Phase I Study of the Administration of T Lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas After High Dose Therapy and Autologous Stem Transplantation (ATLAS)
Phase: PHASE1
Conditions: Hodgkin Disease, Lymphoma, Lymphoma, Non-Hodgkin, Immune System Diseases, Immunoproliferative Disorders, Lymphatic Diseases, Lymphoproliferative Disorders, Neoplasms, Neoplasms by Histologic Type
Sponsor: UNC Lineberger Comprehensive Cancer Center

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 1 of 154
CLINICAL RESEARCH PROTOCOL 
DRUG: 
ATLCAR.CD30 
STUDY NUMBER(S): 
LCCC 1524-ATL 
PROTOCOL(S) TITLE: 
Phase I Study of the Administration of T 
Lymphocytes Expressing the CD30 Chimeric Antigen 
Receptor (CAR) for Prevention of Relapse of CD30+ 
Lymphomas after High Dose Therapy and 
Autologous Stem Transplantation (ATLAS) 
IND NUMBER: 
14688 
SPONSOR: 
Lineberger Comprehensive Cancer Center 
ORIGINAL PROTOCOL DATE: 
March 21, 2016 
AMENDMENT NUMBER: 
Amendment 8 
VERSION NUMBER: 
Version 1.0 
VERSION DATE: 
17 April 2023 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 2 of 154
 
 
 
SUMMARY OF CHANGES 
 
Protocol Amendment #8 
 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the 
CD30 Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas 
after High Dose Therapy and Autologous Stem Transplantation (ATLAS) 
AMENDMENT INCORPORATES: 
_X_  Editorial, administrative changes 
_X_  Scientific changes  
__  Therapy changes  
_X_   Eligibility Changes  
Rationale for amendment: The purpose for this amendment is to remove HTLV testing 
requirements from the inclusion criteria. CAR-T cells and procurement materials may also be 
stored for a total of 25 years (15 years + 10 years archived), and long term follow up requirements 
have been updated to allow for local visits. The protocol has been further reconciled so that language 
throughout the protocol is consistent. The Principal Investigator was also updated to Natalie 
Grover. 
Editorial, administrative changes: 
Appendix organization and numbering and other links and associated updated as appropriate 
Minor mechanical and grammar edits throughout 
Principal Investigator was updated to Natalie Grover, MD 
Scientific changes: 
Section 4.2 
Time and events table footnote 6, HTLV testing removed 
Section 7.2.1 
HTLV testing removed from pre-procurement assessments  
Section 7.5.8 
Biobank repository language updated to state that CAR-T cells and material 
from procurement are to be stored for up to 15 years for subject treatment and 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 3 of 154
 
 
 
safety purposes, furthermore, samples may be archived for a total storage time 
of 25 years (including initial storage and archiving). Multicenter honest broker 
language also added. 
Therapy changes: 
Section 4.2 
Language added to footnote 1 of the Time and Events table to allow for 
changes to long term follow up as follows: NOTE: Follow-up visits for month 
3 and beyond can be conducted locally (i.e., by local health care provider, local 
treating oncologist, etc.). The study team would continue to contact the 
subjects at the long-term follow-up time points and request they visit their 
local healthcare provider to complete the follow-up test and assessments, 
where applicable. The study team would collect clinical information, tests and 
assessments results, other clinical observations from the subject’s medical 
record and their local health care provider. 
Eligibility changes: 
Section 5.3 
Virus testing in exclusion criteria updated to remove HTLV, language now 
reads: Active infection with HIV, HBV, HCV (can be pending at the time of 
cell procurement; only subjects meeting the criteria as so described will be 
infused). (Note: To meet eligibility subjects are required to be negative for 
HIV antibody, negative for Hepatitis B surface antigen, and negative for HCV 
antibody or viral load).  
 
 
 
THE ATTACHED VERSION DATED April 17, 2023 INCORPORATES THE ABOVE 
REVISIONS 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 4 of 154
 
 
 
SUMMARY OF CHANGES 
Protocol Amendment #7 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the 
CD30 Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas 
after High Dose Therapy and Autologous Stem Transplantation (ATLAS) 
AMENDMENT INCORPORATES: 
 X  Editorial, administrative changes 
 X  Scientific changes (IRB approval) 
     Therapy changes (IRB approval) 
      Eligibility Changes (IRB approval) 
Rationale for amendment:  
The purpose of this protocol amendment is to update correlative blood sample collection related 
to RCR testing, function and persistence, and clonality. In relation to RCR testing parameters are 
updating for collection and testing based on the development of long-term gene therapy side effects. 
This amendment allows for the cessation of correlative sample collection when transgene is no 
longer detectable. The data collection system has also been updated.  
 
NOTE: The protocol was transitioned to an eCTD friendly protocol template. Sections of the 
most current protocol may be different than they were prior to the transition. Therefore, the 
references and/or Appendices may not be reflective of the current protocol. 
Editorial, administrative changes: 
 
Mechanical Editing made as needed that include section and appendix reference 
updates. 
Section 13 
Data entry changed from OnCore to Advarra EDC. 
Scientific Change 
Section 4.2 
Time and 
Events Table 
A medical history footnote was added as #3 to detail gene therapy side effects 
to monitor. 
Footnotes 10 and 11: Information in the correlative footnotes was modified and 
consolidated into 1 footnote (#11). It also indicates that Correlative blood 
sample collection will cease if the samples are no longer required for persistence 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 5 of 154
 
 
 
and function or clonality analysis. Persistence and function (11a) descriptions 
have been modified to lower the threshold of copy number detection for sample  
from 1000 copies/ug to 500 copies/ug. Also, if after 1 year transgene is 
undetectable collections for function and persistence will discontinue. For 
clonality (11b), it is indicated that sample collection may cease if detection of 
transgene is < .5% for more than 1 consecutive testing period. For RCR (11c) it 
is updated to indicated that samples will be collected and stored pre-infusion 
AND in the event a subject develops a long-term gene therapy side effect as 
described in Section 7.5.2. The cytokine testing row was removed, and 
associated footnote contents added to the correlatives footnote as sub-bullet 
“11d.”  
As a result of the consolidation and addition of footnotes the footnotes were 
renumbered as needed. 
Section 7.5 
Updated to indicate that correlative blood sample collection will cease if the 
samples are no longer required for persistence and function or clonality analysis 
Section 7.5.1 
Function and persistence testing modified to allow testing to stop if transgene is 
not detected after 1 year. The level of detection was decreased to 500 copies / 
ug DNA from 1000 copies/ug 
Section 7.5.2 
Updated to identify conditions for RCR testing.in the event of long-term gene 
therapy side effects 
Section 7.5.3 
Renamed to “Clonality.” Updated to indicate samples will no longer be collected 
if detection is < 0.5% for more than 1 testing period 
Appendix III 
Footnote 2 for medical history is updated to include gene therapy side effects to 
monitor.  
Abbreviated follow up table correlative sample collection footnotes 3, 4, and 5 
are combined and updated similarly to the main time and events table with the 
exception that in the Clonality sub-bullet (b) transgene detection method is only 
by flow cytometry 
THE ATTACHED VERSION DATED November 24, 2021 INCORPORATES THE 
ABOVE REVISIONS 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 6 of 154
 
 
 
Protocol Amendment #6 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the 
CD30 Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas 
after High Dose Therapy and Autologous Stem Transplantation (ATLAS) 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
X     Scientific changes (IRB approval)         
X     Therapy changes (IRB approval) 
        Eligibility Changes (IRB approval)  
        Other 
 
Rationale for Amendment 
The primary purpose of this amendment is to remove the hematologic parameters for dose limiting 
toxicity (DLT) based on experiences from other CAR-T cell clinical trials and discussion with 
experts in the field. Most of the early hematologic toxicities are likely related to lymphodepleting 
chemotherapy, based on prior clinical trials with fludarabine/bendamustine which found that 60% 
of patients experienced grade 4 neutropenia and 29% of patients experienced grade 4 
thrombocytopenia  [1]. Based on recently reported data, hematologic toxicity from CAR-T seems 
to be longer lasting and delayed more (months as opposed to weeks) in comparison to initial 
expectations for CAR-T cell products[2, 3]. These long-term cytopenias appear to be manageable 
with supportive care and do not seem to be associated with significant adverse events.  
Based on the safety profile we have observed with this vector, as well as our overall experience 
with RCR testing in T cell products and recipient follow-up samples, the testing of transduced T 
cell lines and recipient follow-up samples under this protocol has been amended so that RCR 
testing is no longer to be routinely required.   Subject blood samples will be collected pre-infusion 
and stored so that they are available in the event that the subject develops a new malignancy, and 
follow-up RCR testing is required. 
This amendment also adds an exploratory objective to determine whether there are correlations 
 
In addition, the protocol for long term follow up has been updated to include tracking of delayed 
adverse events and new malignancies, and to allow for increased observation and testing in these 
circumstances, in keeping with best practices.  The window for virus testing has also been 
expanded to 30 days 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 7 of 154
 
 
 
Finally, this amendment allows for additional analysis of collected standard of care biopsy or 
autopsy tissue including assessing potential causes for loss of response to therapy, including, but 
not limited to, the loss of CD30 expression. 
 
Editorial, Administrative Changes 
Updated the term “affiliate” to “multicenter” throughout the protocol. 
Updated the name of the multicenter team from “UNCCN” to “multicenter” throughout the 
protocol. 
Updated staff titles to current titles throughout the protocol. 
Removed language related to use of other IRBs, as all sites in this study must use the UNC 
IRB. 
Updated Section 1.5.2 Clinical Experience with CAR-T cells to indicate that as of July 2018 
there are over 250 clinical trials incorporating CAR-T cells. 
Clarified requirements for quantitative PCR testing in Sections 6.0 and 11.2. 
Clarified the language in Section 4.2 regarding procurement. 
Clarified the language in Sections 6.0 and 11.2 regarding correlative samples. 
Deleted imaging language from Section 6.5, where it did not apply.  This language appears 
where relevant, in Section 6.9. 
Updated Sections 7.3.2 and 7.3.3.2 to reflect that the NIH RAC is currently no longer 
reviewing unexpected SAEs outside of the review conducted at the FDA. As a result, the 
MedWatch 3500A Form should be used instead of the GeMCRIS report form if such an event 
occurs. 
Updated Section 7.3.3.1 IRB Reporting to include the multicenter project manager general 
email box. 
Updated Section 7.3.3.2 FDA Expedited Reporting Requirement for Studies Conducted under 
an IND to remove redundant language found in section 7.1.2 Suspected Adverse Reaction 
(SAR) and to refer to that section for details. 
.Updated Section 9.5.1, Emergency Modifications, in line with current process. 
Updated Section 9.6, Amendments to the Protocol, in line with current practice. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 9 of 154
 
 
 
Updated Sections 6.4 regarding long term follow-up to include tracking delayed adverse 
events and new malignancies, and resulting investigator determination of additional 
observations, testing and sample collection needed.  
Updated Section 6.5.2 regarding RCR testing based on the safety profile for this vector and 
overall experience with RCR testing.  We will continue to collect subject blood samples pre-
infusion and will collect a follow-up sample for RCR testing should the subject develop a new 
malignancy. Testing at 3, 6, and 12 months, as well as archiving annual samples for RCR 
testing, has been eliminated. 
Updated Section 6.5.7 Other Tissue Studies to allow collection of tissue from standard of care 
biopsies at any time after treatment instead of only during the first year. 
Updated Section 6.5.7 to allow collected tissue to also be used to assess for potential causes 
for loss of response to therapy, including, but not limited to, the loss of CD30 expression. 
Updated Appendix F: CRS Toxicity Grading Scale and Management Guidelines to specify that 
the clinical grading criteria is based on NCI CTCAE v4.0.  
Updated Appendix F: CRS Toxicity Grading Scale and Management Guidelines to remove the 
reference to the list of investigators that must approve the use of tocilizumab and/or steroids. 
 
The attached version dated July 2, 2019 incorporates the above revisions 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 10 of 154
 
 
 
 
PROTOCOL AMENDMENT # 5 
 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas after High 
Dose Therapy and Autologous Stem Transplantation (ATLAS) 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
        Scientific changes (IRB approval)         
X     Therapy changes (IRB approval) 
X     Eligibility Changes (IRB approval)  
        Other 
The purpose of this protocol amendment is to modify the eligibility criteria prior to cell infusion 
to allow for imaging results from within 60 days prior to transplant instead of from within 30 days.  
The eligibility criteria prior to cell infusion were also updated to require subjects to have 
autologous transduced activated T-cells that meet the Certificate of Analysis acceptance criteria. 
The protocol has also been amended to clarify that cell procurement may occur either prior to 
peripheral blood stem cell (PBSC) mobilization or after PBSC mobilization. While the previous 
version of the protocol could be read to imply that cell procurement must occur prior to PMSC 
mobilization, there is no safety or manufacturing reason that it must occur in this order.  As long 
as procurement occurs at least 7 days after ending granulocyte-colony stimulating factor (G-CSF), 
procurement may occur after mobilization.   
Additionally, the protocol has been to clarify that the parameters of pheresis will be up to two 
blood volumes instead of requiring a total of two blood volumes.  A total of two blood volumes 
may not be needed for pheresis; therefore, this change allows for less than that amount.   
Finally, the protocol has been amended to include headache as an additional sign and symptom of 
cytokine release syndrome (CRS) and to clarify elements of the CRS grading criteria. 
 
Summary of Changes 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 11 of 154
 
 
 
Section 1.1 Study Synopsis and Section 1.6 Study Rationale and Design have been amended to 
clarify that this is a multicenter study.  The purpose of Amendment 4 was to change the study 
from a single center study to a multicenter study.  These sections were inadvertently not 
updated with that amendment.  
Section 1.6 Study Rationale and Design has been amended to remove the text “prior to 
peripheral blood mononuclear cell (PBMC) mobilization” in order to clarify that procurement 
may occur before or after mobilization. 
Inclusion criterion prior to cell infusion 3.2.7 has been amended to allow for imaging results 
from within 60 days prior to transplant instead of from within 30 days 
Inclusion criterion prior to cell infusion 3.2.11 has been updated from subjects being required 
to have autologous transduced activated T-cells with ≥15% expression of CD30CAR to being 
required to have autologous transduced activated T-cells that meet the Certificate of Analysis 
(CoA) acceptance criteria per recent guidelines from the FDA 
Section 4.2 Cell Procurement has been amended to clarify that the parameters for pheresis will 
be “up to” 2 blood volumes instead of requiring a total of two blood volumes, as a total of two 
blood volumes may not be needed for pheresis. 
Section 4.7 Duration of Follow Up has been updated to clarify that the abbreviated follow up 
procedures are required for subjects who experience disease progression and start alternative 
therapy 
Section 6.1 Time and Events Table has been amended to remove the text “PBSC 
MOBILIZATION FOLLOWED BY” from the second column under “Screening” in order to 
clarify that procurement may occur before or after mobilization.  
Footnote 6 of section 6.1 Time and Events Table has been amended to add the following text 
as the end of the footnote: “Procurement may occur prior to or after PBSC mobilization.  If 
procurement occurs after PBSC mobilization, it must occur at least 7 days after ending use of 
G-CSF.” 
Footnote 8 of section 6.1 Time and Events Table has been amended to allow for imaging 
results at baseline from within 60 days prior to transplant instead of from within 30 days 
Footnotes 10 and 13 of sections 6.1 Time and Events Table have been amended to remove the 
amount of blood to be taken for correlative studies and replaced with an instruction to refer to 
the LCCC 1524-ATL Laboratory Manual. 
Section 6.1.1. Disease Assessment Guidelines for Cutaneous Lymphomas has been amended 
to allow for imaging to be performed within 60 days prior to transplant instead of within 30 
days.   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 12 of 154
 
 
 
Section 6.2.1 Pre-Procurement has also been amended to allow for imaging results from within 
60 days prior to transplant instead of from within 30 days.  It has also been amended to clarify 
that procurement may occur prior to or after PBSC mobilization, and if procurement occurs 
after PBSC mobilization, it must occur at least 7 days after ending use of G-CSF. 
Section 6.2.3 Treatment (D1 Week 0) has been updated to remove the amount of blood sample 
taken for correlative studies and an instruction to refer to the LCCC 1524-ATL Laboratory 
Manual has been added. 
Section 6.9 Assessment of Efficacy has been amended to state that imaging will be performed 
at baseline within 60 days prior to ASCT instead of within 30 days. 
Section 9.3 Registration Procedures has been updated to require registration with the LCCC 
CPO Multicenter Office  
Section 11.2.1 Follow Up Kit Procedures has been removed as this information will now be 
included in the lab manual and provided separately as a handout to participants. 
Section 11.5 - Appendix F: CRS Grading Criteria/Link to CRS Management Guidelines has 
been modified as follows: 
a. 
Headache has been added as a sign or symptom of CRS for the constitutional organ 
system in Table 1: Signs and Symptoms of CRS  
b. 
Grade 4 organ toxicity has been clarified to indicate, that Grade 4 transaminitis is 
characteristic of Grade 3 CRS transaminitis in Table 2: Grading Criteria. This was previously 
indicated in the Grade 3 CRS definition. 
c. 
Grade 5 Death has been added to Table 2: Grading Criteria 
d. 
To require that two doses of tocilizumab be available on site for immediate use for 
each patient treated with CAR-T cells.  The doses must available prior to cell infusion and up 
to 6 weeks following cell infusion. 
Minor editorial changes throughout. 
  
The attached version dated June 15, 2018 incorporates the above revisions 
 
  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 13 of 154
 
 
 
 
 
PROTOCOL AMENDMENT # 4 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas after High 
Dose Therapy and Autologous Stem Transplantation (ATLAS) 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
        Scientific changes (IRB approval)         
X     Therapy changes (IRB approval) 
        Eligibility Changes (IRB approval)  
        Other 
The purpose of this protocol amendment is to make LCCC 1524-ATL a multi-center clinical 
trial. All subjects will receive their CAR T cell infusion at the lead site, the University of North 
Carolina, Chapel Hill.  
Additionally, the protocol has been amended to include a cytokine release syndrome grading 
scale and guidelines for the management of cytokine release syndrome and neurotoxicity. 
 
Summary of Changes 
The list of co-investigators has now been removed from the protocol face page 
Barbara Savoldo, MD, PhD has been indicated as the study’s medical monitor on the protocol 
face page 
Information in regards to neurotoxicity and macrophage activation syndrome, which have been 
observed for other CAR T cell products have been added to Section 1.5.2.1 Toxicities 
Associated with CAR-T cells 
Patient reported outcome measures have been updated from a secondary to an exploratory 
objective/endpoint as a result of these surveys being optional to be presented to the patient and 
to be completed by the patient.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 14 of 154
 
 
 
The primary endpoint has been updated to reference a CRS grading system provided in 
Section 11.6  
The inclusion/exclusion criteria have been updated with a new format to divide out the 
different stages of eligibility determination more clearly 
A history of hypersensitivity reactions to murine protein-containing products has been 
removed from the exclusion criteria 
The study schema has been updated to indicate that LCCC 1524-ATL will now be a multi-
center clinical trial where all enrolled subjects will have CAR T cell infusions at the lead site, 
the University of North Carolina, Chapel Hill. 
Cell dose levels have been updated to include a maximum dose on each dose cohort in order to 
avoid excessive dosing secondary to obesity that could potentially result in toxicity. The 
maximum dose is calculated based on a body surface area of 2.5. 
The definition of DLT has been updated to include a CRS grading system that is outlined in 
Appendix F.  
Section 4.9, study withdrawal, was updated with new protocol template language 
The T&E table and assessments were updated to indicate that infusion will occur at the lead 
site, the University of North Carolina, Chapel Hill 
The T&E table and assessments were updated to remove the week 8 follow-up visit.  
The T&E table and assessments were updated to include response assessments for patients 
with cutaneous T cell lymphoma 
The T&E table and assessments were updated to include additional imaging at 6 months, 12 
months, 18 months and 24 months (or until disease progression) (sections 6.1, 6.3.8, 6.3.10 
and 6.4) 
The footnotes for the T&E table were updated to clarify that the PRO questionnaires are 
optional 
The T&E table and section 6.5.5 were updated to indicate that in the event of CRS and other 
SAE 10 mL blood samples should be collected once a day for the first 3 days. At the discretion 
of the sponsor, a daily sample may be requested for an addition 4 days.  
Section 6.1.1 was added providing disease assessment guidelines for cutaneous lymphomas 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 15 of 154
 
 
 
Section 6.2.1 pre-procurement and section 6.2.2 pre-infusion were updated to indicate more 
clearly that eligibility will be checked at these time points.  
Section 6.2.2 and 6.3.5 were updated to require a dermatology consult for cutaneous 
lymphomas and blood to be taken for leukemia profile and follow cytometry for mycosis 
fungiodes and Sezary syndrome patients.  
Correlative studies were updated to remove the requirement for specific colored tubes 
Section 6.9.1, measurement of disease, was updated to refer to response criteria for 
lymphomatoid papulosis and primary cutaneous ALCL included in section 11.4, Appendix D 
and response criteria for mycosis fungoides and Sezary syndrome included in Section 11.8 
Appendix E. 
Multi-center management language was added to sections 7.3.2, 7.3.3, 9.3, 9.5.1, 9.5.3 
FDA expedited reporting requirements were updated to better detail 21CFR312.32. 
NIH RAC and IBC reporting requirements were more clearly delineated.  
Single subject exception language was updated to be consistent with LCCC’s policy on SSEs.  
Minor typographical errors were fixed throughout the protocol. 
Updated Appendix B: Removing Week8 follow-up visits and assessments 
Addition of Appendix D: Response assessment for cutaneous ALCL/Lymphomatoid papulosis 
in order to assess efficacy in these subjects who are eligible for the LCCC 1524-ATL protocol 
Addition of Appendix E: Response assessment for mycoses fungiodes and Sezary syndrome in 
order to assess efficacy in these subjects who are eligible for the LCCC 1524-ATL protocol 
Addition of Appendix F: CRS Toxicity Grading Scale and Management Guidelines 
Addition of Appendix G: Neurotoxicity Treatment Algorithm 
 
The attached version dated February 2, 2018 incorporates the above revisions 
  
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 16 of 154
 
 
 
PROTOCOL AMENDMENT # 3 
 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas after High 
Dose Therapy and Autologous Stem Transplantation (ATLAS) 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
X     Scientific changes (IRB approval)         
        Therapy changes (IRB approval) 
        Eligibility Changes (IRB approval)  
        Other 
 
Summary of Changes 
Subjects who experience disease progression after receiving a cell infusion(s) will still be 
required to complete abbreviated follow up procedures outlined in Appendix B (Section 11.2).  
Language added to sections 4.6 and 4.8 also clarify this point about abbreviated follow up 
requirements in subjects who experience disease progression. 
Appendix C now describes patient reported outcome measures which will be collected via 
PROMIS Global Health and Physical Function and NCI PRO-CTCAE questionnaires. 
Added Objective 2.2.4 and Endpoint 2.4.4 to clarify the inclusion of collection of Quality of 
life assessments as part of the study assessments   
Added endpoint 2.4.3 to denote how persistence of T cells will be measured 
 
The attached version dated November 10, 2016 incorporates the above revisions 
  
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 17 of 154
 
 
 
 
PROTOCOL AMENDMENT # 2 
 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas after High 
Dose Therapy and Autologous Stem Transplantation (ATLAS) 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
X     Scientific changes (IRB approval)         
        Therapy changes (IRB approval) 
X      Eligibility Changes (IRB approval)  
        Other 
 
Summary of Changes 
Updated the list of Co-Investigators with the addition of Ashley Zanter, MSN, AOCNP; 
Megan Royall McElfresh, PA; Yara Park, MD; Christopher Dittus, DO, MPH; Natalie Grover, 
MD; Angela Spruill, MSN, ANP-BC, OCN; Alicia Pinto, MSN, ANP; Grace Park, PA 
Minor administrative updates throughout the protocol. 
Clarifying language has been added about the Study Sample Biobank Repository including 
storage location, storage time and storage purpose. Please refer to Section 6.7. 
Clarifying language in regards to documentation of AEs or SARs. AEs and SARs collection 
shall begin at the time that the main study consent form is signed by the subject prior to 
ATLCAR.CD30 infusion. This collection should continue through the 6 week follow-up 
period after cellular treatment is discontinued. In addition, any AEs or SARs experienced by 
the subject related to the procurement procedure must also be documented. Please refer to 
Section 7.2. 
Section 6.2.3 and the Time and Events Table footnotes #10 and #13 indicate that 10 mL of 
blood will be drawn at the 3-4 hour post-infusion time point. This amendment increases the 
amount of blood drawn to 16 mL (10 mL in a sodium heparin tube and 6 mL in an EDTA 
tube). 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 18 of 154
 
 
 
Inclusion Criterion 3.1.5 states that CD30+ disease is defined as ≥30% of the neoplastic cells 
stained as positive for CD30. This has been updated to indicate that CD30+ disease requires 
documented CD30 expression by immunohistochemistry based on the institutional 
hematopathology standard. 
Inclusion Criterion 3.1.7 indicates that imaging results are required within 30 days prior to 
transplant. This protocol amendment clarifies that the results may be obtained at a time point 
greater than 30 days from transplant if obtained per the patient’s standard of care and with 
prior sponsor approval. 
Added Section 6.6 and Appendix B to describe the addition of patient reported outcome 
measures which will be collected via PROMIS Global Health and Physical Function and NCI 
PRO-CTCAE questionnaires. These assessments will be optional. Relevant sections of the 
protocol, including the time and events table and foot note #19 of the time and events table, 
were updated to note the inclusion of PRO assessments. 
Section 4.1, Section 4.2 and footnote #6 of the time and events table of the protocol indicated 
that peripheral blood cells will be collected from consenting subjects who meet eligibility for 
cell procurement for creation of ATLCAR.CD30 cells prior to mobilization and collection of 
peripheral blood stem cells (PBSCs). This section was not meant to exclude patients who had 
previously had PBSCs collected and stored for their planned autologous stem cell transplant. 
Previously collected and stored PBSCs can be used as part of the autologous stem transplant 
therapy and blood may be procured for the creation of ATLCAR.CD30 cells any time prior to 
the autologous stem cell transplant even if PBSCs have already been collected and stored for 
transplant. These sections have been thus updated accordingly. 
Section 4.2 (Cell Procurement) has been updated to indicate that a total of 300 mL of blood (in 
up to 3 collections) will be obtained for procurement. 
Sample collection of ~1 mL of serum and ~10 mL of blood has been added in the event of 
cytokine release syndrome or severe toxicity (SAE resulting in hospitalization). Please refer to 
Section 6.5.5 and the time and events table footnote #16. 
Clarified inclusion criterion prior to infusion of ATLCAR.CD30 cells to indicate that although 
ANC, platelet counts and Hg must be measured over 3-5 day time frames they do not need to 
be measured on each day of the timeframe. Instead they may be measured at the beginning and 
the end of the time frame. 
 
