Conditions: Myeloma, Plasma-Cell Myeloma-Multiple
Keywords: Immunotherapy Anti-BCMA-CAR Gene Therapy Adoptive T Cell Therapy Plasma Cell Malignancy
Allocation:  | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
Background:

\- T cells are white blood cells that fight several cancers. One cancer therapy involves removing a persons' T cells, changing them in a lab, and then returning them to the person. Researchers want to see if this helps people with multiple myeloma.

Objective:

\- To test the safety of giving anti-B-Cell Maturation Antigen T cells to people with multiple myeloma.

Eligibility:

\- Adults ages 18-70 with multiple myeloma that has not responded to standard therapies.

Design:

* Participants may be screened with:
* Medical history
* Physical exam
* Blood and urine tests
* Heart tests
* Bone marrow sample
* Multiple scans and X-rays
* Participants will have apheresis. Blood is removed through a needle in an arm. T cells are removed. The rest of the blood is returned through a needle in the other arm.
* The cells will be changed in a laboratory.
* Participants will get 2 chemotherapy drugs over 3 days.
* Two days later, participants will check into the hospital. They will get an intravenous (IV) catheter in an arm or chest vein. They will get the T cells through the IV in 1 infusion.
* After this, participants will stay in the hospital for at least 9 days and stay nearby for 2 weeks. Then they will have blood tests and see a doctor.
* Participants will visit the clinic 1, 2, 3, 4, 6, and 12 months after the infusion, then every 6 months. A bone marrow sample will be taken at the 2-month visit.
* Participants blood will be collected for several years. Participants will have an annual physical at National Institutes of Health (NIH) for 5 years after the infusion. Then for 10 years they will answer health questionnaires.

Detailed description:
BACKGROUND:

* Multiple myeloma (MM) is a malignancy of plasma cells.
* MM is nearly always incurable.
* T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically target malignancy-associated antigens.
* Autologous T cells genetically modified to express CARs targeting the B-cell antigen cluster of differentiation 19 (CD19) have caused complete remissions in a small number of patients with leukemia or lymphoma. These results demonstrate that CAR-expressing T cells have anti-malignancy activity in humans.
* B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the malignant plasma cells of multiple myeloma.
* BCMA is not expressed by normal cells except for plasma cells and some mature B cells.
* We have constructed an anti-BCMA CAR that can specifically recognize BCMA-expressing target cells in vitro and eradicate BCMA-expressing tumors in mice.
* Anti-BCMA-CAR-expressing T cells have not been previously tested in humans.
* We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate

BCMA-expressing MM cells in patients

-Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and neurological toxicities. Elimination of normal plasma cells and unknown toxicities are also possible.

OBJECTIVES:

Primary

-Determine the safety and feasibility of administering T cells expressing an anti- BCMA CAR to patients with MM.

Secondary

* Evaluate the in vivo persistence of anti-BCMA CAR T cells
* Assess for evidence of anti-myeloma activity by anti-BCMA CAR T cells

ELIGIBILITY

* Patients must have measurable MM defined as a serum M-protein greater than or equal to 0.4 g/dL or a urine M-protein greater than or equal to 200 mg/24 hours or an involved serum free light chain (FLC) level greater than or equal to 10 mg/dL (provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma.
* Patients must have previously received at least 3 different treatment regimens for MM.
* Patients must have a normal creatinine and a normal cardiac ejection fraction.
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2 is required.
* Patients on any anticoagulant medications except aspirin are not eligible.
* No active infections are allowed.
* Absolute neutrophil count greater than or equal to 1000/ L, platelet count greater than or equal to 45,000/ L, hemoglobin greater than or equal to 8g/dL
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to 2.5-fold higher than the upper limit of normal
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and the required leukapheresis.
* At least 14 days must elapse between the time of any prior systemic treatment (including corticosteroids) and initiation of protocol treatment.
* Bone marrow plasma cells must be 30% or less of total bone marrow cells 30 days or less prior to the start of protocol treatment.
* The patient's MM will need to be assessed for BCMA expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (NIH). If unstained, paraffinembedded bone marrow or plasmacytoma sections are available from prior biopsies, these can be used to determine BCMA expression by immunohistochemistry; otherwise patients will need to come to the NIH for a bone marrow biopsy or other biopsy of a plasmacytoma to determine BCMA expression. The sample for BCMA expression can come from a biopsy obtained at any time before enrollment.

DESIGN:

* This is a phase I dose-escalation trial
* Patients will undergo leukapheresis
* T-cells obtained by leukapheresis will be genetically modified to express an anti- BCMA CAR
* Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused anti-BCMA-CAR-expressing T cells.
* The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m\^2 daily for 3 days and fludarabine 30 mg/m\^2 daily for 3 days. Fludarabine will be given on the same days as the cyclophosphamide.
* Two days after the chemotherapy ends, patients will receive an infusion of anti- BCMA-CAR-expressing T cells.
* The initial dose level of this dose-escalation trial will be 0.3x10\^6 CAR+ T cells/kg of recipient bodyweight.
* The cell dose administered will be escalated until a maximum tolerated dose is determined for patients in which less than 50% of total bone marrow cells are plasma cells.

With Amendment C, all patients with 50% or greater bone marrow plasma cells will receive 3x10(6) anti-BCMA CAR T cells/kg.

* Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.
* Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after the CAR T-cell infusion.
* Repeat treatments are possible for patients with residual MM and no greater than grade 2 toxicity with an initial treatment.
* Re-enrollment will be allowed for a small number of subjects.

Arms:
arm 1: Dose Escalation with 5 dose levels based on the patients actual bodyweight

Interventions: intervention 1: Cyclophosphamide intervention 2: Fludarabine intervention 3: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells
Intervention descriptions: intervention 1: 300 mg/m\^2 intravenous (IV) over 30 minutes on days -5, -4, and -3 intervention 2: 30 mg/m\^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3 intervention 3: 0.3x10\^6- 15.0x10\^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0

Protocol document:
Prot_SAP_000.pdf: 
1
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Abbreviated Title: Anti-BCMA-CAR T cells 
CC Protocol #: 14-C-0168
OSP#: 1404-1303
IBC#: RD-14-IV-06
NCT#: NCT02215967
Version Date: September 21, 2017
Amendment: H
Title: A Phase I Clinical Trial of T Cells Targeting B-Cell Maturation Antigen for Previously 
Treated Multiple Myeloma
Principal Investigator:                     James N Kochenderfer, M.D. A-F
                                                                                          Experimental Transplantation & Immunology Branch
Center for Cancer Research,
National Cancer Institute, National Institutes of Health
10 Center Drive, Rm. 3-3132, MSC 1203
Telephone:  240-760-6062
Email:  Kochendj@mail.nih.gov
Associate Investigators:  
Jennifer Mann, C.R.N.P., ETIB, CCR, NCI, NIH A-E
Maryalice Stetler-Stevenson M.D., PhD., DTM, 
CCR , NCI, NIH E-F
Ronald Gress, M.D., ETIB, CCR, NCI, NIH A-F
Stephanie Cotton, R.N., OCD, CCR , NCI, NIH A-B
Steven Pavletic, M.D., ETIB, CCR , NCI, NIH A-F
Irina Maric, M.D, CCR, NCI, NIH E-F
Brenna Hansen, R.N., OCD, CCR, NCI, NIH A-B
Dennis Hickstein, M.D., ETIB, CCR, NCI, NIH A-F
Jennifer Nicole Brudno,M.D., OCD, CCR, NCI, NIH 
A-F
David Stroncek, M.D., DTM, CC, NIH E-F
Daniele Avila, C.R.N.P., ETIB, CCR, NCI, NIH A-E
Seth Steinberg, Ph.D., OCD, CCR, NCI, NIH B, E
Fran Hakim, Ph.D, ETIB, CCR, NCI, NIH E-F
Constance Yuan M.D., PhD., DTM, CC, NIH E-F
Bazetta Blacklock-Schuver, R.N., OCD, CCR, NCI, 
NIH A-B
Thomas Hughes, Pharm.D., CC, NIH A-B
Steven Feldman M.D., SB, CCR, NCI, NIH A-F
Tracey Chinn, R.N, ETIB, CCR, NCI, NIH A-B
Referral Contact and Study Coordinator: Judith Lawrence, R.N.
240-760-6173, Fax: 301-451-5667
Email: judith.lawrence@nih.gov


2
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Non-NIH Associate Investigator:
Judith Lawrence, R.N, Leidos Inc., A-B
For each person listed above, roles are identified with the appropriate letter
A.
Obtain information by intervening or interacting with living individuals for research purposes
B.
Obtaining identifiable private information about living individuals
C.
Obtaining the voluntary informed consent of individuals to be subjects
D.
Makes decisions about subject eligibility
E.
Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes
F.
Studying, interpreting, or analyzing de-identified data or specimens for research purposes
G.
Some/all research activities performed outside NIH
Investigational Agents: 
Drug Name:
Anti-BCMA-CAR-
transduced autologous
peripheral blood lymphocytes 
(PBL)
IND Number:
16041
Sponsor:
Center for Cancer Research
Commercial Agents: Cyclophosphamide, Fludarabine


3
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
PRÉCIS 
Background:
x
Multiple myeloma (MM) is a malignancy of plasma cells. 
x
MM is nearly always incurable.
x
T cells can be genetically modified to express chimeric antigen receptors (CARs) that 
specifically target malignancy-associated antigens.
x
Autologous T cells genetically modified to express CARs targeting the B-cell antigen CD19 
have caused complete remissions in a small number of patients with leukemia or lymphoma.  
These results demonstrate that CAR-expressing T cells have anti-malignancy activity in 
humans.
x
B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the 
malignant plasma cells of multiple myeloma.
x
BCMA is not expressed by normal cells except for plasma cells and some mature B cells.
x
We have constructed an anti-BCMA CAR that can specifically recognize BCMA-expressing 
target cells in vitro and eradicate BCMA-expressing tumors in mice.
x
Anti-BCMA-CAR-expressing T cells have not been previously tested in humans.
x
We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate BCMA-
expressing MM cells in patients
x
Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and 
neurological toxicities.  Elimination of normal plasma cells and unknown toxicities are also 
possible.
Objectives:
Primary
x
Determine the safety and feasibility of administering T cells expressing an anti-BCMA CAR 
to patients with MM.
Secondary
x
Evaluate the in vivo persistence of anti-BCMA CAR T cells
x
Assess for evidence of anti-myeloma activity by anti-BCMA CAR T cells
Eligibility:
x
Patients must have measurable MM defined as a serum M-protein 0.4 g/dL or a urine M-
protein PJKRXUVRUDQLQYROYHGVHUXPIUHHOLJKWFKDLQ)/&OHYHO PJG/
(provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma .
x
Patients must have previously received at least 3 different treatment regimens for MM.
x
Patients must have a normal creatinine and a normal cardiac ejection fraction.
x
An ECOG performance status of 0 -2 is required.


4
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
x
Patients on any anticoagulant medications except aspirin are not eligible.
x
No active infections are allowed.
x
$EVROXWHQHXWURSKLOFRXQWP/SODWHOHWFRXQW45,000/P/KHPRJORELQJG/
x
$/7DQG$672.5-fold higher than the upper limit of normal
x
At least 14 days must elapse between the time of any prior systemic treatment (including 
corticosteroids) and the required leukapheresis.
x
At least 14 days must elapse between the time of any prior systemic treatment (including 
corticosteroids) and initiation of protocol treatment.
x
Bone marrow plasma cells must be 30% or less of total bone marrow cells 30 days or less 
prior to the start of protocol treatment.
x
The patient’s MM will need to be assessed for BCMA expression by flow cytometry or 
immunohistochemistry performed at the NIH.  If unstained, paraffin-embedded bone marrow 
or plasmacytoma sections are available from prior biopsies, these can be used to determine 
BCMA expression by immunohistochemistry; otherwise patients will need to come to the 
NIH for a bone marrow biopsy or other biopsy of a plasmacytoma to determine BCMA 
expression.  The sample for BCMA expression can come from a biopsy obtained at any time 
before enrollment.
Design:
x
This is a phase I dose-escalation trial
x
Patients will undergo leukapheresis
x
T-cells obtained by leukapheresis will be genetically modified to express an anti-BCMA 
CAR
x
Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the 
intent of enhancing the activity of the infused anti-BCMA-CAR-expressing T cells.
x
The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m2 daily for 3 days 
and fludarabine 30 mg/m2 daily for 3 days.  Fludarabine will be given on the same days as 
the cyclophosphamide.
x
Two days after the chemotherapy ends, patients will receive an infusion of anti-BCMA-
CAR-expressing T cells.
x
The initial dose level of this dose-escalation trial will be 0.3x106 CAR+ T cells/kg of 
recipient bodyweight.
x
The cell dose administered will be escalated until a maximum tolerated dose is determined
for patients in which less than 50% of total bone marrow cells are plasma cells. With 
Amendment C, all patients with 50% or greater bone marrow plasma cells will receive 3x106
anti-BCMA CAR T cells/kg.
x
Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor 
for toxicity.


5
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
x
Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after the 
CAR T-cell infusion.
x
Repeat treatments are possible for patients with residual MM and no greater than grade 2 
toxicity with an initial treatment.
x
Re-enrollment will be allowed for a small number of subjects.


6
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
TABLE OF CONTENTS 
PRÉCIS........................................................................................................................................... 3 
TABLE OF CONTENTS................................................................................................................ 6 
1 
INTRODUCTION ................................................................................................................ 11 
1.1 
Study Objectives ............................................................................................................ 11 
1.1.1 
Primary Objective................................................................................................... 11 
1.1.2 
Secondary Objectives.............................................................................................. 11 
1.2 
Background and Rationale ............................................................................................. 11 
1.2.1 
Introduction............................................................................................................. 11 
1.2.2 
Multiple myeloma epidemiology and standard treatment ...................................... 11 
1.2.3 
Allogeneic transplantation for MM ........................................................................ 12 
1.2.4 
T-cell gene therapy ................................................................................................. 13 
1.2.5 
Chimeric antigen receptors ..................................................................................... 13 
1.2.6 
BCMA..................................................................................................................... 15 
1.2.7 
Anti-BCMA CAR development and preclinical testing......................................... 18 
1.2.8 
Rationale for immunosuppressive chemotherapy and selection of lymphocyte-
depleting chemotherapy regimen.......................................................................................... 24 
1.2.9 
Rationale for dose-escalation.................................................................................. 25 
1.2.10 Summary of risks and potential benefits................................................................. 26 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT....................................................... 26 
2.1 
Eligibility Criteria .......................................................................................................... 26 
2.1.1 
Inclusion Criteria .................................................................................................... 26 
2.1.2 
Exclusion criteria:................................................................................................... 28 
2.2 
Screening Evaluation...................................................................................................... 29 
2.3 
Registration Procedures.................................................................................................. 30 
3 
STUDY IMPLEMENTATION ............................................................................................ 30 
3.1 
Study Design .................................................................................................................. 30 
3.1.1 
General study plan .................................................................................................. 30 
3.1.2 
Protocol schema...................................................................................................... 32 
3.1.3 
Dose Limiting Toxicity........................................................................................... 33 
3.1.4 
Dose Escalation....................................................................................................... 33 
3.2 
Dose Modifications/Delay.............................................................................................. 35 


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3.3 
Drug Administration ...................................................................................................... 36 
3.3.1 
Leukapheresis ......................................................................................................... 36 
3.3.2 
Anti-BCMA-CAR-expressing T-cell preparation................................................... 36 
3.3.3 
Conditioning chemotherapy and anti-BCMA CAR T-cell administration-this can be 
either inpatient or outpatient................................................................................................. 37 
3.3.4 
Potential repeat treatment ....................................................................................... 38 
3.4 
Protocol Evaluation........................................................................................................ 38 
3.4.1 
Baseline evaluations and interventions................................................................... 38 
3.4.2 
Studies to be performed during the mandatory 9-day inpatient admission after cell 
infusion 40 
3.4.3 
Post-infusion outpatient evaluation......................................................................... 40 
3.5 
Study Calendar............................................................................................................... 43 
3.6 
Gene-therapy-specific follow-up.................................................................................... 47 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria............................ 47 
3.7.1 
Criteria for removal from protocol therapy ............................................................ 47 
3.7.2 
Off-Study Criteria................................................................................................... 48 
3.7.3 
Off Protocol Therapy and Off-Study Procedure..................................................... 48 
4 
CONCOMITANT MEDICATIONS/MEASURES.............................................................. 48 
4.1 
Antibiotic prophylaxis.................................................................................................... 48 
4.2 
Blood product support.................................................................................................... 49 
4.3 
Anti-emetics ................................................................................................................... 49 
4.4 
Granulocyte colony-stimulating factor........................................................................... 49 
4.5 
Avoidance of corticosteroids.......................................................................................... 49 
4.6 
Guidelines for management of common acute toxicities that occur after CAR T cell 
infusions.................................................................................................................................... 50 
5 
BIOSPECIMEN COLLECTION.......................................................................................... 50 
5.1 
CORRELATIVE STUDIES FOR RESEARCH............................................................ 50 
5.1.1 
Biospecimen collection before the start of the conditioning chemotherapy:.......... 50 
5.1.2 
Biospecimen collection after anti-BCMA-CAR T-cell infusion during the required 
hospitalization....................................................................................................................... 50 
5.1.3 
Biospecimen collection during outpatient follow-up.............................................. 51 
5.1.4 
Immunological Testing........................................................................................... 51 
5.1.5 
Additional biopsies and additional blood draws..................................................... 52 


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Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
5.1.6 
Future studies.......................................................................................................... 53 
5.2 
Sample Storage, Tracking and Disposition.................................................................... 53 
5.2.1 
Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF) .............................................................................................................................. 53 
5.2.2 
Protocol Completion/Sample Destruction .............................................................. 54 
5.2.3 
Samples for Genetic/Genomic Analysis ................................................................. 54 
6 
DATA COLLECTION AND EVALUATION..................................................................... 55 
6.1 
Data Collection............................................................................................................... 55 
6.1.1 
Adverse event recording: ........................................................................................ 56 
6.2 
Genomic Data Sharing Plan........................................................................................... 56 
6.3 
Response Criteria .......................................................................................................... 56 
6.3.1 
Important Considerations on response criteria ....................................................... 56 
6.3.2 
International Myeloma Working Group uniform response criteria:....................... 57 
6.4 
Toxicity Criteria............................................................................................................. 59 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
60 
7.1 
Definitions...................................................................................................................... 60 
7.1.1 
Adverse Event......................................................................................................... 60 
7.1.2 
Suspected adverse reaction ..................................................................................... 60 
7.1.3 
Unexpected adverse reaction .................................................................................. 60 
7.1.4 
Serious..................................................................................................................... 61 
7.1.5 
Serious Adverse Event............................................................................................ 61 
7.1.6 
Disability................................................................................................................. 61 
7.1.7 
Life-threatening adverse drug experience............................................................... 61 
7.1.8 
Protocol Deviation (NIH Definition)...................................................................... 61 
7.1.9 
Non-compliance (NIH Definition).......................................................................... 61 
7.1.10 Unanticipated Problem............................................................................................ 61 
7.2 
NCI-IRB and Clinical Director Reporting ..................................................................... 62 
7.2.1 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
62 
7.2.2 
NCI-IRB Requirements for PI Reporting at Continuing Review........................... 62 
7.2.3 
NCI-IRB Reporting of IND Safety Reports............................................................ 62 
7.3 
IND Sponsor Reporting Criteria .................................................................................... 63 


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Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
7.3.1 
Reporting Pregnancy............................................................................................... 63 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria......................................... 64 
7.4.1 
Serious Adverse Event Reports to IBC................................................................... 64 
7.4.2 
Annual Reports to IBC............................................................................................ 64 
7.5 
Data and Safety Monitoring Plan................................................................................... 65 
7.5.1 
Principal Investigator/Research Team .................................................................... 65 
7.5.2 
Sponsor Monitoring Plan........................................................................................ 65 
7.5.3 
Safety Monitoring Committee (SMC) .................................................................... 66 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 66 
9 
COLLABORATIVE AGREEMENTS................................................................................. 68 
9.1 
Cooperative Research and Development Agreement (CRADA)................................... 68 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 68 
10.1 
Rationale For Subject Selection ................................................................................. 68 
10.2 
Participation of Children ............................................................................................ 69 
10.3 
Participation of Subjects Unable to Give Consent ..................................................... 69 
10.4 
Evaluation of Benefits and Risks/Discomforts........................................................... 69 
10.5 
Consent and Assent Process and Documentation....................................................... 70 
10.5.1 Telephone re-consent procedure............................................................................. 70 
10.5.2 Short form consent process for non-English speaking patients.............................. 70 
11 PHARMACEUTICAL INFORMATION............................................................................. 71 
11.1 
Retroviral Vector Containing the anti-BCMA CAR Gene......................................... 71 
11.2 
Cyclophosphamide ..................................................................................................... 71 
11.2.1 Source ..................................................................................................................... 71 
11.2.2 Toxicities................................................................................................................. 71 
11.2.3 Formulation and preparation................................................................................... 72 
11.2.4 Stability and Storage............................................................................................... 72 
11.2.5 Administration procedures...................................................................................... 72 
11.3 
FLUDARABINE........................................................................................................ 72 
11.3.1 Source ..................................................................................................................... 72 
11.3.2 Toxicity................................................................................................................... 73 
11.3.3 Formulation and preparation................................................................................... 73 
11.3.4 Stability and Storage............................................................................................... 73 


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12 References............................................................................................................................. 74 
13 Appendices............................................................................................................................ 82 
13.1 
Appendix A-Performance Status Criteria................................................................... 82 
13.2 
APPENDIX B: Data Collection Elements Required By Protocol.............................. 83 
13.3 
Appendix C:   Guidelines for management of common toxicities that occur after CAR 
T-cell infusions ......................................................................................................................... 85 
13.4 
Appendix D:   Infusion Instructions ........................................................................... 89 


