressure reading of less than 100 mm Hg systolic blood pressure after 
anti-CD19 CAR T-cell infusion if 100 mm Hg is lower than the patients baseline 
systolic blood pressure. 
3) Heart rate greater than 100 beats per minute. 
13. Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood 
pressure and heart rate checked and receive intravenous fluids as appropriate.  These 
patients will also receive an ECG. 
14. A CBC will be obtained twice daily while the patient is inpatient.  If the absolute neutrophil 
count becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 
micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms daily 
for patients over 70 kg in weight only in patients with absolute neutrophil counts less than 
500/microliter.  Filgrastim will be discontinued as soon as the absolute neutrophil count 
recovers to 2000/microliter. 
15. Hypotension is a common toxicity requiring intensive care unit (ICU) admission.  In 
general patients should be kept well-hydrated.  Maintenance I.V. fluids (normal saline (NS) 
should be started on most patients with high fevers especially if oral intake is poor or the 
patient has tachycardia.  I.V. fluids are not necessary for patients with good oral intake and 
mild fevers.  For patients who are not having hypotension or tumor lysis syndrome, a 
generally even fluid balance should be strived for after allowing for insensible fluid losses 
in patients with high fevers.  The baseline systolic blood pressure is defined for this 
protocol as the average of all systolic blood pressure readings obtained during the 24 hours 
prior to the CAR T-cell infusion.  The first treatment for hypotension is administration of 
IV NS boluses.   
• Patients with a systolic blood pressure that is less than 80% of their baseline blood 
pressure and less than 100 mm Hg should receive a 1 L NS bolus.  
•  Patients with a systolic blood pressure less than 90 mm Hg should receive a 1 L 
NS bolus regardless of baseline blood pressure.  
These I.V. fluid management suggestions may need to be modified based on the 
clinical characteristics of individual patients such as pulmonary status, cardiac 
function, edema and other factors. 
16. Patients receiving more than 1 fluid bolus for hypotension should have a stat EKG and 
troponin, and a cardiac echocardiogram as soon as possible. 
ICU Transfer 
Patients should be transferred to the ICU under these circumstances.  Patients not meeting these 
criteria could also require ICU admission at the discretion of the clinical team caring for the patient.  
• Systolic blood pressure less than 75% the patient’s baseline blood pressure and less 
than 100 mm Hg after administration of a 1L NS bolus. 
• Anytime the systolic blood pressure is less than 90 mm Hg after a 1L NS bolus if 90 
mm Hg is less than the patient’s baseline systolic blood pressure. 
• Continuous tachycardia with a heart rate higher than 125 beats per minute on at least 
2 occasions separated by 2 hours. 
• Oxygen requirement of more than a 4L standard nasal cannula 
 


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1. All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG 
and a cardiac echocardiogram within 6 hours of the time of transfer. 
2. Patients with hypotension not responding to IV fluid resuscitation should be started on 
norepinephrine at doses called for by standard ICU guidelines. 
3. Patients should have a cardiac echocardiogram and an EKG within 6 hours of starting 
norepinephrine. 
4. Patients in the ICU should get twice-daily labs (CBC with differential, acute care panel, 
mineral panel, hepatic panel, uric acid, LDH).  Patients in the ICU should also get a daily 
troponin level.  
5. Patients receiving vasopressors should have a cardiac echocardiogram at least every other 
day. 
Immunosuppressive drug administration 
In general, immunosuppressive drugs are administered in a stepwise escalation based on 
toxicity severity.  The first immunosuppressive drug administered is usually tocilizumab.  If 
toxicity does not improve after tocilizumab,  treatment progresses to  intermediate-dose or 
high-dose methylprednisolone.  For certain severe toxicities listed below, high-dose 
methylprednisolone must be given immediately.  
Tocilizumab administration 
Tocilizumab should be administered under the following circumstances if the listed disorders 
are thought to be due to cytokine release from CAR T cells.  Tocilizumab is administered at 
a dose of 8 mg/kg infused IV over 1 hour (dose should not exceed 800 mg). 
• Left ventricular ejection fraction less than 45% by echocardiogram 
• Creatinine greater than 2-fold higher than the most recent level prior to CAR T-cell 
infusion 
• Norepinephrine requirement at a dose greater than 3 micrograms/minute for 36 
hours since the first administration of norepinephrine. 
• Requirement of more than 5 mcg/minute of norepinephrine to maintain systolic 
blood pressure greater than 90 mm Hg 
• Oxygen requirement 40% or greater fraction of inspired oxygen (FIO2) for maintain 
oxygen saturation of >92%. 
• Subjective significant dyspnea and respiratory rate greater than 25 for 2 hours or 
more. 
• PTT or INR>2x upper limit of normal 
• Bleeding possibly related to cytokine-release syndrome 
• Creatine kinase greater than 5x upper limit of normal 
Intermediate-dose methylprednisolone for toxicities not responsive to 
tocilizumab 
1.  Give methylprednisolone 50 mg every 6 hours for any of the toxicities under #19 above that 
don’t improve after tocilizumab administration.  
 


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High-dose methylprednisolone should be given immediately under these 
circumstances:  
1. Give methylprednisolone 200 mg every 6 hours for systolic blood pressure that is less than 
90 mm Hg while the patient is on 15 mcg/minute or higher doses of norepinephrine. If the 
patient has not had tocilizumab, give 8 mg/kg of tocilizumab along with the 
methylprednisolone.   
2. Give methylprednisolone 200 mg every 6 hours for hypotension requiring 15 mcg/minute or 
more of norepinephrine continuously for 8 hours or more.  If the patient has not already had 
tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone. 
3. Give methylprednisolone 200 mg every 6 hours for any left ventricular ejection fraction 30% 
or less.  If the patient has not already had tocilizumab, administer 8 mg/kg tocilizumab in 
addition to methylprednisolone. 
4.  Give methylprednisolone 200 mg every 6 hours for any situation in which pulmonary toxicity   
makes mechanical ventilation likely to be required within 4 hours.  If the patient has not had 
tocilizumab, administer 8 mg/kg tocilizumab in addition to methylprednisolone. 
5. In life-threating toxicity not improving after 200 mg of methylprednisolone, 1000 mg of 
methylprednisolone can be administered. 
 