The attached version dated October 3, 2016 incorporates the above revisions 
  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 19 of 154
 
 
 
 
PROTOCOL AMENDMENT # 1 
LCCC 1524-ATL: Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ Lymphomas after High 
Dose Therapy and Autologous Stem Transplantation (ATLAS) 
 
AMENDMENT INCORPORATES: 
X     Editorial, administrative changes 
X     Scientific changes (IRB approval)         
        Therapy changes (IRB approval) 
X      Eligibility Changes (IRB approval)  
        Other 
 
Summary of Changes 
Added names or corrected spelling of names of co-investigators and minor editorial changes. 
Lugano Classification - Lymphoma Response Criteria provided in Appendix A to the protocol 
and the accompanying reference (#71) cited in Section 10 under References.  
Changed eligibility criterion 3.1.2 to clarify that adults are ≥18 years of age and children 
eligible for enrollment are 3 to 17 years of age. Clarified language in exclusion criteria 3.2.1. 
and 3.2.2 to note requirement timings in relation to cell infusion  
An annual physical exam will be required ONLY for the first 5 years of follow up  
Children will not be allowed to enroll in a dose cohort until a minimum of 2 adult subjects are 
treated at that dose level and complete the follow-up for DLT . 
Statistical Section 8.0 updated to include the stipulation that children are not allowed to enroll 
in a dose cohort until a minimum of 2 adult subjects are treated at that dose level and complete 
their follow-up for  DLT. 
Clarified that the D1/Week 3 visit will be optional. This is an optional visit that will occur if 
the condition of the subject is such that follow up on D1/Week 3 is considered medically 
necessary by the investigator. Added clinical labs to this assessment visit which can be 
performed as needed but are not required. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 20 of 154
 
 
 
Changed DLT definition for ANC to >1,000/µl in Section 4.4.3 
Modified the labs collected at each study visit to include collection of a complete metabolic 
panel  
Added section 6.6 Biobank Repository that explains how the biological samples collected for 
the study will be handled and stored. 
Changed platelet count in inclusion criterion 3.1.6 to 25,000 cells/mm3  
 
The attached version dated April 29, 2016 incorporates the above revisions 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 21 of 154
 
 
 
 
LCCC1524-ATL 
Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ 
Lymphomas after High Dose Therapy and Autologous Stem Transplantation 
(ATLAS) 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to chimeric antigen 
T cell receptor therapy are the confidential and proprietary information of Lineberger 
Comprehensive Cancer Center, and except as may be required by federal, state or local laws or 
regulation, may not be disclosed to others without prior written permission of Lineberger 
Comprehensive Cancer Center. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Conference on Harmonization guidelines, and will make 
a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any amendments, 
and access to all information provided by Lineberger Comprehensive Cancer Center or specified 
designees. I will discuss the material with them to ensure that they are fully informed about 
ATLCAR.CD30 and the study. 
 
 
 
 
Principal Investigator Name (printed) 
Signature 
 
______________________________ 
__________________________ 
Date 
 
_________________ 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 22 of 154
 
 
 
STUDY SUMMARY 
Title:  
Phase I Study of the Administration of T Lymphocytes Expressing the CD30 
Chimeric Antigen Receptor (CAR) for Prevention of Relapse of CD30+ 
Lymphomas after High Dose Therapy and Autologous Stem Transplantation 
(ATLAS) 
Rationale:  
This open label, single-arm multicenter study is designed to identify the 
maximum tolerated dose (MTD) within 3 dose levels of autologous T 
lymphocyte chimeric antigen receptor cells (ATLCAR) targeted against the 
CD30 antigen (ATLCAR.CD30). the CD30 antigen is expressed on almost 
all Hodgkin lymphomas (HLs) at diagnosis and at relapse; and its viability 
as a target has been confirmed with the success of brentuximab vedotin [4], 
an antibody-drug conjugate that targets CD30. Brentuximab vedotin 
produces objective tumor responses in HL, albeit with limited durability and 
serious toxicities reported in 31% of subjects. The hope is that CD30-
directed CAR-T therapy will provide durable responses and improve 
outcomes in adult and pediatric subjects with HL and other CD30+ 
lymphomas. Moreover, ALTCAR.CD30 therapy should reduce the risks of 
long-term complications that are associated with available therapies for HL, 
which is a special concern for pediatric subjects. 
 
Target 
Population: 
Adult and pediatric subjects with relapsed/refractory CD30+ peripheral T 
cell Hodgkin’s and Non-Hodgkin’s lymphoma 
Number of 
Subjects: 
40 subjects 
Primary 
Objectives:  
To determine the safety and tolerability and to estimate the MTD of 
ATLCAR.CD30 post ASCT in subjects with CD30+ lymphoma at high risk 
for relapse 
Secondary 
Objectives: 
To measure the survival of ATLCAR.CD30 in vivo 
To estimate PFS after infusion of ATLCAR.CD30 post ASCT in subjects 
with CD30+ lymphoma at high risk for relapse 
To determine the overall survival after infusion of ATLCAR.CD30 post 
ASCT in subjects with CD30+ lymphoma at high risk for relapse 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 27 of 154
 
 
 
6.1 
Duration of Therapy ............................................................................................65 
6.2 
Duration of Follow-Up .........................................................................................65 
6.3 
Removal of Subjects from Protocol Therapy ....................................................65 
6.4 
Study Withdrawal ................................................................................................65 
7.0 DESCRIPTION OF STUDY PROCEDURES .......................................................67 
7.1 
Clinical Assessments ............................................................................................67 
7.1.1 
Disease Assessment Guidelines for Cutaneous Lymphomas .....................67 
7.2 
Screening and Treatment Assessments ..............................................................69 
7.2.1 
Pre-procurement ............................................................................................69 
7.2.2 
Pre-infusion ....................................................................................................70 
7.2.3 
Treatment (D1 Week 0) .................................................................................72 
7.3 
Short-term Follow-up ..........................................................................................72 
7.3.1 
D1 Week 1 .......................................................................................................72 
7.3.2 
D1 Week 2 .......................................................................................................73 
7.3.3 
D1 Week 3 (Optional Visit) ...........................................................................73 
7.3.4 
D1 Week 4 .......................................................................................................74 
7.3.5 
D1 Week 6 .......................................................................................................75 
7.3.6 
D1 Month 3 .....................................................................................................76 
7.3.7 
D1 Month 6 .....................................................................................................76 
7.3.8 
D1 Month 9 .....................................................................................................77 
7.3.9 
D1 Month 12 ...................................................................................................77 
7.4 
Long Term Follow-Up .........................................................................................78 
7.5 
Correlative Studies: Tests of Function, Persistence and Safety ......................79 
7.5.1 
Function and Persistence Studies .................................................................79 
7.5.2 
RCR Testing by PCR .....................................................................................79 
7.5.3 
Clonality ..........................................................................................................79 
7.5.4 
HAMA Testing ...............................................................................................80 
7.5.5 
Genetic Analysis .............................................................................................80 
7.5.6 
Sample Collection Requirements if CRS or Severe Toxicity Occurs ........80 
7.5.7 
Other Tissue Studies ......................................................................................81 
7.5.8 
Biobank Repository .......................................................................................81 
7.6 
Patient Reported Outcomes Measures ...............................................................83 
7.7 
Assessment of Safety ............................................................................................84 
7.8 
Assessment of Efficacy .........................................................................................84 
7.8.1 
Measurement of Disease ................................................................................84 
8.0 STUDY TREATMENT INFORMATION .............................................................85 
8.1 
Construction of CD30 Vector .............................................................................85 
8.2 
Generation of Transduced Cells .........................................................................85 
8.2.1 
Source Material ..............................................................................................85 
8.2.2 
Activated T Lymphocytes..............................................................................85 
8.2.3 
Retroviral Production ....................................................................................86 
8.2.4 
Transduction ..................................................................................................86 
8.2.5 
Ex Vivo Expansion .........................................................................................86 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 28 of 154
 
 
 
8.2.6 
Freezing ...........................................................................................................86 
8.2.7 
Testing .............................................................................................................86 
8.3 
Potential Toxicities ...............................................................................................87 
9.0 ADVERSE EVENTS ................................................................................................90 
9.1 
Definitions .............................................................................................................90 
9.1.1 
Adverse Event (AE) .......................................................................................90 
9.1.2 
Suspected Adverse Reaction (SAR) ..............................................................90 
9.1.3 
Unexpected AE or SAR .................................................................................91 
9.2 
Documentation of Non-Serious Adverse Events or SARs ................................91 
10.0 SERIOUS ADVERSE EVENT ................................................................................92 
10.1 
Definition of Serious Adverse Event ..................................................................92 
10.2 
Documentation of SAEs or Serious SARs ..........................................................92 
10.2.1 
Timing .............................................................................................................92 
10.2.2 
Documentation and Notification ...................................................................93 
10.3 
Adverse Event Reporting ....................................................................................93 
10.3.1 
IRB Reporting Requirements .......................................................................93 
10.3.2 
Pregnancy .......................................................................................................93 
10.3.3 
FDA Expedited Reporting Requirements ....................................................94 
10.3.4 
Institutional Biosafety Committee (IBC) .....................................................96 
10.4 
Data and Safety Monitoring Plan .......................................................................96 
11.0 STATISTICAL CONSIDERATIONS ....................................................................98 
11.1 
Design, Dose Escalation and MTD .....................................................................98 
11.2 
Sample Size ...........................................................................................................99 
11.3 
Data Analysis Plans..............................................................................................99 
11.3.1 
Safety Analysis of Adverse Event Data ........................................................99 
11.3.2 
Safety Analysis of Laboratory Data ...........................................................100 
11.3.3 
Analysis of Expansion and Persistence of Transduced T Cells ...............100 
11.3.4 
Analysis of Progression Free Survival .......................................................100 
11.3.5 
Analysis of Integration Location and CAR T cell Behavior ....................101 
12.0 STUDY MANAGEMENT......................................................................................102 
12.1 
Institutional Review Board (IRB) Approval and Consent .............................102 
12.2 
Required Documentation ..................................................................................102 
12.3 
Registration Procedures ....................................................................................103 
12.4 
Adherence to the Protocol .................................................................................103 
12.4.1 
Emergency Modifications ............................................................................103 
12.4.2 
Single Subject Exceptions ...........................................................................103 
12.4.3 
Other Protocol Deviations/Violations ........................................................103 
12.5 
Record Retention ...............................................................................................105 
12.6 
Obligations of Investigators ..............................................................................105 
13.0 AUDITING AND MONITORING ........................................................................106 
14.0 AMENDMENTS .....................................................................................................107 
15.0 STUDY DISCONTINUATION .............................................................................108 
16.0 CONFIDENTIALITY ............................................................................................109 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 29 of 154
 
 
 
17.0 REFERENCES .......................................................................................................110 
18.0 APPENDICES .........................................................................................................116 
18.1 
APPENDIX I – Names of Study Personnel......................................................116 
18.2 
APPENDIX II- Revised Response Criteria for Lymphoma ..........................117 
18.3 
APPENDIX III- Lansky and Karnofsky Performance Status .......................119 
18.4 
APPENDIX IV - Abbreviated Follow Up Required After Initiating 
Alternative Therapy...........................................................................................120 
18.5 
APPENDIX V - Patient Reported Outcomes Surveys ....................................122 
18.6 
APPENDIX VI- Response Assessment for Cutaneous ALCL/Lymphomatoid 
Papulosis .............................................................................................................134 
18.7 
APPENDIX VII - Response Assessment for Mycoses Fungoides and Sézary 
Syndrome ............................................................................................................137 
18.8 
APPENDIX VIII- CRS Toxicity Grading Scale and Management Guidelines141 
18.9 
APPENDIX IX - Neurotoxicity Treatment Algorithm ...................................152 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 30 of 154
 
 
 
TABLE OF FIGURES 
Figure 1 
Study Schema ...........................................................................................24 
Figure 2 
Schematic Representation of SFG.CAR.CD30 .....................................85 
 
TABLE OF TABLES 
Table 1  
Group One ................................................................................................52 
Table 2  
Group Two ................................................................................................52 
Table 3  
Group Three .............................................................................................52 
Table 4 
Time and Events Table ............................................................................55 
Table 5 
Study Assessments for LP and ALCL ....................................................68 
Table 6 
Study Assessment s for Mycosis Fungoides and Sézary Syndrome ....69 
Table 7 
Abbreviated Follow-up After Initiating Alternative Therapy ...........120 
Table 8 
CD30+ Lymphoproliferative Disorders (LPDs) – Recommended 
Definitions of CD30+ LPDs ...................................................................134 
Table 9 
Global Response Score for LYP and PCALCL ..................................136 
Table 10 
Modified Severity Weighted Assessment Tool for Mycoses Fungoides and 
Sézary Syndrome ...................................................................................137 
Table 11 
Response in Lymph Nodes* for Mycoses Fungoides and Sézary Syndrome
..................................................................................................................138 
Table 12 
Response in Blood* for Mycoses Fungoides and Sézary Syndrome..139 
Table 13 
Global Response Score for Mycoses Fungoides and Sézary Syndrome140 
Table 14 
Signs and Symptoms of CRS .................................................................141 
Table 15 
CRS Grading ..........................................................................................143 
Table 16  
Adult CRS Treatment Algorithm .........................................................145 
Table 17.  
High dose vasopressors in adult patients .............................................147 
Table 18.  
Pediatric CRS Treatment Algorithm ...................................................148 
Table 19. 
 Definition of hypotension in pediatric patients ..................................150 
Table 20. 
 Definition of tachycardia in pediatric patients ...................................150 
Table 21. 
 High dose vasopressors in pediatric patients .....................................151 
Table 22.  
Neurotoxicity Treatment Algorithm ....................................................152 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 31 of 154
 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALCL 
Anaplastic large cell lymphoma 
ALK-1 
Anaplastic lymphoma kinase 1 
ALL 
Acute lymphoblastic leukemia 
AML 
Acute myeloid leukemia 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated partial thromboplastin time 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate Aminotransferase 
ATL 
Autologous T Lymphocytes 
ATLCAR 
Autologous T Lymphocyte – Chimeric Antigen Receptor 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BOR 
Best Overall Response 
BSA 
Body surface area 
BUN 
Blood Urea Nitrogen 
CAP 
College of American Pathologists 
CAR-T 
Chimeric Antigen Receptor T Cell 
CHOP 
Cyclophosphamide, doxorubicin, vincristine, and prednisone 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL 
Chronic lymphocytic leukemia 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 32 of 154
 
 
 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CoA 
Certificate of Analysis 
CTO 
Clinical Trials Office 
CR 
Complete Response 
CRM 
Continual Reassessment Method 
CRS 
Cytokine Release Syndrome 
CT 
Computer Tomography 
CTLs 
Cytotoxic T-lymphocytes 
DCR 
Disease Control Rate 
DL 
Dose Level 
DLBCL 
Diffuse large B- cell lymphomas 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DSMC 
Data Safety Monitoring Committee 
EBV-CTL 
Epstein-Barr Virus-Specific Cytotoxic T Lymphocytes 
ECHO 
Echocardiography 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
FDA 
Food and Drug Administration  
FL 
Follicular lymphoma 
GCP 
Good Clinical Practice 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 33 of 154
 
 
 
g-CSF 
Granulocyte-colony stimulating factor 
HAMA 
Human Anti-Mouse Antibodies 
HER2 
Human epidermal growth factor receptor 2 
HL 
Hodgkin’s Lymphoma 
HLA 
Human leukocyte antigen 
HLH 
Hemophagocytic lymphohistiocytosis 
LDH 
Lactate dehydrogenase 
LMP-1 
Latent membrane protein (LMP-) 
mAB 
Monoclonal antibodies 
MAS 
Macrophage activation syndrome 
MTD 
Maximum tolerated dose 
MHC 
Major histocompatibility complex 
NHL 
Non-Hodgkin’s Lymphoma 
ORR 
Overall response rate 
PBMCs 
Peripheral blood mononuclear cells 
PFS 
Progression-free survival 
PT 
Prothrombin time 
PTCL 
Peripheral T-cell lymphoma 
Q-PCR 
Quantitative polymerase chain reaction 
RANKL 
Receptor activator of nuclear factor kappa-B ligand 
RCR 
Replication competent retrovirus 
SAE 
Serious Adverse Event 
SCT 
Stem cell transplant 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 34 of 154
 
 
 
TNF 
Tumor necrosis factor 
TNF-R 
Tumor necrosis factor receptor 
TRAIL 
TNF-α-related apoptosis-inducing ligand 
WOCBP 
Women of childbearing potential 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 35 of 154
 
 
 
1.0 INTRODUCTION AND RATIONALE 
1.1 
Study Synopsis 
This open label, single-arm multicenter study is designed to identify the maximum 
tolerated dose (MTD) within 3 dose levels of autologous T lymphocyte chimeric 
antigen receptor cells (ATLCAR) targeted against the CD30 antigen (ATLCAR.CD30). 
This phase I design uses the continual reassessment method (CRM), a Bayesian 
adaptive method for estimating the MTD. Subjects with CD30+ lymphoma at high risk 
of relapse will receive one infusion of ATLCAR.CD30 after undergoing an autologous 
stem cell transplant (ASCT) for treatment of recurrent disease. The study will enroll up 
to a maximum of 18 subjects. Secondary endpoints include evaluation of persistence 
of ATLCAR.CD30 cells in vivo, and progression free survival (PFS). Study 
participants may be given the option to complete patient reported outcomes (PRO) 
questionnaires during the study.  
LCCC1524-ATL builds on the prior clinical trial experience of UNC investigators Drs. 
Dotti and Savoldo during their time at Baylor College of Medicine in Houston Texas. 
Reference in this protocol to their previous related trial experience is referring to work 
done at Baylor College of Medicine Cell and Gene Therapy Program (BCM-CAGT). 
1.2 
Hodgkin’s Lymphoma (HL) Overview 
HL, a malignant neoplasm of immature B cell origin, has an incidence of about 2.4 per 
100,000 per year [6]. Modern radiotherapy and/or chemotherapy regimens have 
dramatically improved the cure rate of subjects with HL. However, despite the 
identification of clinical prognostic factors, and the optimal use of primary and 
secondary treatments, HL remains fatal for more than 15% of subjects [6]. Even in 
subjects who are cured, the morbidity of therapy is substantial and long lasting. New 
therapeutic agents are required therefore not only to further reduce mortality but also 
to alleviate morbidity [7]. 
The commonly accepted standard of care for HL that has relapsed after initial treatment 
with standard chemotherapy is high dose chemotherapy followed by ASCT. While this 
approach is thought to provide better disease free survival than conventional second 
line chemotherapy alone, the relapse rate is over 40% [8]. Therefore, strategies to 
improve outcomes are needed, in particular for subjects at higher risk of relapse (i.e., 
subjects: with failure to achieve complete response post initial treatment OR; who 
relapse within 12 months of initial complete response OR with extranodal involvement 
at time of pre-transplant salvage therapy) [4].. 
In about 40% of cases of HL, tumor cells express viral latency proteins of Epstein Barr 
Virus (EBV) such as LMP-1 and 2 [9]. However, the great majority of HL does not 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 36 of 154
 
 
 
express viral proteins, while they almost invariably express the CD30 protein [10]. 
CD30 expression is routinely used for the diagnosis of HL. 
1.3 
CD30+ Non-Hodgkin’s Lymphoma (NHL) Overview 
Other types of lymphoma also express the CD30 antigen. Anaplastic large cell 
lymphoma (ALCL) is a subtype of peripheral T-cell lymphoma (PTCL) first described 
in 1985. ALCL represents a distinct category of large cell lymphomas defined by a 
strong expression of CD30 on all or most neoplastic cells [11]. It represents <5% of all 
cases of NHL [12]. Three subtypes of ALCL exist including systemic (s) ALK-1 
positive ALCL, ALK-1 negative, and primary cutaneous ALCL. The majority of 
subjects present in an advanced stage, and CHOP chemotherapy represents the most 
commonly used front-line regimen. Unfortunately, particularly for the ALK-1 negative 
and primary cutaneous ALCL, outcomes are poor. Treatment with conventional dose 
chemotherapy following relapse is often not curative. High dose chemo-radiotherapy 
followed by hematopoietic stem cell transplantation, however, may represent an 
effective therapy in these subjects [12, 13] 
CD30+ lymphoproliferative disorders (LPD) of the skin (CD30+ LPD) represent a 
well-defined spectrum of primary cutaneous T-cell lymphomas that have been 
recognized as distinct entities in recent lymphoma classifications [14]. Lympho-matoid 
papulosis and ALCL share the expression of CD30 antigen as a common phenotypic 
hallmark but differ in regard to their clinical and histological features as well as their 
biologic behavior [14]. 
 
CD30+ B-cell lymphomas have been observed and they are most commonly diffuse 
large B-cell lymphomas (DLBCL). In addition, occasional to numerous CD30+ B cells 
have been described in sporadic cases of follicular lymphoma (FL), resembling the 
pattern seen in reactive tonsils and lymph nodes [10]. 
CD30 may be present on activated B or T cells, but not resting mature or precursor B 
or T cells. Benign reactive CD30+ cells tend to be large, immunoblastic-appearing cells 
located at the periphery of germinal centers [10]. 
1.4 
CD30 as a Target Antigen 
CD30 is a transmembrane glycoprotein and is a member of the tumor necrosis factor 
receptor superfamily [10]. CD30 plays a role in regulating the function or proliferation 
of normal lymphoid cells. Members of the tumor necrosis factor (TNF)/TNF-receptor 
(TNF-R) superfamily coordinate the immune response at multiple levels. For example, 
TNF, LTα, LTβ and RANKL provide signals required for lymphoid neogenesis; CD27, 
OX-40, 4-1BB and CD30 deliver costimulatory signals to augment immune responses, 
while pro-apoptotic members such as TNF, CD95L and TRAIL may contribute to the 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 37 of 154
 
 
 
termination of the response [10]. CD30 plays a role in regulating the function or 
proliferation of normal lymphoid cells. Ki-1 (CD30) antigen expression has been used 
to identify ALCL and Reed-Sternberg (RS) cells in Hodgkin's disease [10]. Indeed, 
CD30 is expressed on virtually all Hodgkin’s RS cells, and is therefore a target for both 
antibody based immunotherapy and cellular therapies in almost all subjects with HL 
and in a proportion of those with NHL [10]. 
Initial approaches used an anti-CD30 mAb without a payload in the treatment of 
subjects with Hodgkin’s lymphoma. While this approach was reasonably well tolerated, 
the overall response rate and durability of those responses was quite poor [15, 16]. As 
a result a CD30 monoclonal antibody (MAb) drug conjugate, brentuximab vedotin 
(anti-CD30 mAb linked to monomethyl auristatin E) was generated. This drug 
conjugate is FDA approved for use in subjects with HL after failure of ASCT or in 
those who are not candidates for ASCT after failing at least two prior chemotherapy 
regimens, and in subjects with systemic ALCL who have failed at least one prior 
regimen. FDA granted accelerated approval for these indications in 2011 based on the 
rate of overall response reported in separate single arm phase II trials (n=102 in the HL 
trial; 75% overall response rate (ORR) and 34% complete remission (CR), and n=58 in 
the systemic ALCL trial; 86% ORR, 57% CR). In this latter study, duration of overall 
response was 12.6 months, and duration of CR 13.2 months [17]. Long-term data from 
the HL trial (after median of ~3 years), published in July 2015, reported a median 
overall survival of 40.5 months and PFS of 9.3 months [18]. 
While these data are promising, and support CD30 as a target for treatment, toxicity 
associated with brentixumab vedotin is not insignificant (see brentuximab vedotin 
(Adcetris®) prescribing information November 2014) and substantially due to toxicity 
mediated by the chemotherapic moiety, monomethyl auristatin E. Across both trials, 
the most common adverse reactions (≥20%), regardless of causality, were neutropenia, 
peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract 
infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. Serious 
adverse reactions, regardless of causality, were reported in 31% of subjects. The most 
common serious adverse reactions experienced by subjects with HL included 
peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), 
pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%). The 
most common serious adverse reactions experienced by subjects with systemic ALCL 
were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and 
urinary tract infection. Other important serious adverse reactions reported include 
progressive multifocal leukoencephalopathy (PML), Stevens-Johnson syndrome, and 
tumor lysis syndrome. Infusion related reactions including anaphylaxis have occurred 
with brentuximab vedotin. 
Based on these data, prescribing information for brentuximab vedotin include warnings 
and precautions on peripheral neuropathy, anaphylaxis and infusion reactions, 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 38 of 154
 