11
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
Determine the safety and feasibility of administering T cells expressing an anti-B-cell maturation 
antigen (BCMA) chimeric antigen receptor (CAR) to patients with multiple myeloma (MM).
1.1.2
Secondary Objectives
x
Evaluate the in vivo persistence and ex vivo function of T cells expressing an anti-BCMA 
CAR.
x
Assess infusions of anti-BCMA-CAR-expressing T cells for anti-MM activity.
1.2
BACKGROUND AND RATIONALE
1.2.1
Introduction
Multiple myeloma (MM) is a malignancy of plasma cells that is almost always incurable.  New 
therapies are needed for MM.  Regressions of MM occurring in the setting of allogeneic stem 
cell transplantation (alloHSCT), and particularly after allogeneic donor lymphocyte infusions 
(DLIs), provide evidence that cellular immune responses can have a clinically significant anti-
myeloma effect, but alloHSCT is associated with a significant transplant-related mortality and by 
chronic graft-versus-host disease.1,2 Several patients have obtained lengthy complete remissions 
of lymphoma or chronic lymphocytic leukemia after infusions of autologous T cells that were 
genetically modified to express chimeric antigen receptors (CARs) targeting the B-cell antigen 
CD19.3,4
The lasting complete remissions of MM that sometimes occur in the setting of 
alloHSCT and the encouraging early results obtained treating patients with anti-CD19-CAR-
expressing T cells provide a rationale for attempting to develop CAR-T-cell therapies for MM.  
B-cell maturation antigen (BCMA) is a protein that is expressed by MM cells.5 BCMA is also 
expressed by normal plasma cells and by some normal B cells, but BCMA is not expressed by 
other normal cells.5 The very limited expression of BCMA in normal tissues makes BCMA a 
very promising target for CAR-T-cell therapies.  We have developed an anti-BCMA CAR, and 
we have demonstrated that T cells expressing this CAR have BCMA-specific activity in vitro 
and in vivo.5
Anti-BCMA-CAR-expressing T cells can eradicate MM tumors in mice.5
We 
propose to conduct a phase I clinical trial of anti-BCMA-CAR-expressing T cells.  This clinical 
trial will enroll patients with advanced MM that is progressive despite at least 3 prior therapies.  
Patients enrolled on the trial will receive a single cycle of chemotherapy that is designed to 
decrease endogenous lymphocyte counts because extensive evidence exists that depleting 
endogenous lymphocytes, and possibly other cells, with chemotherapy or total body irradiation 
dramatically increased the anti-tumor activity of adoptively transferred T cells.6-8
After the 
lymphocyte-depleting chemotherapy, patients will receive an infusion of autologous anti-
BCMA-CAR T cells.  The T cell dose will escalate with sequential cohorts of patients until a 
maximum tolerated dose is determined.
1.2.2
Multiple myeloma epidemiology and standard treatment


12
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Multiple myeloma (MM) is a neoplasm of monoclonal plasma cells.9,10 For MM to be 
diagnosed, a patient must have a proliferation of monoclonal plasma cells plus other 
abnormalities such as anemia, renal insufficiency, hypercalcemia, and lytic bone lesions.10 MM
is the second most frequently occurring hematologic cancer in the United States (U.S.).10 An 
estimated 22,350 new cases of MM will be diagnosed in the U.S. in 2013, and an estimated 
10,710 patients will die from MM in the U.S. in 2013.11 Recent improvements in the therapy of 
MM have occurred.9,10,12 These improved treatments have increased the median survival of 
patients with newly-diagnosed MM from 3 years to slightly over 5 years, although the prognosis 
of newly-diagnosed MM patients varies widely.10,12
Current standard non-transplant therapies for MM include various combinations of 
dexamethasone, bortezomib and its analogs, lenalidomide and its analogs, prednisone, 
melphalan, and cyclophosphamide.9,10,12,13 Myeloablative doses of chemotherapy followed by 
autologous stem cell transplantation is a standard therapy for MM patients with good 
performance status, and adequate bone marrow stem cells.10,12 Compared to standard doses of 
chemotherapy for first treatment of MM, administration of myeloablative doses of chemotherapy 
followed by autologous stem cell transplantation improved progression-free survival in most 
trials and overall survival in some trials.10,12 Myeloablative chemotherapy followed by 
autologous transplantation can also be used as a treatment for relapsed MM in some cases.10,12,14
Use of the International Uniform Response Criteria for Multiple Myeloma is the most common 
approach for assessing clinical outcomes in MM.15 Despite the recent improvements in 
treatment, MM remains an almost always incurable disease.12,16,17 Patients obtaining remissions 
of MM almost always relapse.12 The median overall survival of patients with relapsed MM 3 
years or less.16 Survival is shorter for patients treated with lenalidomide plus dexamethasone 
who have received at least 2 prior lines of therapy compared to patients who received only one 
prior line of therapy.18 In patients with MM that was refractory to bortezomib, the median 
overall survival was only 9 months when the patient was also either ineligible for thalidomide or 
lenalidomide, or the patient had MM that was relapsed or refractory to thalidomide or 
lenalidomide.17 Utilizing the immune system to treat MM is one possible way to improve 
therapy of MM.  So far, the clearest evidence of activity of the immune system against MM 
comes from allogeneic transplantation studies.
1.2.3
Allogeneic transplantation for MM
Allogeneic stem cell transplantation (alloHSCT) can cure a fraction of patients with MM.19,20
Myeloablative alloHSCT can induce long-term complete remissions of MM, but also has a 
transplant-related mortality rate (TRM) of 20% to 50%.19,20 The high TRM of myeloablative
alloHSCT led investigators to test nonmyeloablative alloHSCT for MM.19-21 A commonly used 
transplantation strategy is to administer myeloablative chemotherapy plus an autologous stem 
cell transplant and then to conduct a nonmyeloablative alloHSCT a short time later.1,19,20 in 
some studies, this strategy has been shown to yield higher rates of progression-free and overall 
survival when compared to the strategy of 2 sequential autologous stem cell transplants.1,21 One 
recent trial showed an 8-year progression-free survival rate of 22% for patients receiving an 
autologous transplant followed by a nonablative alloHSCT compared to an 8-year progression-
free survival of 12% for patients receiving sequential autologous transplants.1 These results 


1 3
A b brevi ate d Title: A nti- B C M A- C A R T cells 
Versi o n D ate: Se pte m ber 2 1, 2 0 1 7
s h o we d a statisticall y si g nifica nt a d va nta ge f or t h e a ut ol o g o us f oll o we d b y all o H S C T strate g y, 
b ut als o p oi nt o ut t hat t he vast m aj orit y of p atie nts are n ot cure d b y eit her a p pr oac h.  
Beca use ma n y n o n m yel oa blati ve tra n s pla nt re gi me ns t hat ha ve been us e d t o treat M M i ncl u de 
ver y l o w d oses of ra diati o n or c he m ot hera p y, n o n m yel oa bl ati ve a ll o H S C Ts de pe n d o n a n 
i m m u n ol o gic graft- v ers us- m yel o ma effect, a n d re missi o ns of M M that occ ur after 
n o n m yel oa bl ati ve all o H S C T pr o vi de  e vi de nce t hat i m m u ne res p o nses ca n b e effecti ve at 
eli mi nati n g M M. 1, 1 9, 2 0 Direct e vi de n ce t hat l y m p h oc yt es ca n eli mi nate M M c o mes fr o m d o n or 
l y m p h oc yte i nf usi o ns ( D LIs).2, 2 0 T we nt y-t w o t o t we nt y-ei g ht perce n t of p atie nts recei vi n g D LIs 
t o treat persisti n g M M after all o H S C T ha ve ac hie ve d c o m plete remissi o ns ( C Rs). 2, 1 9, 2 0 Of n ote, 
s o me of t hese patie nts o btai ni n g C Rs after D LIs di d n ot recei ve a n y ot her t h era pies ar o u n d t he 
ti me of t heir D LI.2 T hes e res ults de m o nstrate t he a bilit y of t he i m m u ne s yste m t o e ra dicat e M M.  
U nf ort u natel y, b ot h all o H S C T a n d D LI s utilize all o ge nei c l y m p h oc yt es; t heref ore, t he y are 
ass ociate d wit h t he s o meti mes fa tal c o m plicati o n of graft- v ers us- h ost disease2, 1 9, 2 0; i n a d diti o n 
m ost patie nts recei vi n g D LIs f or M M d o n ot o bt ai n C Rs, s o de vel o pi n g of a n effecti ve 
a ut ol o g o us cell ular i m m u ne t hera p y f or M M w o ul d be a maj or a d v a nce.
1. 2. 4 
T-cell ge n e t hera p y
T cells ca n b e pre p are d f or a d o p ti ve tra nsfer b y ge neticall y m odif yi n g t h e T cells t o e x press 
rece pt ors t hat s pecificall y r ec o g nize t u m or-ass oci ate d a nti ge ns.2 2- 2 9 Ge netic m o dificati o n of T 
cells is a q uic k a n d r e lia ble pr ocess, a n d cli nical trials of ge neticall y m o difi e d T cells tar geti n g a 
variet y of mali g na n cies h a ve bee n carrie d o ut. 3, 4, 2 6, 3 0, 3 1 Ge neticall y m o difie d a nti ge n-s pecifi c T 
cells ca n be ge nerate d fr o m pe ri p heral bl o o d m o n o n uclear cells ( P B M C) i n s ufficie nt n u m bers 
f or cli nical treat me nt wit hi n 1 0 da ys.3 Ge neticall y m o dif yi n g T cells wit h ga m maretr o vir us es 
c o nsiste ntl y ca uses hi g h a n d s ustai ne d le vels of e x pressi o n of i ntr o d uce d ge nes wit h o ut i n vitr o 
selecti o n4, 3 0, 3 2, 3 3, a n d ge n etic m o dificati o n of mat ure T cells wit h ga m maretr o vir uses has a l o n g 
hist or y of safet y i n h u ma ns. 3 4- 3 6 T here are t w o ge neral a p pr oac h es f or ge n erati n g a nti ge n-
s pecific T cells b y ge neti c m o dificati o n:   i ntr o d uci n g ge n es enc o di n g nat ural 
T cell rece pt ors 
( T C Rs) or i ntr o d uci n g ge nes e nco di n g c hi meric a nti ge n rece pt ors  ( C A Rs).2 3, 2 5, 2 6, 2 8 C A Rs are 
f usi o n pr otei ns i nc or p orati n g a nti ge n rec o g niti o n m oieties a n d T cell acti v ati o n d o mai ns.2 7, 3 7- 3 9
T he a nti ge n- bi n di n g d o m ai ns of m ost C A Rs c urre ntl y u n der g oi n g c li nical a n d precli nical 
de vel o p me nt ar e a nti b o d y varia ble r e gi o ns. 2 3, 2 7, 3 7, 3 9 T C Rs rec o g nize pe pti des prese nte d b y 
h u ma n le u k oc yte a nti ge n ( H L A) m o lec ules; t heref ore, T C Rs are H LA-restricte d, a n d a p artic ular 
T C R will o nl y be us ef ul i n patie nts e x pressi n g cert ai n H L A m ole c ules 2 3, 2 5, 2 6, 3 7, w hic h li mits t he 
n u m ber of patie nts w h o c o ul d be treate d wit h T cells ge neticall y m o difie d t o e x press a T C R.  I n 
c o ntrast, C A Rs rec o g nize i ntact  cell-s urface pr otei ns a n d gl yc oli pi ds, s o C A Rs are n ot H L A-
restricte d, a n d C A Rs ca n be use d to treat p atie nts re gar dl ess o f t heir H L A t y p es.2 3, 2 6, 4 0- 4 2
1. 2. 5 
C hi meric a nti ge n rece pt ors
Precli nical e x peri me nts e val uati n g C A R-e x pressi n g T cells as ca n cer t hera p y w ere i nitiate d i n 
1 9 9 3. 4 3, 4 4 T hese e x peri me nts le d t o a cli nical trial of C A R-tra ns d uce d T c ells tar geti n g t he 
-
f olate rece pt or o n o v aria n ca ncer cells; n o t u m or re gressi o ns were o bser ve d d uri n g t his cli nical 
trial.4 5 C A Rs t hat were ca pa ble of rec o g niz i n g a v ariet y of t u m or-ass ociate d a nti ge ns h a ve bee n 


14
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
evaluated in many centers.23,37 Preclinical studies have assessed a wide variety of factors that 
could affect in vivo function of CAR-expressing T cells.  Multiple approaches for inserting CAR 
genes into T cells by using gammaretroviruses4,30,32-34,46-48, lentiviruses3,49-52, or transposon 
systems53,54 have been assessed.  Because all methods of T-cell genetic modification require a 
period of in vitro culture, various T-cell culture techniques have been evaluated.3,46,55 Different 
portions of CARs including antigen-recognition moieties, extracellular structural components, 
costimulatory domains such as the cytoplasmic portion of the CD28 protein, and T-cell-
activation moieties such as the signaling domains of the CD3] protein can all be important to the 
in vivo function of CAR-expressing T cells, and all of these portions of CARs remain the subject 
of intensive investigation.37,46,50,56-58 Much of the preclinical work evaluating CARs has been 
performed with CARs targeting the B-cell antigen CD19.7,46-48,53,59,60 Data suggesting that T-cell 
costimulation played an important role in the activity of CAR-expressing T cells in vivo led 
investigators to add signaling moieties from the costimulatory molecule CD28 to CARs.48,57
These studies showed that adding CD28 moieties to CARs enhanced antigen-specific cytokine 
production and proliferation by anti-CD19 CAR T cells.57,61,62 T cells expressing CARs with 
CD28 signaling moieties and CD3] signaling domains were more effective than T cells 
expressing CARs without CD28 moieties at eradicating human leukemia cells from mice.61,62
Subsequently, CARs incorporating other signaling domains from costimulatory molecules such 
as 4-1BB (CD137) were developed.49 Anti-CD19 CARs containing the signaling domains of 
both 4-1BB and CD3] were superior to CARs containing the signaling domains of CD3] without 
any costimulatory domains at eradicating human malignant cells from mice.50,56 Similar to 
CD28, including 4-1BB signaling moieties in CARs led to increased CD19-specific proliferation 
and enhanced in vivo persistence.50 In contrast to T cells expressing a CAR with a CD28 
moiety, the increased in vitro proliferation and prolonged in vivo persistence of T cells 
expressing a 4-1BB-containing CAR occurred whether or not the T cells were exposed to the 
antigen that the CAR recognized.50,56
Results from several clinical trials of anti-CD19 CAR T cells have been reported to date in peer-
reviewed papers; these papers have all reported results from patients receiving autologous CAR-
modified T cells.3,4,30,32,33,63,64 The first evidence of antigen-specific activity of anti-CD19 CAR 
T cells in humans was generated during a clinical trial at the National Cancer Institute in a 
patient who experienced a dramatic regression of advanced follicular lymphoma.32 This clinical 
trial utilized a gammaretroviral vector to introduce an anti-CD19 CAR containing the signaling 
domains of the CD28 and CD3] molecules.32 The anti-CD19 CAR-transduced T cells were 
prepared by using a 24-day in vitro culture process.  The clinical treatment regimen consisted of 
lymphocyte-depleting chemotherapy followed by an infusion of anti-CD19 CAR T cells and a 
course of high-dose interleukin-2 (IL-2).  The first patient treated on this protocol had a large 
disease burden of follicular lymphoma.  This first patient experienced no acute toxicities except 
for a low grade fever that lasted for 2 days, and he obtained a partial remission (PR) that lasted 
for 32 weeks.32 Bone marrow biopsies revealed a complete elimination of extensive bone 
marrow lymphoma that was present before treatment; in addition, normal B-lineage cells were 
completely eradicated from the bone marrow.32 The bone marrow B-cell eradication was 
confirmed by flow cytometry, and it persisted for over 36 weeks.32 B cells were also completely 
absent from the blood during this time, while T cells and other blood cells recovered rapidly.32
Seven months after the anti-CD19 CAR T cell infusion, progressive lymphoma was detected in 
the patient’s cervical lymph nodes.  The lymphoma remained CD19+, so the patient was treated a 


15
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
second time with anti-CD19 CAR T cells.  The first and second treatment regimens were the 
same except the patient received a higher dose of cells with the second treatment.  After the 
second treatment, the patient obtained a second ongoing partial remission.4   
Seven more patients were subsequently treated with the same regimen of chemotherapy, anti-
CD19 CAR T cells, and high-dose IL-2.4 In 4 of 7 evaluable patients on the trial, administration 
of anti-CD19 CAR T cells was associated with a profound and prolonged B-cell depletion.4,32 In 
all 4 patients with B-cell depletion, the depletion lasted for over 36 weeks. The B-cell depletion 
could not be attributed to the chemotherapy that was administered because blood B-cells 
recovered to normal levels in 8 to 19 weeks in patients receiving the same chemotherapy plus 
infusions of T cells targeting NY-ESO or gp100, which are antigens that are not expressed by B 
cells.32 Because normal B cells express CD19, prolonged normal B-cell depletion after anti-
CD19 CAR T-cell infusions demonstrated that CAR-expressing T cells had a powerful ability to 
eradicate CD19+ cells in humans.  All of the patients with long-term B-cell depletion obtained 
either complete or partial remissions of their malignancies, and the 4 patients with long-term B 
cell depletion also developed hypogammaglobulinemia.  Hypogammaglobulinemia in these 
patients was routinely treated with infusions of intravenous immunoglobulins.  Of the eight 
patients treated, seven patients were evaluable for malignancy response; the one patient who was 
not evaluable died with pneumonia caused by influenza A.4 Six of the seven evaluable patients 
had remissions of their malignancies.  Two of the remissions were complete remissions (CRs) of 
CLL.4 Both of these CRs were confirmed by multicolor flow cytometry of bone marrow cells.4
One of these CRs lasted 24 months, and the other is ongoing at 30 months.4 Most patients 
treated with this regimen of chemotherapy, anti-CD19 CAR T cells, and IL-2 experienced 
significant acute toxicities including fever, hypotension, and neurological toxicities such as 
delirium and obtundation.4 All of these toxicities peaked within 10 days after the cell infusion 
and resolved less than 3 weeks after the cell infusion.4 These acute toxicities correlated with
serum levels of the inflammatory cytokines tumor necrosis factor and interferon-J, and T cells 
producing these inflammatory cytokines in a CD19-specific manner were detected in the blood 
of patients after the anti-CD19 CAR T cell infusions.4
1.2.6
BCMA
One candidate antigen for immunotherapies of MM is B-cell maturation antigen (BCMA, 
CD269) 65,66.  BCMA RNA was detected universally in MM cells, and BCMA protein was 
detected on the surface of plasma cells from multiple myeloma patients by several investigators 
67-70.  BCMA is a member of the tumor necrosis factor receptor (TNF) superfamily 71,72.  BCMA 
binds B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) 72-74.  Among 
nonmalignant cells, BCMA has been reported to be expressed mostly by plasma cells and subsets 
of mature B cells 65,66,73,75,76.  Mice deficient in BCMA were healthy and had a normal physical 
appearance 77,78.  BCMA-deficient mice had normal numbers of B cells, but survival of long-
lived plasma cells was impaired 75,77.
A critical factor for any antigen being considered as a target for immunotherapies is the antigen’s 
expression pattern in normal tissues.  BCMA has been reported to be expressed in plasma cells 
and in some B cells but to otherwise have limited expression 65-67,76.  To more completely assess 
the expression pattern of BCMA, we performed quantitative polymerase chain reaction (qPCR) 
on a panel of cDNA samples from a wide range of normal tissues (Figure 1).5 As a positive 
control, we performed qPCR on cDNA from cells of a plasmacytoma that was resected from a 


16
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
patient with advanced MM.5 Ninety-three percent of the cells from the plasmacytoma sample 
were plasma cells as determined by flow cytometry.  The BCMA expression of the 
plasmacytoma sample was dramatically higher than the BCMA expression of any other tissue 
(Figure 1).  Not surprisingly, BCMA cDNA copies were detected in several hematologic tissues 
such as blood leukocytes, bone marrow, spleen, lymph node, and tonsil.  Low levels of BCMA 
cDNA copies were detected in the samples of testis and trachea.  In addition, low levels of 
BCMA cDNA copies were detected in most gastrointestinal organs such as duodenum, rectum, 
and stomach (Figure 1).  One possible explanation for BCMA expression in gastrointestinal 
organs and the trachea was the known presence of plasma cells and B cells in tissues such as 
lamina propria and Peyer’s Patches 79,80.
In Figure, 1 actin cDNA copies and BCMA cDNA copies were measured by qPCR in all of the 
samples, and the results were expressed as the number of BCMA cDNA copies per 105 actin 
cDNA copies.5