In general, stop corticosteroid use when toxicity improves to a tolerable level.  For example, 
in patients with hypotension, stop methylprednisolone  6 to 12 hours after vasopressors are 
no longer needed. 
 
Neurological toxicity 
1. All patients with neurological toxicities other than somnolence and delirium should get a 
neurology consult. 
2. All patients with significant neurological toxicity should get an MRI of the brain. 
3. All patients with significant neurological toxicity should get a lumbar puncture after MRI if 
it is safe to perform a lumbar puncture. 
4. The following patients should receive dexamethasone 10 mg intravenously every 6 hours until 
the toxicities improve.  Note:  for seizures administer standard seizure therapies in addition to 
dexamethasone.  For patients already getting higher doses of corticosteroids for CAR-related 
toxicity, it is not necessary to add dexamethasone 10 mg every 6 hours. Stop dexamethasone 
as soon as toxicity improves to a tolerable level; the duration of dexamethasone use will need 
to be determined on a patient to patient basis. Tocilizumab is possibly not effective for 
neurological toxicity, so it should not be given when patients have isolated neurological 
toxicity. 
1. Inability of patient to follow simple commands such as “squeeze my 
fingers”. 
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3. Somnolence severe enough to potentially limit airway protection 
4. Ataxia severe enough to preclude ambulation 
5. Disorientation to person or place that persists longer than 48 hours 
6. Neurologic toxicity lasting more than 2 hours that is severe enough to 
interfere with activities of daily living (ADLs) 
 
 
 


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14.4 APPENDIX D: CLINICAL STAGING AND TREATMENT OF ACUTE GVHD 108,109 
 
Stage 
Skin 
Liver 
Gut 
1 
Rash < 25% BSAa 
Total bilirubin 2.0-2.9 
mg/dlb 
Diarrhea >500-
1000ml/day, or  
upper GI symptoms 
2 
Rash 25-50% BSA 
Total bilirubin 3.0-6.0 
mg/dl 
Diarrhea 1001-
1500ml/day 
3 
Rash >50% BSA 
Total bilirubin 6.1-15.0 
mg/dl 
Diarrhea 1501 to 
2000 ml/d 
4 
Bullae 
Total bilirubin > 15.0 
mg/dl 
Diarrhea >2000 mL 
/day or severe 
abdominal pain or 
ileus 
aBSA = body surface area; use “rule of nines” or burn chart to determine extent of rash. 
bRange given as total bilirubin.  
Note:  Elevation of transaminase without elevation of bilirubin is not recognized as acute GVHD 
(A note should say “GVHD transaminitis” and mention if biopsy proven or not.) 
c Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.  
The nominal stage is reduced by one if the organ is simultaneously and unequivocally affected by 
a complication other than GVHD. 
 
Clinical Grading of Acute GVHD 108,109  
 
Gradee 
Skin 
Liver 
Gut 
0 (none) 
None 
None 
None 
I 
Stage 1-2 
None 
None 
II 
Stage 3   
Stage 1   
Stage 1 
III 
 
Stage 2-3   
Stage 2-4 
IVd 
Stage 4e  
Stage 4       
Stage 4 
eCriteria for grading given as minimum degree of organ involvement required to confer that grade.  
The highest single organ stage determines the overall grade. 


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dPatients with Stage 4 gut GVHD are usually Grade IV.  Stage 4 gut GVHD can only be a part of 
Grade III when it is not severe enough to cause a substantially impaired performance status.  A 
substantially impaired performance status would be an ECOG performance status of 3 or 4. 
eDesignation of Grade III is appropriate for only scattered bullae. 
The NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-
host Disease defines classic acute GVHD as maculopapular rash, nausea, vomiting, anorexia, 
profuse diarrhea, ileus, or cholestatic hepatitis occurring within 100 days after transplantation or 
DLI 107.  We will define acute GVHD in the same manner for this trial. 
This schema is intended to serve as a guideline and to promote consistency in our clinical practice; 
it may be modified for individual patients as clinical circumstances warrant.  Failure to follow 
these guidelines is not a protocol deviation. 
Grade I GVHD:  
1) Topical corticosteroids (usually 0.1% triamcinolone; 1% hydrocortisone to face) applied to 
rash BID. 
Grade II-IV GVHD:  
1) Methylprednisolone (MP) 1 mg/kg per dose IV, BID for 4 consecutive days. 
2) If no response after 4 days, continue until response (7-day maximum trial); the dose may be 
doubled (4 mg/kg/day). 
3) If response within 7 days, taper as follows: 
a) 0.75 mg/kg per dose IV BID for 2 days. 
b) 0.5 mg/kg per dose IV BID for 2 days. 
c) 0.375 mg/kg per dose IV BID for 2 days. 
d) If clinically appropriate, change MP to oral prednisone to equivalent of IV dose) daily for 
2 days.  MP may be converted to prednisone later in the taper at the investigators’ 
discretion. 
e) After this, steroids will be reduced by 10% of starting oral dose each week until a dose of 
10 mg/day is reached.  Subsequent reductions will be made at the investigators’ discretion. 
f) If GVHD worsens during taper, steroids should be increased to previous dose. 
g) During steroid taper, maintain cyclosporine at therapeutic levels. 
4) If no response is observed within 7 days of MP treatment: 
a) Increase Methylprednisolone to 10 mg/kg per dose IV, BID for 2 days. 
b) If there is no improvement, consideration will be given to using second-line 
immunosuppressive therapy, e.g., tacrolimus, mycophenolic acid, monoclonal antibodies, 
or studies of investigational agents for acute GVHD, if they are available. 
5) Antifungal prophylaxis with agents effective against mould will be started when it is 
anticipated that the patient will be receiving steroids at > 1 mg/kg/day of methylprednisolone 
(or equivalent) for > 2 weeks. Voriconazole, caspofungin, liposomal amphotericin B 
(Ambisome), posaconazole or amphotericin B lipid complex (Abelcet) are valid alternatives.  
During prophylaxis with any of the above agents, fluconazole should be discontinued.  In 
patients with therapeutic cyclosporine levels at the initiation of voriconazole therapy, the 