 
 
hematologic toxicities, serious and opportunistic infections, tumor lysis syndrome, 
hepatotoxicity, pulmonary toxicity, serious dermatologic reactions and embryofetal 
toxicity. In addition, the prescribing information includes a black box warning for PML. 
Brentuximab vedotin has also been evaluated for use as consolidation therapy post 
ASCT in HL subjects at high risk of relapse in a randomized (1:1) placebo controlled 
phase 3 trial (n=329) [4]. The toxicity profile of brentuximab vedotin was similar to 
that reported in the earlier trial; 67% of subjects in the brentuximab vedotin arm 
experienced peripheral neuropathy (13% experienced grade 3 peripheral neuropathy). 
Brentuximab vedotin significantly improved median PFS as compared to placebo (42.9 
months versus 24.1 months). FDA approval for this indication was recently granted. 
Data from brentuximab vedotin trials support CD30 as a therapeutically relevant target 
for the treatment of CD30+ lymphoma, although toxicities associated with its use are 
of concern. Studies evaluating alternative ways to target CD30 that may lead to options 
with reduced toxicity and improved efficacy are warranted. 
1.5 
Chimeric Antigen Receptor (CAR) Redirected T (CAR-T) Cells 
Since HL and NHL are both apparently sensitive to the cellular immune response (graft 
versus lymphoma effect) and antibody treatment, there is interest in combining both 
approaches through the generation of artificial CARs. Chimeric receptors are usually 
generated by joining the heavy and light chain variable regions of a MAb with a linker 
to form a single-chain Fv (scFv) molecule [19]. This scFv is then attached to the 
transmembrane and cytoplasmic portion of T Cell Receptors (TCR) ζ chain via a 
flexible hinge region. Engagement of the extracellular scFv of the chimeric receptor 
results in tyrosine phosphorylation of immune-receptor activation motifs present in the 
cytoplasmic domain, initiating T cell signaling to the nucleus. Human T lymphocytes 
genetically engineered to express these recombinant receptor genes have exhibited 
specific lysis via the perforin/granzyme pathways, as well as cytokine secretion upon 
exposure to tumor cells expressing the cognate target antigen [19]. The advantages of 
CARs over the native antibodies or ligands from which they derive are a consequence 
of their physical association with effector T cells [19-21]. Thus, CAR-T cells can have 
an active biodistribution, with migration through multiple tissue planes along 
chemokine gradients, and can recruit the multiple cytotoxic effector mechanisms 
available to a T cell, rather than the more restricted cytotoxic machinery associated 
with, for example, the Fc component of an antibody. CARs also offer advantages over 
transfer of native αβTCRs of T lymphocytes. Target cell recognition by αβTCRs is 
MHC restricted, precluding the design of a “universal” receptor for the treatment of 
subjects with different HLA polymorphisms. By contrast, CARs, like MAbs, are 
essentially universal as their cytotoxic activity is MHC- unrestricted [20]. Moreover, 
many tumors down-regulate expression of MHC molecules and/or have dysfunctional 
antigen processing machinery, so that the target antigenic epitopes for αβTCR are 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 39 of 154
 
 
 
simply not present. Since CAR-modified T cells bind directly to native proteins 
expressed on the surface of target cells without the need for antigen processing or 
MHC- restricted presentation, they are unaffected by this immune evasion strategy. 
Moreover, CARs can recognize non-protein antigens, unlike conventional αβTCRs 
[21]. 
1.5.1 Extending the Survival of CAR-T Cells 
Despite consistent and robust expression of CAR molecules in T cells, early clinical 
studies of the approach were disappointing. A major problem of CAR-T cells is 
their lack of expansion and persistence in vivo [21]. A number of factors likely 
contribute to these differences but a major contribution is the inability of CAR-
engagement alone to recapitulate the co-stimulatory events that follow the 
physiologic engagement of the native αβTCR. Full activation and proliferation of 
T cells requires not only TCR engagement (first signal) but also co-stimulation 
provided by antigen presenting cells (APCs, second signal) and cytokines (third 
signal) [21, 22]. A multiplicity of these costimulatory receptor-ligand and cytokine 
signals is required, in an optimal temporal and spatial sequence. CAR-T cells lack 
any such costimulation when they engage tumor cells, since these target cells are 
deficient in costimulatory molecule expression (e.g. CD8 0 and CD86) and do not 
release helper cytokines. CAR-T cells cannot receive activation through stimulation 
provided by professional APCs in secondary lymphoid organs since the native 
receptors on CAR-T cells are not specifically directed towards antigens on the hosts’ 
APCs. To compensate for the lack of costimulation following CAR engagement 
[21, 22], costimulatory signaling domains (CD28, OX40, 4-1BB, etc.) have been 
incorporated as part of the CAR itself. Studies using polyclonally activated T 
lymphocytes expressing these novel “second generation” CARs are currently open 
at several institutions [23-32]. 
At the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, 
TX, Dr. Savoldo and Dr. Dotti were Principal Investigators (PIs) on a clinical study 
in which subjects with CD19+ B-cell lymphomas were infused simultaneously with 
two autologous T-cell products [26]. Each product contained cells expressing the 
identical CAR exodomain specific for the CD19 antigen (CD19-specific scFv) 
present on many B-cell derived malignancies. In one product the CAR was coupled 
to the ζ endodomain (first generation) while in the second product the CAR was 
coupled to the CD28 and ζ endodomains (second generation). With this study 
design, each subject acted as “a self-control”, allowing us to directly discover, even 
in a small study with heterogeneous subjects, the consequences of incorporating a 
co-stimulatory endodomain on the fate of engineered T cells in vivo. Six subjects 
with B-cell lymphomas relapsed after multiple cycles of therapy using conventional 
treatments were enrolled into the study. For each subject, two T-cell products 
expressing either CAR.CD19ζ (first generation) or CAR.CD19-28ζ (second 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 40 of 154
 
 
 
generation) were generated. Both cell products were similar by functional and 
phenotypic analyses. Two subjects for each dose level (2x107, 1x108 and 2x108 
cells/m2 dose level 1, 2 and 3, respectively) were infused with both sets of 
CAR.CD19 modified T cells. Infusions were well tolerated without any immediate 
side effects. Expansion and persistence of CAR-T cells in vivo were assessed in the 
peripheral blood by quantitative PCR (Q-PCR) assays specific for CAR.19ζ and 
CAR.19-28ζ transgenes, respectively. Molecular signals for CAR.19-28ζ+ T cells 
increased from 3 hours after infusion to 1-2 weeks post infusion (representing a 2 
to 59 fold expansion). Molecular signals then declined by 6 weeks follow up and 
did not further expand in vivo. By contrast, molecular signals derived from 
CAR.19ζ+ T cells that were detected 3 hours after infusion did not show significant 
expansion thereafter (from 0 to 1 fold expansion), and had become almost 
undetectable by 6 weeks. These data indicate that the infusion of second generation 
CD19- specific CAR-T cells is safe at the doses so far tested and that CD28 does 
indeed provide a co-stimulatory signal in vivo in subjects with B-cell lymphoma 
[26].  
 
1.5.2 Clinical Experience with CAR-T Cells 
As of July 2018, there are over 250 clinical trials incorporating CAR-T cells 
registered as being open in clinicaltrials.gov, across all malignances. In April 2014, 
a review of CAR-T cell trials in hematologic malignancies was published, and 
included a summary of 12 published and 35 ongoing trials (including 3 targeting 
CD30). The majority of published and ongoing trials summarized in this review 
utilized CAR-T targeting CD19. Doses were expressed per m2 or per kg, with 
doses/m2 ranging in trials from 1.5 x107 to 3.3 x109/m2 [33-35]. Overall, as reported 
in the published trials, treatment with CAR-T cells was very well tolerated, and 
evidence of clinical benefits observed [36]. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 41 of 154
 
 
 
Toxicities Associated with CAR-T Cells 
Potential toxicities may be categorized as those related to infusion of T-cells; 
transduction; cross-reactivity with normal tissues; cytokine release syndrome 
(CRS); neurotoxicity; macrophage activation syndrome (MAS) and tumor lysis 
syndrome.  
Infusion of T Cells 
Regarding infusion of T cells, in this study we will be administering transduced 
autologous peripheral blood ATL so there will no risk of alloreactivity. Many 
previous studies have infused much larger numbers of autologous T cells that have 
been activated ex vivo with no adverse effects [37, 38].  
Retroviral Transduction 
Retroviral transduction, discussed in more detail in section 8.3, results in new 
random integrations in host cell DNA, which rarely may cause abnormal or 
uncontrolled proliferation [39]. This effect is much more common with replication-
competent retrovirus (RCR) where each cell receives multiple integrants [40]. We 
will test the producer line and all batches of supernatant with biological assays of 
RCR to exclude this possibility. 
Cross-Reactivity with Normal Tissues 
In terms of cross-reactivity (also described in more detail in Section 8.3), we chose 
to target CD30 since this antigen is only expressed on cells of hematopoietic origin. 
It is not detected on cells of the peripheral blood or on resting lymphocytes, but it 
is only present on a subpopulation of physiologically activated T-cells and on 
thymic medulla[10]. The CD30 knock out mouse shows impaired thymic negative 
selection of T lymphocytes but this does not compromise the development of 
efficient immune responses[41]. We previously showed that CAR.CD30-redirected 
T-cells did not impair the generation of virus specific cytotoxic T-lymphocytes 
(CTLs) ex vivo[42] and CD30 is not expressed in normal tissues like lung and 
fibroblasts (RAC#1003-1034).  
CRS/Tumor Lysis Syndrome 
CRS is a potential major side effect of CAR-T cell therapy and results from the 
release of inflammatory cytokines secondary to T-cell activation. The severity of 
CRS may be related to tumor burden, particularly for therapy involving CAR-T 
cells [36, 43]. CRS may correlate with anticancer activity (although whether the 
severity correlates as well is an outstanding question), and CRS is often 
accompanied by high levels of IL-6 [36]. Symptoms of CRS vary greatly, and may 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 42 of 154
 
 
 
include (but are not limited to) fever, rash, hypoxemia, delirium, hypotension, 
nausea and diarrhea [43]. When associated with CAR-T therapy, symptom onset 
can occur days to weeks after the infusion, perhaps associated with maximal in vivo 
expansion of T cells. Very high doses of T cells may result in early more severe 
reactions, although a clear dose response relationship has not yet been defined [43]. 
Strategies to minimize this syndrome include lowering the dose of CAR T cells and 
treatment with an anti-IL6 receptor antibody, or in severe cases, corticosteroids. 
SAEs resulting from CRS have been reported in subjects receiving CAR-based T 
cell therapies [44, 45]. Morgan and colleagues at the NIH reported a subject with 
widely metastatic colon cancer who received over 1010 T cells modified with a CAR 
targeting HER2 containing two costimulatory moieties (CD28 and 4-1BB) after 
intensive lymphodepletion. This subject developed pulmonary toxicity within 15 
minutes in association with very high cytokine levels followed by cardiac arrest 
and death 4 days later [45]. After extensive investigation and analysis of autopsy 
specimens the investigators concluded that the toxicity may have been due to 
effects of the transgene on pulmonary endothelium. This protocol is very different 
from the current study in that (1) a much higher dose of T cells was given, (2) the 
target was HER-2/neu which has different tissue expression than CD30, and (3) the 
construct contained two costimulatory domains.  
Brentjens and colleagues from Memorial Sloan Kettering Cancer Center reported a 
subject with bulky CLL and extensive previous treatment who received autologous 
T cells transduced with a CD19-28ζ CAR in a dose of 3 x 107/kg after 
lymphodepletion with cyclophosphamide [44]. This subject developed fever, 
hypotension and dyspnea 6 hours post infusion that rapidly progressed. In this 
subject elevated cytokine levels were also seen and an autopsy failed to reveal an 
obvious cause of death. The investigators concluded that sepsis was the most likely 
cause in this heavily pre-treated immunosuppressed subject but could not exclude 
the possibility that a cyclophosphamide induced “cytokine storm” may have 
enhanced modified T cell in vivo activation, and led to tumor lysis syndrome.  
Investigators at the CAGT program at Baylor have given T cells expressing CD19-
specific CAR with or without CD28 co-stimulatory endodomain to 12 subjects with 
B-cell malignancies (2x107 cells/m2, 1x108 cells/m2 or 2x108 cells/m2) and T cells 
expressing Kappa-Light-Chain -specific CAR with CD28 co-stimulatory 
endodomain to 16 subjects with B-cell malignancies or Multiple Myeloma (2x107 
cells/m2, 1x108 cells/m2 or 2x108 cells/m2) with no adverse effects [26] [46]. In 
addition, Dr. Dotti and Dr. Savoldo have recently completed a phase I trial of 
CAR.CD30 in relapsed/refractory CD30+ lymphoma, described in section 1.5.5, 
and did not observe any CRS or other toxicities.     
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 43 of 154
 
 
 
Neurotoxicity 
Neurotoxicity from CAR-T cell therapy can occur as part of cytokine release 
syndrome or as an independent process. The underlying pathophysiology for 
neurologic toxicity from CAR-T therapy is not fully understood. CAR-T cells in 
the central nervous system (CNS) may play a role. However, the heightened 
systemic inflammatory and cytokine state resulting from CAR-T therapy may also 
be a factor. 
The symptoms and manifestations of neurotoxicity are broad and range from 
confusion/altered mental status to seizure to cerebral edema. Routine monitoring is 
critical in patients receiving CAR-T therapy to identify neurologic symptoms early 
and neurology should be consulted for any subjects who exhibit early 
signs/symptoms of neurotoxicity. Early interventions should be employed to 
prevent worsening, especially if therapies are already indicated such as 
corticosteroids. 
Macrophage Activation Syndrome 
Macrophage activation syndrome (MAS) has been found previously in patients 
with acute lymphoblastic leukemia receiving CAR T cell therapy. MAS is 
characterized by pancytopenia, liver insufficiency, coagulopathy and neurological 
symptoms and is thought to be mediated by uncontrolled proliferation and 
activation of T cells leading to macrophage activation and differentiation and 
cytokine production with hemophagocytosis. The pathophysiology of MAS is 
complex, 
but 
appears 
to 
have 
some 
similarities 
to 
hemophagocytic 
lymphohistiocytosis (HLH). Correlative evaluations have shown that hepatic 
biopsy samples in patients with hemophagocytic lymphohistiocytosis including a 
subgroup with macrophage activation syndrome demonstrated the presence of 
CD8+ T cells generating IFN- γ with macrophages generating IL-6 and TNF. There 
was overproduction of IL-18, which may play a role in the polarization of T cells. 
Diagnosis of macrophage activation syndrome is based on pancytopenia, fever, 
elevated AST, ALT, triglycerides and LDH, increased prothrombin time (PT) and 
activated partial thromboplastin time (aPTT) associated with increased number of 
fibrin split products and decreased fibrinogen. Additionally, splenomegaly, 
hepatomegaly and CNS dysfunction characterized by lethargy, irritability, 
disorientation, headache, seizures and coma can be found. 
1.5.3 Rationale for ATLCAR.CD30 in Pediatric Subjects with CD30+ Lymphoma 
HL occurs in both children and adults; the American Cancer Society projects that 
8,500 new cases of HL will be diagnosed in the US in 2016 (3,710 in females and 
4,790 in males). HL is a common malignancy in young adults [47] (ages 15 to 40), 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 44 of 154
 
 
 
peaking 
in 
incidence 
in 
persons 
in 
their 
20s 
[http://www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-
key-statistics]. Although rare in children less than 5 years of age, approximately 
10-15% of HL cases are diagnosed in children and teenagers. The long term impact 
of therapy for HL on quality of life is of special concern given that this disease 
often impacts a much younger cohort of subjects than the typical malignancy. Thus, 
treatment of HL requires a careful balance between providing effective therapy to 
cure the disease while minimizing the toxic effect of therapy that could result in 
excessive long-term treatment-related complications [47].  
Although approximately 90% of limited stage HL subjects are projected to be cured 
with standard of care therapy (i.e., multi-agent chemotherapy ± radiation), many do 
not live their expected life span due to delayed treatment–related toxicities that 
include secondary malignancies and cardiovascular disease [48, 49]. For example, 
the preferred treatment option for early stage I or II non-bulky HL with favorable 
prognosis is the use of chemotherapy (e.g., doxorubicin, bleomycin, vinblastine, 
and dacarbazine; ABVD) with or without involved-field radiation therapy [50-52]. 
In a recent retrospective study, survivors of HL treated with chemotherapy alone 
had a lower incidence of secondary malignancies with a 30-year cumulative 
incidence of 5.8%, compared to 24.7% in HL subjects who received consolidative 
radiation [53]. Given the unclear overall survival advantage, and the long-term 
toxicities associated with consolidative radiation, the use of this modality remains 
controversial in the treatment of HL. In addition, both an increased dose of radiation 
and anthracycline exposure were associated with significantly increased risk of 
cardiovascular complications [54]. While the use of interim PET/CT to guide 
treatment of limited stage disease can identify subjects who need less intensive 
therapy, treatment for those with high-risk disease is more intensive and acute, and 
long-term complications of therapy remain a concern. Furthermore, salvage 
chemotherapy for subjects who relapse includes high-dose chemotherapy followed 
by a stem cell transplant [52]. While effective, the intensity of this approach also 
leads to long-term treatment-related comorbidities such as secondary acute myeloid 
leukemia and myelodysplastic syndrome [55, 56]. Although the two leading causes 
of death in HL survivors are second malignancies and cardiovascular disease, other 
key late complications include atherosclerotic disease, pulmonary disease, and 
endocrine dysfunction such as hypothyroidism and infertility [57]. 
In addition to the risks associated with therapies for HL, current thinking is that the 
success of traditional chemotherapy and radiation-based strategies for the treatment 
of pediatric malignancies has reached a plateau, especially in subjects with 
relapsing or refractory disease [58]. The additive toxicities and limited efficacy of 
conventional regimens in achieving a cure has led to Phase I studies in pediatric 
cancers of immune-based or molecularly targeted therapies to prevent relapse or 
treat minimal disease.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 45 of 154
 
 
 
As noted in section 1.5.2, of the over 250 trials incorporating CAR-T cells 
registered on the https://clinicaltrials.gov/ website, there are currently at least 30 
studies that have allowed for pediatric enrollment with the majority of these trials 
being conducted in CD19+ hematologic malignancies [36, 58]; moreover, these 
approaches are showing promise. For example, a CD19-directed CAR therapy 
study conducted at the Children’s Hospital of Philadelphia reported outcomes in 25 
children with ALL, the majority of whom had received prior SCT [31]. Complete 
remissions were achieved in up to 90% of these subjects, which included 2 children 
previously treated with blinatumomab. In addition, event-free and overall survival 
at 6 months in these subjects were 67% and 78%, respectively and durable 
remissions of up to 24 months have been observed. Other CD19 CARs studies 
enrolling pediatric subjects are also reporting promising outcomes in ALL with 
manageable toxicity [28, 59]. Moreover, CARs are in development targeting other 
lymphoid and myeloid antigens such as CD13, CD20, CD30 and CD33 [58]. 
Clinical trials targeting these antigens are currently ongoing, with promising 
preliminary data reported for ATLCAR.CD30 therapy in relapsed/refractory 
CD30+ lymphomas as discussed in the next section.  
As noted in section 1.4 above, the CD30 antigen is expressed on almost all HLs at 
diagnosis and at relapse; and its viability as a target has been confirmed with the 
success of brentuximab vedotin [4], an antibody-drug conjugate that targets CD30. 
Brentuximab vedotin produces objective tumor responses in HL, albeit with limited 
durability and serious toxicities reported in 31% of subjects. The hope is that CD30-
directed CAR-T therapy, which appears safe thus far (see section 1.5.5), will 
provide durable responses and improve outcomes in adult and pediatric subjects 
with HL and other CD30+ lymphomas. Moreover, ALTCAR.CD30 therapy should 
reduce the risks of long-term complications that are associated with available 
therapies for HL, which is a special concern for pediatric subjects. 
1.5.4 ATLCAR.CD30 
After constructing a CAR targeting CD30 [60, 61], Drs. Savoldo and Dotti 
demonstrated in preclinical studies that T-lymphocytes engineered to express this 
receptor are redirected to kill CD30+ HL cell lines [42, 62].  
The success rate for manufacturing of cells is 100%. At Baylor College of Medicine, 
cell lines have been manufactured for 18 subjects starting from a median of 2.4×107 
PBMCs (range 3.6×106 to 4.9×107). During cell manufacture, 3 subjects became 
ineligible due to rapid worsening of their performance status and 1 subject was not 
infused because his tumor was subsequently shown to be CD30-negative. One 
subject was still in remission and without evidence of disease post SCT and 1 
subject went on to another phase I study. At the time of protocol submission, 3 
subjects were awaiting assessment of eligibility for ATLCAR.CD30 treatment. We 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 46 of 154
 
 
 
therefore consider the number of subjects accrued but unable to receive 
ATLCAR.CD30 cells as limited. Subjects who did not receive treatment were 
ineligible to receive cells post SCT for clinical or other reasons. No subjects were 
unable to receive ATLCAR.CD30 treatment due to issues related to manufacturing 
failure. 
1.5.5 Phase I Trial of ATLCAR.CD30 for Relapsed/Refractory CD30+ Lymphoma 
At Baylor Drs. Savoldo and Dotti recently completed dose escalation in a phase I 
trial designed to determine if ATLCAR.CD30 was safe for therapy of CD30+ HL 
and CD30+ NHL and would persist in these subjects long enough to potentially 
control disease.  
ATLCAR.CD30 were given to 9 subjects (7 with HL and 2 with CD30 + ALCL) 
with relapsed/refractory HL or CD30+ NHL. Eight of the 9 subjects had relapsed or 
progressed after treatment with brentuximab vedotin. Two were treated on dose level 
(DL) 1 (2×107 CAR-T/m2), two on DL2 (1×108) and five on DL3 (2×108), without 
any conditioning regimen before T cell infusion, as mandated by FDA to exclude 
occurrence of “on target-off tumor” toxicities. CAR-T cell infusions produced no 
attributable adverse events, and none of the subjects developed a CRS. Nine subjects 
were evaluable for antitumor responses. At 6 weeks after treatment, 4 subjects had 
stable disease, 1 had PR and 1 had a CR, while 3 subjects (1 of whom with ALCL) 
had disease progression [63]. 
After establishing the safety and persistence of ATLCAR.CD30 in the non-
transplant setting, LCCC1524-ATL is designed to determine if these cells are safe 
for consolidation therapy following autologous transplant and will persist in subjects 
with CD30+ HL or NHL long enough to potentially control or prevent disease after 
high dose therapy and ASCT. 
1.6 
Study Design and Rationale 
ASCT may be the only curative option for subjects with refractory/relapsed 
hematological malignancies. Despite ASCT, disease recurrence remains the major 
cause of treatment failure. Hence development of non-toxic consolidation treatments 
after transplant remains a highly desirable objective, and the adoptive transfer of CTLs 
is one promising approach [64-67].  
In this Phase I multicenter study, peripheral blood will be collected for production of 
ATLCAR.CD30 cells in subjects with CD30+ lymphoma at high risk of relapse post-
transplant, and scheduled to undergo ASCT. Three dose levels will be evaluated to 
identify the MTD in this population: Level 1 = 2 × 107 CAR+ T cells/m2; Level 2 = 1 × 
108/m2; Level 3 = 2 × 108/m2. The total number of cells infused will be calculated on 
the number of CAR-T cells as requested by the FDA. Similar to the prior phase I 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 47 of 154
 
 
 
summarized in section 1.5.5, we will monitor the persistence of these infused cells in 
the peripheral blood of the subjects and whenever lymph nodes are biopsied as per 
routine clinical care during the first year after treatment at the tumor site by measuring 
the level of the transgene by both phenotypic and molecular analyses. Currently, we 
can regularly detect a single transduced cell in 50,000 peripheral blood mononuclear 
cells by real-time PCR amplification. Moreover, because gene persistence and 
expression may not correlate with antitumor effector function, we will also determine 
the functionality of the peripheral blood T cells ex vivo. 
Ex vivo expanded, polyclonally activated T cells have been infused as early as two days 
after stem cell transplant in myeloma subjects without significant side effects [68]. 
However, since the study we propose will be the “first in man” application of 
ATLCAR.CD30+ T cells after ASCT, we will infuse these cells after ASCT once 
hematologic recovery is evident (see section 4.1.2 for this definition). By using this 
conservative approach, we believe we will be able to infuse T cells in an environment 
in which homeostatic mechanisms favor lymphoid expansion [69] without interfering 
with stem cell engraftment. It is now evident that non-myeloablative conditioning is 
required to allow high level expansion of CAR-T cells and obtain optimal anti-tumor 
efficacy [70, 71]. ASCT creates a lymphodepleted environment, with production of 
high levels of homeostatic cytokines such as IL-7 and IL-15 that induce expansion of 
the infused CAR-T cells in the absence of competing endogenous lymphoid cells for 
the homeostatic cytokines [69].  
The ability to combine CAR-based therapies with ASCT will reduce tumor immune 
evasion of this cell therapy. Tumor cells use several mechanisms to evade immune 
responses, by generating hostile chemokine and cytokine milieus or by recruiting 
inhibitory cells such as Tregs and Th2 cells. This may limit the benefits of CAR-based 
therapies [72]. ASCT depletes Tregs and disrupts the tumor microenvironment 
improving the prospects for CAR+ T cell persistence, expansion and anti-tumor activity. 
HL and ALCL in particular will provide a useful model for studying this postulate since 
HL and ALCL cells release inhibitory molecules and ligands (TGFβ, IL-10, Fas-L) and 
attract suppressive T-cell subsets including Th2 and Tregs [73, 74].  
As outlined above, toxicities and even deaths [45, 69] due to “tumor lysis syndrome” 
and “cytokine storms” have occurred in subjects with high tumor burden when they 
received CAR-T cells. This is likely the result of rapid and massive T-cell activation 
through their CAR/costimulatory molecule complex followed by the release of 
cytokines (IFNγ, TNFα, IL-6 etc.). These potentially lethal toxicities should be limited 
if CAR- T cells are infused after ASCT, since the burden of targeted tumor will be 
minimized. [44, 45]. We will collect serum before and after infusion for cytokine 
monitoring, and continue to monitor subjects for 4 hours after infusion.  
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 50 of 154
 
 
 
4.0 STUDY PLAN 
This study is a multicenter, open-label phase I clinical trial testing the hypothesis that the 
administration of ATLCAR.CD30 to subjects with CD30+ lymphoma post autologous 
transplant is safe as evidenced by the rate of DLT. The rate of DLT will be used to 
determine the MTD; see section 4.1.3.2. Three dose levels of ATLCAR.CD30 will be 
evaluated to determine a recommended dose in adult and pediatric subjects. Initially, only 
adults will be enrolled during the dose escalation phase of the study. Once a dose level 
has been tested in at least 2 adults without the occurrence of DLTs during the assessment 
period, children may then be enrolled on that dose level according to the CRM. Each 
subject will receive one injection followed by close monitoring over the subsequent 6 
weeks. See section 7.4 for schedule of longer term follow-up.  
Subjects scheduled to undergo an ASCT at one of the protocol sites for treatment of 
lymphoma will be approached for consent to screening and potential enrollment into 
LCCC1524-ATL. Peripheral blood cells will be collected from consenting subjects who 
meet eligibility for cell procurement for creation of ATLCAR.CD30 cells (see section 
4.1.1) prior to ASCT. The ASCT, including mobilization and collection of PBSCs, 
administration of myeloablative therapy, reinfusion of PBSCs and supportive care 
following transplant will be as per routine standard of care, and not expected to be 
impacted by enrollment into LCCC1524-ATL. Post ASCT, subjects who meet eligibility 
criteria for treatment will receive one infusion of ATLCAR.CD30 cells once there is 
evidence of hematologic recovery as defined in section 4.1.2. Research personnel will 
keep track of any subjects who undergo procurement but do not undergo treatment with 
ATLCAR.CD30 cells, and the reason for withholding treatment. 
4.1 
Study Treatment 
4.1.1 Cell Procurement 
In adult subjects, up to 300 mL total of peripheral blood will be obtained (in up to 
3 collections) for cell procurement. In pediatric subjects, up to 3 mL/kg of 
peripheral blood will be obtained (in up to 3 collections) for cell procurement 
Additionally, leukopheresis leukapheresis may be performed to isolate sufficient 
cells in subjects with a low absolute lymphocyte count or who had inadequate 
peripheral blood collection. 
For pediatric patients (patients under 18 years of age), the total amount of blood 
drawn will not be more than 3 mL (less than 1 teaspoon) per 2.2 lbs. that the child 
weighs. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 51 of 154
 
 
 
4.1.2 ATLCAR.CD30 Cells Administration 
Post ASCT, once the subject has started to experience hematologic recovery 
(defined as ANC ≥500 cells/mm3 for 3 consecutive days, AND platelet count ≥25 
cells/mm3 without transfusion over the preceding 5 days, AND Hg ≥8g/dL without 
transfusion support over preceding 5 days), ATLCAR.CD30 cells will be 
administered as described below. The dose of cells and exact day of cell infusion 
will vary, depending on the cohort enrolled. See section 4.1.3 for dose levels and 
dose escalation rules. This will generally occur between 14 and 20 days following 
infusion of autologous stem cells following high-dose chemotherapy. 
 