17
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
After demonstrating a very restricted expression pattern of BCMA RNA, we carried out an 
assessment of BCMA protein expression by immunohistochemistry (IHC).  As expected, our 
anti-BCMA IHC staining procedure yielded strong staining of BCMA-K562 cells, which 
expressed high levels of BCMA after being transduced with the gene encoding BCMA.  We 
found a lack of BCMA staining with NGFR-K562 negative control cells.5 We went on to 
evaluate BCMA protein expression in normal human organs.  Except for plasma cells, we did not 
detect BCMA protein expression by the cells of any of the organs that we stained.  We detected 
plasma cells expressing cell-surface BCMA in gastrointestinal organs.  BCMA expression by 
normal plasma cells probably accounts for the low levels of BCMA RNA detected in these 
organs because we did not detect BCMA expression by any of the other cells in these organs.  
We detected BCMA-expressing plasma cells in the tonsil.  The organs assessed by IHC and 
found to lack BCMA expression except for plasma cells are shown in Table 1.5 We concluded 
that BCMA expression detected at low levels in some organs by qPCR (Figure 1) was due to 
plasma cells in these organs.
Table 1
adrenal 
bladder 
bone
breast 
cerebellum 
cerebral cortex
duodenum
eye 
fallopian tube 
esophagus 
stomach 
small intestine 
colon 
rectum 
heart 
kidney
liver
lung
ovary 
pancreas 
parathyroid 
pituitary 
placenta 
prostate 
skin 
spinal cord 
spleen 
skeletal muscle
testis 
thymus 
thyroid 
trachea 
cervix 
uterine endometrium
Organs stained for BCMA by immunohistochemistry and   
found to lack of BCMA expression except on plasma cells
For a protein to be an appropriate target for CAR-expressing T cells aimed at MM, the protein 
must be expressed on the surface of MM cells. By flow cytometry of bone marrow samples from 


18
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
patients with MM, we found that 6/10 tested samples uniformly expressed high levels of BCMA 
by flow cytometry.  An example of this flow cytometry staining is shown in Figure 2.
Figure 2
Events
BCMA
As shown in Figure 2, flow cytometry for BCMA (solid line) and isotype-matched control 
staining (dashed line) revealed BCMA expression on the surface of MM cells from a 
plasmacytoma of a patient with MM.5 The plot is gated on plasma cells, which made up 93% of 
the total plasmacytoma cells.  In addition to the flow cytometry studies, we stained tissue 
sections from plasmacytomas of 3 patients with MM.  In all 3 of the samples, the neoplastic 
plasma cells expressed cell-surface BCMA.5
1.2.7
Anti-BCMA CAR development and preclinical testing
Due to the expression pattern of BCMA, we reasoned that BCMA would be an appropriate target 
for CAR-expressing T cells.  To further assess the suitability of BCMA as a target for CAR-
expressing T cells, we designed an anti-BCMA CAR.  The anti-BCMA CAR contained an scFv 
derived from one of two mouse anti-human-BCMA monoclonal antibodies 81.   The anti-BCMA 
CAR also contained the hinge and transmembrane regions of the human CD8D molecule, the 
signaling moiety of the CD28 costimulatory molecule, and the signaling domains of the CD3]
molecule (Figure 3). 
Figure 3
CD28
CD8 hinge+TM
CD3]
Anti-BCMA scFv
3’LTR
5’LTR
We also designed a negative-control CAR named SP6.  The SP6 CAR contained the variable 
regions of the hapten-specific SP6 monoclonal antibody 39.  Except for the different variable 
regions, the sequence of the SP6 CAR was identical to the sequence of the anti-BCMA CAR.  
We ligated DNA encoding each of the CARs that we designed into a gammaretroviral vector that 
has been used in previously in many clinical trials of T-cell gene therapies.4,24,26,32 After 
transductions, we found high levels of cell surface expression of the anti-BCMA CAR on the 
transduced T cells (Figure 4).
Figure 4


19
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
CD8
CD8
CAR+
CAR+
Anti-BCMA CAR
Untransduced
Figure 4 shows anti-BCMA CAR expression on T cells from Donor 1 6 days after transduction 
with gammaretroviruses encoding the anti-BCMA CAR.  Transductions were carried out 2 days 
after the cultures were started, so the T cells had been in culture for a total of 8 days at the time 
of this analysis.  The plots are gated on live, CD3+ lymphocytes.
We also performed a series of in vitro assays to assess the function of anti-BCMA-CAR-
expressing T cells, and we found that BCMA-CAR-expressing T cells exhibit BCMA-specific 
activities including CD107a upregulation and cytokine production in vitro.  These experiments 
showed that anti-BCMA-CAR-expressing T cells are activated in a BCMA-specific manner.


20
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Figure5
BCMA-K562                        NGFR-K562
Anti-BCMA CAR-transduced
Untransduced
BCMA-K562                       NGFR-K562
CD107a
CD107a
CD107a
CD107a
CD8
CD8
CD8
CD8
Figure 5 shows upregulation of CD107a, which indicates degranulation and correlates with 
cytotoxicity82, when anti-BCMA CAR-expressing T cells from Donor 1 were cultured with the 
BCMA-expressing cell line BCMA-K562.  CD107a was not upregulated when anti-BCMA-
CAR-expressing T cells from Donor 1 were cultured for 4 hours with the BCMA-negative 
control cell line NGFR-K562.  Untransduced T cells from Donor 1 did not upregulate CD107a 
when cultured with either BCMA-K562 or NGFR-K562.  The plots are gated on live CD3+
lymphocytes.  The T cells depicted in Figure 5 are from the same cultures as the cells shown in 
Figure 4 and were used in this experiment on the same day of culture as the cells shown in 
Figure 4. 
T cells transduced with the anti-BCMA CAR produced large amounts of IFNJ when they 
were cultured overnight with the BCMA-expressing cell lines BCMA-K562 and RPMI8226 
(Figure 6).  In contrast, the anti-BCMA CARs produced only background levels of IFNJ when 
they were cultured with the BCMA-negative target cell lines NGFR-K562, CCRF-CEM, and 
A549.  The anti-BCMA-CAR-transduced T cells also made minimal IFNJ when cultured without 
any target cell.  The experiment depicted in Figure 6 consisted of culturing the anti-BCMA-
CAR-transduced T cells with the indicated target cell lines overnight and then performing a 
standard IFNJ enzyme-linked immunosorbant assay (ELISA).


21
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Figure 6
Large fractions of anti-BCMA-CAR-transduced T cells produced the cytokines IFNJ, tumor 
necrosis factor (TNF), and interleukin-2 (IL-2) when cultured with the BCMA+ target cell 
BCMA-K562 but not when cultured with the BCMA-negative cell line NGFR-K562 (Figure 7).  
For the assay described in Figure 7, T cells and target cells were cultured together for 6 hours, 
and an intracellular cytokine staining assay was performed to detect the cytokines within the T 
cells as described previously.5 The plots shown in Figure 7 are gated on CD3+ lymphocytes.


22
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Figure 
7
CD4
TNF
CD4
IL-2
CD4
CD4
IFNJ
CD4
TNF
IL-2
CD4
IFNJ
BCMA-K562                          NGFR-K562
BCMA-K562                        NGFR-K562
BCMA-K562                       NGFR-K562
Anti-BCMA-CAR-transduced T cells also proliferated in a BCMA-specific manner.  
Figure 8 shows a carboxyfluorescein diacetate,succinimidyl ester (CFSE) proliferation assay in 
which anti-BCMA-CAR-transduced T cells were cultured for 4 days with either BCMA-K562 
cells or BCMA-negative NGFR-K562 cells.  CFSE was diluted to a greater degree, indicating 
more proliferation, when the T cells were cultured with BCMA-K562 target cells (solid 
histogram in Figure 8) compared to when anti-BCMA-CAR T cells were cultured with BCMA-
negative NGFR-K562 target cells.  The assay was conducted as described previously.5
Figure 8


23
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Normalized event number
CFSE
We established RPMI8226 human multiple myeloma cell line tumors in immunodeficient mice.5
We allowed sizable tumors to develop over 17 to 19 days then we treated the mice with a single 
intravenous infusion of anti-BCMA-CAR-transduced human T cells.  After infusion of anti-
BCMA-CAR T cells, dramatic regressions of all tumors occurred between day 6 and day 15 after 
the T cell infusion, and 100% of mice receiving anti-BCMA-CAR T cells were cured (Figures 9 
and 10).5 In contrast, tumors continued to increase in size in all mice receiving infusions of T 
cells expressing a negative-control CAR designated SP6.  The mice receiving infusions of anti-
BCMA-CAR-transduced T cells had no signs of toxicity during this experiment.
Figure 9
Anti-BCMA CAR
In the experiments depicted in Figures 9 and 10, anti-BCMA-CAR T cells were infused on Day 
0, and no other treatments were administered.  In the experiments reported in Figures 9 and 10, 
there were 10 mice in the anti-BCMA CAR and SP6 groups.  There were 7 mice in the untreated 
group.
Figure 10


24
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Myeloma cells from a plasmacytoma of a patient with MM were specifically killed by 
autologous anti-BCMA-CAR-transduced T cells at low effector: target ratios while autologous T 
cells transduced with the negative control CAR SP6 caused only a low level of cytotoxicity  of 
the myeloma cells in a 4-hour cytotoxicity assay (Figure 11).5 For all effector: a target ratio, the 
cytotoxicity was determined in duplicate, and the results are displayed as the mean +/- the 
standard error of the mean.
Figure 11
1.2.8
Rationale for immunosuppressive chemotherapy and selection of lymphocyte-depleting 
chemotherapy regimen


25
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
We plan to administer a conditioning chemotherapy regimen of cyclophosphamide and 
fludarabine before infusions of anti-BCMA-expressing T cells because substantial evidence 
demonstrates an enhancement of the anti-malignancy activity of adoptively-transferred T cells 
when chemotherapy or radiotherapy are administered before the T cell infusions.6,8,83 In mice, 
administering chemotherapy or radiotherapy prior to infusions of tumor-antigen-specific T cells 
dramatically enhanced the anti-tumor efficacy of the transferred T cells.6,8,25,26,83,84
Administering chemotherapy or radiotherapy enhances adoptive T-cell therapy by multiple 
mechanisms including depletion of regulatory T cells and elevation of T-cell stimulating serum 
cytokines including interleukin-15 (IL-15) and interleukin-7 (IL-7), and possibly depletion of
myeloid suppressor cells and other mechanisms.6,8,84,85 Removal of endogenous “cytokine sinks” 
by depleting endogenous T cells and natural killer cells caused serum levels of important T-cell 
stimulating cytokines such as IL-15 and IL-7 to increase, and increases in T-cell function and 
anti-tumor activity were dependent on IL-15 and IL-7.6 Experiments in a murine xenograft 
model showed that regulatory T cells could impair the anti-tumor efficacy of anti-CD19 CAR T 
cells.86 Myeloid suppressor cells have been shown to inhibit anti-tumor responses.85
Experiments with a syngeneic murine model showed that lymphocyte-depleting total body 
irradiation (TBI) administered prior to infusions of anti-CD19-CAR-transduced T cells was 
required for the T cells to cure lymphoma.7 In these experiments, some mice received TBI, and 
other mice did not receive TBI.  All mice were then challenged with lymphoma and treated with 
syngeneic anti-CD19-CAR T cells.  Mice receiving TBI had a 100% cure rate and mice not 
receiving TBI had a 0% cure rate.7
Strong suggestive evidence of enhancement of the activity of adoptively-transferred T cells has 
been generated in humans.30,87,88 Very few clinical responses have occurred and very little 
evidence of in vivo activity has been generated in clinical trials of anti-CD19-CAR T cells 
administered without lymphocyte-depleting chemotherapy.30,33 In contrast, many regressions 
and evidence of long-term B-cell depletion have occurred in clinical trials in which patients 
received anti-CD19-CAR T cells after lymphocyte-depleting chemotherapy.3,4,32,51 The 
chemotherapy regimen that best increases the anti-malignancy efficacy of CAR-expressing T 
cells is not known, but the most commonly used chemotherapy regimens that have been used in 
clinical trials and that convincingly demonstrate persistence and in vivo activity of adoptively 
transferred T cells have included cyclophosphamide and fludarabine.3,4,31,32,87,88 Both 
cyclophosphamide and fludarabine are highly effective at depleting lymphocytes.87,88 One well-
characterized and commonly used regimen is the combination of 300 mg/m2 of 
cyclophosphamide administered daily for 3 days and fludarabine 30 mg/m2 administered daily 
for three days on the same days as the cyclophosphamide.89 Multiple cycles of this regimen can 
be tolerated by heavily pretreated leukemia patients.89
1.2.9
Rationale for dose-escalation
The clinical trial described in this protocol is planned as a dose escalation in which the number 
of anti-BCMA-CAR T cells administered to patients will be increased with sequential dose 
levels.  The rationale for conducting a dose-escalation trial of a cellular therapy is based on two 
main sources of evidence.  First, the anti-tumor efficacy of adoptively-transferred T cell 
treatments increases as the dose of T cells administered to mice increases.90-92 Second, in the 
setting of allogeneic transplantation, relapsed malignancy is often treated with infusions of 
allogeneic donor lymphocytes (DLIs).93,94 The incidence of graft-versus-host disease, which is 


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caused by T cells attacking allogeneic antigens on host tissues, increases as the dose of T cells 
administered in DLIs increases’.93,94
1.2.10 Summary of risks and potential benefits
This clinical trial is being performed to evaluate a genetically-modified T-cell therapy for 
multiple myeloma, which is an almost always incurable disease.12 Only patients with multiple 
myeloma who have progressive or relapsed myeloma despite at least 3 prior lines of therapy will 
be enrolled. The risks of the study fall into 3 general categories.  First, chemotherapy that could 
cause cytopenias is part of the protocol.  As with any chemotherapy that causes neutropenia and 
thrombocytopenia, this chemotherapy could cause toxicities such as infections and bleeding. The 
second category of toxicity is cytokine-release-type toxicities such as high fevers, hypotension 
and neurological toxicities such as delirium, obtundation, myoclonus, seizures, headache, and 
transient focal neurological toxicities including aphasia and focal paresis.  These cytokine-
release-type toxicities have been detected in other clinical trials of CAR T cells during the first 2 
weeks after anti-CD19 CAR T cells were infused.4,95 In the anti-CD19 CAR trials, these 
toxicities have been transient with toxicities generally resolving within 2 days to 2 weeks.  The 
third main category of toxicity is direct damage to normal tissues by the CAR T cells.  This 
could happen because of unexpected expression of BCMA on normal cells or because of 
unexpected cross-reactivity of the anti-BCMA CAR with proteins other than BCMA in vivo. A 
potential toxicity caused by anti-BCMA CAR T cells damaging normal cells is 
hypogammaglobulinemia due to depletion of plasma cells and a subset of mature B cells.  
Hypogammaglobulinemia has been a complication for many patients on clinical trials of anti-
CD19 CAR-expressing T cells.4,32 . Hypogammaglobulinemia in these patients was routinely 
treated with infusions of intravenous immunoglobulins.4
The potential benefits to subjects enrolling on this trial include the possibility that the anti-
BCMA-CAR T cells can cause a significant anti-myeloma effect.  Many patients enrolled on 
early trials of anti-CD19 CAR T cells obtained prolonged complete remissions of advanced 
malignancies3,4,96, so there is a chance that recipients of anti-BCMA CAR T cells could also 
derive a direct benefit from participation in this trial.  Patients might also derive a benefit from 
knowing that they are contributing to the development of new cellular therapies for cancer.  
Aiding in the development of new therapies might help future patients.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
Note: if a patient meets an eligibility requirement as outlined below, and is enrolled on the 
protocol but then is found to no longer meet the eligibility requirement after enrollment but 
before the start of protocol treatment, the treatment will be aborted.
2.1.1
Inclusion Criteria
2.1.1.1
Multiple Myeloma criteria
x
Clear BCMA expression must be detected on greater than 50% of malignant plasma cells 
from 
either 
bone 
marrow 
or 
a 
plasmacytoma 
by 
flow 
cytometry 
or 


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immunohistochemistry.  These assays must be performed at the National Institutes of 
Health. It is not required that the specimen used for BCMA determination comes from a 
sample that was obtained after the patient’s most recent treatment. BCMA expression 
will need to be documented on the majority of malignant plasma cells at some time after 
the original anti-BCMA CAR T-cell infusion in all patients undergoing a second anti-
BCMA CAR T-cell infusion.  If paraffin embedded unstained samples of bone marrow 
involved with MM or a plasmacytoma are available, these can be shipped to the NIH for 
BCMA staining, otherwise new biopsies will need to be performed for determination of 
BCMA expression.
x
Bone marrow plasma cells must make up 30% or less of total bone marrow cells based on 
a bone marrow biopsy performed within 30 days of the start of protocol treatment.
x
Patients must have received at least 3 different prior treatment regimens for multiple 
myeloma
x
Patients must have measurable MM as defined by at least one of the criteria below.
¾ One or more of these abnormalities defines measurable disease:
¾ Serum M-protein greater or equal to 0.4 g/dl (10 g/l). 
¾ Urine M-protein greater or equal to 200 mg/24 h.
¾ Serum free light chain (FLC) assay: involved FLC level greater or equal to10 mg/dl 
(100 mg/l) provided serum FLC ratio is abnormal.
¾ A biopsy-proven plasmacytoma
2.1.1.2
Other inclusion criteria:
x
Greater than or equal to 18 years of age and less than or equal to age 73.
x
Able to understand and sign the Informed Consent Document.
x
Clinical performance status of ECOG 0-2
x
Patients of both genders must be willing to practice birth control from the time of 
enrollment on this study and for four months after receiving the preparative regimen.
x
Women of child bearing potential must have a negative pregnancy test because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus.
x
Seronegative for HIV antibody.  (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who are HIV seropositive can 
have decreased immune -competence and thus are less responsive to the experimental 
treatment and more susceptible to its toxicities.) 
x
Seronegative for hepatitis B antigen, positive hepatitis B tests can be further evaluated by 
confirmatory tests, and if confirmatory tests are negative, the patient can be enrolled.


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x
Seronegative for hepatitis C antibody unless antigen negative.  If hepatitis C antibody test 
is positive, then patients must be tested for the presence of antigen by RT-PCR and be 
HCV RNA negative.
x
Absolute neutrophil count greater than or equal to 1000/mm3 without the support of 
filgrastim or other growth factors.  
x
Platelet count greater than or equal to 45,000/mm3 without transfusion support 
x
Hemoglobin greater than 8.0 g/dl.  
x
Less than 5% plasma cells in the peripheral blood leukocytes 
x
Serum ALT and AST less or equal to 2.5 times the upper limit of the institutional normal.
x
Serum creatinine less than or equal to 1.3 mg/dL.
x
Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert’s Syndrome 
who must have a total bilirubin less than 3.0 mg/dl.
x
At least 14 days must have elapsed since any prior systemic therapy at the time the 
patient starts the cyclophosphamide and fludarabine conditioning regimen, and patients’ 
toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia 
or vitiligo). 
x
Because this protocol requires collection of autologous blood cells by leukapheresis in 
order to prepare anti-BCMA-CAR T cells, systemic anti-myeloma therapy including 
systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or 
equivalent dose of another corticosteroid are not allowed within 2 weeks prior to the 
required leukapheresis.
x
Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography) and 
no evidence of hemodynamically significant pericardial effusion as determined by an 
echocardiogram within 6 weeks of the start of the treatment protocol.
x
Patients should not take corticosteroids including prednisone, dexamethasone or any 
other corticosteroid for any purpose at doses higher than 5 mg/day of prednisone or 
equivalent dose of another corticosteroid 2 weeks before apheresis and within 2 weeks 
prior to CAR T-cell infusion, and at any time after the CAR T cell infusion.
2.1.2
Exclusion criteria: 
Patients on any anticoagulants except aspirin are not eligible.
x
Patients that require urgent therapy due to tumor mass effects or spinal cord compression.
x
Patients that have active hemolytic anemia.
x
Patients with second malignancies in addition to multiple myeloma are not eligible if the 
second malignancy has required treatment within the past 3 years or is not in complete 
remission. There are two exceptions to this criterion: successfully treated non-metastatic 
basal cell or squamous cell skin carcinoma.   
x
Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.


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x
Active systemic infections (defined as infections causing fevers or requiring anti-
microbial treatment), active coagulation disorders or other major uncontrolled medical 
illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal, 
genitourinary or immune system, history of myocardial infarction, active cardiac 
arrhythmias, active obstructive or restrictive pulmonary disease.
x
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease). 
x
Systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or 
equivalent dose of another corticosteroid are not allowed within 2 weeks prior to either 
the required leukapheresis or the initiation of the conditioning chemotherapy regimen.
x
History of severe immediate hypersensitivity reaction to any of the agents used in this 
study.
x
History of allogeneic stem cell transplantation
x
Patients with CNS metastases or symptomatic CNS involvement (including cranial 
neuropathies or mass lesions and spinal cord compression).
x
Patients with active autoimmune skin diseases such as psoriasis or other active 
autoimmune diseases such as rheumatoid arthritis.
2.2
SCREENING EVALUATION
The following assessments must be completed within 30 days prior to starting the 
chemotherapy conditioning regimen unless otherwise noted (if not, then the evaluation 
must be repeated):
x
Complete history and physical examination, including, weight and vital signs, noting in 
detail the exact size and location of any lesions that exist. 
x
Confirmation of diagnosis of MM by the NCI Laboratory of Pathology and confirmation 
of clear BCMA expression on the majority of malignant plasma cells from either bone 
marrow or a plasmacytoma by flow cytometry or immunohistochemistry. The sample 
used for this BCMA expression analysis can come from any time prior to enrollment on 
the protocol.
x
Bone marrow aspirate and biopsy specifically ask for BCMA immunohistochemistry
staining of the bone marrow biopsy.  Order cytogenetics with interphase FISH and flow 
cytometry on the bone marrow aspirate.  Cytogenetics studies are not required if a written 
report of cytogenetics studies performed at any time are available from an outside 
institution. The bone marrow biopsy must take place at some time after the patient’s 
most recent myeloma treatment. If the patient agrees to future use of specimens when 
screening bone marrow is obtained, reserve one tube of bone marrow aspirate to be sent 
to Fran Hakim’s lab for research purposes.  Attention Jeremy Rose, Bldg 10, room 
12C216 contact phone: 301-594 5339. (A bone marrow biopsy must also be performed 
with in 30 days of starting the protocol treatment to assess for disease burden. See section 
3.1.4 for details.)