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cyclosporine or Tacrolimus dose should be decreased by approximately 50%. In patients with 
therapeutic Sirolimus levels at the initiation of voriconazole therapy, the Sirolimus dose should 
be decreased by approximately 90%. 
6) Determination of GVHD treatment response should be made within 96 hours of starting the 
treatment.  The following are criteria to determine definitions of response to GVHD treatment: 
a) Complete response:  Complete resolution of all clinical signs and symptoms of acute 
GVHD. 
b) Partial Response: 50% reduction in skin rash, stool volume or frequency, and/or total 
bilirubin.  Maintenance of adequate performance status (Karnofsky Score > 70%). 
c) Non-responder: < 50% reduction in skin rash, stool volume or frequency, and/or total 
bilirubin.  Failure to maintain adequate performance status (Karnofsky Score ≤ 70%). 
Progressive disease:  Further progression of signs and symptoms of acute GVHD, and/or 
decline in performance status after the initiation of therapy. 
 
 
 


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14.5 APPENDIX E:  INFUSION INSTRUCTIONS    
Equipment:   
Primary IV tubing (2) 
Secondary IV tubing (1) 
NS (sodium chloride 0.9%) 250cc bags (2) 
IV infusion pump 
Gloves 
Steps: 
Key Points: 
1.     The RN will be informed of the 
approximate time of cell arrival at 
the bedside. 
 
2.  Verify the physician orders: 
- to administer the cells 
- for the date of administration 
- for premedication orders  
- protocol number 
 
a. Premeds are acetaminophen 650 mg PO 
and diphenhydramine 12.5 mg IV. 
3.  Verify that the protocol consent and DPA 
are signed. 
 
4.  Ensure that emergency and monitoring  
equipment are available in the patient’s 
room: 
-  oxygen 
-  suction 
-  vital sign monitor with pulse oximeter 
   and thermometer    
 
5.  Provide patient education covering 
infusion procedure, potential complications 
and associated symptoms to report.  
 


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7.  Measure and record baseline vital signs, 
respiratory and circulatory assessments. 
 
8.  Verify the patency of the patient’s IV 
access. 
A central venous access device such as a 
non-valved PICC line should be used. 
9.  Hang a primary line of 250cc NS at a kvo 
rate - NEW bag and NEW tubing.  
This MUST be ready and infusing prior to 
the cells being delivered to the unit. 
The patient’s primary IV hydration can 
infuse via a separate lumen while the cells 
are infusing, but NO MEDs should be 
administered during this time.  
Have a second bag of 250cc NS and tubing 
ready as an emergency line. 
This will be the dedicated NS line for 
infusing the cells.  Under no circumstances 
are any other substances to be infused into 
the line.   
Cell death occurs quickly – the infusion 
must be initiated immediately.  
Do not infuse medication during the cell 
infusion.  If emergency meds must be 
administered, 
use 
the 
hydration 
or 
emergency NS IV line.  
 This will be the emergency IV solution and 
can be used for medication administration. 
 
Do not use an inline filter for cells.  
10.  The primary RN will be notified 
approximately 10 minutes before the cells 
arrive on the unit.  The cells will be hand 
delivered to the bedside. 
It is critical to be at the bedside awaiting the 
arrival of the cells for infusion.   
 
 
It is critical to be at the bedside awaiting the 
arrival of the cells for infusion; have 
baseline VS, assessment, and IV lines 
hooked up when the cells arrive.  Cell death 
occurs as soon as the cells are removed 
from the laboratory.  Initiate the infusion 
as quickly as possible. 
 
12.  Prior to spiking the cell bag, two RNs 
will perform the identification procedure.  
Both RNs must sign the tag on the cell bag. 
 
13.   Infuse the cells by INFUSION PUMP 
or syringe over 20-30 minutes. 
a. Piggyback the cells into the dedicated 
NS line; use the backflush technique 
to prime the line. 
b.   While the cells are infusing, gently 
agitate the bag of cells every few 
minutes. When the cell bag is 
 
 
 
 
 


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empty, backflush NS to rinse the bag 
and infuse this at the same rate as the 
cells; rinse bag until NS runs clear.  
        c.  Note: in some cases cells will arrive 
from DTM in a syringe.  In this case 
infuse the cells via syringe over 20-30 
minutes in the dedicated NS line 
proximal port, see nursing cellular 
infusion SOP for further details. 
 
This prevents the cells from clumping in the 
bag.  
14.  Measure and record VS before and after 
the cell infusion, q1h x 4, and then q4h after 
completion of the infusion.   
a. Assess and document the    patient’s 
respiratory and circulatory status 
post cell infusion.   
 
15.  Documentation: 
a. After the cells have infused, remove 
the adhesive backed “cell therapy 
product” tag from the cell bag and 
place it on a progress note in the 
patient’s chart.  
b.    Document the cell infusion in   
CRIS using the appropriate screens.  
 