Premedication 
Subjects may be pre-medicated with Benadryl (diphenhydramine) up to 1 
mg/kg IV (max 50mg) and Tylenol (acetaminophen) 10 mg/kg oral (max 
650mg). Alternative antihistamines or anti-pyretics can be used in the case of 
diphenhydramine or acetaminophen hypersensitivity. We will premedicate 
subjects who have a history of reactions to blood products. Steroids should be 
avoided given their detrimental effect on the survival of the infused T cells (see 
exclusion criteria 5). Anti-emetics in appropriate dosage for each subject will 
be prescribed as necessary.  
Cell Administration 
ATLCAR.CD30 cells will be given by a licensed provider via intravenous 
injection over 1-10 minutes through either a peripheral or a central line. The 
expected volume will be 1-50cc.  
Monitoring 
Monitoring will be undertaken according to institutional standards for 
administration of blood products. Subjects will be monitored for at least 4 hours 
post infusion. 
4.1.3 Dose Escalation Rules 
Three dose levels will be evaluated. Using the continual reassessment method 
(CRM), initial cohort of size two will be enrolled at each dose level (see section 
11.), after that subjects are enrolled one at a time until a minimum of 12 subjects is 
treated. Each subject will receive one injection according to the dosing schedules 
listed below. We will start with the lowest cell dose (2×107 cells/m2) given to 
subjects in one of our previous trials employing CAR-T cells including the CD28 
costimulatory endodomain [26], and we will escalate the cell dose to the highest 
cell dose (2×108/m2) given in the same trial [26]. These are also the doses utilized 
in the phase I trial using ATLCAR.CD30 and described in section 1.5.5. All those 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 52 of 154
 
 
 
cell doses were safe. A maximum dose is included for each dose cohort in order to 
avoid excessive dosing secondary to obesity and potentially resulting in toxicity. 
The maximum dose is calculated based on a body surface area of 2.5 m2.  
Note: Initially, only adults will be enrolled during the dose escalation phase of 
the study. Once a dose level has been tested in at least 2 adults without the 
occurrence of DLTs, children may then be enrolled on that dose level according 
to the CRM.  
 
Cell dose Levels 
Table 1 Group One 
Schedule 
ATLCAR.CD302 
Maximum Dose 
Week 0 Day 11 
2x107 cells/m2 
5x107 cells 
 
Table 2 Group Two  
Schedule 
ATLCAR.CD302 
Maximum Dose 
Week 0 Day 11 
1x108 cells/m2 
2.5x108 cells 
 
Table 3 Group Three  
Schedule 
ATLCAR.CD302 
Maximum Dose 
Week 0 Day 11 
2x108 cells/m2 
5x108 cells 
The dose is based on the CAR.CD30 expressing cell. With a lower limit of CAR 
positivity at 15%, even a larger subject (2.0 m2) would receive 2.66 x 109 total cells 
which would still be in the lower range of infused cells as reported by Johnson et 
al. [75].  
1. Only one infusion will be administered, and will be given after stem cell 
transplantation and engraftment as defined in section 4.1.2. 
2. If there are insufficient cells manufactured for a subject to receive their 
proposed dose level, the subject may be infused with a quantity of cells 
consistent with one of the previously cleared dose levels. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 53 of 154
 
 
 
Definition of MTD 
For this study, MTD is defined as the dose that causes DLT (see section 4.1.3.3) 
in 10% of eligible cases. The trial will continue until a minimum of 12 subjects is 
treated. Six additional subjects might be accrued to obtain more data at the current 
MTD. The final MTD will be the dose with estimated probability of the DLT 
closest to the target toxicity rate of 10%. 
Definition of a DLT 
The timeframe for DLT evaluation is from day of infusion through 6 weeks post 
infusion.  
Except as noted below, DLT will be defined as any of the following that may, after 
consultation with the FDA, be considered possibly, probably, or definitely related 
to the study cellular products: 
• Grade 3 and 4 cytokine release syndrome (CRS*) that persists beyond 72 hours, 
or any Grade 5 CRS 
• Any other ≥ Grade 3 non- hematologic toxicity, including allergic reactions to 
T cell infusions  
*Grade 3 and 4 expected CRS reactions seen with the use of CAR-based 
immunotherapy such as (but not limited to) fever and hypotension requiring pressor 
support will not be considered a DLT unless it persists beyond 72 hours.  
CRS toxicity will be graded according to the toxicity scale outlined in section 18.8 
(APPENDIX VIII- CRS Toxicity Grading Scale and Management Guidelines). 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 54 of 154
 
 
 
Supportive Care 
Subjects will receive supportive care for acute or chronic toxicity, including blood 
components or antibiotics, and other intervention as appropriate. 
4.1.4 Concomitant Medications/Treatments 
Ideally, subjects should not receive other antineoplastic agents for at least 6 weeks 
post T cells (for purposes of evaluation) however, subjects with progressive disease 
may receive other therapy if needed at the discretion of their attending physician. 
If subjects receive other therapy adverse event reporting will cease after the initial 
6-week assessments outlined in section 4.2 are completed. These subjects will 
continue to be monitored after PD according to the Time and Events Table in 
APPENDIX IV - Abbreviated Follow Up Required After Initiating Alternative 
Therapy (section 18.4).  
If subjects experience PD after the initial 6-week assessment period following the 
cell infusion has been completed, they should be followed according to the Time 
and Events Table in APPENDIX IV - Abbreviated Follow Up Required After 
Initiating Alternative Therapy(section 18.4). 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 55 of 154
 
 
 
4.2 
Time & Events Table 
Table 4 
Time and Events Table 
Study Assessments 
Screening1 
ATLCAR 
Treatment 2 
Follow-up 
Pre-
procurem
ent 
ASCT AS PER STANDARD OF CARE 
Pre-infusion 
of ATLCAR. 
CD30 cells 
Wk 
0 
D11 
Wk 
1 
D11 
Wk 
2 
D11 
(Opti
onal)
Wk 
3 
D11 
Wk 
4 
D11 
Wk 
6 
D11 
Mth 
3 
D11 
Mth 
6 
D11 
Mth 
9 
D11 
Mth 
12 
D11 
Every 
6mths 
x 4 yrs1 
Yearly1,17 
History3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical exam 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X1* 
Check Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Performance 
status1 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
Pregnancy test2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PFTs and EF4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff 5, 19 
X5 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Virus testing6 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procurement of 
cells 
After 
screening
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
metabolic panel7 
X7* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Tumor Imaging9 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X9 
 
Thyroid function10 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 56 of 154
 
 
 
Correlative 
Samples11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
X11,17 
HAMA testing12 
 
X12 
 
 
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity13 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
CoA 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
Infusion of ATL 
CAR.CD30 
 
 
X15 
 
 
 
 
 
 
 
 
 
 
 
PRO 
Questionnaires 
(optional)16 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tissue Studies 
See Section 7.5.7 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 57 of 154
 
 
 
Key to Time and Events Table Footnotes 
1. Screening includes tests to confirm eligibility for both procurement and treatment; 
NOTE: some pre-infusion screening tests may not be performed until the day of 
infusion. A window of +/-3 days will apply to all study visits for the first 8 weeks 
unless otherwise noted below. A window of +/-10 days will apply to every 3 
months study visits, and a window of +/-30 days will apply to visits separated by 
≥ 6 months. Yearly follow-up visits during long-term follow-up for a total of 15 
years. *An annual physical exam will be required ONLY for the first 5 years of 
follow up. NOTE: Follow-up visits for month 3 and beyond can be conducted 
locally (i.e., by local health care provider, local oncologist, etc.).  The study team 
would continue to contact the subjects at the long-term follow-up points and 
request they visit their local healthcare provider to complete the follow-up test and 
assessments, where applicable.  The study team would collect clinical information, 
tests and assessments results, other clinical observations from the subject’s 
medical record and their local health care provider.  
2. Serum pregnancy testing will be done in female subjects of childbearing potential 
within 72 hours prior to procurement and repeated 72 hours prior to infusion. 
3. Medical history must include collecting the following information: 1. New 
malignancy(ies) 2. New incidence or exacerbation of pre-existing neurologic 
disorder 3. New incidence or exacerbation of a prior rheumatologic or other 
autoimmune disorder 4. New incidence of a hematologic disorder and 5. New 
incidence of infection (potentially product related). 
4. PFTs = pulmonary function tests and includes forced expiratory volume in 1 
second (FEV1), forced vital capacity (FVC) and diffusing capacity (DLCO); 
EF=ejection fraction evaluated via MUGA or ECHO. These will be evaluated 
within 3 months prior to transplant. 
5. CBC includes complete blood count with diff and platelets. *NOTE: Pre-
procurement, only Hg is necessary, and if a serum Hg has already been performed 
within 7 days of procurement as part of SOC pre-transplant work-up, it does not 
need to be repeated. Prior to ATLCAR.CD30 treatment, CBC with diff and 
platelets must be performed within 24 hours prior to infusion. CBC with diff and 
platelets performed as needed on D1/Week 3. 
6. HIV, HBV, HCV testing required for confirmation that no active infection exists; 
results can be pending at the time of cell procurement; only those samples 
confirming lack of active infection will be used to generate transduced cells. Virus 
testing may be performed up to 30 days prior to procurement. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 58 of 154
 
 
 
7. See section 8.2, procurement happens after pre-procurement screening and prior 
to ASCT. Procurement may occur prior to or after PBSC mobilization. If 
procurement occurs after PBSC mobilization, it must occur at least 7 days after 
ending use of G-CSF 
8. Complete Metabolic Panel (CMP): includes BUN, creatinine, Na, K, Cl, CO2, 
glucose, calcium, albumin, total protein, total bilirubin, ALT, AST, and alkaline 
phosphatase. NOTE: *Pre-procurement, only creatinine, bilirubin, and AST is 
necessary, and if these tests have already been performed within 7 days of 
procurement as part of SOC pre-transplant work-up (i.e. as part of CMP), they do 
not need to be repeated. Prior to ATLCAR.CD30 treatment, a CMP must be 
performed within 24 hours prior to infusion. CMP performed as needed on 
D1/Week 3. 
9. To assess disease status, imaging will be performed at baseline (within 60 days 
prior to ASCT) and at 6-8 weeks following the infusion. The choice of imaging 
will depend on what studies have been most informative in following the subject’s 
disease (i.e., PET, CT scans, MRI, nuclear imaging). In subjects who do not have 
documented disease progression at the 6 weeks scan, another scan will occur at 6 
months, 12 months, 18 months and 24 months (with a +/- 1 month window), until 
documentation of disease progression. If imaging studies are performed at other 
times after treatment on this study; that data will be collected, and information 
gained will be used for this study. 
Response assessment for subjects with cutaneous T cell lymphoma  
a. Will be performed at the same time point outlined above in the Time and Events Table and 
by the few exceptions outlined in section 7.1.1.  
b. Notable differences in the follow up for these subjects are outlined in section 7.1.1 based 
on consensus guidelines. 
c. Consult with a dermatologist will be required within 14 days prior to transplant. 
10. Thyroid function (T3, Free T4 and TSH) will be monitored in view of changes 
seen in subjects receiving CD30 antibody.  
11. Correlative analysis will include the following. Correlative blood sample 
collection will cease if the samples are no longer required for persistence and 
function or clonality analysis. 
a. Persistence and Function: The analyses will be used to monitor persistence and function 
(if applicable) in peripheral blood and will include immunophenotyping as well as 
quantitative polymerase chain reaction (qPCR) to detect transgene persistence and 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 59 of 154
 
 
 
functional assays such as in vitro reactivation of PBMCs in subjects for whom the 
appropriate reagents are available. Quantitative real-time PCR to detect the transgenes will 
be collected pre-lymphodepletion, pre-dosing (approximately 19 mL of blood), at 3 – 4 
hours post infusion (approximately 16 mL of blood), 1, 2-, 3-, 4- and 6-weeks visits post 
each T-cell infusion and then at the 3-, 6-, 9-, and 12-months visits. Persistence and 
function will be continued for up to one-year post-CAR T cell infusion. If a transgene copy 
number is > 500 copies/μg DNA, then samples to determine transgene copy numbers will 
be collected every 6 months after the first year until transgene copy number is < 500 
copies/μg DNA at which time samples will then be collected yearly for up to a total of 15 
years. If transgene is no longer detectable by PCR after 1-year post-final CAR T infusion, 
then collection for function and persistence will discontinue. See Section 7.5.1 and the 
Laboratory Manual for the amount of blood collected/type of tube used for all of the 
correlative studies.  
b. Clonality: If the transgene is detected at > 0.5% either flow cytometry (if feasible) or by 
qPCR at the 6-month sample collection timepoint, then PCR to detect retroviral integrant 
clonality and integrant locus will be performed. This analysis will continue every 6 months 
until detection is < 0.5% for up to 5 years. After this time, it will be collected annually. If 
the level of detection is < 0.5% at 6-months, samples will be collected annually and may 
be archived. Samples will no longer be collected if detection is < 0.5% for more than 1 
consecutive testing period. See Section 7.5.3.  
c. RCR: For replication competent retrovirus (RCR) testing, subject blood samples will be 
collected and stored pre-infusion. The pre-infusion sample will only be tested if the subject 
develops a long-term gene therapy side effect as described in Section 7.5.2. Additional 
samples for RCR testing will only be collected and subsequently analyzed in the event that 
the subject develops a long-term gene therapy side effect as described in Section 7.5.2.  
d. Cytokine Testing: Serum collected before and 3-4 hours after infusion for cytokine 
testing. 
12. Serum from blood drawn for functional studies at baseline and week 6 will be 
stored for measurement of human anti-mouse antibodies (HAMA). These studies 
will be performed in the event of a suspected immunologic reaction. See section 
7.5.4 for additional details. 
13. Data on all adverse experiences/toxicities per CTCAE v4.0 regardless of 
seriousness must be collected for documentation purposes only for 6 weeks after 
dosing of the study drug/biologic. Adverse event data collection will cease in 
subjects that receive any other hemopoietic cell product or receive therapy for 
relapse of their primary malignancy. Data on disease status will continue to be 
collected as appropriate.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 60 of 154
 
 
 
a. If CRS signs and symptoms occur (see APPENDIX VIII- CRS Toxicity Grading Scale and 
Management Guidelines), a serum sample (~1 mL) for IL-6 analysis and 20 mL of blood 
should be collected before instituting treatment for CRS. Subsequent 20 mL blood samples 
should be collected once a day for the first 3 days. At the discretion of the sponsor, a daily 
sample may be requested for an additional 4 days. See section 7.5.6 for additional details. 
b. Serum (~1 mL) and 20 mL of blood should also be collected in the event of serious 
toxicities that develop that require hospitalization. Subsequent 20 mL blood samples 
should be collected once a day for the first 3 days. At the discretion of the sponsor, a daily 
sample may be requested for an additional 4 days. See section 7.5.6 for additional details. 
c. An additional blood sample of approximately 20 mL may be collected if any subject 
develops an AE or event of clinical significance that is thought to be at least possibly related 
to the CAR T cells. 
14. CoA generated at completion of required studies for production/QA of cells. 
15. ATLCAR.CD30 cells infused after evidence of hematologic recovery post ASCT, 
see section 4.1.2 for definition of recovery. This will generally occur between 14 
and 20 days following infusion of autologous stem cells following high-dose 
chemotherapy. All subjects will receive their ATLCAR.CD30 infusion at the lead 
site, the University of North Carolina, Chapel Hill. 
16. Patient reported outcomes (PRO) will be measured by the PROMIS Global Health 
and Physical Function questionnaires and selected items from the NCI PRO-
CTCAE (see section 7.6 and APPENDIX V - Patient Reported Outcomes Surveys) 
(optional). PRO questionnaires will only be offered to adult study participants. 
PRO questionnaires will first be given at time of screening consent. On the day of 
infusion, subjects will fill out questionnaires prior to infusion. These 
questionnaires are optional and may not be given to all subjects.  
17.  Long Term Follow Up:  If a subject develops a delayed adverse event that is 
related to the trial drug, then more frequent (2-4 times per year) clinical 
observation may be indicated.  Appropriate follow up will be conducted based on 
a particular subject’s prior test results.  The investigator will determine the 
additional testing and sample collection that is needed.  New malignancies and 
delayed adverse events will be recorded during long term follow-up.     

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 61 of 154
 
 
 
5.0 STUDY POPULATION 
Unless otherwise noted, subjects must meet all of the following criteria to participate: 
5.1 
Inclusion Criteria for Prior to Cell Procurement 
1. Informed consent explained to, understood by and signed by subject/guardian; 
subject/guardian given copy of the procurement/screening informed consent.  
2. 3 to 17 years of age for pediatric subjects, ≥18 years of age for adults; NOTE: children 
will not be allowed to enroll in a dose cohort until a minimum of 2 adult subjects were 
enrolled and complete their DLT assessment follow-up at that dose level. 
3. Diagnosis of recurrent HL with a treatment plan that will include high dose 
chemotherapy with/without total body irradiation and autologous cell transplantation.  
4. NHL subjects with ALK negative CD30+ anaplastic large-cell lymphomas, CD30+ 
ALCL regardless of ALK status, with chemotherapy-sensitive relapse, CD30+ high-
risk DLBCL, CD30+ cutaneous T cell lymphoma, or CD30+ mycosis fungoides who 
are otherwise eligible for transplant, are eligible for this study. 
5. Karnofsky or Lansky score of > 60% (APPENDIX III- Lansky and Karnofsky 
Performance Status) 
6. Evidence of adequate organ function as defined by: 
The following is required prior to procurement (NOTE: labs do not need to be 
redrawn if they have already been performed as part of SOC pre-transplant work-up; 
Subject must be eligible to receive ASCT) 
• Hgb ≥ 8.0g/dL  
• Bilirubin ≤1.5 times the upper limit of normal (ULN) 
• AST ≤ 3 times ULN 
• Serum creatinine ≤1.5 times ULN 
• Cardiac and pulmonary function that is adequate for ASCT 
7. In women of child-bearing potential (WOCBP), a negative serum pregnancy test within 
72 hours prior to procurement. WOCBP are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 62 of 154
 
 
 
8. Considered at high risk for relapse as defined by: 
The presence of ≥1 of the following: failure to achieve CR post initial treatment; 
relapsed disease with an initial remission duration of <12 months; or extranodal 
involvement at the start of pre-transplant salvage therapy.  
9. 
WOCBP should be willing to use 2 methods of birth control or be surgically sterile 
or abstain from heterosexual activity for the course of the study, and for 6 months 
after the study is concluded. WOCBP are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. The two birth control 
methods can be composed of: two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. The male partner of WOCBP subjects 
enrolled into the trial should be instructed to use a condom by their female partner 
enrolled in the trial. 
5.2 
Inclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells 
1. Informed consent explained to, understood by and signed by subject/guardian; 
subject/guardian given copy of informed consent.  
2. 3 to 17 years of age for pediatric subjects, ≥18 years of age for adults; NOTE: children 
will not be allowed to enroll in a dose cohort until a minimum of 2 adult subjects were 
enrolled and complete their DLT assessment follow-up at that dose level. 
3. Diagnosis of recurrent HL with a treatment plan that will include high dose 
chemotherapy with/without total body irradiation and autologous cell transplantation.  
4. NHL subjects with ALK negative CD30+ anaplastic large-cell lymphomas, CD30+ 
ALCL regardless of ALK status, with chemotherapy-sensitive relapse, CD30+ high-
risk DLBCL, CD30+ cutaneous T cell lymphoma, or CD30+ mycosis fungoides who 
are otherwise eligible for transplant, are eligible for this study. 
5. CD30+ disease (result can be pending at the time of cell procurement, but must be 
confirmed prior to treatment with ATLCAR.CD30 cells); NOTE: CD30+ disease 
requires documented CD30 expression by immunohistochemistry based on the 
institutional hematopathology standard. 
6. Evidence of adequate organ function as defined by: 
The following is required prior to infusion of ATLCAR.CD30 cells: 
• 
Absolute neutrophil count (ANC) ≥500 cells/mm3 for 3 consecutive days; Note: 
ANC may be measured at the beginning and the end of a time frame expanding at 
least 3 days and does not need to be evaluated on each individual day AND  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 63 of 154
 
 
 
• 
Platelet count ≥25,000 cells/mm3 without transfusion over preceding 5 days; Note: 
Platelets may be measured at the beginning and the end of a time frame expanding 
at least 5 days and does not need to be evaluated on each individual day AND 
• 
Hg ≥8g/dL without transfusion support over preceding 5 days; Note: Hg may be 
measured at the beginning and the end of a time frame expanding at least 5 days 
and does not need to be evaluated on each individual day 
• 
Bilirubin ≤1.5 times the upper limit of normal (ULN)  
• 
AST ≤ 3 times ULN 
• 
Serum creatinine ≤1.5 times ULN 
• 
Pulse oximetry of > 90% on room air  
7. Imaging results from within 60 days prior to transplant (used as baseline measure for 
documentation of disease status).  
8. In women of child-bearing potential (WOCBP), a negative serum pregnancy test 
within 72 hours prior to procurement and again 72 hours prior to infusion is required.  
9. Karnofsky or Lansky score of > 60% (APPENDIX III- Lansky and Karnofsky 
Performance Status) 
10. Considered at high risk for relapse as defined by: 
• The presence of ≥1 of the following: failure to achieve CR post initial treatment; 
relapsed disease with an initial remission duration of <12 months; or extranodal 
involvement at the start of pre-transplant salvage therapy.  
11. Subjects must have autologous transduced activated T-cells that meet the Certificate 
of Analysis (CoA) acceptance criteria. 
12. WOCBP should be willing to use 2 methods of birth control or be surgically sterile, 
or abstain from heterosexual activity for the course of the study, and for 6 months 
after the study is concluded. WOCBP are those who have not been surgically 
sterilized or have not been free from menses for >1 year. The two birth control 
methods can be composed of: two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. The male partner of WOCBP subjects 
enrolled into the trial should be instructed to use a condom by their female partner 
enrolled in the trial.   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 64 of 154
 
 
 
5.3 
Exclusion Criteria  
Subjects meeting any of the following exclusion criteria will not be able to participate in 
this study: 
1. Received any investigational agents or received any tumor vaccines within the 
previous six weeks prior to cell infusion.  
2. Received anti-CD30 antibody-based therapy within the previous 4 weeks prior to 
cell infusion  
3. Pregnant or lactating 
4. Tumor in a location where enlargement could cause airway obstruction.  
5. Current use of systemic corticosteroids at doses >10mg/day prednisone or its 
equivalent; those receiving ≤10mg may be enrolled at discretion of investigator. 
6. Active infection with HIV, HBV, HCV (can be pending at the time of cell 
procurement; only subjects meeting the criteria as so described will be 
infused). Note: To meet eligibility subjects are required to be negative for HIV 
antibody, negative for Hepatitis B surface antigen, and negative for HCV antibody 
or viral load.  
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 65 of 154
 
 
 
6.0 STUDY CONDUCT 
6.1 
Duration of Therapy 
Therapy in LCCC1524-ATL involves just one infusion of ATLCAR.CD30 cells. 
Treatment with one infusion will be administered unless:  
• Subject decides to withdraw from study treatment, OR 
• General or specific changes in the subject’s condition render the subject unacceptable 
for further treatment in the judgment of the investigator. 
6.2 
Duration of Follow-Up 
Subjects will be followed for up to 15 years or until death, whichever occurs first. Subjects 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.   
Subjects who experience disease progression and start alternate therapy after receiving a 
cell infusion(s) will still be required to complete abbreviated follow up procedures outlined 
in APPENDIX IV - Abbreviated Follow Up Required After Initiating Alternative Therapy 
(section 18.4).   
6.3 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from protocol therapy and the PI notified when any of the criteria 
listed in section 6.1 apply. The reason for discontinuation of protocol therapy will be 
documented on the eCRF.   
In case a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if she or he may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented in 
both the medical records and in the eCRF. 
6.4 
Study Withdrawal 
If a subject decides to withdraw from the study (and not just from protocol therapy) an 
effort should be made to complete and report study assessments as thoroughly as 
possible. At the time of withdrawal, the investigator should attempt to establish as 
completely as possible the reason for the study withdrawal.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 66 of 154
 
 
 