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x
All patients must have flow cytometry staining of bone marrow or plasmacytoma cells 
for BCMA by Dr. Stetler-Stevenson’s lab (NCI Laboratory of Pathology).
x
EKG
x
MRI of spine and pelvis (only if clinically indicated in patients with back pain or pelvic 
pain or a history of plasmacytomas of spine or pelvic bones are present) 
x
MRI of the brain-within 6 weeks of protocol treatment start.
x
If necessary to document progressive disease obtain a skeletal X-ray survey
x
Donor venous assessment
x
Antibody screen for Hepatitis B and C; HIV, HTLV-I/II, T. cruzi (Chagas agent), West 
Nile, and syphilis (RPR)
x
Cardiac echocardiograph-within 6 weeks of protocol treatment start.
x
(Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), 
Inorganic Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin, LDH, Total Protein, Total CK, Uric Acid)
x
CBC with differential and platelet count
x
Serum immunofixation electrophoresis
x
Serum immunoglobulin free light chains
x
Glucose-6-phosphate dehydrogenase (G6PD) deficiency screening
x
Thyroid panel 
x
Serum Cortisol
x
ȕ-HCG pregnancy test (serum or urine) on all women of child-bearing potential 
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office  ncicentralregistration-l@mail.nih.gov.
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
3.1.1
General study plan  


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This protocol is a phase I dose-escalation study of autologous T cells that are genetically 
modified to express an anti-BCMA CAR.
The protocol will enroll patients with multiple myeloma that is progressive or relapsed despite at 
least 3 prior lines of therapy.  Patients will be evaluated for general health, and multiple 
myeloma staging will be carried out.  An assessment of BCMA expression will be an important 
part of the eligibility screening.  Patients enrolled on the study will undergo leukapheresis, and 
anti-BCMA-CAR-expressing T cells will be generated by transducing the patient’s T cells with a 
gammaretrovirus encoding the anti-BCMA CAR.  During the time of T-cell preparation, the 
patients will receive a conditioning chemotherapy regimen of cyclophosphamide 300 mg/m2
daily for 3 days and fludarabine 30 mg/m2 IV daily for 3 days on the same days.  This is an 
extensively-used chemotherapy regimen that can be easily administered on an outpatient basis.  
Two days after the end of the conditioning chemotherapy, patients will receive a single infusion 
of anti-BCMA-CAR-expressing T cells.  A minimum 9-day hospitalization will be required after 
the cell infusion to monitor closely for acute toxicities. Patients are required to stay within 60 
minutes driving time from the Clinical Center until day 14 after the CAR T-cell infusion.
Patients will then be evaluated for toxicity and multiple myeloma will be staged 2 weeks and 1, 
2, 3, 4, 6, 9, and 12 months after the infusion.
A small number of subjects may be eligible for re-enrollment if a patient is removed from the 
protocol BEFORE receiving any protocol therapy, and would be required to meet all eligibility 
criteria at the time of re-enrollment. Patients will be assigned a new sequential study number for 
the re-enrollment study period. Any cryopreserved cells produced from a patient who was 
removed from the study can be used to treat that patient after re-enrollment. We do not anticipate 
changes in the risk profile for the initial versus re-enrollment.


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3.1.2
Protocol schema
Leukapheresis
In vitro generation of 
Anti-BCMA-expressing
T cells (9-11 days)
Pretreatment staging
Infusion of recipient with
Anti-BCMA-CAR-expressing T-Cells
(Inpatient for 9-days minimum post 
infusion)
Potential repeat treatments for patients with 
persistent myeloma
Follow-up 2 weeks and 1, 2, 3, 4, 6, 9, and 12 
months post-infusion. Then every 6 months 
up to 5 years post-infusion.
Outpatient or inpatient 
cyclophosphamide plus fludarabine 
conditioning chemotherapy
Patient Baseline evaluation


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3.1.3
Dose Limiting Toxicity
Dose-limiting toxicities are defined as follows:
o Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T 
cells or the fludarabine and cyclophosphamide chemotherapy and lasting more 
than 7 days
o Grade 4 toxicities possibly or probably related to the study interventions
The following specific toxicities will not be dose-limiting toxicities:
o
Neutropenia (ANC<500/PL) lasting 9 days or less
o
Anemia (Hgb<8 g/dL) lasting 7 days or less
o
Grade 4 thrombocytopenia lasting 25 days or less
o
Grade 3 thrombocytopenia
o
Hypotension requiring treatment with vasopressors for 72 hours or less.  The 72
hours is measured from the first institution of vasopressors even if vasopressors 
are temporarily discontinued and then re-started..
o
Fever
o
All cytopenias except neutropenia, anemia, and thrombocytopenia
o
Aasymptomatic electrolyte disturbances regardless of grade
3.1.4
Dose Escalation
The trial will be a dose-escalation with 4 dose levels based on the patient’s actual bodyweight.
As of amendment C, the number of anti-BCMA-CAR-expressing T cells transferred for each 
dose level will be as shown in the Dose Escalation Schedule below. for patients in which less 
than 350% of total bone marrow cells are plasma cells. 
Dose Escalation Schedule
Dose Level
Dose of IND Agent * 
Level 1
0.3x106 CAR+ T cells per kg of recipient bodyweight
Level 2
1.0x106 CAR+ T cells per kg of recipient bodyweight 


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Abbreviated Title: Anti-BCMA-CAR T cells 
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Each dose level will include a minimum of 3 patients. There will be a minimum of 9 days 
between the CAR T-cell infusion of a patient and the start of the conditioning chemotherapy 
regimen for the next patient. This will cause a 14 day delay between sequential CAR T-cell 
infusions.
Patients will be enrolled sequentially; therefore, enrollment will not proceed to a higher dose 
level until all patients have been treated in the prior cohort.  If sufficient cells cannot be grown to 
meet the criteria for the assigned dose level but sufficient cells can be grown to meet the 
requirements of one dose level lower than the assigned dose level, the patient will be enrolled in 
the appropriate dose level for the number of cells infused. If a DLT occurs in an additional 
patient entered at a lower dose due to cell growth limitations, accrual will continue at this level 
as described in the dose-escalation scheme below.  Accrual will be halted at the higher level until 
the cohort at the lower level is complete as described below. If sufficient cells cannot be 
produced to infuse the number of cells called for by one dose level lower than the called for dose 
level, the treatment will be aborted.  A second attempt will be made to prepare cells for the 
patient if the patient agrees and if the patient still meets all eligibility criteria. 
Should none of the first 3 patients treated on a dose level experience a DLT accrual can start on 
the next higher dose level after a 14-day delay following CAR T-cell infusion of the third 
patient.  Should 1 of 3 patients experience a dose limiting toxicity a particular dose level,  three 
more patients would be treated at that dose level to confirm that no greater than 1/6 patients have 
a DLT prior to proceeding to the next higher level.  If 1/6 patients have a DLT at a particular 
dose level, accrual can proceed to the next higher dose level after a 14-day delay following
treatment of the 6th patient. If a level with 2 or more DLTs in 3-6 patients has been identified, 3 
additional patients will be accrued at the next-lowest dose for a total of 6, in order to further 
characterize the safety of the maximum tolerated dose.  
Starting with Amendment E, only patients with less than 30% bone marrow plasma cells 
documented on a bone marrow biopsy will be enrolled. We have already treated 4 patients on 
dose level 4 (9x106 CAR+ T cells/kg).  One of 4 low-dose patients experienced a DLT on dose 
level 4.  If 2 more patients can be treated on this dose level without a DLT, we will declare dose 
level 4 the maximum tolerated dose and proceed to treat 8 patients on an expansion cohort as 
described on page 35 of the protocol. If 2 more patients cannot be treated on Dose Level 4 
without a DLT, we will hold discussions with the FDA and NCI IRB to ask to proceed with a 
Level 3
3.0x106 CAR+ T cells per kg of recipient bodyweight 
Level 4
9.0x106 CAR+ T cells per kg of recipient bodyweight


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Abbreviated Title: Anti-BCMA-CAR T cells 
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lower dose to be determined at that time. Regarding the expansion cohort of 8 patients, if more 
than 1 patient on this expansion cohort has a DLT, enrollment on the expansion cohort will stop.
The maximum tolerated dose is the dose at which a maximum of 1 of 6 patients has a DLT.  
After a maximum tolerated dose is defined, additional patients can be treated on this trial.  Up to
8 total additional recipients can be treated after an MTD is established. If cell growth limitations 
preclude administration of the maximum tolerated dose, the patient will receive as many cells as 
possible up to the maximum tolerated dose. This patient will be replaced in the dose escalation 
by the next enrolled patient. If it proves to be technically impossible or impractical to achieve 
the higher dose levels due to cell production constraints and a maximum tolerated dose has not 
been reached, the highest achievable dose level will be declared the maximum feasible dose.
Dose escalation will follow the rules outlined in the Table below.
Number of Patients with 
DLT
at a Given Dose Level
Escalation Decision Rule
0 out of 3
Enter up to 3 patients at the next dose level
> 2
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose 
(highest dose administered).  Up to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously 
at that dose.
1 out of 3
Enter up to 3 more patients at this dose level.
x
If 0 of these 3 patients experience DLT, 
proceed to the next dose level.
x
If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is
declared the maximally administered dose.  
UP to three (3) additional patients will be 
entered at the next lowest dose level if only 3 
patients were treated previously at that dose.
<1 out of 6 at highest dose 
level below the maximally 
administered dose
This is the MTD and is generally the recommended 
phase 2 dose.  At least 6 patients must be entered at 
the recommended phase 2 dose.
3.2
DOSE MODIFICATIONS/DELAY
Other Toxicity:


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o
Patients may be removed from further treatment if they have active infections defined as 
infections causing fevers or infections requiring anti-microbial therapy that arise while 
patients are on-study but before the CAR T-cell infusion; however such patients are 
eligible for treatment if they meet all eligibility criteria after the infection resolves.  
o
If a patient experiences a grade 3 or greater toxicity (with the exception of cytopenias 
including neutropenia, lymphopenia, anemia, or thrombocytopenia) while on-study 
before the CAR T-cell infusion, the CAR T-cell infusion must be delayed until the 
toxicity improves to a grade 2 or less.
3.3
DRUG ADMINISTRATION
3.3.1
Leukapheresis
The patient will undergo a 10-15 liter leukapheresis (generally, 12 liters will be processed to 
target a yield of 6-10 x109 lymphocytes) in the Department of Transfusion Medicine (DTM) 
Dowling Apheresis Clinic according to DTM standard operating procedures.  The procedure 
requires dual venous access, and takes approximately 3-4 hours to complete.  A central line will 
be placed if peripheral venous access is not sufficient. 
3.3.2
Anti-BCMA-CAR-expressing T-cell preparation
After cells are obtained by apheresis, further cell processing to generate anti-BCMA CAR-
expressing T cells will occur in the DTM according to standard operating procedures (SOPs).
Either freshly-collected cells or cryopreserved cells can be used to initiate the cell-preparation 
process. Peripheral blood mononuclear cells will be isolated. Sufficient cells for 3 complete cell 
productions will be retained in the Department of Transfusion Medicine; the excess cells will be 
sent to the ETIB Preclinical Core for cryopreservation at 100 to 200 million PBMC per vial.
Contacts in the ETIB preclinical core are Fran Hakim and Jeremy Rose (301-594-5339). The 
anti-CD3 monoclonal antibody OKT3 will be used to stimulate T-cell proliferation. Two and 3
days after the start of the T-cell cultures, the cells will be transduced by exposing them to a 
supernatant containing replication-incompetent gammaretroviruses encoding the anti-BCMA 
CAR.  The cells will continue to proliferate in culture until the day of infusion.  Anti-BCMA-
CAR T cells will be infused between day 8 and day 11 of culture. Ten vials of the infused cells 
will be cryopreserved and stored in the ETIB preclinical core. Each vial will contain 20 million 
cells.
Before infusion, the percentage of T cells expressing the anti-BCMA CAR will be determined by 
flow cytometry, and this percentage of BCMA+ T cells will be used in calculating the total 
number of cells to be infused to meet the dose requirements of the dose-escalation plan described 
in 3.1.4.  In addition to flow cytometry, further testing of the cells will take place prior to 
infusion to evaluate for microbial contamination, replication-competent retroviruses, and 
viability.  Details of this testing can be found in the appropriate DTM SOPs. When a patient is no 
longer eligible for retreatment on this protocol due to meeting any of the off-study criteria listed 
in section 3.7.2, any remaining cryopreserved pretreatment PBMC collected on this protocol will 
be transferred from the Department of Transfusion Medicine to the Principle Investigator of this 
protocol for storage in the ETIB preclinical core and possible use in research. 


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3.3.3
Conditioning chemotherapy and anti-BCMA CAR T-cell administration-this can be 
either inpatient or outpatient
3.3.3.1
Overall summary of the treatment plan
Drug
Dose 
Days
Cyclophosphamide 
300 mg/m2 IV infusion over 
30 minutes 
Daily x 3 doses on days -5,
-4, -3
Fludarabine
30 mg/m2 IV infusion over 
30 minutes administered 
immediately following the 
cyclophosphamide on day -
5, -4, -3
Daily x 3 doses on days -5,
-4, -3
Anti-BCMA CAR T cells
Variable. 
One time dose on day 0
3.3.3.2
Detailed treatment plan
Retreatment decisions will be decided on a case-by-case basis to include discussion with FDA.
Day -5, -4, and -3:  Patients will receive pre-hydration with 1000 mL 0.9% sodium chloride I.V. 
over 1 to 3 hours. 
Patients will receive anti-emetics following NIH Clinical Center guidelines, but dexamethasone 
will not be administered.  One suggested regimen is ondansetron 16 to 24 mg orally on days -5, 
-4, and -3 before chemotherapy (I.V. ondansetron can be substituted).    Patients should be 
provided with anti-emetics such as lorazepam and prochlorperazine to use at home.  
Next on days -5, -4, and -3, cyclophosphamide at a dose of 300 mg/m2 I.V. will be diluted in 100 
ml 5% dextrose solution and infused over 30 minutes.  After the cyclophosphamide on days -5, -
4, and -3, patients will receive 30 mg/m2 I.V. fludarabine in 100 mL 0.9% sodium chloride over 
30 minutes.  Note: in patients with a creatinine clearance of 30- 70 ml/minute/1.73m2 , the 
daily dose of fludarabine will be reduced by 20%.
Following the fludarabine infusion, patients will receive 1000 mL 0.9% sodium chloride I.V. 
over 1-2 hours. Furosemide will be given if needed.
Days -2 and -1:  No interventions except as needed for general supportive care such as anti-
emetics.  To minimize bladder toxicity, patients should increase normal oral fluid intake to at 
least 2 L/day.
Day 0:  Anti-BCMA CAR T cells will be administered.  Premedication for the cell infusion will 
be given approximately 30 minutes prior to the infusion.  The premedications are acetaminophen 
650 mg orally and diphenhydramine 12.5 mg IV.  Cells are delivered to the patient care unit 
from the Department of Transfusion Medicine.  Prior to infusion, the cell product identity label is 
double-checked by two authorized staff (MD or RN), and identification of the product and 


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Abbreviated Title: Anti-BCMA-CAR T cells 
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documentation of administration are entered in the patient’s chart as is done for blood banking 
protocols.  The cells are to be infused intravenously over 20 to 30 minutes via a central line with 
non-filtered tubing, gently agitating the bag during infusion to prevent cell clumping.  Cells may 
arrive on the unit in a syringe instead of a bag.  In this case, the cells can be administered to the 
patient by pushing the cells through a free flowing normal saline line per nursing SOP, but still 
must be infused over 20-30 minutes.  Details of the infusion procedure are included in section 
13.3.
Days 1 to 9: Mandatory hospitalization for observation and treatment as necessary. In addition, 
patients are required to stay within 60 minutes driving time from the Clinical Center until day 14 
after the CAR T-cell infusion.
Guidelines for dealing with toxicities that often occur after CAR T cell infusions including 
hypotension, fever and tachycardia are given in Appendix 5.A CBC will be obtained daily.  If the 
absolute neutrophil count becomes less than 500/microliter, filgrastim will be initiated at a dose 
of 300 micrograms daily subcutaneously for patients under 70 kg in weight and at a dose of 480 
micrograms daily for patients over 70 kg in weight.  Filgrastim will be given daily and then
discontinued as soon as the absolute neutrophil count recovers to 2000/microliter.
3.3.4
Potential repeat treatment
Patients obtaining any response except progressive disease are potentially eligible for a repeat 
treatments consisting of conditioning chemotherapy followed by an infusion of anti-BCMA CAR 
T cells.  Retreatment will be at least 2 months after the original treatment.  The dose of anti-
BCMA CAR T cells administered during repeat treatments will be the dose level currently 
enrolling patients receiving initial CAR T-cell infusions.  The repeat treatments will include the 
same conditioning chemotherapy as the initial treatment. 
To be eligible for repeat treatments, patients must have not experienced a DLT with their first 
treatment.  Patients must also meet the same eligibility requirements listed in Section 2.1.
BCMA expression must be documented after the first anti-BCMA CAR infusion and before the 
second BCMA CAR T-cell infusion. The patients must undergo screening evaluation as listed in 
Section 2.2 except infectious disease serology, and brain MRI are not required to be repeated 
unless clinically indicated. In addition, serum will be screened for human anti-mouse antibodies
(HAMA) by ELISA in all patients being considered for retreatment, and patients with HAMA 
reactivity that first appears after an initial anti-BCMA T-cell infusion will not be eligible for re-
treatment.  Follow-up testing for retreatment will be the same as for the first treatment. The 
patient maybe re-enrolled on the the study as a new patient to allow this re-treatment and these 
patients will be considerd in the total sample size for this study. A maximum of 2 total 
treatments can be administered to any one patient, and at least 2 months must elapse between the 
first treatment and the second treatment.
3.4
PROTOCOL EVALUATION
3.4.1
Baseline evaluations and interventions
The following tests must be completed within 14 days of the start of the conditioning 
chemotherapy regimen:
x
Patients must have a central venous access before the time of cell infusion.  This might 
require placement of a non-valved P.I.C.C line or other device.


39
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Version Date: September 21, 2017
x
Physical exam with vital signs and oxygen saturation
x
CT scan of chest, abdomen, and pelvis or PET scan (only if necessary for staging)
x
Skeletal survey.  Additional scans and x-rays may be performed if clinically indicated 
based on patients’ signs and symptoms.
x
If necessary for staging: serum immunofixation electrophoresis 
x
250 microgram cosyntropin stimulation test if suspicious for adrenal insufficiency based 
on low serum sodium or high serum potassium or hypotension or a history  of adrenal 
insufficiency or other clinical indications
x
24-hour urine collection with immunofixation electrophoresis timed urine, and
creatinine for creatinine clearance calculation
x
Serum immunoglobulin free light chains
x
Anti CMV antibody titer, HSV serology, and EBV panel, T cruzi serology, toxoplasmosis 
serology (Note: patients who are known to be positive for any of the above do not need to 
be retested; may be performed within 3 months of chemotherapy start date)
x
Serum will be sent for measles IgG, Rubella IgG, VZV IgG, and pneumococcal 
antibodies (Ab) 23 serotypes
x
Blood will be collected for research purposes.  Draw 12 CPT tubes (8 mL each of blood 
will be collected prior to initiation of the conditioning chemotherapy regimen. This is a 
total of 96 mL of blood. Some of this blood will be used for immunology assays and 
some will be used for RCR assays. This blood can be collected on different days as long 
as a total of 12 CPT tubes are collected prior to cell initiation of the chemotherapy.  Send 
to Dr. Fran Hakim’s, Pre-Clinical Core lab; Attention Jeremy Rose, Bldg 10, room 
12C216 contact phone: 301-594-5339.
x
In addition to the CPT tubes, draw 16 mL of blood to obtain serum for research purposes 
(2 SST tubes, 8 mL per tube) within 3 days prior to the start of the chemotherapy.  Send 
to Dr. Fran Hakim’s, Pre-Clinical Core lab; Attention Jeremy Rose, Bldg 10, room 
12C216 contact phone: 301-594-5339.
The following tests must be completed within 7 days of the start of the conditioning 
chemotherapy regimen:
x
TBNK 
x
Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), 
Inorganic Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin, LDH, Total Protein, Total CK, Uric Acid (to be repeated on  the first day of the 
chemotherapy at the discretion of the PI)
x
E2-microglobulin 
x
Serum quantitative immunoglobulins
x
ABO typing


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x
Ionized calcium
x
CBC with differential and platelet count(to be repeated on  the first day of the 
chemotherapy at the discretion of the PI)
x
PT/PTT
x
Urinalysis; if results are abnormal, send for urine culture
x
ȕ-HCG pregnancy test (serum or urine) on all women of child-bearing potential
3.4.2
Studies to be performed during the mandatory 9-day inpatient admission after cell 
infusion
x
Vital signs including pulse oximetry will be monitored q1h x 4 hours after completion of 
the CAR T cell infusion and every 4 hours otherwise unless otherwise clinically 
indicated.
x
Daily physical exam
x
CBC twice a day from day 0 until day 10 with differential every 24 hours. After day 10 
do a CBC with differential daily until discharge.
x
TBNK on the day of CAR T-cell infusion (day 0) and day 7 after infusion
x
Chemistries twice a day starting from day 0 to day 10 .After day 10 do chemistries once a 
day until discharge: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, Uric Acid )
x
Serum C-reactive peptide (CRP) within 7 days of day -5 before initiation of 
chemotherapy and daily while hospitalized.
x
PT/PTT 7 days after cell infusion
x
Other tests will be performed, as clinically indicated.
x
Research blood:  Every Monday, Wednesday, and Friday during hospitalization, starting 
on the first Monday, Wednesday, or Friday after the day of CAR T-cell infusion and 
lasting up to 14 days after infusion of anti-BCMA-CAR-transduced T cells, 56 mL of 
patient peripheral blood will be obtained (6 CPT tubes 8 mL each and 1 SST tube 8 mL).  
Attention Jeremy Rose, Bldg 10, room 12C216 contact phone: 301-594-5339.
3.4.3
Post-infusion outpatient evaluation
After completion of therapy the patient will be followed for potential complications related to 
anti-BCMA–CAR T-cell infusion. The patient will be seen at the NIH in follow-up to evaluate 
disease status and late problems related to anti-BCMA –CAR T-cell infusion at days +14, +30, 
+60, +90, and +120; and at 6, 9, and 12 months after anti-BCMA –CAR T-cell infusion. After 
12 months, the patient will be seen every 6 months up to five years. At these times patients will 
have the following tests performed to determine clinical response:


41
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
x
6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for 
immunological testing. Attention Jeremy Rose, Bldg 10, room 12C216 contact phone: 
301-594-5339.
x
1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  Attention 
Jeremy Rose, Bldg 10, room 12C216 contact phone: 301-594-5339.
Note: after the first year of follow-up, research blood will be reduced to 4 CPT tubes 
(32 mL total) during required protocol visits.
x
CT scan of chest, abdomen, and pelvis or PET scan at outpatient follow-up appointments 
starting 1 month after infusion (only if a plasmacytoma was detected before treatment)
x
Physical exam with vital signs and oxygen saturation
x
(Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, 
Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), 
Inorganic Phosphorus, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin, LDH, Total Protein, Total CK, Uric Acid)
x
E2-microglobulin
x
TBNK
x
Blood for serum quantitative immunoglobulins
x
Ionized calcium
x
CBC with differential
x
Urinalysis: if results are abnormal, send for urine culture
x
Serum immunofixation electrophoresis 
x
24-hour urine collection with immunofixation electrophoresis timed urine (can be 
omitted if not needed for staging after day 30. This is required for all patients 
pretreatment and at the day 14 and day 30 follow-up appointments).Serum 
immunoglobulin free light chains
x
At the 2 month follow-up, a bone marrow aspirate and biopsy will be collected.  Aspirate 
must be sent for flow cytometry to the lab of Dr. Maryalice Stetler-Stevenson.  BCMA 
staining must be requested for the flow cytometry.  BCMA immunohistochemistry should 
also be requested on the bone marrow biopsy. This may also be performed at day +30 if 
clinically indicated.
x
At the day +180, day +270, and +1 year time points only, serum will be sent for measles 
IgG, Rubella IgG, VZV IgG, and pneumococcal antibodies (Ab) 23 serotypes
x
For patients with ongoing responses a second bone marrow aspirate and biopsy will be 
performed at the 6-month follow-up appointment. Aspirate must be sent for flow 
cytometry to the lab of Dr. Maryalice   Stetler-Stevenson.  BCMA staining must be 
requested for the flow cytometry.  BCMA immunohistochemistry should also be 
requested on the bone marrow biopsy.