 
 
 
 
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/09/2020
Page 1 of 18
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: 
James N. Kochenderfer, M.D.
STUDY TITLE: 
Anti-CD30 T Cells with Fully-Human Binding Domains for 
Treating 
CD30-expressing 
Lymphomas 
including 
Anaplastic Large Cell Lymphomas
STUDY SITE:
NIH Clinical Center
Cohort:
Affected Patients
Consent Version:
09/09/2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
James Kochenderfer, MD. by phone at 240-760-6062 or Email: kochendj@mail.nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The immune system plays many important roles in the body, such as helping the body fight 
infections. The immune system is also known to affect cancer cells. “T” lymphocytes, or T 
cells, are a type of white blood cell and a major part of the immune system. T cells can 
recognize and destroy many different tumors, particularly types of leukemias or lymphomas. 
Unfortunately, most tumors have developed ways of escaping the monitoring by the immune 
system for foreign
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/09/2020
Page 2 of 18
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
or abnormal cells and continue to grow in an uncontrolled manner. We are looking at ways to 
manipulate the T cells in the immune system, so that they will more efficiently find and kill 
tumor cells.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You have been diagnosed with a lymphoma (such as: angioimmunoblastic T-cell lymphoma, 
anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified, diffuse 
large B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, grey 
zone lymphoma, enteropathy-associated T-cell lymphoma, or extranodal NK/T-cell 
lymphoma, nasal type) that has not been controlled by other therapies, meaning that the cancer 
cells have continued to grow or, if you did achieve a remission, the cancer has recurred after 
or during treatment. You may have also received an allogeneic transplant because 
chemotherapy (drug therapy) and/or immunotherapy and/or radiation therapy did not control 
your cancer growth. For these lymphomas, there are no treatment options that have been 
proven to cure the cancer. Unfortunately, many lymphomas quickly develop resistance to 
standard treatment options and ultimately become completely resistant to conventional drug 
or antibody therapy.  Thus, there is a need to find new approaches for the treatment 
lymphomas. You should discuss with your referring doctor and the NIH doctor’s other 
treatment options that might be available to you so that you feel that you have made the best 
choice for your disease at this time.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
Up to 79 patients will take part in this research study.
DESCRIPTION OF RESEARCH STUDY
What will happen if you take part in this research study? 
Before you begin the study
You will need to have the following exams, tests or procedures to find out if you can be in the 
study. Most of these exams, tests or procedures are part of regular cancer care follow up. 
However, there are some extra exams, tests and procedures that you will need to have if you 
take part in this study. If you have had some of them recently, you may not have to do them 
again.
These tests include:
•
Physical examination
•
Routine blood and urine tests
•
Blood tests for viruses and other disease-causing organisms
•
Echocardiogram and EKG of your heart
•
Bone marrow biopsy
•
CT scan (head, neck, chest, abdomen and pelvis) and/or PET scan
•
MRI of your head
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/09/2020
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During the study
First, you will undergo an apheresis procedure that will remove cells from your blood.  
Apheresis is a procedure for obtaining certain blood cells, such as white blood cells, without 
removing most blood cells. It is a process person undergoes when giving routine platelet 
donations.
Next, we will manipulate your cells in a laboratory so that they can recognize your lymphoma. 
Specifically, we will genetically modify your T cells and grow them in the laboratory. We 
hope that these T cells will decrease the amount of cancer you have. However, it is possible 
that these cells will not have this effect. We will be using a type of virus (lentivirus) that 
encodes a gene for an anti-CD30 receptor in making these anti-CD30 T cells. Your cancer 
cells express the CD30 protein on their surface. This CD30 protein will serve as a target for 
the anti-CD30 T cells.
If it is not possible after 2 attempts to prepare at least enough cells for you to get the number 
of cells needed by the protocol, you will not be able to be treated on this protocol.
This study is a “dose escalation” study. The purpose of dose escalation is to determine the safe 
dose of anti-CD30 T cells. There will be five dose levels of anti-CD30 T cells. The first patients 
enrolled get the smallest dose and the dose is increased when a level has been determined to 
be safe. You can discuss this with the study doctors to find out which dose of anti-CD30 T 
cells you will be receiving.
After you have had cells removed from your blood, you will receive two FDA approved drugs 
(chemotherapy) named cyclophosphamide and fludarabine, over a period of 3 days. The 
purpose of the chemotherapy is to enhance the activity of the anti-CD30 T cells. You receive 
a slightly higher amount of cyclophosphamide than some of the first patients on this trial to 
better enhance this activity. This is a standard chemotherapy regimen that is often used to treat 
certain types of leukemia. The chemotherapy can be given while you are an outpatient, and a 
hospital admission is not necessary. It is possible that after you have the cells removed from 
your blood, your lymphoma may be growing quickly. You may need to receive standard 
chemotherapy with your oncologist who referred you to this trial, before you can receive the 
clinical trial therapy. If this happens, you may be able to re-enroll in the study after your 
lymphoma is better controlled.
Two days after the chemotherapy ends, you will be admitted to the hospital as an inpatient and 
receive the anti-CD30 T cells. The anti-CD30 T cells are given as a single intravenous (IV) 
infusion. You will need to have a “central line”, an IV catheter (or tube) placed in a large vein 
in your arm or chest for this infusion. If you have a catheter in place already, this could possibly 
be used, or you may need to have an added central line placed. All patients that take part in 
this study must stay in the hospital for close observation for at least 9 days after the cell 
infusion, and patients must stay within 60 minutes driving distance for 2 weeks after the cell 
infusion. This is because in our experience with similar treatments we have noticed side-effects 
including fevers, fatigue, low blood pressure, and others that have been most severe between 
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4 and 9 days after cell infusion. You may have to stay in the hospital longer to manage these 
side effects if they occur.
You will be watched closely during the anti-CD30 T cell infusion for signs of a reaction. While 
other types of genetically modified T cells have been given to many patients, infusion of anti- 
CD30 T cells is a new approach that is being studied in this protocol. There is always a chance 
that we will not be able to genetically-modify your cells or be able to grow the cells in the 
laboratory. If we are not able to successfully prepare the minimal number of cells that  we 
believe are needed to help control the cancer in our first attempt to produce the cells, we will 