• The subject should be asked if they are willing to allow for the abstraction of relevant 
information from their medical record in order to meet the long term follow up (e.g., 
survival) objectives outlined in the protocol.   
• A complete final evaluation at the time of the subject’s study withdrawal should be 
obtained with an explanation of why the subject is withdrawing from the study.   
• If the subject is noncompliant and does not return for an end of study follow up 
assessment, this should be documented in the eCRF.  
• If the reason for removal of a subject from the study is an adverse event, the principal 
specific event will be recorded on the eCRF.  
Excessive subject withdrawals from protocol therapy or from the study can render the 
study un-interpretable; therefore, unnecessary withdrawal of subjects should be avoided. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 67 of 154
 
 
 
7.0 DESCRIPTION OF STUDY PROCEDURES 
7.1 
Clinical Assessments 
Clinical assessments will be performed as outlined in the Time & Events Table. 
7.1.1 Disease Assessment Guidelines for Cutaneous Lymphomas 
Lymphomatoid papulosis (LP) or primary cutaneous anaplastic large cell lymphomas (ALCL): 
This is by definition a skin only disease.  
1. Bone marrow biopsy is not required 
2. Imaging will be done:  
• Pre-transplant (not required at procurement) to assess that there isn’t 
unexpected nodal or visceral disease. Imaging should be performed within 60 
days prior to transplant.  
o If scans show any enlarged lymph nodes >1.5cm at baseline then that 
subject will be treated as systemic lymphoma and followed as outlined in 
the Time & Events Table in section 4.2 for other lymphomas   
o If the baseline scans performed prior to transplant are negative there will be 
no further imaging and response will be based on assessment of skin disease 
on physical exam performed as outlined in the Time & Events Table in 
section 4.2.   
3. Dermatology consult: 
• Subjects will need to see a dermatologist within 30 days prior to transplant.   
• They will need to see a dermatologist at the week 6 visit.  
• Thereafter they can be followed by the oncologist or dermatologist. 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 68 of 154
 
 
 
Table 5 
Study Assessments for LP and ALCL 
Study 
Assessments 
LP or ALCL 
Screening 
ATLCAR 
Treatment 
Follow-Up 
Pre-
procure-
ment 
Pre-
Transplant 
W0D1 
W1D1 
W2D1 
W3D1 
W4D1 
W6D1 
Dermatology 
consult 
 
X 
 
 
 
 
 
X 
Tumor imaging 
 
X* 
 
*if LN >1.5cm at baseline then perform scans per 
the Time & Events Table 
*If scans negative at baseline then response based 
on physical exam the Time & Events Table 
Mycosis fungoides or Sézary syndrome: 
1. Bone marrow biopsy is not required 
2. Imaging will be done:  
• Pre-transplant (not required at procurement). Imaging should be performed 
within 60 days prior to transplant. 
o If scans show any enlarged lymph nodes >1.5cm at baseline then that 
patient will have repeat scans performed at the 6 week assessment. 
Thereafter scans will only be performed if there is a partial response or 
better in the skin disease on physical exam performed as outlined in the 
Time & Events Table  
o If the baseline scans performed prior to transplant are negative there will 
be no further imaging and response will be based on assessment of skin 
disease on physical exam performed as outlined in the Time & Events 
Table.   
3. Peripheral blood will be sent for flow cytometry/ leukemia profile.  
• Pre-transplant (within 30 days prior to transplant): 
o If this assessment shows no disease involvement in blood then it does 
not need to be repeated 
o If this assessment shows disease involvement in blood then it should be 
repeated  
 at 6 weeks post cell infusion 
 at 3 months post cell infusion 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 69 of 154
 
 
 
 Thereafter this assessment should be repeated only to confirm 
complete remission (CR) based on skin exam   
4. Dermatology consult: 
• Subjects will need to see a dermatologist within 30 days prior to 
transplant.   
• They will need to see a dermatologist at the week 6 visit after the cell 
infusion.  
• Thereafter they can be followed by the oncologist or dermatologist.   
Table 6 
Study Assessment s for Mycosis Fungoides and Sézary Syndrome 
Study 
Assessments 
Mycosis 
fungoides and 
Sézary 
syndrome 
Screening 
ATLCAR 
Treatment 
Follow-Up 
Pre-
procure-
ment 
Pre-
Transplant 
W0D1 
W1D1 
W2D1 
W3D1 
W4D1 
W6D1 
M3D1 
Blood for 
flow 
cytometry/ 
leukemia 
profile 
 
X 
 
 
 
 
 
X 
X 
Dermatology 
consult 
 
X 
 
 
 
 
 
X 
 
Tumor 
imaging 
 
X 
 
If scans show any enlarged LN >1.5cm at baseline, 
then repeat scans performed at the 6 week 
assessment. Thereafter scan if PR or better in skin 
disease 
If baseline scan negative: repeat imaging only if PR 
or better in skin disease post cell infusion 
7.2 
Screening and Treatment Assessments 
7.2.1 Pre-procurement  
Check eligibility 
Clinical evaluation: complete history, Karnofsky or Lansky performance status 
Laboratory studies:   
• Pregnancy Test: serum pregnancy testing will be done in female 
subjects of childbearing potential (within 72 hours prior to procurement) 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 70 of 154
 
 
 
• Pulmonary function tests: Including FEV1, FVC and DLCO 
• Ejection Fraction 
• HIV, HBV, HCV testing required (see footnote #6 of Time & Events 
Table) 
• Only labs listed below are required (within 7 days of procurement) 
NOTE: if the following lab tests have already been performed within 7 
days of procurement as part of SOC pre-transplant work-up (i.e., as part 
of hematology labs or CMP collected which includes BUN, creatinine, 
Na, K, Cl, CO2, glucose, calcium, albumin, total protein, total bilirubin, 
ALT, AST, alkaline phosphatase), they do not need to be repeated: 
o Hg 
o AST 
o Bilirubin 
o Serum creatinine 
Imaging: To assess disease status, imaging will be performed at baseline (within 60 
days prior to ASCT). The choice of imaging will depend on what studies have been 
most informative in following the subject’s disease (i.e., PET, CT scans, MRI, nuclear 
imaging). If subject has cutaneous lymphoma see section 7.1.1 for details. 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS 
Global Health Scale, PROMIS Physical Function, and selected questions from NCI 
PRO-CTCAE. Administered at time of screening consent.  
Procurement: See section 4.1.1; to take place prior to ASCT. Procurement may 
occur prior to or after PBSC mobilization. If procurement occurs after PBSC 
mobilization, it must occur at least 7 days after ending use of G-CSF. 
7.2.2 Pre-infusion 
Check eligibility  
Clinical evaluation: History, physical examination, Karnofsky or Lansky performance 
status 
Laboratory studies:   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 71 of 154
 
 
 
• Pregnancy Test: serum pregnancy testing will be done in female 
subjects of childbearing potential (within 72 hours prior to infusion) 
• Pulse Oximetry 
• CBC with differential and platelets: (required within 24 hours prior to 
infusion) 
• CMP: (required within 24 hours prior to infusion) BUN, creatinine, Na, 
K, Cl, CO2, glucose, calcium, albumin, total protein, total bilirubin, 
ALT, AST, alkaline phosphatase 
• Thyroid function: obtained pre-infusion 
• Dermatology consult needed for cutaneous lymphomas only 
• Blood taken for leukemia profile and flow cytometry (mycosis 
fungiodes and Sezary syndrome patients only) 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies: Including in vitro reactivation of 
PBMCs in subjects for whom the appropriate reagents are available 
and immunophenotyping  
o Replication competent retrovirus (RCR): Sample collected pre-
infusion for PCR testing  
o Quantitative PCR 
o HAMA testing  
o Cytokine testing: obtained pre and post infusion  
Toxicity: Toxicity will be assessed according to the NCI CTCAE v. 4.0.  
CoA: Generated at completion of required studies for production/QA of cell (available 
prior to planned infusion) 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE. This will be collected on the day of infusion prior to infusion.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 72 of 154
 
 
 
7.2.3 Treatment (D1 Week 0) 
ATLCAR.CD30 cells infused after evidence of hematologic recovery post ASCT, see 
section 4.1.2 for definition of recovery. This will generally occur between 14 and 20 
days following infusion of autologous stem cells following high-dose chemotherapy. 
All subjects will receive their ATLCAR.CD30 infusion at the lead site, the University 
of North Carolina, Chapel Hill.  
Laboratory studies:   
• Blood Sample for Correlative Studies (see section 7.5 and LCCC1524-
ATL Study Laboratory Manual) 
o Function and persistence studies: 3-4 hours post infusion 
o Quantitative PCR: 3-4 hours post infusion Genetic analysis (see 
Section 7.5.5) 
Toxicity: Toxicity will be assessed according to the NCI CTCAE v. 4.0, CRS Toxicity 
Grading Scale (See APPENDIX VIII- CRS Toxicity Grading Scale and Management 
Guidelines).  
7.3 
Short-term Follow-up 
7.3.1 D1 Week 1 
Clinical evaluation: History, physical examination 
Laboratory studies:   
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Cytokine testing 
o Genetic analysis (see Section 7.5.5) 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 73 of 154
 
 
 
Toxicity: Toxicity will be assessed according to the NCI CTCAE v. 4.0, CRS 
Toxicity Grading Scale (See APPENDIX VIII- CRS Toxicity Grading Scale and 
Management Guidelines).  
Patient reported outcome questionnaires for adult subjects (optional): PROMIS 
Global Health Scale, PROMIS Physical Function, and selected questions from NCI 
PRO-CTCAE  
 
7.3.2 D1 Week 2 
Clinical evaluation: history, physical examination, Karnofsky or Lansky performance 
status. 
Laboratory studies:   
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Cytokine testing 
o Genetic analysis (see Section 7.5.5) 
Toxicity:  Toxicity will be assessed according to the NCI CTCAE v. 4.0, CRS Toxicity 
Grading Scale (See APPENDIX VIII- CRS Toxicity Grading Scale and Management 
Guidelines).  
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
7.3.3 D1 Week 3 (Optional Visit) 
Note: This is an optional visit that will occur if the condition of the subject is such that 
follow up on D1/week 3 is considered medically necessary by the investigator. Clinical 
labs may be performed as needed but are not required. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 74 of 154
 
 
 
Clinical evaluation: History, physical examination 
Laboratory studies:   
• CBC with differential and platelets (performed as needed) 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
(performed as needed) 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies: optional 
o Quantitative PCR: optional 
o Genetic analysis (optional at this time point - see Section 7.5.5) 
Toxicity: Toxicity will be assessed according to the NCI CTCAE v. 4.0, CRS 
Toxicity Grading Scale (See APPENDIX VIII- CRS Toxicity Grading Scale and 
Management Guidelines).  
Patient reported outcome questionnaires for adult subjects (optional): PROMIS 
Global Health Scale, PROMIS Physical Function, and selected questions from NCI 
PRO-CTCAE  
7.3.4 D1 Week 4 
Clinical evaluation: History, physical examination 
Laboratory studies:   
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Genetic analysis (see Section 7.5.5) 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 75 of 154
 
 
 
Toxicity: Toxicity will be assessed according to the NCI CTCAE v. 4.0, CRS Toxicity 
Grading Scale (See APPENDIX VIII- CRS Toxicity Grading Scale and Management 
Guidelines).  
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
7.3.5 D1 Week 6 
Clinical evaluation: History, physical examination 
Laboratory studies:   
• CBC with differential and platelets 
• Dermatology consult needed for cutaneous lymphomas only 
• Blood taken for leukemia profile and flow cytometry (mycosis 
fungiodes and Sezary syndrome patients only). 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o HAMA testing  
o Genetic analysis (see Section 7.5.5) 
Imaging: Imaging to assess disease status (PET, CT scans, MRI, nuclear imaging) 6-8 
weeks following the infusion. The choice of imaging will depend on what studies have 
been most informative in following the subject’s disease. If subject has cutaneous 
lymphoma see section 7.1.1 for details.  
Toxicity: Toxicity will be assessed according to the NCI CTCAE v. 4.0, CRS Toxicity 
Grading Scale (See APPENDIX VIII- CRS Toxicity Grading Scale and Management 
Guidelines).  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 76 of 154
 
 
 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
 
7.3.6 D1 Month 3 
Clinical evaluation: history, physical examination, Karnofsky or Lansky performance 
status. 
Laboratory studies:   
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Blood taken for leukemia profile and flow cytometry (mycosis 
fundgiodes and Sezary syndrome patients only) 
• Thyroid function 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Genetic analysis (see Section 7.5.5) 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
7.3.7 D1 Month 6 
Clinical evaluation: history, physical examination, Karnofsky or Lansky performance 
status. 
Laboratory studies:   
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 77 of 154
 
 
 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Genetic analysis (see Section 7.5.5) 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
Imaging: Imaging to assess progression (PET, CT scans, MRI, nuclear imaging) at 6 
months +/- 1 month following the infusion. The choice of imaging will depend on 
what studies have been most informative in following the subject’s disease. 
7.3.8 D1 Month 9 
Clinical evaluation: history, physical examination, Karnofsky or Lansky performance 
status. 
Laboratory studies:   
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Genetic analysis (see Section 7.5.5) 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
7.3.9 D1 Month 12 
Clinical evaluation: history, physical examination, Karnofsky or Lansky performance 
status. 
Laboratory studies:   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 78 of 154
 
 
 
• CBC with differential and platelets 
• CMP: BUN, creatinine, Na, K, Cl, CO2, glucose, calcium, albumin, 
total protein, total bilirubin, ALT, AST, alkaline phosphatase 
• Thyroid function  
• Blood Sample for Correlative Studies (see section 7.5) 
o Function and persistence studies 
o Quantitative PCR 
o Genetic analysis (see Section 7.5.5) 
Patient reported outcome questionnaires for adult subjects (optional): PROMIS Global 
Health Scale, PROMIS Physical Function, and selected questions from NCI PRO-
CTCAE  
Imaging: Imaging to assess progression (PET, CT scans, MRI, nuclear imaging) at 6 
months +/- 1 month following the infusion. The choice of imaging will depend on what 
studies have been most informative in following the patient’s disease. 
7.4 
Long Term Follow-Up 
Quantitative real-time PCR to detect transgene copy numbers will be collected pre-
infusion, 3-4 hours post infusion, 1, 2, 3, 4 and 6 weeks post- T cell infusion, 3, 6, 9, and 
12 months post- T cell infusion and then yearly for a total of 15 years. If transgene copy 
number is >1000 copies/1μg DNA, then samples to determine transgene copy numbers 
will be collected every 6 months after the first year until transgene copy number is <1000 
copies/1μg DNA at which time samples will then be collected yearly for a total of 15 
years. 
If at 6 months post- T cell infusion, transgene is detected at >0.5% by flow cytometry 
then PCR to detect retroviral integrant clonality and integrant locus will be performed 
and will continue every 6 months until detection is <0.5%. Samples will then be collected 
annually and may be archived for a total of 15 years. If the level of detection is less than 
0.5%, samples will be collected annually and may be archived. Follow up will continue 
for 15 years.   
If a subject develops a delayed adverse event that is related to the trial drug, then more 
frequent (2-4 times per year) clinical observation may be indicated.  Appropriate follow 
up will be conducted based on a particular subject’s prior test results.  The investigator 
will determine the additional testing and sample collection that is needed.  New 
malignancies and delayed adverse events will be recorded during long term follow-up. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 79 of 154
 
 
 
Regarding annual genetic analysis through year 15, see Section 7.5.5. 
7.5 
Correlative Studies: Tests of Function, Persistence and Safety 
The following investigations will be used to monitor function and persistence in peripheral 
blood and safety of transduced T-cells at time-points indicated in the Time and Events 
Table. A maximum of the lesser of 50 mL or 2 mL/kg of body weight of blood will be 
drawn on any one day for these assays. If a subject’s hemoglobin is less than 8.0 g/dL at 
any of the evaluation times, the amount of blood drawn for the evaluation will be reduced 
and may be obtained over more than one venipuncture, if necessary. If there is insufficient 
blood, samples archived for RCR testing if needed, and Quantitative real-time PCR, will 
be the first priorities. Note: the studies are not necessarily performed at the time of blood 
collection. Correlative blood sample collection will cease if the samples are no longer 
required for persistence and function or clonality analysis. 
7.5.1 Function and Persistence Studies 
These will include immunophenotyping (when possible) as well as quantitative 
polymerase chain reaction (qPCR) to detect transgene persistence. When applicable, 
functional assays will be performed, such as in vitro reactivation of PBMCs in subjects 
for whom the appropriate reagents are available. 
7.5.2 RCR Testing by PCR 
Subject blood samples will be collected pre-infusion and stored. Samples will also be 
collected and both samples analyzed if the subject develops any of the following long-
term gene therapy side effects: 
• New malignancy(ies) 
• Exacerbation of a pre-existing or new incidence of a neurologic disorder 
• Exacerbation of a prior or new incidence of a rheumatologic or other autoimmune 
disorder 
• New incidence of a hematologic disorder 
• New incidence of infection (potentially product-related). 
7.5.3 Clonality 
If the transgene is detected at > 0.5% by either flow cytometry (if feasible) or by qPCR 
at the 6-month sample collection timepoint, then PCR to detect retroviral integrant 
clonality and integrant locus will be performed. This analysis will continue every 6 
months until detection is < 0.5% for up to 5 years. After this time, it will be collected 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 80 of 154
 
 
 
annually. If the level of detection is < 0.5% at 6-months, samples will be collected 
annually and may be archived. Samples will no longer be collected if detection is < 
0.5% for more than 1 consecutive testing period. 
7.5.4 HAMA Testing 
Serum from blood drawn for functional studies at baseline and at week 6 will be stored 
for measurement of HAMA. These studies will be performed in the event of a suspected 
immunologic reaction. 
7.5.5 Genetic Analysis 
RNAseq, DNA and other genomic analysis may be performed on the ATLCAR.CD30 
products and on blood samples collected 3-4 hours post infusion, 1, 2, 3 (optional), 4, 
and 6 weeks post T cell infusion, 3, 6, 9, and 12 months post infusion and yearly for a 
total of 15 years post infusion. These analyses will be used to determine the integration 
location of CAR.CD30. Differential integration locations of these samples will then be 
compared to CAR T cell behavior to see if integration location affects CAR T cell 
behavior such as expansion, persistence and trafficking. Previously, with CD19-
targeted T cells, it has been observed that disruption of TET2 promotes the therapeutic 
efficacy of the CAR T cells [76]. The epigenetic profile of these TET2 disrupted T cells 
showed features consistent with altered T cell differentiation and a central memory 
phenotype, at the peak of expansion. 
7.5.6 Sample Collection Requirements if CRS or Severe Toxicity Occurs 
A serum sample (~1 mL) for IL-6 analysis and ~20 mL of blood should be collected 
from any subject who develops signs and symptoms of CRS. This sample should be 
collected before treatments are administered to alleviate CRS symptoms. Subsequent 
20 mL blood samples should be collected once a day for the first 3 days. At the 
discretion of the sponsor, a daily sample may be requested for an additional 4 days.  
In addition, a serum sample, (~1 mL) for IL-6 analysis and ~20 mL of blood should be 
collected in any subject who develops a SAE (i.e., requiring hospitalization) related to 
the cell infusion. Subsequent 20 mL blood samples should be collected once a day for 
the first 3 days. At the discretion of the sponsor, a daily sample may be requested for 
an additional 4 days. 
An additional blood sample of approximately 20 mL may be collected if any subject 
develops an AE or event of clinical significance that is thought to be at least possibly 
related to the CAR T cells. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 81 of 154
 
 
 
7.5.7 Other Tissue Studies 
If biopsy of accessible lymph nodes or other tissue is required at any time after 
treatment, a sample of this will be used to assess presence of transduced peripheral 
blood T-cells in association with the tumor. Additionally, this tissue may be used to 
assess for potential causes for loss of response to therapy, including, but not limited to, 
the loss of CD30 expression. 
If bone marrow trephine biopsy or tumor biopsy is required at any time after treatment, 
a sample of this will be used to assess presence of transduced peripheral blood T-cells 
in association with the tumor. Additionally, this tissue may be used to assess for 
potential causes for loss of response to therapy, including, but not limited to, the loss 
of CD30 expression. 
If the subject dies, an autopsy may be requested. If an autopsy is granted, tissue may 
be requested to assess presence of transduced cells. Additionally, the autopsy tissue 
may be used to assess for potential causes for loss of response to therapy, including, 
but not limited to, the loss of CD30 expression. 
7.5.8 Biobank Repository 
Subjects participating in this trial will be asked to consent to allow researchers to store 
their biological specimens. Participants in this trial will also be required to sign a 
separate HIPAA authorization form to allow investigators to review their medical 
records.  
ATLCAR.CD30 cells will be stored at the GMP facility according to standard 
procedures. Other specimens collected during this study as described in section 7.5.7 
of this protocol will be stored at the University of North Carolina at Chapel Hill in the 
immunotherapy laboratory in locked liquid nitrogen tanks with controlled access. The 
samples will be labeled with the study ID number and date and time of sample 
collection.   
The purpose of this repository or biobank is to store samples for immediate or future 
analyses to answer study-related questions, not to increase general knowledge outside 
the parameters of the study. These goals will be accomplished using several different 
kinds of specimens collected during the study as described. These specimens include: 
• Tissue samples from standard of care biopsies of the bone marrow, lymph nodes 
and/or extramedullary tumor 
• Unused ATLCAR.CD30 cells after a determination has been made that the 
subject is not a candidate for re-infusion or has already undergone re-infusion. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 82 of 154
 
 
 
• Unused additional material collected during procurement (peripheral blood 
mononuclear cells) 
• Leftover tissue obtained for any standard of care procedure that may provide 
additional information about ATLCAR.CD30 cell therapy. 
For example, analyses will be performed to assist in determining if the ATLCAR.CD30 
cells are associated with the tumor and if the ATLCAR.CD30 cells are present.  
Tissues donated from bone marrow biopsies, lymph nodes, extramedullary tumor 
biopsies, or any leftover tissue obtained through standard of care procedures that may 
provide additional information about ATLCAR.CD30 cell therapy will be stored for 15 
years in the repository. After 15 years, these samples will be destroyed. 
ATLCAR.CD30 cells will be kept for 5 years and destroyed thereafter.  
Information about the patient’s disease will be linked to the specimens stored in the 
repository database. Immunotherapy laboratory-associated research staff, LCCC 
Bioinformatics staff who support the database and the LCCC Data Warehouse, and 
researchers with IRB-approval for access to personal health information for each 
subject in this study will be able to link specimens to relevant medical information. 
Some results from laboratory analyses that occurred during the patient’s participation 
in the clinical study may also be included. This information may be important for 
understanding how the patient’s cancer developed and responded to treatment. 
Storage Time: 
• CAR-T cells and material from procurement are to be stored for up to 15 years for 
subject treatment and safety purposes. If storage of the CAR-T cells and/or extra 
material from procurement is no longer deemed necessary as determined by the 
Principal Investigator with appropriate consult, as needed (e.g., attending 
physician, treating physicians, etc.), the CAR-T cells and/or the extra material 
from procurement may be released for archiving or destruction earlier than 15 
years. At the time of release determination by the Principal Investigator, if the 
subject did not consent for their specimens to be used for further research or quality 
assurance/quality control (QA/QC) activities, the specimens will be destroyed. 
The subject may withdraw their consent at any time to prevent the use of their 
specimens for further research or QA/QC activities. Withdrawing of consent will 
result in the destruction of the samples at 15 years or at the time consent is 
withdrawn if this occurs after the initial 15 years in storage. 
o 
Archived samples will be stored in the GMP lab (the ACT facility) and will 
be designated in the inventory system for use in laboratory research and/or 
QA/QC activities.  Samples will be de-identified when they are used for 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 83 of 154
 
 
 
laboratory research or QA/QC activities. Total storage time (initial storage 
and archiving) may be up to 25 years, and then the samples will be destroyed. 
• Tissue obtained from bone marrow biopsies, extramedullary tumor biopsies, or 
any leftover tissue obtained through standard of care procedure or as outlined as 
part of the protocol that may provide additional information about 
ATLCAR.CD30 cell therapy will be stored for up to 15 years. 
Provision of Data to Correlative Scientists 
Identification and Role of the Study Coordinator as the Honest Broker 
The study coordinator will be in charge of collecting and maintaining all data points and 
data management. The study coordinator should have adequate training to enter, manage, 
and deidentify data. The study coordinator will provide a unique study number to each 
enrolled subject. All documentation and samples will be labeled with the unique study 
number. The correlative teams will only be provided this unique study ID number as 
opposed to any other patient identifiers. The clinical team will be the only people able to 
access identifiable data and the study coordinator will be a conduit to provide the de-
identified data to the correlative team.  
Requests for a data 
Identifiable data will not be given out to any correlative investigators at any time. 
Multicenter and UNC correlative Investigators may ask the study coordinator for a specific 
data set, and the study coordinator will return a deidentified data set. This data may only 
be used for purposes of the study. Any use other than directly related to the study must be 
approved by the IRB of record. If there is a need for an investigator to access identifiable 
data during the study, then a new IRB application will need to be submitted from that 
investigator detailing the reasons needed to access that data. The study coordinator will 
also ensure that correlative results are not returned from the correlative team to the clinical 
team to dictate treatment or follow-up decisions unless this is specifically approved by the 
IRB of record and delineated in the clinical protocol.  
7.6 
Patient Reported Outcomes Measures 
Patient reported outcome measures will be collected on adult study participants who agree 
to fill out questionnaires at the scheduled clinic visits. The PROMIS questionnaires 
corresponding to Global Health (PROMIS GHS SF v1.0-1.1) and Physical Function 
(PROMIS Physical Function SF20a) (www.nihpromis.org) and selected symptom 
questions from the NCI PRO-CTCAE will be administered (see APPENDIX V - Patient 
Reported Outcomes Surveys).  
Adult subjects who experience disease progression following an initial or subsequent cell 
infusion may be asked to complete a final set of questionnaires if they are willing. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 84 of 154
 
 
 