42
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Version Date: September 21, 2017
x
For each bone marrow aspirate performed, send one tube of bone marrow aspirate to Fan 
Hakim’s lab for research purposes.  Attention Jeremy Rose, Bldg 10, room 12C316 
contact phone: 301-594 5339.
x
Gene-therapy-specific follow-up must be carried out as described in section 3.6


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Abbreviated Title: Anti-BCMA-CAR T cells 
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3.5
STUDY CALENDAR
Follow up
Procedures a
Screening/
Baseline
Pre-cell 
infusion
/ Day 0
Day 
+7b
Day+14 
and  
Day+30
(+/- 5
days)
Day 
+60
(+/- 7
days)
Day 
+90
(+/- 7
days)
Day 
+120
(+/- 10
days)
Day 
+180
(+/- 14
days)
Day 
+270
(+/- 14
days)
Day 
+365
(+/- 30
days)
Every 6 
month
after day 
365(+/-
30 days)
up to 5 
years
Clinical Assessments
History and PE
X
X
X
X
X
X
X
X
X
X
X
Vital signs, O2 
saturation
X
X
X
X
X
X
X
X
X
X
X
Height, weight
X
X
Performance Score
X
X
Laboratory Assessments
CBC with differential  
X
X
X
X
X
X
X
X
X
X
X
Sodium, Potassium 
Chloride, CO2, 
Creatinine, Glucose, 
BUN, Albumin, Calcium, 
Magnesium, Inorganic 
Phosphorus, Alkaline 
Phosphatase, ALT, AST, 
T. Bilirubin, D. Bilirubin, 
LDH, Total Protein, CK, 
Uric Acid
X
X
X
X
X
X
X
X
X
X
X
Serum C-reactive peptide
Xh
Xm
Xm
PT/PTT 
Xh
X
Ionized calcium
Xh
X
X
X
X
X
X
X
X
Thyroid panel
XK


44
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Follow up
Procedures a
Screening/
Baseline
Pre-cell 
infusion
/ Day 0
Day 
+7b
Day+14 
and  
Day+30
(+/- 5
days)
Day 
+60
(+/- 7
days)
Day 
+90
(+/- 7
days)
Day 
+120
(+/- 10
days)
Day 
+180
(+/- 14
days)
Day 
+270
(+/- 14
days)
Day 
+365
(+/- 30
days)
Every 6 
month
after day 
365(+/-
30 days)
up to 5 
years
E2-microglobulin 
Xh
X
X
X
X
X
X
X
X
Quantitative 
immunoglobulins 
Xh
X
X
X
X
X
X
X
X
Anti-CMV, HSV, EBV, 
t.cruzi,toxoplasma 
Xh,j
Antibody screen for 
Hepatitis B and C; HIV, 
HTLV-I/II, T. cruzi 
(Chagas agent), West Nile,
and syphilis (RPR)
X
TBNK  
Xh
X
X
X
X
X
X
X
X
X
X
G6PD
XK
Urinalysis (culture prn) 
X
X
X
X
X
X
X
X
X
24 hr urine with 
immunofixation
electrophoresis timed 
urine
Xh
X
Xf
Xf
Xf
Xf
Xf
Xf
Xf
24 hr urine Creatinine 
Clearance
Xh
ABO typing
Xh
Serum immunoglobulin 
free light chains
X
X
X
X
X
X
X
X
X


45
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Follow up
Procedures a
Screening/
Baseline
Pre-cell 
infusion
/ Day 0
Day 
+7b
Day+14 
and  
Day+30
(+/- 5
days)
Day 
+60
(+/- 7
days)
Day 
+90
(+/- 7
days)
Day 
+120
(+/- 10
days)
Day 
+180
(+/- 14
days)
Day 
+270
(+/- 14
days)
Day 
+365
(+/- 30
days)
Every 6 
month
after day 
365(+/-
30 days)
up to 5 
years
Serum immunofixation
electrophoresis
X
X
X
X
X
X
X
X
X
Radiological Assessments
Skeletal Survey
X
CT chest, abdomen, 
pelvis f
Xh
Xi
X
X
X
X
X
X
X
PET f
Xh
Xi
X
X
X
X
X
X
X
Brain MRI
X
Spine and Pelvis MRI e
X
Other 
Specific 
Assessments
Serum Cortisol
Xk
250 microgram
cosyntropin test c
Xh
EKG, echocardiogram
X
RCR
X
X 
 
X
X 
Xg
Central Venous catheter 
placement 
X
Donor Venous 
Assessment
X
Response Evaluation
Bone marrow 
aspirate/biopsy d  
X
Xl
X
Xe


46
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Follow up
Procedures a
Screening/
Baseline
Pre-cell 
infusion
/ Day 0
Day 
+7b
Day+14 
and  
Day+30
(+/- 5
days)
Day 
+60
(+/- 7
days)
Day 
+90
(+/- 7
days)
Day 
+120
(+/- 10
days)
Day 
+180
(+/- 14
days)
Day 
+270
(+/- 14
days)
Day 
+365
(+/- 30
days)
Every 6 
month
after day 
365(+/-
30 days)
up to 5 
years
Research Blood 
X
X 
X
X
X
X
X
X
X
X
Adverse Events
X 
X
X
X
X
X
X
X
X
X
Concomitant Medications 
X
X 
X
X
X
X
X
X
X
X
X
Measles IgG, Rubella IgG, 
VZV IgG, Pneumococcal 
antibodies 23 serotypes
Xh
X
X
X
a see section 2.2and section 3.3.1 for details
b see section 3.4.2 for details of testing during hospitalization
c only if cortisol<18 mg/dL or clinical suspicion of adrenal insufficiency
d bone marrow biopsy will include flow cytometry, BCMA expression, cytogenetics, amyloid staining, and molecular studies of each sample.
e only if clinically indicated
fif useful for staging
g only at 2, 3, 4, 5 year point, see section 3.6 for details
h only at baseline
i only D+30, no CTs or PETs indicated at D+14
j Patients who are known to be positive for any of these tests do not need to be retested; may be performed within 3 months of chemotherapy start 
date
k only at Screening
l only Day  30 if clinically indicated
m Done Daily during hositalization


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Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
3.6
GENE-THERAPY-SPECIFIC FOLLOW-UP
x
Long-term follow up of patients receiving gene transfer is required by the FDA and must 
continue even after the patient comes off the study. Physical examinations will be 
performed and documented annually for 5 years following cell infusion to evaluate long-
term safety.  After 5 years, health status data will be obtained from surviving patients via 
telephone contact or mailed questionnaires for 10 additional years for a total of 15 years 
after cell infusion.  Blood will need to be collected at least annually for long-term follow-
up of gene therapy.
x
Persistence of CAR transduced cells will be assessed by quantitative PCR and/or flow 
cytometry at 1, 2, 3, 4, 6 and 12 months after cell infusion, or until CAR-expressing cells 
are no longer detectable.  If any patient shows a high level of persistence of CAR gene 
transduced cells or an increasing population of CAR gene transduced T cells at month 6 
or later (by FACS staining or qPCR), the previously archived samples will be subjected 
to techniques that would allow the identification of predominant clonal populations of  
transduced cells.
x
Patients’ blood samples will be obtained and undergo analysis for detection of replication 
competent retroviruses (RCR) by PCR prior to cell infusion and at 3, 6, and 12 months 
post cell administration.  Blood samples will be archived annually thereafter if all 
previous testing has been negative with a brief clinical history.
3.7
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 30 days following the last dose of study therapy.
3.7.1
Criteria for removal from protocol therapy
Note that the treatment consists of a conditioning chemotherapy regimen followed by a T-cell 
infusion, so off-treatment criteria mainly apply to eligibility for potential repeat treatments and 
cancellation of cell infusion for toxicity arising during the conditioning chemotherapy. Patients 
will be taken off treatment for the following:
x
Greater than grade 3 toxicity attributable to anti-BCMA CAR T cells makes patients
ineligible for repeat treatments.
x
The patient no longer meets the eligibility criteria for the protocol after enrolling but 
before start of the chemotherapy conditioning regimen.  If the reason that the patient is 
not eligible can be rapidly resolved within 2 weeks, the treatment can proceed if not, the 
patient will be off-study.
x
The patient receives any other treatment for multiple myeloma except bisphosphonates 
and repeat treatment on this protocol.  Bisphosphonates are allowed when administered to 
prevent osteopenia more than 2 months after the anti-BCMA-CAR T-cell infusion.  If a 
patient receives corticosteroids in doses greater than 5 mg/day of prednisone or an 
equivalent dose of another corticosteroid, the patient will be off-treatment.


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Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
x
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment on this study in the judgment of the investigator.
x
Participant requests to be withdrawn from active therapy
x
Investigator discretion
x
Positive pregnancy test
3.7.2
Off-Study Criteria
Patients will be taken off study for the following:
x
The patient voluntarily withdraws
x
There is significant patient noncompliance
x
Death
x
PI decision to end this study 
x
The patient no longer meets the eligibility criteria for the protocol after enrolling but 
before start of the chemotherapy conditioning regimen.
x
Development of progressive or relapsed multiple myeloma after anti-BCMA CAR T 
cell infusion in patients not desiring or not eligible for re-treatment on this protocol.
x
The patient receives any anti-myeloma therapy except bisphosphonates.
Bisphosphonates are allowed 2 months or more after the CAR T-cell infusion.
x
Taking corticosteroids for any reason after CAR T-cell infusion in a total cumulative 
dose of more than 30 mg of prednisone or equivalent
Note: Patients must be followed until all adverse events have resolved to grade 2 or less with the 
exception of lymphopenia and alopecia.  If an adverse event is not expected to resolve to grade 2 
or less this will be noted in the patient medical record and the patient will be taken off study. In 
addition, all patients must be followed for the gene therapy specific follow up as outlined in 
section 3.6 prior to being removed from study.
3.7.3
Off Protocol Therapy and Off-Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off
protocol therapy and when a subject is taken off-study. A Participant Status Update Form from 
the web site(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
ANTIBIOTIC PROPHYLAXIS
x
Patients with a CD4 T-cell count less than 200 will be maintained on pneumocystis 
prophylaxis with trimethoprim-sulfamethoxazole 1 double-strength tablet every Monday-


49
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Wednesday-Friday. If patients cannot tolerate trimethoprim sulfamethoxazole, an 
alternative pneumocystis prophylaxis will be used.
x
Patients with serum IgG level less than 400 mg/dL will receive intravenous 
immunoglobulin replacement as needed to maintain an IgG level above 400 mg/dL, if the 
patient has serious bacterial infections.  An example of an intravenous immunoglobulin 
infusion to be used for this purpose would be Gammunex 500 mg/kg given as a single 
dose.  Intravenous immunoglobulin infusions should be preceded by premedication with 
diphenhydramine and acetaminophen, and rate of infusion should be started at low rates 
and escalated in a step-wise manner.
x
Empiric Bacterial Antibiotics
x
Neutropenic patients will start on broad spectrum antibiotics with a first fever of 38.30C 
or greater or two fevers of 38.0 separated by at least 1 hour and concomitant ANC < 
500/ml. 
x
Aminoglycosides will be avoided unless clear evidence of sepsis.
4.2
BLOOD PRODUCT SUPPORT
x
Leukocyte filters will be utilized for all blood and platelet transfusions with the exception 
of the CAR-transduced T cell infusions to decrease sensitization to transfused WBC and 
decrease the risk of CMV infection.
x
Patients who are seronegative for CMV should receive CMV-negative blood products 
whenever possible.
x
Using daily CBC’s as a guide, the patient will receive platelets and packed red blood cells 
(PRBC’s) as needed.  Attempts will be made to keep Hgb >8.0 gm/dl, and platelets 
>10,000/mm3.  All blood products with the exception of the CAR-transduced T cells will 
be irradiated.  Leukocyte filters will be utilized for all PRBC and platelet transfusions to 
decrease sensitization to transfused WBC’s and decrease the risk of CMV infection.
4.3
ANTI-EMETICS
Anti-emetics will follow NIH Clinical Center Guidelines (except that corticosteroids will be 
avoided).
4.4
GRANULOCYTE COLONY-STIMULATING FACTOR
A CBC will be obtained daily while the patient is inpatient.  If the absolute neutrophil count
becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 micrograms daily 
for patients under 70 kg in weight and a dose of 480 micrograms daily for patients over 70 kg in 
weight only in patients with absolute neutrophil counts less than 500/microliter.  Filgrastim will 
be discontinued as soon as the absolute neutrophil count recovers to 1500/microliter.
4.5
AVOIDANCE OF CORTICOSTEROIDS
Patients should not take corticosteroids including prednisone, dexamethasone or any other 
corticosteroid at a dose equivalent to 5 mg/day or more of prednisone for any purpose without 
approval of the Principle Investigator.


50
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
4.6
GUIDELINES FOR MANAGEMENT OF COMMON ACUTE TOXICITIES THAT OCCUR AFTER 
CAR T CELL INFUSIONS
These are guidelines only. It is understood that treatment of these toxicities must be 
individualized for each patient.  Not following the exact recommendations in Section 13.3 is not 
a protocol deviation.
5
BIOSPECIMEN COLLECTION
Bio specimen collection on this protocol will consist of blood draws and acquisition of bone 
marrow aspirates and possible biopsies of plasmacytomas for research purposes.
5.1
CORRELATIVE STUDIES FOR RESEARCH
5.1.1
Biospecimen collection before the start of the conditioning chemotherapy:
x
One heparinized syringe containing 5 to 8 mL of bone marrow aspirate to be sent to Fran 
Hakim’s lab.  Attention Jeremy Rose, Bldg 10, room 12C316 contact phone: 301-594
5339.It will be used in functional assays to see if anti-BCMA-CAR T cells can recognize 
the patient’s multiple myeloma cells.
x
Blood will be collected for research purposes.  A total of 12 CPT tubes (8 mL each of 
blood will be collected prior to initiation of the conditioning chemotherapy regimen. This 
is a total of 96 mL of blood. Some of this blood will be used for immunology assays and 
some will be used for RCR assays. This blood can be collected on different days as long 
as a total of 12 CPT tubes are collected prior to the start of the chemotherapy and within 
14 days of the start of the chemotherapy.  Send to Dr. Fran Hakim’s, Pre-Clinical Core 
lab; Attention Jeremy Rose, Bldg 10, room 12C216 contact phone: 301-594-5339.
x
16 mL of blood will be drawn to obtain serum for research purposes (2 SST tubes, 8 mL 
per tube) within 14 days prior to the start of the chemotherapy.  Send to Dr. Fran 
Hakim’s, Pre-Clinical Core lab; Attention Jeremy Rose, Bldg 10, room 12C216 contact 
phone: 301-594-5339.
x
An apheresis is required to obtain cells used to prepare the anti-BCMA CAR T cells that 
are administered on this protocol. After sufficient cells are processed for all possible
clinical needs, the left over apheresis cells can be cryopreserved for research use. Note 
that these cells would simply be discarded if not used for research.
x
Specimens will be cryopreserved and assays will be performed retrospectively.
5.1.2
Biospecimen collection after anti-BCMA-CAR T-cell infusion during the required 
hospitalization
Every Monday, Wednesday, and Friday during hospitalization, starting on the first Monday, 
Wednesday, or Friday after the CAR T-cell infusion and lasting up until 14 days after infusion of 
anti-BCMA-CAR-transduced T cells, 56 mL of patient peripheral blood will be obtained (6 CPT 
tubes 8 mL each and 1 SST tube 8 mL). Attention Jeremy Rose, Bldg 10, room 12C216 contact 
phone: 301-594-5339.


51
Abbreviated Title: Anti-BCMA-CAR T cells 
Version Date: September 21, 2017
Additional research blood may be collected at any time during the clinical course at the 
discretion of the PI (within the volume restriction limits) allowing for the research studies 
already outlined in this protocol to be performed at the time of an unanticipated clinical event, if 
necessary to address the objectives of the study.
5.1.3
Biospecimen collection during outpatient follow-up
x
Patients will return for outpatient follow-up clinic visits 2 weeks, 1 month, 2  months, 3 
months, 4 months, 6 months, 9 months and 12 months after the anti-BCMA- CAR T-cell 
infusion. After the 12-month follow-up appointment patients will return for follow-up
every 6 months.  The specimens listed below will be performed at each outpatient clinic 
visit during the first year of follow up.
¾ 6 CPT tubes of Research Blood (48 mL) will be collected to obtain blood for 
immunological testing. Attention Jeremy Rose, Bldg 10, room 12C216 contact 
phone: 301-594-5339.
¾ 1 SST tube (8 mL) of Research Blood will be obtained for serum collection.  
Attention Jeremy Rose, Bldg 10, room 12C316 contact phone: 301-594-5339.
After 1 year research blood collected will be reduced to 4 CPT tubes at each visit.
x
At the 2 month follow-up only, bone marrow aspirate and biopsy will be performed and 
the aspirate will be cryopreserved.  
x
Only for patients with ongoing responses, a second bone marrow aspirate and biopsy will 
be performed at the 6-month follow-up appointment, and the aspirate will be 
cryopreserved.
5.1.4
Immunological Testing
x
T-cell assays: Direct immunological monitoring will consist of quantifying CD3+ T cells 
that express the anti-BCMA CAR by quantitative PCR, and/or by flow cytometry.  These 
assays will be performed to measure the persistence and estimate the proliferation of the 
infused CAR+ T cells.  A quantitative PCR assay or a flow cytometry assay will be used 
to quantitate CAR+ T cells at all post-infusion time-points up to at least 3 to 6 months 
after infusion, and CAR+ T cell analysis will continue until the CAR+ T cell level drops 
to undetectable levels unless a stable low level of CAR+ T cells is present at more than a 
year after infusion.  The absolute number of CAR+ PBMC will be estimated by 
multiplying the percentage of CAR+ PBMC by the absolute number of lymphocytes plus 
monoctyes per microliter of blood.  Ex vivo immunological assays will be used to 
measure the BCMA-specific functional activity of the CAR+ T cells and will consist of 
assays such as intracellular cytokine staining and anti-CD107a degranulation assays. 
Immunological assays will be standardized by the inclusion of pre-infusion recipient 
PBMC and in some cases an aliquot of the engineered T cells cryopreserved at the time 
of infusion. 
x
Serum cytokine levels will also be measured by enzyme-linked immune sorbent assays.   