make a second attempt to produce the cells if you give us permission to do so even if you have 
already received the chemotherapy part of the protocol at the time. This second attempt to 
produce cells will probably not be necessary.
When you are finished with the cell infusion
You will need to come for a clinic visit two weeks after your cell infusion, for blood work and 
a visit with one of our doctors. You will also need to return to clinic for evaluation of your 
overall health and your lymphoma 1, 2, 3, 4, 6, 9 and 12 months after the cell infusion.
After 12 months, follow up for patients with ongoing responses, which means the lymphoma 
has not progressed, will continue every 6 months for up to 3 years and then annually after your 
T-cell infusion. At the follow-up visits we will evaluate your general health, and we will assess 
your lymphoma. Blood is drawn at all follow-up visits. Note that all these follow-up visits are 
only needed for patients with ongoing responses.
There is the possibility that you may need to be treated with anti-CD30 CAR T cells a second 
time if there is still lymphoma left. For you to be treated again, your lymphoma would have 
had to have some response to the earlier anti-CD30 CAR T-cells. You will only be treated 
again if the doctors decide it is safe and the treatment may further shrink your lymphoma. 
There will also need to be enough cells from your first apheresis collection to make the 
retreatment. We will not be able to re-collect cells. You can be treated up to three times, which 
consist of your first treatment and two re-treatments. If your lymphoma progresses after you 
have received your anti-CD30 T-cell infusion(s), you will be removed from the study to start 
other treatment options. If your lymphoma does not progress, we ask that you do not take any 
other treatments. We also ask that you do not take any corticosteroid medications such as 
prednisone or dexamethasone. Corticosteroids and some other medications including 
chemotherapy will damage the anti-CD30 T cells. They may become less able to fight and get 
rid of cancer. If you take other treatments or corticosteroids, we can also not tell how well the 
anti-CD30 T cells are working, and you will be removed from the study. You will be followed 
by your home oncologist who will receive a detailed summary of your case. They will be told 
what monitoring tests need to be performed and about possible problems can occur. We 
encourage early communication of any problems with us so that we can aid in deciding the 
best treatment approach.
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Gene-therapy-specific follow-up
You will be followed on a separate protocol once you are off treatment. Because we do not 
know the long-term side effects of gene therapy, we will ask you to take part in long term 
follow up for the next 15 years. The Food and Drug Administration (FDA) requires that people 
who receive gene therapy be watched even after they complete the study. We will ask you 
questions about your health and ask you to have a physical exam every year. We will also 
collect your blood over the next several years. If you return to your referring doctor after 
treatment here, we will ask you to have your doctor send us a copy of your physical exam and 
your blood samples. We will collect blood samples right after you receive the cells, and at 3, 
6 and 12 months after treatment (2 teaspoons each time). We may also collect your blood over 
the next several years after 12 months if you have had any previous tests that show a lentivirus 
in your blood. This testing will help us learn if the cells have grown or changed in your body. 
For this reason, we ask that you continue to provide us with a current address and telephone 
number, even after you complete this research study.
At the time of your death, no matter the cause, we may request consent from your family for 
an autopsy. This will allow us to obtain important information about the safety of this 
experimental treatment. Please discuss this with your family to inform them of this potential 
request.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study 
because we don’t know how this therapy would affect your baby or your unborn child. If you 
are a woman who can become pregnant, or are the partner of a woman who can become 
pregnant, you will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 4 months after you finish the last cell infusion for 
men, and for 12 months after you finish your last cell infusion for women. If you are a man, 
you should not donate sperm during the study treatment and for 4 months after you finish the 
last cell infusion.
If you think that you or your partner is pregnant, you should tell your study doctor or nurse at 
once.
Effective forms of birth control include:
•
abstinence
•
intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
TESTS FOR RESEARCH
An important part of this study is testing the effects of this treatment on your tumor and 
immune system. The following blood samples and tests will be done while you take part in 
this study:
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Research blood samples
Blood will be drawn frequently during your treatment. Most of the blood draws will be to 
check your health during and after the cell infusion. In addition, some blood samples are drawn 
for research purposes. Added blood draws might be necessary to investigate T cell responses 
and serum cytokine levels in cases of clinical events such as rapid regressions of malignancy 
or toxicity. These samples are to study how your immune system is changed from the cell 
therapy. Some of the samples may be used for other or future research conducted by the 
investigational team or other researchers inside and/or outside of NCI or the NIH. In general, 
4 tablespoons will be drawn at each clinic visit or every Monday, Wednesday, and Friday 
during the inpatient stay. There will also be about a 1 tablespoon draw the day you receive the 
cells and the first Sunday afterwards. On one occasion before the treatment a larger amount of 
blood (8 tablespoons) will be drawn. The NIH has set a limit on the largest amount of blood 
that can be taken for research. This limit is based on your age. For adults, no more than 37 
tablespoons can be taken over an 8- week period.
Lumbar Puncture
If you have a form of lymphoma that has a tendency to spread to the lining of the brain or 
spinal cord (called the leptomeninges) or if there is any concern that this might have occurred, 
you may also require a lumbar puncture to determine whether you would require special 
therapy that should not be delayed while participating on an experimental protocol. The 
procedure uses local anesthesia to numb the skin in the lower back, and a very thin needle 
draws fluid from the area below the spinal cord. Approximately one-to-three teaspoons of the 
fluid that bathes the spinal cord (called the cerebrospinal fluid) would be removed and 
examined for tumor cells. 
Bone Marrow Biopsies
A bone marrow biopsy is performed before the start of treatment. You may need to have added 
bone marrow biopsies during the study if there is lymphoma in your bone marrow before you 
start the study and if you are in remission after your anti-CD30 T cell infusion. These bone 
marrow biopsies are performed to make sure there is also no cancer in your bone marrow. 
These biopsies are needed for participation on the study to evaluate your tumor but also for 
research tests.
Tumor Sampling
Before or at the end of cell therapy, we may ask your permission to perform a biopsy of your 