7.7 
Assessment of Safety 
All subjects who received a CAR.CD30 T-cell infusion will be included in the safety 
analysis. Each subject will be assessed periodically for the development of any toxicity 
according to the Time & Events Table. Toxicity will be assessed according to the NCI 
CTCAE v4.0 and CRS toxicity will be graded according to the toxicity scale outlined in 
APPENDIX V - Patient Reported Outcomes Surveys. 
7.8 
Assessment of Efficacy 
To assess disease status, imaging will be performed at baseline (within 60 days prior to 
ASCT) and at 6-8 weeks, 6 months, 12 months, 18 months and 24 months (or until 
documented disease progression) following the infusion. The choice of imaging will 
depend on what studies have been most informative in following the subject’s disease (i.e., 
PET, CT scans, MRI, nuclear imaging). If imaging studies are performed at other times 
after treatment on this study; that data will be collected and information gained will be used 
for this study. 
7.8.1 Measurement of Disease 
This study will use the Lugano Classification Lymphoma Response Criteria [74].  
The response criteria are defined in APPENDIX II- Revised Response Criteria for 
Lymphoma:. 
The response criteria for lymphomatoid papulosis and primary cutaneous ALCL are 
defined in Section 18.6 APPENDIX VI: Response Assessment for Cutaneous 
ALCL/Lymphomatoid Papulosis. 
The response criteria for mycosis fungoides and Sezary syndrome are defined in 
Section 18.7 APPENDIX VII - Response Assessment for Mycoses Fungoides and 
Sézary Syndrome. 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 86 of 154
 
 
 
studies show improved cell transduction when both anti-CD3 and anti-CD28 
antibodies are combined. 
8.2.3 Retroviral Production 
A retroviral producer line has been generated for the construct at Baylor College of 
Medicine. A master cell-bank of producer cells has been generated and tested to 
exclude production of replication competent retrovirus and infection by Mycoplasma, 
HIV, HBV, HCV and others. Supernatant collected from the master-cell bank was 
filtered, aliquoted and rapidly frozen and stored at -80°C.  
All batches of retroviral supernatant have been tested for sterility and to exclude RCR 
as issued with the Certificate of Analysis (CoA) and as directed by the SOPs and IND 
14688 
8.2.4 Transduction 
ATL are transduced on day 3-4 after initiation as described previously using 
recombinant Fibronectin fragment CH-296 (RetronectinTM, Takara Bio, USA) coated 
plates or bags. Virus is attached to retronectin by incubating producer supernatant in 
coated plates or bags. Cells are then transferred to virus coated plates or bags. 
8.2.5 Ex Vivo Expansion 
After transduction transgenic ATL will be expanded feeding them with IL-7 and IL-15 
twice a week to reach sufficient numbers as previously described [77]. After 
transduction a small number of cells will be removed to evaluate for transduction 
efficiency using flow cytometry. 
8.2.6 Freezing 
When sufficient number for cell infusion is achieved, cells will be collected and frozen 
following previously validated SOPs. Cells will be also tested for cytotoxicity against 
CD30+ tumor cells and CD30 negative cell lines to check receptor function. All lines 
will be checked for identity, phenotype and microbiological culture and cryopreserved 
prior to administration according to SOPs. The results will be reviewed by QA prior to 
issuing a CoA. 
8.2.7 Testing 
Products that meet study specific release criteria, as detailed on the CoA that 
accompany each infusion product, will be infused as per Section 4.1.2. 
If a positive sterility testing result is reported after the product was infused, the FDA 
and other relevant parties would be notified as per our manufacturing SOP. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 87 of 154
 
 
 
8.3 
Potential Toxicities 
Potential toxicities may be categorized as those related to: infusion of T cells; transduction; 
cross-reactivity with normal tissues; cytokine release syndrome; neurotoxicity; 
macrophage activation syndrome and tumor lysis syndrome. In addition to the information 
presented below, also see Sections 1.5.2., APPENDIX VIII- CRS Toxicity Grading Scale 
and Management Guidelines. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 88 of 154
 
 
 
Retroviral Transduction 
There has been concern that even a single retroviral integration can contribute to 
oncogenesis. Insertional upregulation of cellular proto-oncogenes was the main cause 
of 5 serious adverse events in two different X-chromosomal linked severe combined 
immunodeficiency (X-SCID) gene therapy trials. The French study reported 4 cases. 
Fischer’s group replaced the missing common gamma chain (γc) in X-SCID patients 
with ex vivo retroviral transduction of autologous stem cells. Four of 11 treated patients 
developed T-ALL associated with a single retroviral integrant[78, 79]. The integration 
site of the retrovirus was similar. More recently a case of leukemia has also been 
reported in a second study in SCID patients conducted in the UK. It is likely that 
correction of common-gamma chain deficiency and related immunodeficiency 
syndromes represent special cases. The γc is a shared component of IL-2, IL-4, IL-7, 
IL-9 and IL-15. Hence it is a crucial component of T- cell proliferation and 
thymogenesis. A proliferative advantage is expected for progeny of stem cells with 
functional γc. In female carriers of X-SCID there is a pattern of non-random X-
inactivation in T-cells, B-cells, and NK-cells[80]. Moreover a patient with X-SCID 
developed substantial numbers of T-cells following reversion of the mutant allele in a 
single hemopoietic stem cell[81]. High efficiency retroviral transduction of human 
stem cells is difficult to achieve even with GALV pseudotyping. It is likely that in X-
SCID, few truly pluripotent stem cells were transduced and the stem cell pool 
expressing the highest level of transgene (due to integration at a transcriptionally active 
site) then undergo numerous doublings to restore the entire T-cell compartment. 
Random mutations caused by this supra-physiological proliferation combined with 
retroviral integration in a transcriptionally active region led to leukemogenesis.  
Our proposal should have a very different risk profile than that reported by Morgan and 
colleagues and summarized in Section 1.5.2 [45]. Large doses of transduced T-cells (in 
the order of 1010 cells) were administered to patients that received prior 
lymphodepletion and no leukemogenesis occurred. Although the inclusion of the CD28 
endodomain in the CAR may enhance proliferation of transgenic T-cells in response to 
the CD30 antigen, there is no reason to believe this effect will lead to uncontrolled T-
cell expansion. Ex vivo and published in vivo data using several artificial T-cell 
receptors shows that CD28 sustains limited and temporary expansion over 
approximately 3 weeks[82]. Our recent clinical trial using CD19-CAR-specific T-cells 
including the CD28 endodomain also indicates that these T-cells expand significantly 
for only 2-3 weeks and then they decline without evidence of further expansion [26]. 
Thereafter, the cells maintain the expression of the transgene, but proliferate further 
only in the presence of both antigen and exogenous cytokines.  
To date, more than 200 patients have received genetically modified cells in clinical 
trials including patients we have treated on our protocols using retrovirally marked 
autologous marrow[83] or retrovirally marked EBV-CTLs[64, 84, 85]. In none of these 
has malignancy caused by retroviral transduction been reported. However, there is a 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 89 of 154
 
 
 
possibility that the vector could randomly integrate into a site that could lead to 
leukemogenesis.  
Current intensive regimens to treat relapsed lymphoma describe subsequent secondary 
malignancy rates in excess of 10%[86]. In light of this, the natural history and poor 
prognosis of advanced lymphoma, and given the entire previous experience with 
retroviral gene therapy, we feel that the risks of retroviral induced leukemogenesis are 
small and are justified in this patient group. 
Cross-reactivity 
CD30 can be expressed by activated T-cells and NK cells. Direct toxicity to these cells 
due to targeting of their CD30 molecules by transduced cells is possible. In case of this 
eventuality, a number of therapeutic maneuvers are available. Corticosteroids in doses 
used to treat graft-versus host-disease (GvHD) will deplete the majority of circulating 
transduced cells.  
CD30 is also expressed on first trimester decidua so there may be a risk of miscarriage 
in females of child-bearing potential if the cells persist long term. To evaluate this risk 
we will add a question about miscarriage to our annual follow up evaluation in these 
patients and report any such events in our annual IND report. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 90 of 154
 
 
 
9.0 ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a drug) 
in a subject or clinical investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment. An 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 product, 
whether or not related to the medicinal product.   
Hospitalization for elective surgery or routine clinical procedures that are not the result 
of an AE (e.g., surgical insertion of central line) need not be considered AEs and should 
not be recorded as an AE. Disease progression should not be recorded as an AE, unless 
it is attributable by the investigator to the study therapy. 
9.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.   
Causality assessment to a study investigational product is a medical judgment made in 
consideration of the following factors: temporal relationship of the AE to study 
investigational product exposure, known mechanism of action or side effect profile of 
study treatment, other recent or concomitant drug exposures, normal clinical course of 
the disease under investigation, and any other underlying or concurrent medical 
conditions. Other factors to consider in considering investigational product as the cause 
of the AE: 
• Single occurrence of an uncommon event known to be strongly associated with 
investigational product exposure (e.g., angioedema, hepatic injury, Stevens-
Johnson Syndrome) 
• One or more occurrences of an event not commonly associated with 
investigational product exposure, but otherwise uncommon in the population 
(e.g., tendon rupture); often more than one occurrence from one or multiple 
studies would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 91 of 154
 
 
 
• An aggregate analysis of specific events observed in a clinical trial that indicates 
the events occur more frequently in the investigational product treatment group 
than in a concurrent or historical control group 
9.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure (IB) 
for an unapproved investigational product or package insert/summary of product 
characteristics for an approved product). Unexpected also refers to AEs or SARs that 
are mentioned in the IB as occurring with a class of investigational product or as 
anticipated from the pharmacological properties of the investigational product, but are 
not specifically mentioned as occurring with the particular investigational product 
under investigation.   
9.2 
Documentation of Non-Serious Adverse Events or SARs 
For non-serious AEs or SARs, documentation shall begin at the time the main study 
consent form is signed by the subject prior to ATLCAR.CD30 infusion and continues 
through the 6 week follow-up period after treatment is discontinued. In addition, any AEs 
or SARs experienced by the subject related to the procurement procedure must also be 
documented. 
Collected information should be recorded in the Case Report Forms (CRF) for that subject. 
Please include a description of the event, its severity or toxicity grade, onset and resolved 
dates (if applicable), and the relationship to the study drug. Documentation should occur 
at least monthly. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 92 of 154
 
 
 
10.0 SERIOUS ADVERSE EVENT 
10.1 
Definition of Serious Adverse Event 
An AE or SAR is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of existing 
hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions; 
• 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, that may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in the definition. For 
reporting purposes, also consider the occurrences of pregnancy as an event which must 
be reported as an important medical event. 
*Hospitalization for anticipated or protocol specified procedures such as administration of 
chemotherapy, central line insertion, metastasis interventional therapy, resection of 
primary tumor, or elective surgery, will not be considered serious adverse events. 
Pregnancy that occurs during the study must also be reported as an SAE. 
10.2 
Documentation of SAEs or Serious SARs 
10.2.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs caused 
by a protocol-mandated intervention will be collected (e.g. SAEs related to invasive 
procedures such as biopsies, medication washout.  
For any other experience or condition that meets the definition of an SAE or a serious 
SAR, recording of the event must begin from day 1 of study treatment and continue 
through the 6 week follow-up period after treatment is discontinued. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 93 of 154
 
 
 
10.2.2 Documentation and Notification 
These events (SAEs or Serious SARs) must be recorded in the SAE console within 
Oncore™ for that subject within 24 hours of learning of its occurrence. For multicenter 
sites, the multicenter Project Manager must be notified via email of all SAEs within 24 
hours of learning of its occurrence. SAEs must be recorded on the MedWatch 3500A 
report form. 
10.3 
Adverse Event Reporting 
10.3.1 IRB Reporting Requirements 
UNC: 
The UNC IRB will be notified of all SAEs that qualify as an Unanticipated Problem as 
per the UNC IRB Policies using the IRB’s web-based reporting system within 7 days 
of the Investigator becoming aware of the problem. Please note, these events must be 
reported to the sponsor within 24 hours of learning of the occurrence.  
Multicenter sites:   
The UNC IRB will be notified of all SAEs that qualify as an Unanticipated Problem as 
per the UNC IRB Policies using the IRB’s web-based reporting system within 7 days 
of the Investigator becoming aware of the problem. Please note, these events must be 
reported to the sponsor within 24 hours of learning of the occurrence. 
10.3.2 Pregnancy  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject at UNC or at a multicenter site, occurring 
while the subject is on study, or within 30 days of the subject’s last dose of study 
product should be recorded as SAEs. The subject is to be discontinued immediately 
from the study. 
For multicenter sites, the pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to the Multicenter Project Manager immediately via email 
(CPOMultiCenter@med.unc.edu) or facsimile to 919-966-4300. The female subject 
should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy and 
must document the outcome of the pregnancy (either normal or abnormal outcome) and 
report the condition of the fetus or newborn to the Multicenter Project Manager. If the 
outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 94 of 154
 
 
 
the Investigator should report the abnormal outcome as an AE. If the abnormal outcome 
meets any of the serious criteria, it must be reported as an SAE.   
10.3.3 FDA Expedited Reporting Requirements  
A sponsor must report any suspected adverse reaction (SAR) that is both serious and 
unexpected and related to the cellular product to the FDA. All deaths in the study should 
be reported expeditiously to FDA regardless of attribution if they occur within 30 days 
of the infusion of the study cells. Additionally, all grade 4 or greater product infusion 
reactions, cytokine release syndrome and/or neurologic toxicity must be reported in an 
expedited fashion. Please refer to section 9.1.2 for the definition of an SAR. 
The sponsor must submit each IND safety report on a MedWatch Form 3500A.  
Timing  
FDA must be notified of potential serious risks within 15 calendar days after the 
sponsor determines the event requires reporting. FDA must be notified of 
unexpected fatal or life-threatening suspected adverse reactions as soon as possible 
but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information. The sponsor must be notified of the SAE by the investigator within 24 
hours of the event. If the results of a sponsor’s investigation show that an adverse 
event not initially determined to be reportable is reportable, the sponsor must report 
such suspected adverse reaction in an IND safety report as soon as possible, but in 
no case later than 15 calendar days after the determination is made.  
Follow-Up  
The sponsor must promptly investigate all safety information it receives. Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and as such the Multicenter Project Manager should be 
updated within 24 hours of the information becoming available via a follow-up 
MedWatch Form 3500A. 
Notification of Investigators  
The sponsor must notify all participating investigators (i.e., all investigators to 
whom the sponsor is providing cell infusion 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, but in no case later than 15 calendar 
days after the sponsor determines that the information qualifies for reporting.    

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 95 of 154
 
 
 
Process  
If the sponsor deems that an event is both a serious adverse reaction (SAR) AND 
unexpected, it must also (in addition to OnCore®) be recorded on the MedWatch 
Form 3500A. Unexpected adverse events or adverse reaction refers to an event or 
reaction that is not listed in the Investigator’s Brochure or is not listed at the 
specificity or severity that has been observed; or if an investigator’s brochure is not 
required or available, is not consistent with the risk information described in the 
general investigation plan or elsewhere in the current IND application.   
The MedWatch 3500A form and supporting documents defining the event and 
causality should be sent to the electronic mailbox (CPOMultiCenter@med.unc.edu; 
primary route of submission) (or facsimile (919) 966-4300 (back-up)) of the 
Multicenter Project Manager along with supporting documentation defining the 
event and causality. 
The 
MedWatch 
3500a 
form 
can 
be 
accessed 
at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.ht
m. 
Additional Reporting Requirements  
The following additional items must be reported via IND safety report: 
• Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor, that suggest a significant risk to humans exposed 
to the cell infusion.  
• Findings from animal or in vitro testing. The sponsor must report any 
findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the cell 
infusion, such as reports of mutagenicity, teratogenicity, or carcinogenicity, 
or reports of significant organ toxicity at or near the expected human 
exposure. 
• Increased rate of occurrence of serious suspected adverse reactions. 
• All deaths in the study regardless of attribution if they occur within 30 
days of the infusion of the study cells.  
• Any product infusion reactions grade ≥4. 
• Any occurrence of cytokine release syndrome (CRS) grade ≥4.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 96 of 154
 
 
 
• Any occurrence of neurotoxicity grade 4. 
Additional Guidance  
Please refer to 21CFR312.32 and “Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies” for additional information 
and reporting requirements. All IND Safety Reports will be submitted in 
accordance with these regulations/guidances.     
10.3.4 Institutional Biosafety Committee (IBC) 
In addition to the local IRB, any qualifying serious adverse events (SAEs) must be 
reported to the Institutional Biosafety Committee (IBC). The IBC is responsible for 
reviewing recombinant DNA research conducted at or sponsored by the institution for 
compliance with NIH Guidelines as specified in Section III, Experiments covered by 
the NIH Guidelines and approving those research projects that are found to conform 
with the NIH Guidelines. As such, the IBC is charged with ensuring compliance with 
all surveillance, data reporting and adverse event reporting requirements set forth in the 
NIH Guidelines. The UNC study coordinator will be responsible for notifying the 
Regulatory Associate within 48 hours should any reportable event occur. 
10.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of subject safety in this trial 
with periodic reporting to the Data and Safety Monitoring Committee (DSMC). Dr. Grover 
will discuss any DLT event as it occurs, and in consultation with the study statistician, 
make a decision regarding continued accrual and dose escalation as appropriate. In addition, 
this triad will evaluate any unexpected toxicities as they occur, and determine if any 
changes to toxicity monitoring are required. 
Meetings/teleconferences will be held with the team at a frequency dependent on study 
accrual, and in consultation with the study Biostatistician. These meetings will include the 
investigators as well as study coordinators, data coordinators, regulatory associates, 
clinical data management associates, and any other relevant personnel the principal 
investigators may deem appropriate. At these meetings, the research team will discuss all 
issues relevant to study progress, including enrollment, safety, regulatory, data collection, 
etc. 
The team will produce summaries or minutes of these meetings. These summaries will be 
available for inspection when requested by any of the regulatory bodies charged with the 
safety of human subjects and the integrity of data including, but not limited to, the oversight 
(Office of Human Research Ethics (OHRE) Biomedical IRB, the Oncology Protocol 
Review Committee (PRC) or the North Carolina TraCS Institute Data and Safety 
Monitoring Board (DSMB)).   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 97 of 154
 
 
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the study 
on a regular (quarterly to annually) basis, with the frequency of review based on risk and 
complexity as determined by the UNC Protocol Review Committee. The UNC PI will be 
responsible for submitting the following information for review: 1) safety and accrual data 
including the number of subjects treated; 2) significant developments reported in the 
literature that may affect the safety of participants or the ethics of the study; 3) preliminary 
response data; and 4) summaries of team meetings that have occurred since the last report. 
Findings of the DSMC review will be disseminated by memo to the UNC PI, PRC, and the 
UNC IRB and DSMB. 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 98 of 154
 
 
 
11.0 STATISTICAL CONSIDERATIONS 
11.1 
Design, Dose Escalation and MTD 
This Phase I dose-escalation trial is designed to evaluate the safety of ATLCAR.CD30 cells. 
Dose-limiting toxicity is defined in section 4.1.3.3. Dose escalation is guided by the 
continual reassessment method (CRM) [87] in order to determine the MTD of 
ATLCAR.CD30 cells. For this study, MTD is defined as the dose that causes DLT in 10% 
of eligible cases. Three dose levels are being evaluated namely, 2x107 cells/m2, 1x108 
cells/m2, and 2x108 cells/m2. Based on our previous trials, we expect a shallow dose-
toxicity curve for the doses proposed in this trial. In this trial, CRM is implemented based 
on one parameter model in O’Quigley et al. [87], with DLT probability at each dose 
modeled as aib, where constants a are (0.0281, 0.0568, 0.1) and parameter b is being 
estimated. The prior distribution for b is exponential with mean 1 Subjects are assigned in 
cohorts of size 2 until the first DLT is observed or the highest dose 2x108 cells/m2 is reached 
without DLT in the first two subjects assigned to 2x108 cells/m2 (initial dose escalation). 
After that assignments are determined by the CRM and subjects are assigned one at a time. 
Pediatric subjects will not be allowed to enroll at a dose until 2 adult subjects are enrolled 
and complete their follow-up at that dose level. To reduce the probability of treating 
subjects at unacceptable toxic dose levels, we employ modifications to the original CRM 
and do not allow skipping untried doses when the dose is escalated. Subject enrollment 
starts at the lowest dose level.  
Two subjects will initially be allocated to the lowest dose level and followed for 6 weeks 
post IV injection of ATLCAR.CD30 cells for evaluation of DLTs. If any of the two subjects 
initially enrolled develop DLTs, the trial will be suspended, and dose levels might be re-
evaluated. As soon as the first DLT is observed, dose assignment will be guided by the 
CRM from that point on. Otherwise, we will continue assigning subjects in cohorts of 2 at 
escalating doses until either a DLT is observed or the highest dose is reached without a 
DLT in the first two subjects. After that subjects will be assigned one at a time.   
The trial will be suspended, and dose levels re-evaluated as soon as, at the lowest dose, 2 
DLTs are observed out of a total of 2 subjects, 3 DLTs out of a total of 3-7 subjects, or 4 
DLTs out of more than 7 subjects. 
DLTs that occur within 6 weeks after infusion will be factored into the CRM calculations 
to determine the recommended dose for the subsequent subject. During the study, real-time 
monitoring of subject toxicity outcome will be performed in order to implement estimation 
of the dose-toxicity curve and determine dose level for the next subject cohort using one 
of the pre-specified dose levels. If there is a need to assign a new subject when some of the 
current subjects are still being followed for DLT, each subject still in follow-up will be 
temporarily counted as x DLTs out of 1, where x is the remaining follow-out time fraction. 
For example, if a subject has been followed for 2 out of 6 weeks, subject will be counted 
as (1-2/6) = 2/3 of a DLT out of 1 subject. This is a conservative way to account for subjects 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 99 of 154
 
 
 
still in follow-up. The assignment for a new subject is then determined using the CRM. 
When the two initial subjects are being followed for DLT at a given dose, additional 
subjects might be enrolled at a dose prescribed by the CRM using the rule above for 
imputing temporary DLT for subjects still in follow-up. This applies to pediatric subjects 
as well as long as there are 2 adult subjects with full 6 week follow-up for DLT at that dose. 
At the discretion of the investigator pediatric subjects can be assigned to a dose one level 
lower than specified by the CRM. During the dose escalation part guided by the CRM (after 
the first DLT is observed), subjects with insufficient cells manufactured and therefore 
infused with a quantity of cells consistent with a dose lower than the one prescribed by the 
CRM will be included in the CRM calculations with the weight of 0.5. This will allow us 
to use data from these subjects and, at the same time, not to bias the dose calculated by the 
CRM downward. If the number of such subjects exceeds 3, we will consider increasing the 
sample size of the dose escalation part of the study. 
11.2 
Sample Size 
The trial will continue until a minimum of 12 subjects is treated. Six additional subjects 
might be accrued to obtain more data. Assignment of these subjects will be guided by the 
CRM. However, a lower dose can be chosen for assignment. Depending on subject 
availability, a maximum of 18 subjects will be accrued into this Phase I trial. The final 
MTD will be the dose with estimated probability of the DLT closest to the target toxicity 
rate of 10%. All subjects, adult and pediatric, will be included in MTD estimation. We 
therefore expect to enroll between 12-18 subjects into this trial. 
11.3 
Data Analysis Plans 
11.3.1 Safety Analysis of Adverse Event Data 
All subjects who received the ATLCAR.CD30 infusion will be included in the safety 
analysis. Adverse event data and corresponding toxicity grades six weeks after T-cell 
infusion and during long-term follow-up will be summarized in the form of tables. 
Incidence tables will be generated to summarize incidence of subjects reporting at least 
one episode of each specific adverse event, incidence of adverse events causing 
withdrawal and incidence of serious adverse events. The total number of episodes for 
each event reported (Frequency Table), the severity and attribution to study therapy of 
each episode reported (Severity Table and Attribution Table) will also be displayed.  
Listings of adverse events by subjects will include the time to onset, the duration of 
each event, the severity of each event, and the relationship of the event to study therapy, 
whether it was a serious event, and whether it caused withdrawal. Safety data will be 
summarized for the overall subject group and by dose levels.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 100 of 154
 
 
 
11.3.2 Safety Analysis of Laboratory Data 
Laboratory data, which includes CBC, BUN, creatinine, and liver function tests, will 
be examined in different ways. Descriptive statistics (means, standard deviations, 
medians and ranges) at pre-infusion, and at 1, 2, 4, 6 weeks post- T-cell infusion will 
be calculated. Laboratory data collected at 3-month intervals for the first year will also 
be summarized. A scatter diagram depicting laboratory values at each time point for 
each subject will also be generated. In order to analyze changes in laboratory values, a 
shift table with Stuart-Maxwell chi-square analysis of the change in the normal range 
from pre-infusion to post infusion time points (using high, normal, low) will be 
performed. When appropriate, these tables are collapsed and the McNemar’s test 
applied in place of the Stuart-Maxwell test. These statistical tests will be primarily 
performed for the overall subject group.  
11.3.3 Analysis of Expansion and Persistence of Transduced T Cells 
The frequency of T cells transduced with the vector (T cells expressing will be 
summarized at pre and post-infusion time points using mean ± SD, medians and ranges 
to evaluate their expansion and persistence. Changes in each of these T cells from pre-
infusion to each time point of post-infusion will be assessed and compared using paired 
t-tests, or when appropriate, the Wilcoxon signed ranks test. Paired comparisons of 
these T cells within a subject at each time point will also be performed. These analyses 
will be performed in the overall subject group. 
Plots of growth curves will be generated to graphically illustrate patterns of T-cell 
expansion. Plots will be generated to depict patterns of survival and expansion of T 
cells for each of the two vectors. Longitudinal modeling techniques such as the random 
coefficient mixed model will be employed to model each of the repeatedly-measured 
T cells. These models account for variation in individual-level intercepts and slopes 
over the follow-up time. Thus, we will be able to model proliferation of T cells over 
time and estimate the magnitude of expansion or decline of T cells. We will include 
dose level as an independent variable in the model to account for different doses 
received by subjects.  
Alternative strategies to analyze these outcomes include calculation of area under the 
curve over time for T cell frequencies or piecewise longitudinal models based on 
apparent trends from plots of growth curves. Despite the small subject numbers, a data-
dense study will be generated due to the repeat measurements on proliferation, immune 
function, etc. on each subject. The modeling strategies proposed here are amenable to 
these types of data but will however be considered exploratory and interpreted with 
caution due to limited study power.  
11.3.4 Analysis of Progression Free Survival 
PFS is defined in section 3.2.1. We will estimate PFS using the Kaplan-Meier method.  