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x
Gene expression studies will be performed on patient multiple myeloma cells and on the 
infusion CAR T cells of each patient.  Methods used will be either Nanostring and/or 
RNAseq (RNA sequencing).
x
Patients’ blood samples will be obtained and undergo analysis for detection of replication 
competent retroviruses (RCR) by PCR prior to cell infusion and at 3 and 6 months, 
and at one year post cell administration.  Blood samples will be archived annually
thereafter if all previous testing has been negative with a brief clinical history. If a patient 
dies or develops neoplasms during this trial, efforts will be made to assay a biopsy 
sample for RCR. If any post-treatment samples are positive, further analysis of the RCR 
and more extensive patient follow-up will be undertaken, in consultation with the FDA.   
RCR PCR assays detect the Gibbon Ape Leukemia Virus (GALV) envelop gene and are 
performed under contract by the National Gene Vector Laboratory at Indiana University  
The results of these tests are maintained by the contractor performing the RCR tests and 
by the ETIB research team.
x
Due to nature of these studies, it is expected that expansion of specific T-cell clones will 
be observed as T-cell proliferate in response to the targeted antigen.  Therefore, care will 
be taken to track T-cell persistence, but presence of an oligoclonal T cell population does 
not indicate an insertional mutagenesis event.  If any patient shows a high level of 
persistence of CAR gene transduced cells or an increasing population of CAR gene 
transduced T cells at month 6 or later (by FACS staining or qPCR), the previously 
archived samples will be subjected to techniques that would allow the identification of 
predominant clonal populations of  transduced cells.  Such techniques may include T cell 
cloning or LAM-PCR.  If a predominant or monoclonal T cell clone derived from CAR 
gene transduced cells is identified during the follow-up, the integration site and sequence 
will be identified and subsequently analyzed against human genome database to 
determine whether the sequences are associated with any known human cancers.  If a 
predominant integration site is observed, the T cell cloning or LAM-PCR test will be 
used at an interval of no more than three months after the first observation to see if the 
clone persists or is transient.  In all instances where monoclonality is persistent and 
particularly in instances where there is expansion of the clone, regardless of whether or 
not the sequence is known to be associated with a known human cancer, the subject 
should be monitored closely for signs of malignancy, so that treatment, if available, may 
be initiated early.
5.1.5
Additional biopsies and additional blood draws
Patients might be asked to undergo biopsies or additional blood draws for research purposes. 
Additional blood draws might be necessary to investigate T cell responses and serum cytokine 
levels in cases of clinical events such as rapid regressions of malignancy or toxicity.  These 
research biopsies are optional and patients can participate in this trial whether or not they agree 
to undergo biopsies for research purposes.  These biopsies will only be performed if minimal 
morbidity is expected based on the procedure performed and the granulocyte and platelet count.  
Biopsy tissue will be processed in the NIH Department of Pathology. Studies will be performed 
to evaluate the antigen expression by the tumor and to evaluate the reactivity of lymphocyte from 
these biopsies. In addition the presence of transduced cells may be quantitated.


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5.1.6
Future studies 
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study the patient provides 
consent for this. However, this research may only be done if the risks of the new questions were 
covered in the consent document. If new risks are associated with the research (e.g. analysis of 
germ line genetic mutations) a protocol amendment will be required and informed consent will 
be obtained from all research subjects to whom these new studies and risks pertain.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
5.2.1
Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF)
x
Samples will be ordered in CRIS and tracked through Clinical Trial Data Management 
system.  Should a CRIS screen not be available,the CRIS downtime procedures will be 
followed.  Samples will not be sent outside NIH without IRB notification and an 
executed MTA. 
x
Patient blood and tissue samples, collected for the purpose of research under IRB 
approved protocols of the Experimental Transplantation and Immunology Branch, may 
be archived by the ETIB Preclinical Development and Clinical Monitoring Facility 
(PDCMF). All data associated with archived clinical research samples is entered into the 
ETIB PDCMF’s Microsoft Excel databases on frozen cells and serum. These databases 
are stored on the NCI group drive in the ETIB ‘PRECLINSERVICE’ folder. Access to 
this folder is limited to PDCMF staff and ETIB clinical staff, requiring individual login 
and password. All staff in the PDCMF laboratory receive annually updated NIH/CIT 
training and maintain standards of computer security.
x
The data recorded for each sample includes the patient ID, trial name/protocol number, 
date drawn, treatment cycle/post-transplant time point, cell source (e.g. peripheral blood, 
marrow,) as well as box and freezer location. Patient demographics that correlate 
treatment outcomes and therapies with the samples can be obtained only through the 
NCI/ETIB clinical records. As of January 2007, all newly received samples receive a 
unique bar code number, which is included in the sample record in the PDCMF database. 
Only this bar code is recorded on the sample vial and the vials will not be traceable back 
to patients without authorized access to the PDCMF database. All non-coded samples 
previously archived will be stripped of identifiers prior to distribution for any use other 
than as a primary objective of the protocol under which they were collected.
x
Samples are stored in freezers.  . All samples will be labeled solely with a bar code 
(which includes the date, and serially determined individual sample identifier). The key 
will be available to a restricted number of ETIB investigators and associate investigators 
on the protocol. Coded samples will be stored frozen at -20°, -80° or liquid nitrogen 
vapor phase to -180 C according to the stability requirements in a single location under 
the restricted control of the PDCM Facility of ETIB.
x
Access to samples from a protocol for research purposes will be by permission of the 
Principal Investigator of that protocol in order to be used (1) for research purposes 
associated with protocol objectives for which the samples were collected, or (2) for a new 


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research activity following submission and IRB approval of a new protocol and consent, 
or (3) for use only as unlinked or coded samples under the OHSRP Exemption Form 
guidelines stipulating that the activity is exempt from IRB review. Unused samples must 
be returned to the PDCMF laboratory. Samples, and associated data, will be stored 
permanently unless the patient withdraws consent. If researchers have samples remaining 
once they have completed all studies associated with the protocol, they must be returned 
to the PDCMF laboratory.
x
These freezers are located onsite at the Preclinical Service laboratory (12C216) (-85° 
freezer) or in ETIB common equipment space (CRC/3-3273).
5.2.2
Protocol Completion/Sample Destruction 
x
Once research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the 
original protocol under which the samples or data were collected and either an IRB 
approved protocol and patient consent or an OHSRP exemption indicating that the 
activity is exempt from IRB review.
x
The PDCMF staff will report to the Principal Investigators any destroyed samples, if 
samples become unsalvageable because of environmental factors (ex. broken freezer or 
lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a 
researcher. 
x
The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher.  Freezer problems, lost 
samples or other problems associated with samples will also be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI.
5.2.3
Samples for Genetic/Genomic Analysis
Samples will use for gene expression analysis will be RNAseq and/or NanostringTM.
These studies will be used to determine gene expression in multiple myeloma cells and 
infusion CAR T cells.  The purpose of these studies is to assess gene expression at the 
RNA level not to study germline mutations.
5.2.3.1
Description of the scope of genetic/genomic analysis
RNAseq and/or NanostringTM will be used to determine gene expression in multiple myeloma 
cells and infusion CAR T cells.  The purpose of these studies is to assess gene expression at the 
RNA level not to study germline mutations. One purpose of these studies is to determine if 
different levels of gene expression in malignant cells are associated with response to CAR T-cell 
therapy.  Another purpose of these studies is to determine if different levels of gene expression in 
infusion CAR T cells are associated with anti-malignancy responses caused by CAR T cells or 
persistence of CAR T cells.


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5.2.3.2 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study has obtained 
a Certificate of Confidentiality, which helps to protect personally identifiable research 
information. The Certificate of Confidentiality allows investigators on this trial to refuse to 
disclose identifying information related to the research participants, should such disclosure have 
adverse consequences for subjects or damage their financial standing, employability, insurability 
or reputation. The informed consent includes the appropriate coverage and restrictions of the 
Certificate of Confidentiality.
5.2.3.3 Management of Results
The analyses that we perform in our laboratory are for research purposes only; they are not 
nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid. 
Therefore, we do not plan to inform participants of the results of testing on the tissue and blood 
that is performed in our research lab. However, subjects will be contacted if a clinically 
actionable gene variant is discovered. Clinically actionable findings for the purpose of this study 
are defined as disorders appearing in the American College of Medical Genetics and Genomics 
recommendations for the return of incidental findings that is current at the time of primary 
analysis. 
(A 
list 
of 
current 
guidelines 
is 
maintained 
on 
the 
CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists) Subjects who 
still remain on the study will be contacted at this time with a request to provide a blood sample to 
be sent to a CLIA certified laboratory. The CLIA testing may be funded by the PI or the CCR. If 
the research findings are verified in the CLIA certified lab, the subject will be referred to the NCI 
Genetics Branch for genetic counseling on the implications of the results. Subjects that do not 
wish to return to the NCI will be referred to a local genetics health care provider (at their 
expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
Note: Subjects must remain on the study in order to maintain up to date contact information and 
to have results returned. Subjects opting for voluntary withdrawal from the study are to be 
informed at the time that results cannot be returned once this has been done.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
Data will be prospectively collected and entered in real time into the Cancer Center Clinical Data 
System database (NCI C3D database) (information at http://ccrtrials.nci.nih.gov). It is expected 
that clinical data be entered into C3D no later than after 10 business days of the occurrence. The 
NCI PI and research nurse will have access to these data via web access.
The medical record will maintain complete records on each patient including any pertinent 
supplementary information obtained from outside laboratories, outside hospitals, radiology 
reports, laboratory reports, or other patient records. The NCI C3D will serve as the primary 
source from which all research analyses will be performed.  


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Data collection will include the eligibility criteria checklist, patient history, specialty forms for 
pathology, radiology, toxicity monitoring, and relapse data and an off-study summary sheet, 
including a final assessment by the treating physician. After patients are seen in clinic at each 
scheduled follow up, the database will be updated in real-time. 
All data obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with NIH security standards. Primary and final analyzed 
data will have identifiers so that research data can be attributed to an individual human subject 
participant.
End of study procedures: Data will be stored according to HHS , FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
6.1.1
Adverse event recording:
x Grade 1 adverse events will not be recorded.
x Grade 2 adverse events that will be recorded:
a. Unexpected events that are possibly, probably, or definitely related to the 
research.
b. Expected events that are probably or definitely related to the study interventions
will be recorded only for the first year after the infusion..
c. All Infections proven by culture, PCR, antigen detection or other laboratory 
methods will be recorded for the first year after infusion regardless of attribution.
d. Any serious events that are deemed clinically significant by the PI
x All grade 3, 4, and 5 adverse events will be recorded regardless of attribution.
6.2
GENOMIC DATA SHARING PLAN
Unlinked genomic data will be deposited in the database of genotypes and phenotypes (dbGaP) 
in compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
Responses will be categorized by using the International Uniform Response Criteria for Multiple 
myeloma.15 Multiple myeloma staging will be conducted at the 2 week follow-up appointment 
and at each subsequent follow-up appointment.  The appropriate staging studies will need to be 
determined for each patient because of the variability in multiple myeloma.   
6.3.1
Important Considerations on response criteria
x
Response criteria for all categories and subcategories of response except CR and sCR are 
applicable only to patients who have ‘measurable’ disease by at least one of the three 
measurements as defined below
x
All responses must be confirmed to be stable in two evaluations made at any time.
6.3.1.1
Definition of measurable disease


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Any one or combination of these abnormalities defines measurable disease:
x
Before amendment E: Serum M-protein greater or equal to 1 g/dl (10 g/l). 
x
After amendment E: Serum M-protein greater or equal to 0.4 g/dl (10 g/l). 
x
Urine M-protein greater or equal to 200 mg/24 h.
x
Serum FLC assay: involved FLC level greater or equal to10 mg/dl (100 mg/l) provided 
serum FLC ratio is abnormal.
x
Presence of a biopsy-proven plasmacytoma
6.3.1.2
Laboratory tests for measurement of M-protein
x
Serum M-protein level is quantitated using densitometry on SPEP except in cases where 
the SPEP is felt to be unreliable such as in patients with IgA monoclonal proteins 
migrating in the beta region.  If SPEP is not available or felt to be unreliable (e.g., in 
some cases of IgA myeloma) for routine M-protein quantitation during therapy, then 
quantitative immunoglobulin levels on nephelometry or urbidometry can be accepted.  
However, this must be explicitly reported, and only nephelometry can be used for that 
patient to assess response and SPEP and nephelometric values cannot be used 
interchangeably.
x
Urine M-protein measurement is estimated using 24-h UPEP only.  (Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended)
6.3.1.3
Suggested follow-up to meet response criteria 
x
Patients with measurable disease by both SPEP and UPEP need to be followed by both
SPEP and UPEP for response assessment and categorization;
x
Except for assessment of sCR, CR, and VGPR, patients with “measurable disease” 
restricted to the SPEP will need to be followed routinely only by SPEP; 
x
Patients with “measurable disease” restricted to the UPEP will need to be followed 
routinely only by UPEP;
x
Patients with “measurable disease” in either SPEP or UPEP or both will be assessed for 
response only based on these two tests and not by the FLC assay; 
x
FLC response criteria are only applicable to patients without measurable disease in the 
serum or urine, and to fulfill the requirements of the category of sCR; 
x
Bone marrow is required only for categorization of CR 
x
For good clinical practice patients should be periodically screened for light chain escape 
with UPEP or serum FLC assay.
x
Plasmacytomas can be staged with CT scans
6.3.2
International Myeloma Working Group uniform response criteria: 


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6.3.2.1
Stringent Complete Remission (sCR)
x
CR as defined below plus
o
Normal FLC ratio and
o
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence or flow cytometry (only1 bone marrow evaluation is needed).
6.3.2.2
Complete Remission (CR) 
x
Negative immunofixation on the serum and urine and
x
Disappearance of any soft tissue plasmacytomas and
x
5% or less plasma cells in bone marrow (only 1 bone marrow evaluation is needed)
x
No evidence of progressive or new bone lesions if radiographic studies were performed
(X-Rays not required in absence of clinical indication)
Comments: To be considered a CR, 
x
Both serum and urine immunofixation must be carried out and be negative regardless of 
the size of baseline M-protein in the serum or urine; 
x
Patients with negative UPEP values pretreatment still require UPEP testing to confirm 
CR and exclude light chain or Bence–Jones escape 
6.3.2.3
Very Good Partial Remission (VGPR) 
x
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or
x
90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 h
x
No evidence of progressive or new bone lesions if radiographic studies were performed 
(X-Rays not required in absence of clinical indication)
6.3.2.4
Partial Remission (PR)
x
50% or greater reduction of serum M-protein and
x
90% or greater reduction in 24-h urinary M-protein (or to less than 200mg per 24 h) and
x
50% or greater reduction in the size of soft tissue plasmacytomas, if present at baseline
x
No evidence of progressive or new bone lesions if radiographic studies were performed 
(X-Rays not required in absence of clinical indication)
Only if the serum and urine M-protein are not measurable (as per definition in section 
6.2.1.1),
x
50% or greater decrease in the difference between involved and uninvolved FLC levels 
is required (in lieu of the serum and urine M-protein criteria).
If serum and urine M-protein are not measurable and serum FLC assay is also not 
measurable,  


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x
Before amendment E: 50% or greater reduction in plasma cells is required in lieu of M-
protein evaluation (provided baseline bone marrow plasma cell percentage was 30% or 
greater)
x
After amendment E: bone marrow plasma cell will not be used for PR evalution.
6.3.2.5
Stable Disease (SD) 
x
Not meeting criteria for CR, VGPR, PR or progressive disease 
(Not recommended for use as an indicator of response; stability of disease is best described by 
providing the time to progression estimates)
Comments:
x
All response categories require two consecutive assessments made at any time before the 
institution of any new therapy; 
x
Confirmation with repeat bone marrow biopsy not needed.
x
Presence/absence of clonal FHOOVLVEDVHGXSRQWKHțȜUDWLR$QDEQRUPDOțȜUDWLRE\
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells 
IRUDQDO\VLV$QDEQRUPDOUDWLRUHIOHFWLQJSUHVHQFHRIDQDEQRUPDOFORQHLVțȜUDWLRQRI
greater than 4:1 or less than 1:2.
6.3.2.6
Progressive Disease (PD)a
Requires one or more of the following:
x
Increases of greater or equal to 25% from the lowest post-treatment (nadir) value in
o
Serum M-component (minimum absolute increase of 0.5g/dl) or
o
Urine  M-component (minimum absolute increase of 200mg/24h) or
o
Percentage of bone marrow plasma cells (minimum absolute percentage of 10%)
o
Size of bone lesions or soft tissue plasmacytoma
o
Only in patients without measurable serum and urine M-protein levels:  The 
difference between involved and uninvolved FLC levels.  The absolute increase must 
be >10 mg/dL.   The FLC ratio must be abnormal.
x
Definite development of new bone lesions or new plasmacytoma
x
Development of hypercalcemia solely attributable to the disease (corrected serum 
calcium >11.5 mg/dL)
aAll relapse categories require 2 consecutive assessments made at any time before 
classification as relapse or progression or institution of a new therapy.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 


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Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
7.1
DEFINITIONS
7.1.1
Adverse Event
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted above in 
Section 6.1.
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per sections7.2 , 7.3 and 7.4.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
7.1.2
Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.
7.1.3
Unexpected adverse reaction


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An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
7.1.4
Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
7.1.5
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
x
A congenital anomaly/birth defect.
x
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
7.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
7.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death.
7.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP)
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.
7.1.10 Unanticipated Problem


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Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
7.2
NCI-IRB AND CLINICAL DIRECTOR REPORTING
7.2.1
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director:
x
All deaths, except deaths due to progressive disease
x
All Protocol Deviations
x
All Unanticipated Problems
x
All non-compliance
Reports must be received within 7 days of PI awareness via iRIS.
7.2.2
NCI-IRB Requirements for PI Reporting at Continuing Review
The protocol PI will report to the NCI-IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:
x
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 
7.2.3
NCI-IRB Reporting of IND Safety Reports


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Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB.
7.3
IND SPONSOR REPORTING CRITERIA
An investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a or equivalent, any serious adverse event, whether or not considered drug related, including 
those listed in the protocol or investigator brochure and must include an assessment of whether 
there is a reasonable possibility that the drug caused the event.
x
All Grade 5 (fatal) events (except death due to progressive disease) must be 
reported via email within 24 hours.  A complete report must be submitted within one 
business day. 
x
All other serious adverse events including deaths due to progressive disease must 
be reported within one business day
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor.
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov
and to the CCR PI and study coordinator.
7.3.1
Reporting Pregnancy
7.3.1.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”.
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting 
that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium 
and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented.
If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it.
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
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The same timelines apply when outcome information is available.
7.3.1.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study treatment, 
and for 4 months after finish the last cell infusion
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until (120 days) after the last 
dose after last cell infusion should, if possible, be followed up and documented.
7.4
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
7.4.1
Serious Adverse Event Reports to IBC
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of  anti-BCMA CAR T cells as soon as possible 
but in no event later than 7 calendar days of initial receipt of the information. Serious adverse  
events that are unexpected and associated with the use of the anti-BCMA CAR-expressing T
cells, but are not fatal or life-threatening, must be reported to the NIH IBC as soon as possible, 
but not later than 15 calendar days after the investigator’sinitial receipt of the information.
Adverse events may be reported by using the FDA Form 3500a.
7.4.2
Annual Reports to IBC
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to IBC in lieu of a separate report.  Please include the IBC 
protocol number on the report.
7.4.2.1
Clinical Trial Information
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information: 
x
the title and purpose of the trial
x
clinical site
x
the Principal Investigator
x
clinical protocol identifiersparticipant population (such as disease indication and general 
age group, e.g., adult or pediatric); 
x
the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons
x
the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed, 
x
if the trial has been completed, a brief description of any study results. 