cancer. If we can safely perform a biopsy without general anesthesia or significant risk of 
danger or discomfort to you, a sample may be removed through a surgical procedure or with 
a needle biopsy. A surgeon will go over the details before the procedure and will ask you to 
sign a separate consent. The primary risks are pain from the needle insertion and a slight risk 
of infection, bleeding, or injury to the nearby tissue. Biopsies are performed under sterile 
conditions to prevent infections. We may also ask your permission to perform a biopsy for 
research. The tissue from this biopsy is used to see how the CAR T cells are affecting the 
tumor or to see if a new tumor is lymphoma. Any biopsies would only be performed with your 
permission. The biopsy also has to be determined safe by the Principle Investigator of this trial 
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and the physician or physicians that would perform the biopsy. Some of the samples may be 
used for other or future research studies by the investigational team or other researchers. 
This future research might directly study malignancy of the same type that you have, or it 
could focus on other areas of research.
CT SCAN
You may have a CT (Computed Tomography) scan of areas as needed for disease assessment) at 
1-month, 2-month, 3-month, 4-month, 6-month, 9-month and 12 months after T cell infusion. This 
may include areas such as the neck, chest, abdomen and pelvis. If is necessary, we may use contrast 
agent enhanced CT scans. The CT scanner is a doughnut-shaped machine that uses x-rays to create 
computer pictures showing the inside of your body.  During the procedure, you will need to lie 
still on a table inside the CT machine.  The table will move you in and out of the machine during 
the scan and you will be instructed to hold your breath.  The scan itself will only take a few minutes 
to complete, the entire visit will take about 30 minutes. 
PET SCAN
You may have PET (Positron Emission Tomography) scan at 1-month, 2-month, 3-month, 4-
month, 6-month, 9-month and 12-months if needed to stage disease.  The PET scanner is a 
doughnut-shaped machine that uses x-rays combined with a dose of a radioactive substance (tracer) 
to create computer pictures showing the inside of your body.  
Before the scan, you will have a radioactive substance injected into your arm after which, you will 
need to wait for approximately 30 minutes for the substance to be absorbed.  After 30 minutes, 
you’ll lie on a narrow, padded table and be positioned for the scan.  The scan itself is painless and 
won’t make much noise.  During this time, you will need to lie very still.  It will take about another 
30 minutes to complete. 
RISKS OR DISCOMFORTS OF PARTICIPATION
Because the CD30 protein is on normal B and T cells (types of white blood cells or immune 
cells) as well as on your cancer, the anti-CD30 T cells might cause a fleeting or prolonged 
decrease in the number of normal B and T cells. Because B and T cells are involved in 
protection against infections, this decrease in B and T cell number might lead to a greater risk 
of infections. We do not know if a decrease in normal B and T cells will cause problems with 
infections. We take steps to deal with the increased risk of infection or actual infections.
The anti-CD30 T cells we will be giving you have been changed to express the anti-CD30 part 
that targets the T cells to the cancer by using a virus (retrovirus). Although this retrovirus is 
not active, there is the rare possibility that it may cause infection. The cells could also cause 
you to develop another type of cancer in your blood cells, although we think this is very 
unlikely. Other gene-modified T cells have been given to hundreds of individuals before, and 
in no patient receiving T-cell gene therapy has an infection or cancer developed that was 
shown to be caused by the retrovirus used.
Some patients died on different studies that used CAR T cells that use a different target, called 
CD19, which is on some lymphomas and leukemias. Several other patients have been treated 
with anti-CD19 CAR T cells without major adverse effects. Many patients receiving anti-
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CD19 CAR T cells at many hospitals have developed fever and fatigue that can last for up to 
2 weeks after cell infusion. Some patients that have received similar treatments have developed 
low blood pressure. A small number of patients developed a temporary decrease in heart 
function after being treated on similar study at this institute. Their heart function later returned 
to normal levels and the other participants in the study have not had decreased heart function. 
One patient on an anti-CD19 CAR T-cell study had tumor lysis syndrome, which is a release 
of toxins from destroyed tumor cells. This tumor lysis syndrome was treated and caused no 
long-term problems for the patient. Patients at risk of tumor lysis syndrome will receive 
medication to prevent this complication. Neurological toxicities such as a temporary loss of 
the ability to speak, temporary confusion, and temporary difficulty walking have occurred in 
several patients.
Some laboratory testing suggests that CD30 is present in a woman’s uterus during pregnancy 
and certain parts of the menstrual cycle. It is possible that the anti-CD30 T cells could damage 
the uterus, or the unborn baby in pregnant women. For this and other reasons, pregnant women 
and women having menstrual periods should not participate in the trial.
Potential risks of anti-CD 30 T cells infusion include:
Likely:
Less Likely:
Rare:
• Fever
• Chills
• Shortness of breath (these 
side effects may last a few 
hours)
• Fatigue
• Somnolence (excessive 
sleeping)
• Low antibody levels which 
might need antibody 
replacement infusions
• Infections caused by 
immunosuppression
• Mild rash
• Headache
• General feeling of being unwell 
(malaise)
• Lung congestion
• Severe rash
• Itching
• Cytokine Release Syndrome (release of 
substances from T cells that can cause 
many side-effects) including
o
Fever
o
Fast heart rate
o
Low Blood Pressure
o Possible intensive care unit 
admission
o Mechanical ventilation
o Rare cases, death.
• Death
• Permanent 
kidney 
damage
• Coma
• Permanent 
neurologic 
impairment
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Likely:
Less Likely:
Rare:
• Low blood pressure
• Tumor lysis syndrome (rapid breakdown 
of tumor that can cause side-effects)
o Possible intensive care unit 
admission
o Fast heart rate
o Possible kidney damage that 
will most likely be temporary
o Possible breathing problems 
that might in rare cases need 
mechanical ventilation 
(breathing machine)
• Temporary decreased cardiac function
• Temporary liver function test elevation
• Temporary decrease in blood counts 
(may last up to few weeks)
Likely:
Less Likely:
Rare:
• Temporary low calcium, phosphorous, 
albumin in the blood
• Muscle inflammation and pain
• Increase in bleeding times
• Temporary neurological changes, ex: 
confusion, difficulty speaking, decreased 
balance, seizures, tremor (shaking) of 
hands, poor balance
• Graft versus Host Disease (GVHD) 
possible ONLY if you have had an 
allogeneic stem cell transplant
• Damage to a woman’s uterus
• Fainting
As this is a new experimental therapy, new unexpected side effects may happen and cause your 
condition to worsen.
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Potential risks of Cyclophosphamide:
Likely:
Less Likely:
Rare:
•
Low blood counts
• Nausea and vomiting
• Painful and bloody urination
• Sterility
• Water retention
• Hair loss
• Heart damage
• Secondary leukemia (a 
different type of cancer)