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 101 of 154
 
 
 
11.3.5 Analysis of Integration Location and CAR T cell Behavior 
Differential CAR-T cell behavioral analysis will be described by comparing 
CAR.CD30 integration location with CAR-T cell behaviors such as expansion, 
persistence and trafficking. Logistic regression will be used with loss of response to the 
experimental therapy as an outcome to assess potential causes for loss of responses. 
Additionally, we will assess the correlations between CAR T cell behavior and the 
integration locations of CAR.CD30. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 102 of 154
 
 
 
12.0 STUDY MANAGEMENT 
12.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
Prior to a subject’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. 
12.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided 
to the Clinical Protocol Office (CPO) at the University of North Carolina. 
• A copy of the official IRB approval letter for the protocol and informed consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-investigators 
who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate documentation  
• Financial Disclosures 
• CAP and CLIA Laboratory certification numbers and institution lab normal values 
• Executed clinical research contract 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 103 of 154
 
 
 
12.3 
Registration Procedures 
All subjects must be registered with the LCCC CPO Multicenter Office at the University 
of North Carolina before enrollment to study. To register a subject call the Multicenter 
office at 919-966-7359 Monday-Friday 8:30 am – 5:00 pm EST. Scan and email the 
Multicenter Project Manager (CPOMultiCenter@med.unc.edu; preferred) or fax (919-966-
4300) the registration form, signed informed consents, signed eligibility form and all 
source documents to confirm eligibility. Eligibility may be confirmed by the UNC Study 
Coordinator for subjects treated at UNC. When sending registration request with eligibility 
documentation, please allow 24 hours for source to be reviewed.  
12.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol. 
12.4.1 Emergency Modifications 
UNC and multicenter site investigators may implement a deviation from, or a change 
of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior UNC 
or their respective institution’s IRB/IEC approval/favorable opinion.   
For any such emergency modification implemented, a UNC IRB modification form 
must be completed by UNC Research Personnel within five (5) business days of 
making the change. 
12.4.2 Single Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger Comprehensive 
Cancer Center Investigator Initiated Trials under any circumstances. Other types of 
single subject exceptions may be allowed if proper regulatory review has been 
completed in accordance with Lineberger Comprehensive Cancer Center’s Single 
Subject Exceptions Policy. 
12.4.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 104 of 154
 
 
 
• Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
An unplanned protocol variance is considered a violation if the variance meets any of 
the following criteria:  
• Has harmed or increased the risk of harm to one or more research participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the investigator(s). 
• Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
Protocol Deviations: UNC or multicenter site personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  
Protocol Violations: Violations should be reported by UNC personnel within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.  
Unanticipated Problems: 
Multicenter Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined by 
UNC’s IRB must also be reported to the Multicenter Project Manager. The Regulatory 
Associate will report the event to the UNC IRB using the IRB’s web-based reporting 
system. Examples of such UPs include a lost or stolen laptop computer that contains 
sensitive study information. 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by UNC’s 
IRB must be reported by the Regulatory Associate using the IRB’s web-based 
reporting system.   

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 105 of 154
 
 
 
12.5 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator. In 
the case of a study with a drug seeking regulatory approval and marketing, these documents 
shall be retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
12.6 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study subjects. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 106 of 154
 
 
 
13.0  AUDITING AND MONITORING 
The multicenter team of the UNC LCCC will serve as the coordinating center for this trial. 
Data will be collected through a web based electronic data capture system, Advarra EDC. 
Other study institutions will be given a password to directly enter their own data onto the web 
site via electronic case report forms (eCRFs). Multicenter personnel will coordinate and 
manage data for quality control assurance and integrity. 
All data will be collected and entered into Advarra EDC by research coordinators from UNC 
LCCC and participating institutions. The investigators at each site will allow monitors to 
review all source documents supporting data entered into Advarra EDC. The UNC Clinical 
Data Management Associate can be reached at 919-843-2742 or 1-877-668-0683. 
All data will be monitored and source data will be verified on selected subjects. Participating 
sites must send source documents to LCCC upon request, for remote monitoring review. 
Queries will be issued on an ongoing basis on all subjects. Participating sites should respond 
to data queries within 14 days of receipt.  
As an investigator initiated study, this trial will also be audited by the Lineberger 
Comprehensive Cancer Center Compliance Committee every six or twelve months, depending 
on the participation of multicenter sites. 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 107 of 154
 
 
 
14.0 AMENDMENTS 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator at UNC. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
subject, a revised consent form might be required.   
The written amendment, and if required the amended consent form, must be sent to UNC’s 
IRB for approval prior to implementation.   
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 108 of 154
 
 
 
15.0 STUDY DISCONTINUATION  
Both Lineberger Comprehensive Cancer Center and the Principal Investigator reserve the 
right to terminate the study at the investigator’s site at any time. Should this be necessary, 
Lineberger Comprehensive Cancer Center or a specified designee will inform the appropriate 
regulatory authorities of the termination of the study and the reasons for its termination, and 
the Principal Investigator will inform the IRB/IEC of the same. In terminating the study, 
Lineberger Comprehensive Cancer Center and the Principal Investigator will assure that 
adequate consideration is given to the protection of the subjects’ interests. 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 109 of 154
 
 
 
16.0 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Lineberger Comprehensive Cancer Center. However, authorized 
regulatory officials, IRB/IEC personnel, Lineberger Comprehensive Cancer Center and its 
authorized representatives are allowed full access to the records. 
Identification of subjects and eCRFs shall be by initials, screening and treatment numbers 
only. If required, the subject's full name may be made known to an authorized regulatory 
agency or other authorized official. 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 110 of 154
 
 
 
17.0 REFERENCES 
1. 
Jain, N., et al., A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in 
previously treated patients with CLL. Oncotarget, 2017. 8(13): p. 22104-22112. 
2. 
Cordeiro, A., et al., Late Effects of CD19-Targeted CAR-T Cell Therapy. Blood, 2018. 
132: p. 3. 
3. 
Shaefer, A., et al., Cytopenias after Chimeric Antigen Receptor T-Cells (CAR-T) Infusion; 
Patterns and Outcomes. Biology of Blood and Marrow Transplantation, 2019. 25(3): p. 
S171. 
4. 
Moskowitz, C.H., et al., Brentuximab vedotin as consolidation therapy after autologous 
stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or 
progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet, 2015. 385(9980): p. 1853-62. 
5. 
Cheson, B.D., et al., Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol, 2014. 32(27): p. 3059-68. 
6. 
Yung, L. and D. Linch, Hodgkin's lymphoma. Lancet, 2003. 361(9361): p. 943-51. 
7. 
Ng, A.K. and P.M. Mauch, Late complications of therapy of Hodgkin's disease: 
prevention and management. Curr Hematol Rep, 2004. 3(1): p. 27-33. 
8. 
Kewalramani, T., et al., Progressive disease following autologous transplantation in 
patients with chemosensitive relapsed or primary refractory Hodgkin's disease or 
aggressive non-Hodgkin's lymphoma. Bone Marrow Transplant, 2003. 32(7): p. 673-9. 
9. 
Roskrow, M.A., et al., Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the 
treatment of patients with EBV-positive relapsed Hodgkin's disease. Blood, 1998. 91(8): 
p. 2925-34. 
10. 
Falini, B., et al., CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis 
factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood, 1995. 
85(1): p. 1-14. 
11. 
Hsu, S.M., et al., Hodgkin's Disease and Anaplastic Large Cell Lymphoma Revisited. 1. 
unique cytokine and cytokine receptor profile distinguished from that of non-hodgkin's 
lymphomas. J Biomed Sci, 1995. 2(4): p. 302-313. 
12. 
Jacobsen, E., Anaplastic large-cell lymphoma, T-/null-cell type. Oncologist, 2006. 11(7): 
p. 831-40. 
13. 
Gascoyne, R.D., et al., Prognostic significance of anaplastic lymphoma kinase (ALK) 
protein expression in adults with anaplastic large cell lymphoma. Blood, 1999. 93(11): p. 
3913-21. 
14. 
Yamaguchi, T., et al., Expression of chemokines and chemokine receptors in cutaneous 
CD30+ lymphoproliferative disorders. Br J Dermatol, 2006. 154(5): p. 904-9. 
15. 
Schnell, R., et al., Current strategies of antibody-based treatment in Hodgkin's disease. 
Ann Oncol, 2002. 13 Suppl 1: p. 57-66. 
16. 
Foyil, K.V. and N.L. Bartlett, Anti-CD30 Antibodies for Hodgkin lymphoma. Curr 
Hematol Malig Rep, 2010. 5(3): p. 140-7. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 111 of 154
 
 
 
17. 
Pro, B., et al., Brentuximab vedotin (SGN-35) in patients with relapsed or refractory 
systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol, 2012. 
30(18): p. 2190-6. 
18. 
Gopal, A.K., et al., Durable remissions in a pivotal phase 2 study of brentuximab vedotin 
in relapsed or refractory Hodgkin lymphoma. Blood, 2015. 125(8): p. 1236-43. 
19. 
Pule, M., H. Finney, and A. Lawson, Artificial T-cell receptors. Cytotherapy, 2003. 5(3): 
p. 211-26. 
20. 
Eshhar, Z., et al., Specific activation and targeting of cytotoxic lymphocytes through 
chimeric single chains consisting of antibody-binding domains and the gamma or zeta 
subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A, 1993. 
90(2): p. 720-4. 
21. 
Dotti, G., B. Savoldo, and M. Brenner, Fifteen years of gene therapy based on chimeric 
antigen receptors: "are we nearly there yet?". Hum Gene Ther, 2009. 20(11): p. 1229-39. 
22. 
Dotti, G., et al., Design and development of therapies using chimeric antigen receptor-
expressing T cells. Immunol Rev, 2014. 257(1): p. 107-26. 
23. 
Brentjens, R.J., et al., Safety and persistence of adoptively transferred autologous CD19-
targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. 
Blood, 2011. 118(18): p. 4817-28. 
24. 
Kochenderfer, J.N., et al., B-cell depletion and remissions of malignancy along with 
cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-
transduced T cells. Blood, 2012. 119(12): p. 2709-20. 
25. 
Porter, D.L., et al., Chimeric antigen receptor-modified T cells in chronic lymphoid 
leukemia. N Engl J Med, 2011. 365(8): p. 725-33. 
26. 
Savoldo B, R.C., Liu E et al., CD28 costimulation improves expansion and persistence of 
chimeric antigen receptor-modified T cells in lymphoma patients. J Cin Invest, 2011. 121: 
p. 1822-1826. 
27. 
Cruz, C.R., et al., Infusion of donor-derived CD19-redirected virus-specific T cells for B-
cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood, 
2013. 122(17): p. 2965-73. 
28. 
Lee, D.W., et al., T cells expressing CD19 chimeric antigen receptors for acute 
lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. 
Lancet, 2015. 385(9967): p. 517-28. 
29. 
Kochenderfer, J.N., et al., Chemotherapy-refractory diffuse large B-cell lymphoma and 
indolent B-cell malignancies can be effectively treated with autologous T cells expressing 
an anti-CD19 chimeric antigen receptor. J Clin Oncol, 2015. 33(6): p. 540-9. 
30. 
Kochenderfer, J.N., et al., Donor-derived CD19-targeted T cells cause regression of 
malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood, 
2013. 122(25): p. 4129-39. 
31. 
Maude, S.L., et al., Chimeric antigen receptor T cells for sustained remissions in 
leukemia. N Engl J Med, 2014. 371(16): p. 1507-17. 
32. 
Brown, C.E., et al., Bioactivity and Safety of IL13Ralpha2-Redirected Chimeric Antigen 
Receptor CD8+ T cells in Patients with Recurrent Glioblastoma. Clin Cancer Res, 2015. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 112 of 154
 
 
 
33. 
Till, B.G., et al., CD20-specific adoptive immunotherapy for lymphoma using a chimeric 
antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood, 
2012. 119(17): p. 3940-50. 
34. 
Till, B.G., et al., Adoptive immunotherapy for indolent non-Hodgkin lymphoma and 
mantle cell lymphoma using genetically modified autologous CD20-specific T cells. 
Blood, 2008. 112(6): p. 2261-71. 
35. 
Jensen, M.C., et al., Antitransgene rejection responses contribute to attenuated 
persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor 
redirected T cells in humans. Biol Blood Marrow Transplant, 2010. 16(9): p. 1245-56. 
36. 
Maus, M.V., et al., Antibody-modified T cells: CARs take the front seat for hematologic 
malignancies. Blood, 2014. 123(17): p. 2625-35. 
37. 
Laport, G.G., et al., Adoptive transfer of costimulated T cells induces lymphocytosis in 
patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected 
hematopoietic cell transplantation. Blood, 2003. 102(6): p. 2004-13. 
38. 
Rapoport, A.P., et al., Restoration of immunity in lymphopenic individuals with cancer by 
vaccination and adoptive T-cell transfer. Nat Med, 2005. 11(11): p. 1230-7. 
39. 
Li, Z., et al., Murine leukemia induced by retroviral gene marking. Science, 2002. 
296(5567): p. 497. 
40. 
Vanin, E.F., et al., Characterization of replication-competent retroviruses from nonhuman 
primates with virus-induced T-cell lymphomas and observations regarding the 
mechanism of oncogenesis. J Virol, 1994. 68(7): p. 4241-50. 
41. 
Amakawa, R., et al., Impaired negative selection of T cells in Hodgkin's disease antigen 
CD30-deficient mice. Cell, 1996. 84(4): p. 551-62. 
42. 
Savoldo, B., et al., Epstein Barr virus specific cytotoxic T lymphocytes expressing the 
anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. 
Blood, 2007. 110(7): p. 2620-30. 
43. 
Lee, D.W., et al., Current concepts in the diagnosis and management of cytokine release 
syndrome. Blood, 2014. 124(2): p. 188-95. 
44. 
Brentjens, R., et al., Treatment of chronic lymphocytic leukemia with genetically targeted 
autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. 
Mol Ther, 2010. 18(4): p. 666-8. 
45. 
Morgan, R.A., et al., Case report of a serious adverse event following the administration 
of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular 
therapy : the journal of the American Society of Gene Therapy, 2010. 18(4): p. 843-851. 
46. 
Ramos CA, S.B., Liu E et al., Clinical Responses In Patients Infused With T Lymphocytes 
Redirected To Target κ-Light Immunoglobulin Chain. Blood, 2013. 122: p. abstract #21. 
47. 
Thomas, R.K., et al., Epidemiology and etiology of Hodgkin's lymphoma. Ann Oncol, 
2002. 13 Suppl 4: p. 147-52. 
48. 
Stathis, A. and A. Younes, The new therapeutical scenario of Hodgkin lymphoma. Ann 
Oncol, 2015. 
49. 
van Nimwegen, F.A., et al., Cardiovascular disease after Hodgkin lymphoma treatment: 
40-year disease risk. JAMA Intern Med, 2015. 175(6): p. 1007-17. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 113 of 154
 
 
 
50. 
Herbst, C., et al., Combined modality treatment improves tumor control and overall 
survival in patients with early stage Hodgkin's lymphoma: a systematic review. 
Haematologica, 2010. 95(3): p. 494-500. 
51. 
Laskar, S., et al., Consolidation radiation after complete remission in Hodgkin's disease 
following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine 
chemotherapy: is there a need? J Clin Oncol, 2004. 22(1): p. 62-8. 
52. 
NCCN, NCCN Practice Guidelines in Oncology for Hodgkin Lymphoma. 2015. 
53. 
Barbaro, P.M., et al., Reduced incidence of second solid tumors in survivors of childhood 
Hodgkin's lymphoma treated without radiation therapy. Ann Oncol, 2011. 22(12): p. 
2569-74. 
54. 
Maraldo, M.V., Guisti, F., Vogelius, I.R. Lundemann, M., , Cardiovascular disease after 
treatment for Hodgkin's lymphoma: an analysis of nine collaborative EORTC-LYSA 
trials. The Lancet Haematology, 2015. 2(11): p. e492-e502. 
55. 
Aleman, B.M., et al., Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood, 
2007. 109(5): p. 1878-86. 
56. 
Howe, R., et al., Secondary myelodysplastic syndrome and acute myelogenous leukemia 
are significant complications following autologous stem cell transplantation for 
lymphoma. Bone Marrow Transplant, 2003. 32(3): p. 317-24. 
57. 
Ng, A.K., A. LaCasce, and L.B. Travis, Long-term complications of lymphoma and its 
treatment. J Clin Oncol, 2011. 29(14): p. 1885-92. 
58. 
Huang, M.A., D.K. Krishnadas, and K.G. Lucas, Cellular and Antibody Based 
Approaches for Pediatric Cancer Immunotherapy. J Immunol Res, 2015. 2015: p. 
675269. 
59. 
Grupp, S.A., et al., Chimeric antigen receptor-modified T cells for acute lymphoid 
leukemia. N Engl J Med, 2013. 368(16): p. 1509-18. 
60. 
Hombach, A., et al., An anti-CD30 chimeric receptor that mediates CD3-zeta-
independent T-cell activation against Hodgkin's lymphoma cells in the presence of 
soluble CD30. Cancer research, 1998. 58(6): p. 1116-1119. 
61. 
Hombach, A., et al., T cells engrafted with a recombinant anti-CD30 receptor target 
autologous CD30(+) cutaneous lymphoma cells. Gene therapy, 2001. 8(11): p. 891-895. 
62. 
Di Stasi, A., et al., T lymphocytes coexpressing CCR4 and a chimeric antigen receptor 
targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. 
Blood, 2009. 113(25): p. 6392-402. 
63. 
Ramos C, B.B., Liu E, Chimeric T cells for therapy of CD30+ Hodgkin and Non- 
Hodgkin Lymphomas (HL & NHL). Mol Ther, 2015. 23(1). 
64. 
Rooney, C.M., et al., Infusion of cytotoxic T cells for the prevention and treatment of 
Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood, 1998. 
92(5): p. 1549-55. 
65. 
Bollard, C.M., et al., Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's 
disease. J Exp Med, 2004. 200(12): p. 1623-33. 
66. 
Rosenberg, S.A., et al., Adoptive cell transfer: a clinical path to effective cancer 
immunotherapy. Nat Rev Cancer, 2008. 8(4): p. 299-308. 
67. 
Savoldo, B., et al., Treatment of solid organ transplant recipients with autologous Epstein 
Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood, 2006. 108(9): p. 2942-9. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 114 of 154
 
 
 
68. 
Rapoport, A.P., et al., Combination immunotherapy using adoptive T-cell transfer and 
tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. 
Blood, 2011. 117(3): p. 788-97. 
69. 
Klebanoff, C.A., et al., Sinks, suppressors and antigen presenters: how lymphodepletion 
enhances T cell-mediated tumor immunotherapy. Trends Immunol, 2005. 26(2): p. 111-7. 
70. 
Dudley, M.E., et al., Adoptive cell transfer therapy following non-myeloablative but 
lymphodepleting chemotherapy for the treatment of patients with refractory metastatic 
melanoma. J Clin Oncol, 2005. 23(10): p. 2346-57. 
71. 
Morgan, R.A., et al., Cancer regression in patients after transfer of genetically 
engineered lymphocytes. Science, 2006. 314(5796): p. 126-9. 
72. 
Gajewski, T.F., Y. Meng, and H. Harlin, Immune suppression in the tumor 
microenvironment. J Immunother, 2006. 29(3): p. 233-40. 
73. 
Marshall, N.A., et al., Immunosuppressive regulatory T cells are abundant in the reactive 
lymphocytes of Hodgkin lymphoma. Blood, 2004. 103(5): p. 1755-62. 
74. 
Barath, S., et al., Immunoregulatory T cells in the peripheral blood of patients with 
Hodgkin's lymphoma. Acta Haematol, 2006. 116(3): p. 181-5. 
75. 
Johnson, L.A., et al., Gene transfer of tumor-reactive TCR confers both high avidity and 
tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating 
lymphocytes. J Immunol, 2006. 177(9): p. 6548-59. 
76. 
Fraietta, J.A., et al., Determinants of response and resistance to CD19 chimeric antigen 
receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nature Medicine, 2018. 
24(5): p. 563-571. 
77. 
Xu, Y., et al., Closely related T-memory stem cells correlate with in vivo expansion of 
CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood, 2014. 123(24): p. 3750-
9. 
78. 
Hacein-Bey-Abina, S., et al., A serious adverse event after successful gene therapy for X-
linked severe combined immunodeficiency. The New England journal of medicine, 2003. 
348(3): p. 255-256. 
79. 
Hacein-Bey-Abina, S., et al., LMO2-associated clonal T cell proliferation in two patients 
after gene therapy for SCID-X1. Science (New York, N.Y.), 2003. 302(5644): p. 415-419. 
80. 
Puck, J.M., et al., Prenatal test for X-linked severe combined immunodeficiency by 
analysis of maternal X-chromosome inactivation and linkage analysis. The New England 
journal of medicine, 1990. 322(15): p. 1063-1066. 
81. 
Uribe, L. and K.I. Weinberg, X-linked SCID and other defects of cytokine pathways. 
Seminars in hematology, 1998. 35(4): p. 299-309. 
82. 
Maher, J., et al., Human T-lymphocyte cytotoxicity and proliferation directed by a single 
chimeric TCRzeta /CD28 receptor. Nature biotechnology, 2002. 20(1): p. 70-75. 
83. 
Brenner, M.K., et al., Gene marking to determine whether autologous marrow infusion 
restores long-term haemopoiesis in cancer patients. Lancet (London, England), 1993. 
342(8880): p. 1134-1137. 
84. 
Heslop, H.E., et al., Long-term restoration of immunity against Epstein-Barr virus 
infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nature 
medicine, 1996. 2(5): p. 551-555. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 115 of 154
 
 
 
85. 
Heslop, H.E., et al., Long-term outcome of EBV-specific T-cell infusions to prevent or 
treat EBV-related lymphoproliferative disease in transplant recipients. Blood, 2010. 
115(5): p. 925-35. 
86. 
Gilliland, D.G. and J.G. Gribben, Evaluation of the risk of therapy-related MDS/AML 
after autologous stem cell transplantation. Biology of blood and marrow transplantation : 
journal of the American Society for Blood and Marrow Transplantation, 2002. 8(1): p. 9-
16. 
87. 
O'Quigley, J., M. Pepe, and L. Fisher, Continual reassessment method: a practical design 
for phase 1 clinical trials in cancer. Biometrics, 1990. 46(1): p. 33-48. 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 116 of 154
 
 
 
 
18.0 APPENDICES 
18.1 
APPENDIX I – Names of Study Personnel 
 
Sponsor: 
Lineberger Comprehensive Cancer Center 
Principal Investigator: 
Natalie Grover, MD 
Assistant Professor 
Division of Hematology 
170 Manning Drive  
3142 Houpt Building 
Campus Box 7305 
Chapel Hill, NC  27599  
E-mail: Natalie_grover@med.unc.edu  
Phone: (919) 843-5968 
Medical Monitor: 
Barbara Savoldo, MD, PhD 
E-mail: barbar@email.unc.edu  
Clinical Trials Office: 
Lineberger Comprehensive Cancer Center  
The University of North Carolina at Chapel Hill  
450 West Drive, 3rd Floor,  
Chapel Hill, NC 27599-7295 
Biostatistician: 
Anastasia Ivanova, PhD 
3103c Mcgavran-Greenberg Hall 7420 
Email: aivanova@bios.unc.edu  
Phone: (919) 843-8086 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 117 of 154
 
 
 
18.2 
APPENDIX II- Revised Response Criteria for Lymphoma 
(Cheson, et al. J Clin Oncol. 2014;32(27):3059-68) 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 118 of 154
 
 
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 119 of 154
 
 
 
18.3 APPENDIX III- Lansky and Karnofsky Performance Status 
 
Lansky 
Karnofsky 
Score Description 
Score Description 
100 
Fully active, normal 
100 
Normal, no complaints, no 
evidence of disease 
90 
Minor restrictions with 
strenuous physical activity 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease 
80 
Active, but gets tired more 
quickly 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Both greater restriction of, and 
less time spent in, active play 
70 
Cares for self, unable to carry on 
normal activity or do active work 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities 
60 
Required occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Lying around much of the day, 
but gets dressed; no active play; 
participates  
in all quiet play and activities 
50 
Requires considerable assistance 
and frequent medical care 
 
40 
Mostly in bed; participates in 
quiet activities 
40 
Disabled, requires special care and 
assistance 
30 
Stuck in bed; needs help even 
for quiet play 
30 
Severely disabled, hospitalization 
indicated. Death not imminent 
20 
Often sleeping; play is entirely 
limited to very passive activities 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Does not play nor get out of bed 
10 
Moribund, fatal processes 
progressing rapidly. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 120 of 154
 
 
 
18.4 
APPENDIX IV - Abbreviated Follow Up Required After Initiating Alternative 
Therapy 
Subjects should not receive other antineoplastic agents for at least 6 weeks post T cell 
infusion (for purposes of evaluation). Subjects who experience disease progression after 
a cell infusion may receive other therapy if needed at the discretion of their attending 
physician. If subjects receive other therapy they will come off study for adverse event 
reporting after the 6-week assessments outlined in section 4.2 are completed. Subsequent 
follow up assessments for subjects post progression are outlined in the table below. If 
subjects initiate alternative therapy after they have completed the initial 6-week follow up 
period for the cell infusion, they should be contacted as outlined below. The timing for 
each visit relates to the last cell infusion received by the subject. Follow up kits and 
instructions will be provided to subjects who initiate alternative therapy. Blood samples 
should be collected by a local health care provider as outlined in the laboratory manual.  
Table 7 
Abbreviated Follow-up After Initiating Alternative Therapy 
Assessments1 
Post Disease Progression Follow Up 
Month 3 D1 
Month 6 D1 
Month 12 D1 
Yearly 
History2 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
Correlative Samples,3 
X 
X 
X 
X 
Survival 
X 
X 
X 
X 
Footnotes for the Abbreviated Follow-up After Initiating Alternative Therapy T&E Table 
1. A window of +/-10 days will apply to the every 3 months study visits, and a window 
of +/-30 days will apply to visits separated by ≥ 6 months. Yearly follow-up visits are 
required during long-term follow-up for a total of 15 years or until death.   
2. History and performance status information will be collected via the phone contact. 
Survival will also be documented. Medical history must include collecting the 
following information: 1. New malignancy(ies) 2. New incidence or exacerbation of 
pre-existing neurologic disorder 3. New incidence or exacerbation of a prior 
rheumatologic or other autoimmune disorder 4. New incidence of a hematologic 
disorder and 5. New incidence of infection (potentially product related). 
3. Correlative analysis will include the following. Correlative blood sample collection 
will cease if the samples are no longer required for function and persistence or clonality 
analysis. 
a. Persistence and Function: The analyses will be used to monitor persistence and 
function of adoptively transferred cells in peripheral blood and will include 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 121 of 154
 