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7.4.2.2
Progress Report and Data Analysis
Information obtained during the previous year's clinical and non-clinical investigations, 
including: 
x
a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system
x
a summary of all serious adverse events submitted during the past year
x
a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications
x
if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death
x
a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability. 
7.5
DATA AND SAFETY MONITORING PLAN
7.5.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular biweekly basis when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator. Adverse 
events will be reported as required above. Any safety concerns, new information that might 
affect either the ethical and or scientific conduct of the trial, or protocol deviations will be 
immediately reported to the IRB using iRIS and to the Sponsor. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.5.2
Sponsor Monitoring Plan
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on:
x
Informed consent process
x
Eligibility confirmation
x
Drug administration and accountability


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x
Adverse events monitoring
x
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct
7.5.3
Safety Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NCI-IRB continuing review date.   
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.   For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
STATISTICAL CONSIDERATIONS
The primary endpoint of this trial is to determine the safety of administering anti-BCMA-CAR-
expressing T cells to patients with relapsed or persistent B-cell malignancies.  Secondary 
objectives of this trial are to measure any anti-malignancy effect that might occur, to assess the 
feasibility of administering anti-BCMA-CAR-expressing T cells, and to measure persistence and 
function of anti-BCMA-CAR-expressing T cells. 
The trial was to be a dose-escalation with 5 dose levels.  The number of anti-BCMA-CAR-
expressing T cells transferred for each cohort was originally to be as follows: 
Dose level 1
0.3x106 CAR+ T cells per kg of recipient bodyweight
Dose level 2
1.0x106 CAR+ T cells per kg of recipient bodyweight 
Dose level 3
3.0x106 CAR+ T cells per kg of recipient bodyweight 
Dose level 4
9.0x106 CAR+ T cells per kg of recipient bodyweight
Dose level 5
15.0x106 CAR+ T cells per kg of recipient bodyweight
As of amendment E, we have completed accrual to the first 3 dose levels using the approach 
described in the next 3 paragraphs. Each dose level will include a minimum of 3 patients.  There 
will be a minimum of 7 days between the start of the conditioning chemotherapy regimen for 
sequential patients.  Patients will be enrolled sequentially; therefore, enrollment will not proceed 
to a higher dose level until all patients have been treated in the prior dose level.  If sufficient cells 
cannot be grown to meet the criteria for the assigned cohort, the patient will receive the dose of 


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cells called for by one dose level lower than the assigned cohort. If sufficient cells cannot be 
grown to meet the dose requirement called for one dose level lower than the assigned cohort, the 
treatment will be aborted. If a DLT occurs in an additional patient entered at a lower dose due to 
cell growth limitations, accrual will continue at this level as described in the dose-escalation 
scheme below.  Accrual will be halted at the higher level until accrual at the lower level is 
complete as described above.
Should none of the first 3 patients treated on a dose level experience a DLT, accrual can start on 
the next higher dose level after a 14-day delay following treatment of the third patient.  Should 1 
of 3 patients experience a dose limiting toxicity a particular dose level,  three more patients 
would be treated at that dose level to confirm that no greater than 1/6 patients have a DLT prior 
to proceeding to the next higher level.  If 1/6 patients have a DLT at a particular dose level, 
accrual can proceed to the next higher dose level. If a level with 2 or more DLTs in 3-6 patients 
has been identified, 3 additional patients will be accrued at the next-lowest dose for a total of 6, 
in order to further characterize the safety of the maximum tolerated dose.  The maximum 
tolerated dose is the dose at which a maximum of 1 of 6 patients has a DLT.  After a maximum 
tolerated dose is defined, additional patients can be treated on this trial: up to 8 total additional 
recipients can be treated after a MTD is established in order to better define safety and toxicity at 
that dose level.
If cell growth limitations preclude administration of the maximum tolerated 
dose, the patient will receive as many cells as possible up to the maximum tolerated dose. 
DLTs that occur in the cohort of patients receiving a repeat treatment will not affect the dose 
escalation of patients receiving an initial treatment. However, excessive DLTs among re-
treatments will result in a discontinuation of this practice. Specifically, if 2-3 of the first 3 
patients re-treated, 3 or more of the first 6 re-treated patients, 4 or more out of the first 9 re-
treated patients, or greater than 1/3 of the total patients receiving a repeat treatment experiences 
a DLT during repeat treatment, then repeat treatments will be discontinued altogether.
As of Amendment E, we have decided to not enroll patients on dose level 5.  The plan for the 
future of this protocol is to further explore dose level 4, 9.0x106 CAR T cells/kg.  We have 
already treated 4 patients on dose level 4 (9x106 CAR+ T cells/kg).  One of 4 low-dose patients 
experienced a DLT on dose level 4.  If 2 more patients can be treated on this dose level without a 
DLT, we will declare dose level 4 the maximum tolerated dose and proceed to treat 8 patients on 
an expansion cohort as described on page 35 of the protocol. If 2 more patients cannot be treated 
on Dose Level 4 without a DLT, we will hold discussions with the FDA and NCI IRB to ask to 
proceed with a lower dose to be determined at that time.  Regarding the expansion cohort of 8 
patients, if more than 1 patient on this expansion cohort has a DLT, enrollment on the expansion 
cohort will stop.  We plan to treat a maximum of 10 more patients on this protocol (2 more on 
dose level 4 followed by an expansion cohort of 8 patients).  We have decided to not explore 
dose level 5.  As indicated in section 3.3.4, patients may be re-enrolled on the study as new 
patients to allow re-treatment, and these patients will be considered both times in the total sample 
size for the study. With 18 patients enrolled as of January 5, 2017, and an additional planned 
accrual of up to 10 patients, the trial will enroll no more than 30 patients including up to 2
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The degree of persistence of anti-BCMA-CAR-transduced T cells will be evaluated by a 
quantitative measure (flow cytometry or quantitative PCR) in all patients.  Anti-malignancy 
effects will be measured by clinical response and categorized according to the International 
Uniform Response Criteria for Multiple Myeloma (Section 6.2 ). The clinical multiple myeloma 
responses will be interpreted cautiously in the context of a pilot study which may be used to 
guide parameters for study in future protocols if warranted.
All other evaluations of secondary objectives will be performed using exploratory techniques. 
No formal adjustment for multiple comparisons will be used since the evaluations are being done 
to generate hypotheses.
9
COLLABORATIVE AGREEMENTS
9.1
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
There is a CRADA for this protocol, with Bluebird Bio , Inc. for the development of lentiviral 
based chimeric antigen receptors (CAR) vectors that target the B cell maturation antigen 
(BCMA) for the treatment of Multiple Myeloma.
CRADA #2936 has been executed between Bluebird Bio, Inc. and the NCI.
10 HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION
x
The patients to be entered in this protocol have multiple myeloma which is an almost 
always incurable disease; moreover, patients will have progressive or relapsed myeloma 
despite at least 3 prior therapies.  These patients have limited life expectancies.  Subjects 
from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests that differences in 
disease response would be expected in one group compared to another.  Efforts will be 
made to extend accrual to a representative population, but in this preliminary study, a 
balance must be struck between patient safety considerations and limitations on the 
number of individuals exposed to potentially toxic and/or ineffective treatments on the 
one hand and the need to explore gender and ethnic aspects of clinical research on the 
other hand.  If differences in outcome that correlate to gender or to ethnic identity are 
noted, accrual may be expanded or a follow-up study may be written to investigate those 
differences more fully.
x
Multiple myeloma (MM) remains an incurable disease despite recent advances in
therapy.
x
Over the last 40 years and throughout the most recent era of improved therapy with novel 
agents, the depth of the disease response to therapy (including T- cells targeting B-cell 
maturation antigen) has remained the single most predictive factor for event free and 
overall survival in MM
x
Therefore, improving the rate and depth of responses remains a high priority for clinical 
research in MM.


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x
This justifies the enrollment of all subjects with MM eligible for T- cells targeting B-cell 
maturation antigen in this phase I/II study in an attempt to improve the clinical outcome 
while feasibility and safety are being evaluated.
x
Because patients on previous trials of CAR T cells have experienced hypotension, 
tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function.  
In many cases these toxicities were severe enough to require intensive care unit 
admission. We will limit enrollment to patients 70 years of age or less because based on 
our admittedly limited experience with prior CAR-T cell clinical trials, younger patients 
tolerate and recover from these toxicities better than elderly patients.
10.2 PARTICIPATION OF CHILDREN
Children will not be enrolled on this study.  Multiple myeloma is extremely uncommon in 
children; moreover, since the efficacy of this experimental procedure is unknown, it does not 
seem reasonable to expose children to this risk without further evidence of benefit.  
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.4 DOOVXEMHFWVDJHZLOOEHRIIHUHGWKHRSSRUWXQLW\WRILOO
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed.
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The experimental treatment has a chance to provide clinical benefit though this is unknown.  A 
goal of this study is to improve upon the number of patients who may benefit from adoptive cell 
therapy by using genetically-modified T-cells.  This specific protocol is being performed to 
evaluate a genetically modified T-cell therapy for multiple myeloma, which is an almost always 
incurable disease.  Only patients with multiple myeloma who have progressive or relapsed 
myeloma despite at least 3 prior lines of therapy will be enrolled. The risks of the study fall into 
3 general categories.  First, chemotherapy that could cause cytopenias is part of the protocol.  As 
with any chemotherapy that causes neutropenia and thrombocytopenia, this chemotherapy could 
cause toxicities such as infections and bleeding. The second category of toxicity is cytokine-
release type toxicities such as high fevers, hypotension and neurological toxicities such as 
delirium, obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities 
including aphasia and focal paresis.  These cytokine-release-type toxicities have been detected in 
other clinical trials of CAR T cells during the first 2 weeks after anti-BCMA CAR T cells were 
infused.4,95 The third main category of toxicity is direct damage to normal tissues by the CAR T 


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cells.  This could happen because of unexpected expression of BCMA on normal cells or because 
of unexpected cross-reactivity of the anti-BCMA CAR with proteins other than BCMA in vivo.  
Another potential toxicity of anti-BCMA CAR T cells is hypogammaglobulinemia due to 
depletion of plasma cells and mature B cells.  Hypogammaglobulinemia has been a complication 
of many patients on clinical trials of anti-BCMA CAR-expressing T cells.4,32
Hypogammaglobulinemia in these patients was routinely treated with infusions of intravenous 
immunoglobulins.4
The gammaretroviral vector used in this trial inserts into the T-cell DNA of patients, so in theory, 
insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any of the 
hundreds of patients treated with mature T cells that were genetically modified by 
gammaretroviral vectors.34-36
The success of this clinical trial cannot be predicted at this time.  Because all patients in this 
protocol have advanced multiple myeloma and limited life expectancies the potential benefit is 
thought to outweigh the potential risks.  It is also anticipated that this study will provide 
scientific information relevant to tumor immunotherapy.  
10.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The patient, along with family members or friends, will be presented with a detailed description 
of the protocol treatment.  The specific requirements, objectives, and potential advantages and 
disadvantages will be presented.  The Informed Consent document is given to the patient who is 
requested to review it and to ask questions prior to agreeing to participate in the treatment 
portion of this protocol.  The patient will be reassured that participation on trial is entirely 
voluntary and that he/she can withdraw or decide against treatment at any time without adverse 
consequences.The permission for additional biopsies for research will be obtained from patients 
at the time of the biopsy procedure. The research nurse, Principal Investigator or his designee is 
responsible for obtaining written informed consent from the patient.
10.5.1 Telephone re-consent procedure
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.  
A fully executed copy will be returned via mail for the subject’s records.  The informed consent 
process will be documented on a progress note by the consenting investigator and a copy of the 
informed consent document and note will be kept in the subject’s research record.
10.5.2 Short form consent process for non-English speaking patients
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 


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Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2) and 21 CFR 50.27 (b) (2).  The summary 
that will be used is the English version of the extant IRB approved consent document. Signed 
copies of both the English version of the consent and the translated short form will be given to 
the subject or their legally authorized representative and the signed original will be filed in the 
medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a 
family member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible). 
We request prospective IRB approval of the use of the short form process and will notify the IRB 
at the time of continuing review of the frequency of the use of the Short Form.
11 PHARMACEUTICAL INFORMATION  
11.1 RETROVIRAL VECTOR CONTAINING THE ANTI-BCMA CAR GENE 
The retroviral vector supernatant (PG13-MSGV-11D5-3CD828Z B1) encoding a chimeric 
antigen receptor (CAR) directed against B-cell maturation antigen (BCMA) was prepared and 
preserved following cGMP conditions in the Surgery Branch Vector Production Facility 
(SBVPF). The retroviral vector utilizes the MSGV retroviral vector backbone and consists of 
7007 bps including the 5' LTR from the murine stem cell virus (promoter), packaging signal 
including the splicing donor (SD) and splicing acceptor sites,  the anti-BCMA  CAR protein 
containing a signal peptide from human CD8-alpha, 11D5-3 light chain variable region (11D5-3
VL), linker peptide, 11D5-3 heavy chain variable region (11D5-3 VH), CD8 (hinge and 
transmembrane), CD28 (cytoplasmic region), and TCR zeta (cytoplasmic region), followed by 
the murine stem cell virus 3'LTR. The physical titer was determined by RNA dot blot according 
to sponsor certificate. 
The supernatant will be stored at –80 C or shipped on dry ice and stored in the Dept. of 
Transfusion Medicine, NIH or at Cryonix, Rockville, MD. Both storage facilities are equipped 
with around-the-clock temperature monitoring. Upon request, supernatant will be delivered on 
dry ice to be used in in vitro transductions of T cells. There will be no re-use of the same unit of 
supernatant for different patients. Retroviral titer has been shown to be stable after immediate 
thawing and immediate use. Handling of the vector should follow the guidelines of Biosafety 
Level-2 (BSL-2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at
http://bmbl.od.nih.gov/sect3bsl2.htm
11.2 CYCLOPHOSPHAMIDE
11.2.1 Source
Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from 
commercial sources and is supplied as a lyophilized powder in various vial sizes.
11.2.2 Toxicities


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1) Nausea and vomiting - variable; symptomatically improved with standard anti-emetics 
and/or benzodiazepines [e.g., lorazepam].
2) Water retention – cyclophosphamide may rarely provoke the syndrome of inappropriate 
antidiuretic hormone secretion and resultant hyponatremia, usually manifested 12-48 hours 
after IV administration, necessitating frequent accurate assessment [q 1-2 hours] of intake, 
urine output and urine specific gravity. This effect can be counteracted by furosemide. 
Fluid restriction is not feasible during administration of high dose cyclophosphamide.
3) Cardiomyopathy - cyclophosphamide may cause severe, sometimes lethal, hemorrhagic 
myocardial necrosis or congestive cardiomyopathy. Patients may present with congestive 
cardiomyopathy as late as 2 weeks after the last dose of cyclophosphamide. The clinical 
syndrome has been observed in patients receiving the dose of cyclophosphamide used in 
this protocol. In an attempt to minimize this complication, patients with significant cardiac 
dysfunction are excluded from this protocol [see patient eligibility]. Congestive failure is 
managed according to standard medical therapeutics.
4) Hemorrhagic cystitis – this is a serious, potentially life-threatening complication related to 
injury of the bladder epithelium by cyclophosphamide metabolites.
5) Although sub-clinical hematuria is not uncommon at this dose level, clinically significant 
hematuria or serious hemorrhage can usually be avoided by maintaining a high urine 
volume and frequent voidings and the administration of Mesna. Diuresis is maintained for 
24 hours after completion of last dose by parenteral infusions of normal saline with 
potassium chloride. Careful monitoring of serum and urine electrolytes is mandated. 
Furosemide may be required to ensure this diuresis. Continuous bladder irrigation may be 
used for control of significant hematuria.
6) Sterility
7) Less common but serious complications include pulmonary fibrosis and secondary 
malignancies. Less common but reversible toxicities include alopecia and skin rash.
11.2.3 Formulation and preparation 
Reconstituted with sterile water for injection to yield a final concentration of 20 mg/ml as 
described in the package insert.
11.2.4 Stability and Storage
Vials are stored at room temperature. Following reconstitution as directed with sterile water for 
injection, cyclophosphamide is stable for 24 hours at room temperature or 6 days when kept at 2-
8°C.  Once diluted for administration, cyclophosphamide will be provided an expiration date 
based on the standards set by the NIH CC Pharmacy Department.
11.2.5 Administration procedures
The cyclophosphamide used in this regimen will be given as Intravenous infusion over 30
minutes. 
11.3 FLUDARABINE
11.3.1 Source 
Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department 
from commercial sources and is supplied as a white, lyophilized powder. Each vial contains 50 


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mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH.  
Fludarabine is stored at room temperature.
11.3.2 Toxicity 
Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, nausea, vomiting, 
stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin rashes, myalgia, headache, 
agitation, hearing loss, transient episodes of somnolence and fatigue, auto-immune hemolytic 
anemia, auto-immune thrombocytopenia, paresthesias, peripheral neuropathy, renal, and 
pulmonary toxicity (interstitial pneumonitis). Severe fatal CNS toxicity presenting with loss of 
vision and progressive deterioration of mental status were encountered almost exclusively after 
very high doses of fludarabine monophosphate. Such toxicity has only rarely been demonstrated 
at the 25-30 mg/m2/day dosage of fludarabine. Very rarely described complications include 
transfusion-associated graft-versus-host disease, thrombotic thrombocytopenic purpura, and liver 
failure. Tumor lysis syndrome following fludarabine administration has been observed, 
especially in patients with advanced bulky disease. Opportunistic infections (protozoan, viral, 
fungal, and bacterial) have been observed post-fludarabine, especially in heavily pre-treated 
individuals, and in individuals receiving fludarabine combined with other agent.
11.3.3 Formulation and preparation 
FLUDARA IV should be prepared for parenteral use by aseptically adding Sterile Water for 
Injection, USP. When reconstituted with 2 ml of Sterile Water for Injection, each ml of the 
resulting solution will contain 25 mg of Fludarabine Phosphate, 25 mg of mannitol, and sodium 
hydroxide to adjust the pH to 7–8.5. Fludarabine will be diluted in 100 to 125ml of either 5% 
dextrose in water or 0.9% sodium chloride, and infused IV over 30 minutes.
11.3.4 Stability and Storage 
Reconstituted FLUDARA IV should be stored in the refrigerator between 36 and 46 degrees F. 
Because reconstituted FLUDARA IV contains no antimicrobial preservative, care must be taken 
to assure the sterility of the prepared solution. Once diluted for administration, fludarbine will be 
provided an expiration date based on the standards set by the NIH CC Pharmacy 
DepartmentAdministration procedures
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium 
chloride, USP over 15 to 30 minutes.  Dose reduction for renal impairment
For Creatinine Clearance of 30-70 mL/min/1.73m2 there will be a 20% dose reduction. If the 
Creatinine Clearance is less than 30mL/min/1.73m2, Fludarabine will not be administered.  


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


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13.2 APPENDIX B: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL 
All of the following elements will be recorded in the C3D database:
A. Patient Enrollment
x
Date of birth, age, gender, race, ethnicity
x
Height
x
Weight
x
Performance Status
x
Date of original diagnosis
x
Stage at diagnosis
x
Plasmacytoma present: Yes or No
x
Tumor Histology and date of confirmation
x
BCMA expression by tumor type of tissue studied and date of confirmation
x
Date of Informed Consent signature, consent version and date of registration
x
Baseline History/Physical
x
Baseline Symptoms 
x
Prior therapy
x
Prior radiation
x
Prior Bone Marrow Biopsy that includes the percent of plasma cells and the percent 
of BCMA cells
x
Findings of consultations done at screening
B. Study Drug administration and response for each course of therapy given
x
Dates anti-BCMA-CAR-transduced T cells given
x
Dose level, actual dose, schedule and route given
x
Height, weight, and body surface area at start of each course
x
Response assessment for each restaging performed
x
Concomitant medications will not be collected in C3D
C. Laboratory and Diagnostic Test Data
1.
All Clinical laboratory and diagnostic test results done at screening and until day 
30 post infusion with the following exceptions:
Diagnostic tests which are not specified in the protocol, and if the results are not 
needed to document the start or end of an adverse event that requires reporting.
Serologies-CMV, HSV, EBV, toxoplasmosis, adenovirus (patient and donor)
TTV data 
2. All staging studies including serum protein electrophoresis, urine protein 
electrophoresis, serum free light chains, bone marrow biopsy reports, flow 
cytometry reports, serum immunoglobulin reports including beta-2 microglobulin,


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complete blood count and differential reports, serum creatinine reports, TBNK 
results, serum protein, urine albumin, serum calcium (including ionized), ESR and 
CRP results. MRI, X-ray (including skeletal survey), and CT scan results will 
only be reported if they were used for staging.
D. Adverse Events
Please see section 6.1.1 Adverse Event Recording
E. Tumor response and measurements
x
Restaging studies performed at protocol specified time points and as clinically 
indicated.
x
Any physical exam findings will be collected as Adverse Events and labs results.
x
Years 5-15 follow-up is only for survival.
F. Off study
x
Date and reason for off study
x
Date and cause of death
x
Autopsy findings
x
PI decision to end this study


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


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Version Date: September 21, 2017
1.
Any history of syncope or near-syncope within 1 month before Anti BCMA CAR T-cell 
infusion or any time after CAR T-cell infusion.
2. Any blood pressure reading of less than 90 mm Hg systolic blood pressure after anti-
BCMA CAR T-cell infusion.
3. Heart rate greater than 100 beats per minute.
Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood pressure 
and heart rate checked and receive intravenous fluids as appropriate. These patients will also 
receive an ECG.
Hypotension is a common toxicity requiring intensive care unit (ICU) admission.  In general 
patients should be kept well-hydrated.  Maintenance I.V. fluids (normal saline (NS) should be 
started on most patients with high fevers especially if oral intake is poor or the patient has 
tachycardia.  I.V. fluids are not necessary for patients with good oral intake and mild fevers.  
For patients who are not having hypotension or tumor lysis syndrome, a generally even fluid 
balance should be strived for after allowing for insensible fluid losses in patients with high
fevers.  The baseline systolic blood pressure is defined for this protocol as the average of all 
systolic blood pressure readings obtained during the 24 hours prior to the CAR T-cell infusion.  
The first treatment for hypotension is administration of IV NS boluses.  
x
Patients with a systolic blood pressure that is 80% or less of their baseline blood 
pressure and less than 100 mm Hg should receive a 1 L NS bolus. 
x
Patients with a systolic blood pressure less than 85 mm Hg should receive a 1 L NS 
bolus regardless of baseline blood pressure. 
These I.V. fluid management suggestions may need to be modified based on the clinical 
characteristics of individual patients such as pulmonary status, cardiac function, edema and other 
factors.
10. Patients receiving fluid boluses for hypotension should have a stat EKG and troponin, and a 
cardiac echocardiogram within 24 hours.
11. Patients should be transferred to the ICU under these circumstances.  Patients not meeting 
these criteria could also require ICU admission at the discretion of the clinical team caring 
for the patient.
x
Systolic blood pressure 75% or less than the patient’s baseline blood pressure and 
less than 100 mm Hg after administration of a 1L NS bolus.
x
Anytime the systolic blood pressure is less than 85 mm Hg after a 1L NS bolus.
x
Continuous tachycardia with a heart rate higher than 125 beats per minute on 2 
occasions separated by at least 4 hours.
x
Oxygen requirement of more than a 4L standard nasal cannula
x
Greater than grade 2 neurological toxicity