• Skin rash
• Bleeding
Potential risks of Fludarabine:
Likely:
Less Likely:
Rare:
• Low blood counts
• Long-term reduction of 
lymphocyte counts which 
could increase the risk of 
infection
• Infection
• Seizures, coma, blindness and 
even death
• Inflammation in the lungs
• Kidney damage
Gene Therapy Risk of Cancer and Other Diseases
We are unsure if this type of gene therapy will cause you to become sick in the future. It is 
possible that it may cause your immune system or nerves not to work well or cause a sickness 
of your blood cells or even a cancer (for example leukemia). We do not know if you will 
develop any of these disorders, but you need to be aware of this possible risk. Children in 
France and England received gene therapy for a disease of the immune system. Most of the 
children were cured but 5 children out of 20 later developed leukemia and one died. Experts 
who looked at these cases thought that the gene therapy caused the leukemia in these children. 
Because you will be receiving a gene therapy that is very different from the gene therapy that 
these children received, the chance of this therapy causing a second cancer may be lower. In 
fact, hundreds of patients have received T-cell gene therapies like the one that you will receive 
without any of them developing a cancer that caused by the T-cell gene therapy. To watch you 
for this risk we will be testing your blood as described before.Graft-Versus-Host Disease 
(GVHD): 
This is only for patients that have previously received an allogenic transplant only. Early 
(acute) GVHD, which generally occurs in the first 100 days  after transplantation and 
sometimes occurs after donor lymphocyte infusion, may occur following infusion of the anti-
CD30 T cells. Mild acute GVHD (skin rash only) is treated with topical steroid lotions. More 
severe acute GVHD can cause blistering of the skin, abdominal pain and diarrhea, disturbances 
in liver function and jaundice and needs strong treatment including steroids, which are given 
intravenously (through the vein). Occasionally, severe acute GVHD can be fatal. Delayed or 
chronic GVHD may also occur. Typically occurring after the first 100 days following 
transplantation, it also can occur after donor lymphocyte infusion, and may occur after anti-
CD30 T cell therapy. Symptoms include dryness of the mouth and eyes, skin rash, joint 
stiffness, weight loss, liver damage (including jaundice), and lung damage leading to cough 
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and shortness of breath. This is treated with drugs that suppress the immune system, such as 
cyclosporine and steroids given by mouth. Chronic GVHD can at times be present for the rest 
of your life. Both acute and chronic GVHD, and the drugs we use to treat them, can place 
patients at significant risk for infections, which can be life-threatening. Blood Draws:
Blood will be drawn often during your treatment. Most of the blood draws will be to watch 
your health during and after the lymphocyte infusion. In addition, some blood samples will be 
drawn for research purposes. Added blood draws might be necessary to investigate T cell 
responses and serum cytokine levels in cases of clinical events such as rapid regressions of 
malignancy or toxicity. These samples will be used to study how your immune system is 
affected by the cell therapy, a graft-versus-tumor response and graft-versus-host disease (if it 
occurs).  Some of the samples may be used for other or future research conducted by the 
investigational team or other researchers. In general, 20 to 70 ml of blood (4 to 12 teaspoons) 
will be drawn at each clinic visit or inpatient hospital day. Side effects of repeated blood 
sampling depend in part on how the blood is drawn. If through a central venous catheter, you 
risk the catheter. This can cause a serious blood stream infection that requires admission to the 
hospital to give you antibiotics through the vein. If blood is drawn through a needle into your 
skin, side-effects could include pain and bruising in the area where the blood was drawn. Other 
side-effects can include lightheadedness, or rarely, fainting. If you have too much blood taken 
over a prolonged period, your red blood cell count may drop (this is called “anemia”). As a 
precaution, we will check your red blood cell level, and give you iron treatment or a blood 
transfusion if needed.
Intravenous Catheter:
In order to receive this treatment, you will need to have a central venous catheter. This catheter 
is placed under the skin of the arm and threaded to a major vein in the chest. There are several 
types of catheters including those which must be removed after each treatment (temporary 
type) and those which may be kept longer (permanent type). These options will be discussed 
with you. The risks associated with placing some catheters include pain, bleeding, infection 
and collapsed lung. The long-term risks of the catheter include infection and clotting of your 
veins. If these occur, it may be necessary to remove the catheter. These risks will be explained 
to you in more detail at the time of insertion.
Bone marrow aspiration and biopsy:
A bone marrow biopsy is performed by inserting a needle into a bone of the hip. In the 
aspiration part of the procedure, a small amount of liquid bone marrow is removed, and in the 
biopsy part, a tiny solid piece of bone marrow is removed. You may feel a pressure sensation 
when the needle is being inserted and a pulling sensation and brief pain as the marrow is 
withdrawn. The amount of marrow taken is very small and will not change your body's ability 
to form blood cells. Potential complications of this procedure are local bleeding, pain at the 
site, and infection. Both are very rare. Bleeding can be stopped by applying local pressure and 
an infection can be treated with antibiotics.
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Lumbar Puncture:
There is very minor discomfort when the numbing medicine is injected into the skin. It may 
cause pain at the site where the needle goes in and the spinal fluid is taken.  There is a small 
risk of infection or bleeding. A third or fewer patients may experience some headache while 
the body replaces the fluid that is removed.
Apheresis: 
The risks of apheresis are similar to whole blood donation and include pain and bruising at the 
needle insertion site in the arms, lightheadedness, dizziness, nausea, and rarely fainting due to a 
rare reflex reaction to needle placement and to the temporary decrease in blood volume during 
apheresis.  You may also feel tingling around your mouth or in your fingers caused by a blood 
thinner given during the procedure.  The nurses will give you a calcium containing antacid to chew 
to reduce the tingling.  All the symptoms usually go away within a few minutes of stopping the 
procedure.   We ask that you eat a meal before coming to donate, and avoid caffeine, to prevent 
lightheadedness or dizziness that might occur.  You will be asked to remain in the chair/bed for a 
few minutes after the donation is completed, and to sit down and relax for about 15 minutes after 
the donation.  This is done so that staff can observe you to make sure that you feel entirely well 
before you leave our department.
Optional Biopsies: 
You may be asked to undergo a biopsy for research purposes. Tumor biopsies can be 
performed as an outpatient surgical procedure or can be done by a specialist using the CT 
scanner or ultrasound machine to guide the biopsy needle into the tumor to ensure accuracy. 
There are risks associated with the biopsies, which can include pain and bleeding at the biopsy 