 
 
immunophenotyping as well as quantitative polymerase chain reaction (qPCR) to 
detect transgene persistence and by functional assays such as in vitro reactivation 
of PBMCs in subjects for whom the appropriate reagents are available. Quantitative 
real-time PCR to detect the transgenes will be collected at the 3-, 6-, 9-, and 12-
months visits. Function and persistence will be continued for up to one-year post-
CAR T cell infusion. If a transgene copy number is >500 copies/μg DNA, then 
samples to determine transgene copy numbers will be collected every 6 months 
after the first year until transgene copy number is <500 copies/μg DNA at which 
time samples will then be collected yearly for up to a total of 15 years. If transgene 
is no longer detectable by PCR after 1-year post-final CAR T infusion, then 
collection for function and persistence will discontinue. See Section 7.5 and the 
Laboratory Manual for the amount of blood collected/type of tube used for all of 
the correlative studies.  
b. Clonality: If the transgene is detected at > 0.5% by flow cytometry at the 6-month 
sample collection timepoint, then PCR to detect retroviral integrant clonality and 
integrant locus will be performed. This analysis will continue every 6 months until 
detection is < 0.5% for up to 5 years. After this time, it will be collected annually. 
If the level of detection is < 0.5% at 6-months, samples will be collected annually 
and may be archived. Samples will no longer be collected if detection is < 0.5% for 
more than 1 consecutive testing period. See Section 7.5.3.  
c. RCR: For replication competent retrovirus (RCR) testing, subject blood samples 
will be collected and stored pre-infusion. The pre-infusion sample will only be 
tested if the subject develops a long-term gene therapy side effect as described in 
Section 7.5.2. Additional samples for RCR testing will only be collected and 
subsequently analyzed in the event that the subject develops a long-term gene 
therapy side effect as described in Section 7.5.2.  
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 122 of 154
 
 
 
18.5 
APPENDIX V - Patient Reported Outcomes Surveys 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 123 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 124 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 125 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 126 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 127 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 128 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 129 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 130 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 131 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 132 of 154
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 133 of 154
 
 
 
 
 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 137 of 154
 
 
 
18.7 
APPENDIX VII - Response Assessment for Mycoses Fungoides and Sézary 
Syndrome 
Table 10 
Modified Severity Weighted Assessment Tool for Mycoses Fungoides 
and Sézary Syndrome 
Body Region 
% BSA in Body 
Region 
Assessment of Involvement in Patient's Skin 
Patch* 
Plaque† 
Tumor‡ 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior trunk 
13 
 
 
 
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Thighs 
19 
 
 
 
Legs 
14 
 
 
 
Feet 
7 
 
 
 
Groin 
1 
 
 
 
Subtotal of lesion 
BSA 
 
 
 
 
Weighting factor 
 
×1 
×2 
×4 
Subtotal lesion 
BSA × weighting 
factor 
 
 
 
 
NOTE. mSWAT score equals summation of each column line. 
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted Assessment Tool. 
*Any size lesion without induration or significant elevation above the surrounding uninvolved skin; 
poikiloderma may be present. 
†Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
‡Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin and/or 
vertical growth. 
(Reference: Olsen EA, et al. J Clin Oncol 2011;29(18): 2598-2607) 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 141 of 154
 
 
 
18.8 
APPENDIX VIII- CRS Toxicity Grading Scale and Management Guidelines 
Version 2.0 (November 2, 2017) 
BACKGROUND 
Immunotherapies in cancer care are becoming more widely available.  As these therapies 
are being used more commonly, clinicians must be aware of their unique toxicities and the 
optimal strategies that are recommended for the management of these toxicities.  One 
toxicity in particular associated with these immunotherapies is cytokine release syndrome 
(CRS).  This life-threatening toxicity, if not managed both appropriately and in a timely 
manner, can lead to multi-organ failure and death. 
Cytokine release syndrome has been observed with several different immunotherapies, 
including monoclonal antibodies, bi-specific antibodies, T-cell checkpoint inhibitors, and 
novel T-cell therapies.  It is characterized by widespread activation and proliferation of 
lymphocytes leading to an abundant release of inflammatory cytokines well above 
physiologic levels.  This cytokine storm can manifest in many ways from constitutional 
symptoms to cardiovascular and neurologic compromise.  Management of this cytokine 
release 
storm 
involves 
both 
supportive 
care, 
and 
if 
clinically 
warranted, 
immunosuppression that blunts the aggressive cytokine response.  However, 
administration of immunosuppressive therapies may also counter the desired immune 
response against targeted tumor cells.  Thus, it is important that clinicians be prudent and 
reserve certain immunosuppressive strategies for the most appropriate clinical scenario.  
Thus, an algorithm that defines different grades of CRS and the corresponding therapy is 
necessary to guide clinicians in the delivery of appropriate care. 
SIGNS/SYMPTOMS & CLINICAL GRADING 
Severity of cytokine release syndrome is variable and may be influenced by tumor burden 
at the time of treatment with the immune-directed therapy or other pre-existing 
comorbidities.  Clinical grading is important for appropriate management. Organ systems 
affected by CRS and their corresponding signs and symptoms are listed below in Table 14 
and criteria for clinical grading are outlined below in Table 15. 
Table 14 
Signs and Symptoms of CRS 
Organ System 
Signs/Symptoms 
Constitutional 
Fever, rigors, malaise, fatigue, anorexia, headache, 
myalgias/arthralgias, nausea/ vomiting 
Dermatologic 
Rash 
Gastrointestinal 
Nausea/vomiting/diarrhea 
Respiratory 
Tachypnea, hypoxemia (potentially requiring supplemental 
oxygen/ventilation) 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 142 of 154
 
 
 
Organ System 
Signs/Symptoms 
Cardiovascular 
Tachycardia, hypotension 
Coagulation 
Disseminated intravascular coagulation (DIC) characterized by 
elevated D-dimer, hypofibrinogenemia, bleeding 
Renal 
Azotemia 
Hepatic 
Transaminitis, hyperbilirubinemia 
Neurologic 
Altered mental status, confusion, delirium, aphasia, hallucinations, 
tremor, seizures, ataxia 
CRS Grading/Severity 
The outlined clinical grading criteria, based on NCI CTCAE v4.0, is designed to guide 
clinicians in the management of CRS.  Many of the signs and symptoms associated with 
CRS can also be attributable to other common complications of cancer therapy such as 
neutropenic fever, other infectious complications, and tumor lysis syndrome.  Thus, in 
applying the criteria below, clinicians should exercise appropriate clinical judgement in 
each patient-specific scenario in an effort to distinguish true CRS from other cancer 
treatment-related toxicities.  This will ensure appropriate delivery of care and avoidance of 
therapies that may otherwise not be indicated. 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 144 of 154
 
 
 
Tocilizumab can be administered in Grade 2-4 CRS, resulting in a rapid reversal of 
symptoms.  If there is a lack of clinical improvement, a second dose can be repeated. 
Dosing: 
- 
< 30 kg: 12 mg/kg IV over 1 hour for one dose. May repeat another 12 mg/kg dose 
in 8 hours if there is a lack of clinical response to the initial dose. May repeat up to 3 
additional doses after the initial dose (with at least an 8 hour interval between consecutive 
doses). 
- 
≥ 30 kg: 8 mg/kg IV over 1 hour for one dose (Max individual dose: 800 mg). May 
repeat another 8 mg/kg dose in 8 hours if there is a lack of clinical response to the initial 
dose (maximum of 3 additional doses after the initial dose with at least an 8 hour interval 
between consecutive doses). 
- 
NOTE: Two doses of tocilizumab should be available on site for immediate use for 
each patient treated with CAR-T cells. These doses must be available prior to cell infusion 
and up to 6 weeks following cell infusion. 
 
Corticosteroids 
Steroids may be utilized in the setting of severe CRS with neurologic symptoms along with 
targeted cytokine therapies (i.e. tocilizumab), in severe CRS that is refractory to 
tocilizumab therapy, or as monotherapy for patients with isolated neurologic toxicities 
without systemic CRS.  Steroids exhibit a non-specific immune inhibition.  Intravenous 
dexamethasone is the preferred steroid to be initiated if steroids are warranted due to 
neurological symptoms given improved CNS penetration.  Methylprednisolone can be used 
as an alternative.  With appropriate response, steroids can be tapered rapidly over a few 
days.  Dosing is as follows. 
• Dexamethasone; 
o Adult: 4-10 mg (max single dose 10 mg) IV q 6 hours 
o Pediatrics: 0.1 mg/kg (max single dose 10 mg) IV q 6 hours  
• Methylprednisolone 
o Adults: 1-2 mg/kg/day IV 
o Pediatrics: 1-2 mg/kg/day IV; max daily dose 125 mg 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 145 of 154
 
 
 
TREATMENT ALGORITHM 
Important Considerations 
The following adult and pediatric treatment algorithms serve as a framework for the 
management of patients with CRS and are not meant to replace physician discretion.  Given 
that each patient will require thorough clinical evaluation for proper management, an 
attending physician should be notified at the first signs/symptoms suggestive of CRS and 
should be involved in each therapeutic decision made throughout the progression of care.  
This includes supportive and pharmacologic interventions, as well as escalation of care 
from the floor to ICU-level care. 
Initiation of tocilizumab and/or steroids for CRS from CAR-T therapy must be approved 
by one of the attendings listed in the link provided: 
http://intranet.unchealthcare.org/intranet/hospitaldepartments/uncsct/cell_therapy_resourc
es 
 
Table 16  
Adult CRS Treatment Algorithm 
Signs/Symptoms 
Management 
Grade 1 CRS 
• Fever (≥ 38.00 C) 
• +/- additional constitutional 
symptoms (rigors, malaise, fatigue, 
anorexia, myalgias/arthralgias, 
nausea/vomiting) 
• Renal:  Scr >ULN – 1.5 x ULN 
and/or 
o Scr 1.5 – 2.0 x above baseline 
and/or 
o Scr increase > 0.3 mg/dL from 
baseline 
• Hepatic:  AST/ALT > ULN – 2.5 x 
ULN 
• Complete infectious workup 
(Cultures, Chest XR/CT, etc.) 
• Daily weights; accurate I/Os 
• Vital signs q30 mins. until symptom 
resolution 
• Initiate empiric antibiotics  
• Supportive measures: 
acetaminophen prn fevers; 
ondansetron or prochlorperazine prn 
nausea/vomiting; 
meperidine/morphine prn rigors 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 146 of 154
 
 
 
o T.bili > ULN – 1.5 x ULN 
Grade 2 CRS 
• CV:  Hypotension (SBP <90 mmHg or 
≥ 20%  decrease in baseline SBP or 
DBP) +/- asymptomatic tachycardia 
• Pulmonary:  Decreased O2 saturation 
(≤88%) 
• Renal:  Scr ≥ 1.5 – 3.0 x ULN and/or 
o Scr 2.0 – 3.0 x above baseline 
• Hepatic:  AST/ALT > 2.5 – 5.0 x 
ULN and/or 
o T. Bili > 1.5 – 3.0 x ULN 
• Continue monitoring and supportive 
measures outlined under Grade 1 CRS 
• Supplemental O2 up to 40% to 
saturation ≥93% 
• Fluid bolus: 1000 mL IV over 1-2 
hours;  
• Low dose vasopressor (Table 17) if 
unresponsive to fluid bolus 
• Tocilizumab 8 mg/kg IV over 1 hour 
x 1 dose (Max individual dose: 800 
mg); may repeat every 8 hours for a 
max of 3 additional doses if no 
improvement from initial dose 
 
Grade 3 CRS 
• CV:  Hypotension (SBP <90 mmHg or 
≥ 20%  decrease in baseline SBP or 
DBP) unresponsive to fluids and low 
dose vasopressors given for grade 2 
CRS (Table 17) +/- symptomatic 
tachycardia 
• Pulmonary:  Decreased O2 saturation 
(≤88%) requiring >40% to achieve 
saturation ≥93% 
• Neuro:  Neurologic symptoms 
(confusion, AMS, seizure) 
• Renal:  Scr > 3.0 – 6.0 x ULN and/or 
o Scr > 3.0 x above baseline or > 
4.0 
• Continue monitoring and supportive 
measures outlined under Grade 1 and 
2 CRS 
• Increase supplemental O2 to achieve 
saturation ≥93%  
• High dose or multiple vasopressors 
(Table 17) 
• Tocilizumab as outlined in Grade 2 
CRS 
• Dexamethasone 10 mg IV q6h if 
neurologic symptoms present or 
refractory to tocilizumab 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 147 of 154
 
 
 
• Hepatic:  AST/ALT > 5.0 – 20.0 x 
ULN and/or 
o T. Bili > 3.0 -10.0 x ULN 
Grade 4 CRS 
• CV:  Persistent hemodynamic 
instability (hypotension and 
tachycardia refractory to aggressive 
fluids and pressor support) 
• Pulmonary:  Hypoxic respiratory 
failure: O2 saturation ≥93% not able to 
be achieved with supplemental O2 
(nasal cannula, non-rebreather) 
• Neuro:  Neurologic symptoms 
(confusion, AMS, seizures) 
• Renal:  Scr > 6.0 x ULN 
• Hepatic:  AST/ALT > 20.0 x ULN 
and/or 
o T. Bili > 10.0 x ULN 
• Continue monitoring and supportive 
measures outlined in Grade 1, 2, and 3 
CRS 
• Continue/initiate vasopressors, 
tocilizumab, and dexamethasone as 
outlined in Grade 3 CRS 
• Ventilatory support 
• Dialysis if indicated (CVVHD or 
HD) 
 
 
Table 17.  
High dose vasopressors in adult patients 
Vasopressor 
Dose (high dose)* 
Norepinephrine 
≥ 20 mcg/min monotherapy 
Dopamine 
≥ 10 mcg/kg/min 
Phenylephrine monotherapy 
≥ 200 mcg/min 
Epinephrine 
≥ 10 mcg/min 
Vasopressin + additional vasopressor 
Vasopressin + norepinephrine equivalent 
of ≥ 10 mcg/min 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 148 of 154
 
 
 
*Vasopressors at doses lower than those outlined are considered low dose vasopressors 
 
Table 18.  
Pediatric CRS Treatment Algorithm  
Signs/Symptoms 
Management 
Grade 1 CRS 
• Fever (≥ 38.00 C) 
• +/- additional constitutional symptoms 
(rigors, malaise, fatigue, anorexia, 
myalgias/arthralgias, nausea/vomiting) 
• Renal:  Scr >ULN – 1.5 x ULN and/or 
o Scr 1.5 – 2.0 x above baseline 
and/or 
o Scr increase > 0.3 mg/dL from 
baseline 
• Hepatic:  AST/ALT > ULN – 2.5 x 
ULN and/or 
o T.bili > ULN – 1.5 x ULN 
• Complete infectious workup 
(Cultures, Chest XR/CT, etc.) 
• Daily weights; accurate I/Os 
• Vital signs q30 mins. until symptom 
resolution 
• Initiate empiric antibiotics  
• Supportive measures: 
acetaminophen prn fevers; 
ondansetron or prochlorperazine prn 
nausea/vomiting; 
meperidine/morphine prn rigors 
Grade 2 CRS 
• CV:  Hypotension +/- asymptomatic 
tachycardia (Table 19 & Table 20) 
• Pulmonary:  Decreased O2 saturation 
(≤88%) 
• Renal:  Scr ≥ 1.5 – 3.0 x ULN and/or 
o Scr 2.0 – 3.0 x above baseline 
• Hepatic:  AST/ALT > 2.5 – 5.0 x 
ULN and/or 
o T. Bili > 1.5 – 3.0 x ULN 
• Continue monitoring and supportive 
measures outlined under Grade 1 CRS 
• Supplemental O2 up to 40% to 
saturation ≥93% 
• Fluid bolus: 20 mL/kg (Max: 1000 
mL) IV over 1-2 hours;  
• Low dose vasopressor (Table 21) if 
unresponsive to fluid bolus 
• Tocilizumab 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 149 of 154
 
 
 
o - <30 kg: 12 mg/kg IV over 1 
hour x 1 dose; May repeat every 
8 hours for a max of 3 additional 
doses if no improvement from 
initial dose 
o - ≥30 kg: 8 mg/kg IV over 1 hour 
x 1 dose (Max individual dose: 
800 mg); may repeat every 8 
hours for a max of 3 additional 
doses if no improvement from 
initial dose 
Grade 3 CRS 
• CV:  Hypotension unresponsive to 
fluids and low dose vasopressors given 
for grade 2 CRS +/- symptomatic 
tachycardia (Table 19 & Table 20)) 
• Pulmonary:  Decreased O2 saturation 
(≤88%) requiring >40% to achieve 
saturation ≥93% 
• Neuro:  Neurologic symptoms 
(confusion, AMS, seizure) 
• Renal:  Scr > 3.0 – 6.0 x ULN and/or 
o Scr > 3.0 x above baseline or > 4.0 
• Hepatic:  AST/ALT > 5.0 – 20.0 x 
ULN and/or 
o T. Bili > 3.0 -10.0 x ULN 
• Continue monitoring and supportive 
measures outlined under Grade 1 and 
2 CRS 
• Increase supplemental O2 to achieve 
saturation ≥93%  
• High dose or multiple vasopressors 
(Table 21) 
• Tocilizumab as outlined in Grade 2 
CRS 
• Dexamethasone 0.1 mg/kg (Max 10 
mg) IV q6h if neurologic symptoms 
present or refractory to tocilizumab 
 
Grade 4 CRS 
• CV:  Persistent hemodynamic 
instability (hypotension and 
tachycardia refractory to aggressive 
fluids and pressor support) 
• Continue monitoring and supportive 
measures outlined in Grade 1, 2, and 3 
CRS 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 150 of 154
 
 
 
• Pulmonary:  Hypoxic respiratory 
failure: O2 saturation ≥93% not able 
to be achieved with supplemental O2 
(nasal cannula, non-rebreather) 
• Neuro:  Neurologic symptoms 
(confusion, AMS, seizures) 
• Renal:  Scr > 6.0 x ULN 
• Hepatic:  AST/ALT > 20.0 x ULN 
and/or 
o T. Bili > 10.0 x ULN 
• Continue/initiate vasopressors, 
tocilizumab, and dexamethasone as 
outlined in Grade 3 CRS 
• Ventilatory support 
• Dialysis if indicated (CVVHD or 
HD) 
 
Table 19. 
 Definition of hypotension in pediatric patients 
Age 
Hypotension (SBP) 
0 – 28 days 
< 60 mmHg 
1 – 12 months 
< 70 mmHg 
1 – 10 years 
< 70 mmHg + (age x 2) 
>10 years 
< 90 mmHg 
  
Table 20. 
 Definition of tachycardia in pediatric patients 
Age 
Tachycardia (HR at Rest) 
Tachycardia (HR while 
Awake) 
0 – 3 months 
> 160 BPM 
> 205 BPM 
3 months – 2 years 
> 160 BPM 
> 190 BPM 
2 – 10 years 
> 90 BPM 
> 140 BPM 
>10 years 
> 90 BPM 
> 100 BPM 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 151 of 154
 
 
 
 
Table 21. 
 High dose vasopressors in pediatric patients 
Vasopressor 
Dose (high dose)* 
Norepinephrine 
≥ 2 mcg/kg/min 
Dopamine 
≥ 10 mcg/kg/min 
Phenylephrine monotherapy 
≥ 5 mcg/kg/min 
Epinephrine 
≥ 1 mcg/kg/min 
Vasopressin  
> 100 milliunits/kg/hr 
*vasopressors at doses lower than those outlined are considered low dose vasopressors 
References 
1. Maude SL, Barrett D, Teachey DT, Grupp S. Managing cytokine release syndrome 
associated with novel T cell-engaging therapies. J Cancer 2014;20(2):119-122. 
2. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-195. 
3. Frey NV, Levine BL, Lacey SF, et al. Refractory cytokine release syndrome in 
recipients of chimeric antigen receptor (CAR) T cells. Blood 2014;124(21):2296. 
4. National Cancer Institute Common Terminology Criteria for Adverse Events v4.03; 
2010. Available online at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html (accessed 
11/28/2015). 
 
 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 152 of 154
 
 
 
18.9 
APPENDIX IX - Neurotoxicity Treatment Algorithm 
Version 1.0, November 2, 2017 
BACKGROUND 
Neurotoxicity from CAR-T therapy can occur as part of cytokine release syndrome (CRS) 
or as an independent process. The underlying pathophysiology for neurologic toxicity from 
CAR-T therapy is not fully understood. CAR-T cells in the CNS may play a role. However, 
the heightened systemic inflammatory and cytokine state resulting from CAR-T therapy 
may also be a factor, as other therapies associated with increased cytokine levels have also 
been associated with neurologic toxicities, such as high-dose interleukin-2 (IL-2) and 
blinatumomab. 
The symptoms and manifestations of neurotoxicity are broad and range from 
confusion/altered mental status to seizures. Routine monitoring is critical in patients 
receiving CAR-T therapy to identify neurologic symptoms early and neurology should be 
consulted for any patients that exhibit early signs/symptoms of neurotoxicity. Early 
interventions should be employed to prevent worsening, especially if therapies are already 
indicated such as corticosteroids. 
Neurotoxicity grading should follow CTCAE v4.03. 
**Note that tocilizumab has no clear role in managing CAR-T-induced neurotoxicity, 
largely because tocilizumab is not thought to penetrate the central nervous system (CNS).  
If neurotoxicity occurs with concomitant CRS then tocilizumab should be employed per 
CRS management algorithm to treat CRS, but for neurotoxicity in the absence of CRS, 
tocilizumab should generally not be used.** 
 
Table 22.  
Neurotoxicity Treatment Algorithm 
Signs/Symptoms 
Management 
Grade 1-2 neurotoxicity, excluding seizures 
• Non-life threatening symptoms which 
may include: moderate headaches not 
responding to oral medications, 
confusion, dizziness, hallucinations, 
tremor, or psychiatric changes.  
• Notify covering providers, including 
oncology (CAR-T) attending 
physician. 
• Ensure other etiologies have been 
excluded as much as possible, such as 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 153 of 154
 
 
 
• Grade 1: Symptoms are mild and do 
not substantially impair function. 
• Grade 2: Symptoms are moderate and 
may impair function such as 
conducting instrumental activities of 
daily living (IADL’s) like self-
administering medications or using a 
telephone, but NOT activities of daily 
living (ADL’s) such as dressing, 
walking or bathing. 
• Any generalized seizures should be 
managed as grade 3 or greater 
events (see below). 
infection or toxicity from other 
medications. 
• If not already admitted, admit to 
inpatient for grade 2 or rapidly 
worsening grade 1. 
• Daily neurological exam including 
mini-mental status exam. 
• Consider urgent MRI brain with and 
without contrast. 
• Consider lumbar puncture to evaluate 
for infection. If sufficient material is 
available these samples may also be 
used for CAR T cell and cytokine 
analysis. 
Grade 3 neurotoxicity or any non-sustained / non-recurrent generalized seizures 
• Symptoms may be severe and impair 
ADL’s (listed above). Symptoms may 
include  
confusion/altered mental status, 
disorientation, aphasia, tremor, stupor, 
loss of consciousness, hallucinations, 
unstable balance, cranial nerve deficits, or 
psychiatric changes. 
• Any non-sustained / non-recurrent 
generalized seizures should be 
managed as a grade 3 neurological 
event. 
• Likely or definite strokes should be 
managed as a grade 4 neurological 
event. 
• Notify covering providers, including 
oncology fellow and oncology (CAR-
T) attending 
• If not already admitted, admit to 
inpatient floor bed with seizure 
precautions.  Consider stepdown / 
ICU, particularly if event is a seizure. 
• Neurological exam at least every 8 
hours plus daily mini-mental status 
exam. 
• Consult neurology service. 
• Obtain urgent MRI brain with and 
without contrast if feasible. 
• Obtain lumbar puncture to 
evaluate for infection if feasible. If 
sufficient material is available 
these samples may also be used for 
CAR T cell and cytokine analysis. 

LCCC1524-ATL 
Administration of T lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) 
for Prevention of Relapse of CD30+ Lymphomas after High Dose Therapy and Autologous 
Stem Transplantation (ATLAS) 
Confidential
ATLCAR.CD30 
Page 154 of 154
 
 
 
• Give corticosteroids as indicated 
below for any grade 3 neurotoxicity 
or for generalized seizures of any 
duration. 
• Dexamethasone: 
o Adults: 10 mg IV q6h 
o Pediatrics: 0.1 mg/kg (Max 10 
mg) IV q6h 
• Continue corticosteroids until 
symptoms have improved to Grade 
1 or resolved completely. 
• If seizure activity, add 
levetiracetam 500 mg PO BID 
and/or other antiepileptics as 
appropriate. 
Grade 4 neurotoxicity, any recurrent / sustained generalized seizures, or any stroke 
• Life threatening symptoms including 
recurrent or sustained generalized 
seizures, or obtundation. 
• Likely strokes should be managed as 
grade 4 neurological events until if 
and when stroke is excluded as a 
probable diagnosis. 
• Notify covering providers, including 
oncology fellow and oncology (CAR-
T) attending. 
• Manage as grade 3 event as above, 
but admit to ICU. 
• If stroke is felt to be possible, call 
CODE STROKE and notify Brain 
Attack Team (BAT). 
References: 
1. 
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood 2014;124(2):188-195. 
2. 
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: 
recognition and management. Blood 2016;127(26):3321-3330.