site. The biopsies to be performed are exclusively for research purposes and will not benefit 
you. It might help other people in the future. You will be asked at the time of the procedure if 
you are willing to have this biopsy.
What are the risks of radiation from being in the study? 
During your participation in this research study, you may be exposed to radiation from CT scans 
of your neck, chest, abdomen and pelvis, CT guided biopsies and 18FDG-PET/CT scans each year.  
The amount of radiation exposure you will receive from these procedures is equal to approximately 
22.4 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans and 18FDG-PET/CT scans that you get in this study will expose you to the roughly 
the same amount of radiation as 74.7 years’ worth of background radiation. Being exposed to too 
much radiation can cause harmful side effects such as an increase in the risk of cancer.  The risk 
depends on how much radiation you are exposed to. Please be aware that about 40 out of 100 
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people (40%) will get cancer during their lifetime, and 20 out of 100 (20%) will die from cancer. 
The risk of getting cancer from the radiation exposure in this study is 2.2 out of 100 (2.2%) and of 
getting a fatal cancer is 1.1 out of 100 (1.1%).
If you can become pregnant, we will perform a pregnancy test before exposing you to radiation. 
You must tell us if you may have become pregnant within the previous 14 days because the 
pregnancy test is unreliable during that time
Contrast Agent enhanced CT scans risks:
If contrast dye is used, there is a chance of developing an allergic reaction from the contrast 
material, which may cause symptoms ranging from mild itching or a rash to severe difficulty 
breathing, shock or rarely, death.  The contrast material may also cause kidney problems.  The 
study doctors will do a blood test prior to the test to confirm that it is safe you to receive the 
contrast.
For IV contrast if used: You may feel discomfort when the contrast material is injected. You may 
feel warm, flushed, get a metallic taste in your mouth or, rarely, may make you vomit or feel sick 
to your stomach.  
For oral contrast if used:  You may experience vomiting, nausea, cramping, bloating, constipation 
or diarrhea after drinking the contrast.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
It is unknown at this time whether anti-CD30 T cell infusions will improve survival or have 
any benefit for patients with lymphomas. If accepted by your body, the cell infusion may 
decrease the amount of your cancer. Your participation in this experimental treatment may 
also help us advance the understanding and treatment of lymphomas with T-cell therapies, so 
your participation could help other patients.  We do not know if you will receive personal 
medical benefit from taking part in this study. These potential benefits could include shrinking 
of your tumor or lessening of your symptoms, such as pain, that are caused by the cancer .
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
To be eligible for this protocol, you may or may not have already received an allogeneic 
HSCT. Prior to this, you have received some of the conventional therapies for your disease. 
Before deciding whether to participate in this clinical trial, you may consider other treatments 
such as:
•
Other forms of chemotherapy, radiation, surgery, or immune therapies, without 
being in a study.
•
You may be eligible for other experimental therapies.
•
Another option is not to receive any further therapy at all, other than comfort care, 
also called palliative care. This type of care reduces tiredness, appetite problems and 
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
other problems caused by the cancer. It does not treat cancer directly. Instead, it tries 
to improve how you feel. Comfort care tries to keep you as active and comfortable 
as possible.
You should discuss with your referring doctor and the NIH doctors whether any of these 
treatments might represent a reasonable treatment option for your disease.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:
•
if he/she believes that it is in your best interest
•
if your disease comes back during treatment (you may also be eligible for a second 
infusion of the anti-CD30 T cells if this happens)
•
if you have side effects from the treatment that your doctor thinks are too severe
•
if new information shows that another treatment would be better for you
•
if you become pregnant
•
if the study doctor decides to end the study
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part 
in the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Dr. Kochenderfer or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon 
request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for 
conflicts of interest. This process is detailed in a Protocol Review Guide. You may ask your 
research team for a copy of the Protocol Review Guide or for more information. Members of 
the research team who do not work for NIH are expected to follow these guidelines, but they 
do not need to report their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study. This is allowed under federal rules and is not 
a conflict of interest.
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 09/09/2020
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying 
human samples. They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved. Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses. These specimens and data will be stripped of identifiers such as name, 
address or account number, so that it may be used for future research on any topic and shared 
broadly for research purposes. Your specimens and data will be used for research purposes 
only and will not benefit you. It is also possible that the stored specimens and data may never 
be used. Results of research done on your specimens and data will not be available to you or 
your doctor. It might help people who have cancer and other diseases in the future.
If you do not want your stored specimens and data used for future research, please contact us 
in writing and let us know that you do not want us to use your specimens and/or data. Then 
any specimens that have not already been used or shared will be destroyed and your data will 
not be used for future research. However, it may not be possible to withdraw or delete materials 
or data once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study.
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid.  Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
•
If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.
•
Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
•
Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:
•
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.
•
National Institutes of Health Intramural Institutional Review Board
•
The study Sponsor or his agent(s)
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
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Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (2)
Version Date: 09/09/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Jim 
Kochenderfer, M.D., Building 10, Room 12C121, Telephone:  240-760-6062. You may also call 
the NIH Clinical Center Patient Representative at 301-496-2626, or the NIH Office of IRB 
Operations at 301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Consent to Participate in a Clinical Research Study
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Version Date: 09/09/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
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