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Version Date: September 21, 2017
12. All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG 
and a cardiac echocardiogram at the time of transfer.
13. Patients with hypotension not responding to IV fluid resuscitation should be started on 
norepinephrine at doses called for by standard ICU guidelines.
14. Patients should have a cardiac echocardiogram and an EKG within 24 hours of starting 
norepinephrine.
15. Patients in the ICU should get twice-daily labs (CBC with differential, acute care panel, 
mineral panel, hepatic panel, uric acid, LDH.  Patients in the ICU should also get a daily 
troponin level). 
16. Anecdotal evidence suggests that the IL-6 receptor blocker tocilizumab can be an effective 
treatment for cytokine-release syndrome toxicities after CAR T-cell infusions. Tocilizumab 
should be administered under the following circumstances if the listed disorders are thought 
to be due to cytokine release from CAR T cells.  Tocilizumab is administered at a dose 8 
mg/kg infused IV over 1 hour (dose should not exceed 800 mg).
x
Left ventricular ejection fraction 40% or less by echocardiogram
x
Creatinine greater than 2.5-fold higher than the most recent level prior to CAR T-
cell infusion
x
Norepinephrine requirement of 3 Pg/min or more for 36 hours since the first 
administration of norepinephrine even if norepinephrine administration was not 
continuous.
x
Systolic blood pressure of 90 mm Hg cannot be maintained with norepinephrine.
x
Oxygen requirement 55% or greater fraction of inspired oxygen (FIO2) for more 
than 2 continuous hours.
x
Dyspnea that is severe enough to potentially require mechanical ventilation.
x
PTT or INR>2x upper limit of normal
x
Clinically-significant bleeding
x
Creatine kinase greater than 5x upper limit of normal for greater than 2 days
17. THERE IS NO EVIDENCE THAT TOCILIZUMAB HELPS NEUROLOGICAL 
TOXICITY, SO IT SHOULD NOT BE ADMINISTERED FOR THIS PURPOSE.
18. If no improvement in hypotension or tachycardia occurs within 6 hours of tocilizumab 
infusion, consider other agents such as methylprednisolone 1 mg/kg every 12 hours or 
etanercept.
19. Avoid meperidine due to seizure risk.
20. In the setting of cytokine-release syndrome, patients with a left ventricular ejection fraction 
of 30% or less and patients who in the opinion of an ICU physician is at significant risk of 


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Version Date: September 21, 2017
needing intubation in the next 4 hours should be given methylprednisolone 100 mg every 6 
hours.
21. Some patients may experience decreases in serum immunoglobulins.  Replacement of 
serum IgG with intravenous IgG is recommended for serum IgG levels below 400 mg/dL.  
22. In general, follow standard vaccination practices including an annual influenza vaccination 
in the absence of data to suggest otherwise.
23. All patients with grade 2 or greater neurological toxicities should get a neurology consult.
24. The following patients should receive dexamethasone 10 mg intravenously every 6 hours 
until the toxicities improve to Grade 1 or resolve or until at least 8 doses of dexamethasone 
have been given.
1. Patients with Grade 3 or 4 neurological toxicities except that 
dexamethasone is not recommended for isolated Grade 3.
2. Any generalized seizure


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Version Date: September 21, 2017
13.4 APPENDIX D: INFUSION INSTRUCTIONS   
Equipment:  
Primary IV tubing (2)
Secondary IV tubing (1)
NS (sodium chloride 0.9%) 250cc bags (2)
IV infusion pump
Gloves
Steps:
Key Points:
1.  On the morning of infusion the primary 
RN will be notified of the approximate 
time TIL cells will be ready (usually 
between 11AM and noon).
2.  Verify the physician orders:
- to administer the cells
- for the date of administration
- for premedication orders 
- protocol number
x
Premeds are acetaminophen 650 mg 
PO and diphenhydramine 12.5 mg 
IV.
3.  Verify that the protocol consent and 
DPA are signed.
4.  Ensure that emergency and monitoring
equipment are available in the patient’s 
room:
- oxygen
- suction
- vital sign monitor with pulse oximeter
and thermometer   


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Version Date: September 21, 2017
5.  Provide patient education covering 
infusion procedure, potential complications 
and associated symptoms to report. 
7.  Measure and record baseline vital signs, 
respiratory and circulatory assessments.
8.  Verify the patency of the patient’s IV 
access.
A central venous access device such as a 
non-valved PICC line should be used.
9.  Hang a primary line of 250cc NS at a 
kvo rate - NEW bag and NEW tubing. 
This MUST be ready and infusing prior to 
the cells being delivered to the unit.
The patient’s primary IV hydration can 
infuse via a separate lumen while the cells 
are infusing, but NO MEDs should be
administered during this time.
Have a second bag of 250cc NS and tubing 
ready as an emergency line.
This will be the dedicated NS line for 
infusing the cells.  Under no circumstances 
are any other substances to be infused into 
the line.  
Cell death occurs quickly – the infusion 
must be initiated immediately. 
Do not infuse medication during the cell 
infusion.  If emergency meds must be 
administered, 
use 
the 
hydration 
or 
emergency NS IV line. 
This will be the emergency IV solution 
and 
can 
be 
used 
for 
medication
administration.
Do not use an inline filter for cells.
10.  The primary RN will be notified 
approximately 10 minutes before the cells 
arrive on the unit.  The cells will be hand 
delivered to the bedside.
It is critical to be at the bedside awaiting 
the arrival of the cells for infusion.  
It is critical to be at the bedside awaiting 
the arrival of the cells for infusion; have 
baseline VS, assessment, and IV lines 
hooked up when the cells arrive.  Cell 
death occurs as soon as the cells are 
removed from the laboratory.  Initiate the 
infusion as quickly as possible.
12.  Prior to spiking the cell bag, two RNs 
will perform the identification procedure.  


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Both RNs must sign the tag on the cell bag.
13.   Infuse the cells by infusion pump over 
20  minutes.
a. Piggyback the cells into the 
dedicated NS line; use the backflush 
technique to prime the line.
b. While the cells are infusing, gently
agitate the bag of cells every few 
minutes to prevent clumping in the 
bag. When the cell bag is empty, 
backflush NS to rinse the bag and 
infuse this at the same rate as the cells; 
rinse bag until NS runs clear.
Note, when very small cell doses are 
given, the cells will arrive at the 
bedside in a syringe.  In these cases, 
the cells should be manually infused
over 20 minutes via the syringe.
14.  Measure and record VS before and 
after the cell infusion, q1h x 4and then q4h 
after completion of the infusion.  
a. 
 
Assess 
and 
document 
the    
patient’s respiratory and circulatory 
status post cell infusion.
15.  Documentation:
a.  After the cells have infused, remove 
the adhesive backed “cell therapy 
product” tag from the cell bag and 
place it on a progress note in the 
patient’s chart. 
b.  Document the cell infusion in  
CRIS using the appropriate screens.  

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
14-C-0168 
PRINCIPAL INVESTIGATOR: 
James N. Kochenderfer, M.D. 
STUDY TITLE:  
A Phase I Clinical Trial of T-Cells Targeting B-Cell Maturation Antigen for Previously 
Treated Multiple Myeloma 
Continuing Review Approved by the IRB on 12/17/18 
Amendment Approved by the IRB on 10/16/17 (H) 
Date posted to web: 01/01/19   
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH
STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical 
or research treatments they would want to receive (such as blood transfusions).  If you have such 
beliefs, please discuss them with your NIH doctors or research team before you agree to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.
Why is this study being done? 
The immune system plays many important roles in the body such as helping the body fight 
infections.  The immune system is also known to affect cancer cells. “T” lymphocytes, or T cells, 
are a type of white blood cell and a major component of the immune system.  T cells have been 
shown to be capable of recognizing and destroying a number of different cancers.  Unfortunately, 
most cancers have developed ways of escaping the monitoring by the immune system for foreign 
or abnormal cells and continue to grow in an uncontrolled manner.  Thus, we are looking at ways 
to manipulate the immune system, in particular the T cell component, so that it will more efficiently 
recognize and kill tumor cells. We have developed an experimental procedure for patients with 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 2 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
multiple myeloma that progressing despite standard therapies.  This procedure uses your own 
blood cells. Specifically, it uses your own T cells which are manipulated in a research lab and then 
given back to you.  The purpose of this study is to see if it is safe to administer these T cells to 
people with multiple myeloma. This T cell therapy is a type of “gene therapy” and is very closely 
monitored by the Food and Drug Administration (FDA) and other regulatory agencies. The risks 
of gene therapy will be described later in this document.   
Why are you being asked to take part in this study? 
You have been diagnosed with multiple myeloma that has not been controlled with standard 
therapies, meaning that the cancer cells are growing despite your prior treatments or, if you did 
achieve a remission, the cancer has recurred after your most recent treatment.  Treatment for 
multiple myeloma that persists after standard therapies is primarily aimed at improving quality and 
perhaps length of life because multiple myeloma is almost never curable.  Unfortunately, multiple 
myeloma usually develops resistance to standard treatment options and ultimately becomes 
completely resistant to conventional therapies.  Thus, there is a need to find new approaches for 
the treatment of multiple myeloma.   
How many people will take part in this study? 
Up to 30 patients will take part in this research study. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  However, there are some extra exams, tests and procedures that you 
will need to have if you take part in this study. If you have had some of them recently, they may 
not need to be repeated.
These tests include: 
x
Physical examination 
x
Routine blood and urine tests 
x
Blood tests for viruses and other disease causing organisms 
x
Echocardiogram and EKG of your heart 
x
Bone marrow biopsy 
x
CT scan (chest, abdomen and pelvis) or PET scan, MRI of your head, and skeletal 
survey 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 3 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
During the study 
First, you will undergo an apheresis procedure that will remove cells from your blood.  Apheresis 
is a procedure for obtaining certain blood cells, such as white blood cells, without removing most 
blood cells.  It is a process persons undergo when giving routine platelet donations.
Next, we will manipulate your cells in a laboratory so that they are capable of recognizing your 
multiple myeloma.  Specifically, we will genetically modify your T cells and grow them in the 
laboratory.  We hope that these T cells will decrease the amount of cancer you have.  However, it 
is possible that these cells will not have this effect.  We will be using a type of virus (retrovirus) 
that encodes a gene for an anti-B-cell maturation antigen (BCMA) receptor in making these anti-
BCMA T cells.  Your multiple myeloma cells express the BCMA protein on their surface.  Multiple 
myeloma is a cancer of plasma cells. Normal plasma cells make antibodies, which play a role in 
fighting infections. Normal plasma cells also express the BCMA protein.  This BCMA protein will 
serve as a target for the anti-BCMA T cells. 
This study will be conducted as a “dose escalation”.  The purpose of dose escalation is to determine 
the safe dose of anti-BCMA T cells.  There are four dose levels of anti-BCMA T cells, but accrual 
has finished on the first 3 dose levels. The first patients enrolled get the smallest dose and the dose 
is increased when a level has been determined to be safe.  You can discuss this with the study 
doctors to find out which dose of anti-BCMA T cells you will be receiving.
After you have had cells removed from your blood, you will receive 2 FDA approved drugs 
(chemotherapy) named cyclophosphamide and fludarabine, over a period of 3 days. The purpose 
of the chemotherapy is to enhance the activity of the anti-BCMA T cells.  This is a standard 
chemotherapy regimen that is often used to treat certain types of leukemia.  The chemotherapy can 
be administered on an outpatient basis, which means hospital admission is not necessary to receive 
this chemotherapy. If you have removed from the protocol BEFORE receiving any protocol 
therapy, you may be eligible for re-enrollment in the study. 
Two days after the chemotherapy ends, you will be admitted to the hospital as an inpatient and 
receive the anti-BCMA T cells.  The anti-BCMA T cells will be given to you as a single 
intravenous (IV) infusion.  You will need to have a “central line”, and IV catheter (or tube) placed 
in a large vein in your arm or chest for this infusion. If you have a catheter or a port-a-cath in place 
already, this could be used to receive the cell infusion.   All patients that participate in this study 
will be required to stay in the hospital for close observation for at least 9 days after the cell infusion, 
and patients must stay within 60 minutes driving distance for 2 weeks after the cell infusion.  This 
is because in our experience with similar treatments we have noticed side-effects including fevers, 
fatigue, low blood pressure, and others that have been most severe between 6 and 9 days after cell 
infusion.
You will be closely watched during the anti-BCMA cell infusion for signs of a reaction.  While 
other types of genetically-modified T cells have been administered to many patients, infusion of 
anti-BCMA T cells is a new approach that is being evaluated in this protocol.  There is always a 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 4 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
chance that we will not be able to genetically-modify your cells or be able to grow the cells in the 
laboratory.  If we are not able to successfully prepare the minimal number of cells that we believe 
are needed to help control the tumor in our first attempt to produce the cells, we will make a second 
attempt to produce the cells if you give us permission to do so even if you have already received 
the chemotherapy part of the protocol at the time.    This second attempt to produce cells will 
probably not be necessary. 
For patients who still have disease after receiving anti-BCMA T cells the first time, repeated 
infusions might be possible.  In order for a repeat infusion to be possible, you must not have 
experienced severe toxicities with their first infusion, and you must meet the original eligibility 
requirements for enrollment on the trial.  Repeat treatments will also include the same 
chemotherapy as the first treatment.   
When you are finished taking the drugs (treatment) 
You will need to come for a clinic visit two weeks after your cell infusion, for blood work and a 
brief visit with one of our doctors. You will also need to return to clinic for evaluation of your 
overall health and your multiple myeloma 1, 2, 3, 4, 6, 9 and 12 months after the cell infusion. 
After 12 months, follow up for patients with ongoing responses, which means the multiple 
myeloma has not progressed, will continue every 6 months for up to 5 years after your T-cell 
infusion.  At the follow-up visits we will evaluate your general health, and we will assess your 
multiple myeloma.  Blood will be drawn at all follow-up visits.  Note that all of these follow-up 
visits are only required for patients with ongoing responses.
If your multiple myeloma progresses, you will be removed from the study to pursue other options.  
As long as your multiple myeloma does not progress, we ask that you do not take any other 
treatments.  We also ask that you do not take any corticosteroid medications such as prednisone or 
dexamethasone.  If you do take other treatments or if you take corticosteroids, we will not be able 
to interpret the results of the anti-BCMA T cells, and you will be removed from the study. You 
will also be followed by your home oncologist who will receive a detailed summary of your case 
and blood tests and other investigations that need to be performed and potential problems that may 
arise.  We encourage early communication of any problems with us so that we can assist in 
deciding the best treatment approach. 
Gene-therapy-specific follow-up  
Because we do not know the long-term side effects of gene therapy, we will collect your blood 
over the next several years, frequently at first and then less frequently.  We can obtain the blood 
needed for these studies at your regular follow-up visits as long as you are on the study.  If you are 
removed from the study, we still need to conduct these gene-therapy follow-up visits according to 
FDA regulations.  If you return to your referring physician after receiving therapy here, we will 
ask you to have your physician send your blood specimens here for this testing, which will decrease 
the inconvenience to you.  This testing will determine if the cells have grown or changed in your 
body.  We will test your blood immediately before you receive the cells, and then at 3, 6, and 12 


MEDICAL RECORD 
CONTINUATION SHEET for either:
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 5 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
months.  If all of the tests are normal and show no change, we will collect blood from you every 
year after that to store in case you develop symptoms later.  According to FDA requirements, we 
need you to return annually to the NIH for a physical examination for five years after your receive 
the cells.  After that time we will be sending you a questionnaire to get information regarding your 
health for the next ten years, for a total follow-up time period of 15 years.  For this reason, we ask 
that you continue to provide us with a current address and telephone number, even after you 
complete this research study.  At the time of your death, no matter the cause, we may request 
permission for an autopsy in order to obtain vital information concerning the safety of this 
experimental therapy approach.  Please discuss this request with your family to inform them of 
your wishes. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this therapy would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for at least 6 months after you finish the last cell infusion.  If the anti-
BCMA T cells are still detected in your blood longer than 6 months after your treatment, your 
doctors will recommend that you not become pregnant until the anti-BCMA T cells are not 
detectable in your blood.  If you think that you or your partner is pregnant, you should tell your 
study doctor or nurse at once. If you are a man, you should not donate sperm during the study 
treatment and for 4 months after you finish the last cell infusion. 
 Effective forms of birth control include:
x
abstinence  
x
intrauterine device (IUD) 
x
hormonal [birth control pills, injections, or implants] 
x
tubal ligation 
x
vasectomy 
Tests for Research 
An important part of this study is testing the effects of this treatment on your tumor and immune 
system. The following blood samples and tests will be done while you participate in this study:  
How will my samples and data be used? 
This study aims to perform laboratory studies (research) to better understand how the immune 
system fights cancer cells and to make more effective cell treatments. We plan to keep some of 


MEDICAL RECORD 
CONTINUATION SHEET for either:
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 6 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
your specimens and data that we collect while you are participating on this study to use in our 
research labs. 
We will use some of the samples we collect (blood, tissue) to perform a number of genetic tests. 
This includes RNA sequencing on your samples.  The human genome is the material in our cells 
that includes thousands of genes.  Genes are the building blocks of our cells that make and maintain 
our body.  A gene provides instructions to individual cells to make proteins through a middle step 
of making RNA. Proteins are the substances that are involved in all of our body’s chemical 
processes.  
The purpose of RNA sequencing is to learn about the expression of different genes in your cancer 
cells and in your CAR T cells.  Our goal is not to look into genetic abnormalities that could be 
inherited by you or passed along to your children, but in the course of studying gene expression, 
there is a slight chance that we could find evidence of an inherited disorder or a genetic disorder 
that could be passed along to your children.  The slight possibility of this happening is covered 
below under “Incidental and Secondary Findings”.
Incidental and Secondary Findings 
Because we might accidentally collect a small amount of normal tissue when we sample your 
tumor, it is possible, but unlikely, that we could identify possible changes in your RNA that are 
not related to this research.  These are known as “incidental medical findings”.  
x
Genetic changes that are related to diseases  
x
Genetic changes that are not known to cause any disease
x
Genetic changes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations.
The analyses that we perform in our laboratory are for research purposes only; they are not nearly 
as sensitive as the tests that are performed in a laboratory that is certified to perform genetic testing. 
Changes that we observe unrelated to our research may or may not be valid.  Therefore, we do not 
plan to inform you of the results of testing on your samples that is performed in our research lab.  
However, in the unlikely event that we discover a finding that is believed to be clinically important 
based on medical standards at the time we first analyze your results, we will contact you if you 
still remain on the study.  This could be many years in the future.  We will ask if you would like 
to meet with a credentialed genetic healthcare provider for genetics education and counseling 
(either in clinic or via phone conference).  The NIH will offer to pay for confirmation of the 
incidental genetic finding.  You will have an additional tube of blood drawn to verify the findings 
we have seen in our lab. If the results are verified, you will be re-contacted and offered a referral 
to a genetic healthcare provider to discuss the results.  


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STUDY NUMBER: 14-C-0168 
CONTINUATION: page 7 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
It is possible that none of the studies described above in this section will be performed. 
Storage and release of samples, genomic data, and health information 
Portions of your samples, genomic data, and health information will be stored for an unlimited 
period of time to be used in future research.   
Research blood samples
Blood will be drawn frequently during your treatment.  Most of the blood draws will be to monitor 
your health during and after the cell infusion.  In addition, some blood samples will be drawn for 
research purposes. Additional blood draws might be necessary to investigate T cell responses and 
serum cytokine levels in cases of clinical events such as rapid regressions of malignancy or 
toxicity.  These samples will be used to study how your immune system is affected by the cell 
therapy. Some of the samples may be sent to investigators outside of the NIH for future research.  
In general, 4 tablespoons will be drawn at each clinic visit or every Monday, Wednesday, and 
Friday during the inpatient stay. On one occasion before the treatment a larger amount of blood (8 
tablespoons) will be drawn. The NIH has set a limit on the maximum amount of blood that can be 
taken for research. This limit is based on your age. For adults, no more than 37 tablespoons can be 
taken over an 8-week period. 
Bone Marrow Biopsies 
Before you begin treatment on this protocol and at the time of the 2-month follow up appointment, 
bone marrow biopsies will be scheduled. Several patients have also required a bone marrow biopsy 
at the 1-month follow-up for clinical purposes.  These biopsies are required for participation on 
the study to evaluate your tumor but also for research tests.  A bone marrow biopsy will also be 
scheduled for the 6-month follow-up visit only for patients with ongoing responses.
Possible Additional Biopsies 
In very rare instances, we may also ask your permission to perform an additional biopsy for 
research or clinical purposes.  These additional biopsies could be bone marrow biopsies or biopsies 
of tumors that could be multiple myeloma.   The tissue from this biopsy will be used for research 
purposes, to determine whether there is evidence of an immune response to the tumor or to 
determine if a newly discovered tumor is actually multiple myeloma.  Any biopsies would only be 
performed with your permission, and if the biopsy is determined to be safe by the Principle 
Investigator of this trial and the additional physician or physicians that would actually perform the 
biopsy. Some of the samples may be used for other or future research conducted by the 
investigational team or other researchers.  This future research might directly study malignancy of 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 8 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
the same type that you have, or it could focus on other areas of research. Your permission for this 
will be obtained at the time of the biopsy. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study? 
Because the BCMA protein is found on normal plasma cells as well as on your cancer, the anti-
BCMA T cells might cause a fleeting or prolonged decrease in the number of normal plasma cells.  
A small number of B cells also express BCMA, so a slight decrease in B-cell counts might occur.  
Because plasma cells make antibodies that are involved in protection against infections, this 
decrease in plasma cell number might lead to a greater risk of infections because of low blood 
antibody levels.  We do not know if a decrease in normal plasma cells will cause problems with 
infections and several steps can be taken to deal with an increased risk of infection or actual 
infections, such as giving antibodies intravenously, which is a standard treatment given to many 
patients with immune deficits. 
The anti-BCMA T cells we will be giving you are exposed to a type of virus (retrovirus) in order 
to insert the anti-BCMA gene that gives the T cells the ability to recognize multiple myeloma.  
Although this retrovirus is not active, there is the rare possibility that it may cause infection.  This 
has never happened to any of the hundreds of patients who received T cells that were modified 
with similar viruses.  The anti-BCMA T cells could also cause you to develop another type of 
cancer in your blood cells, although we think this is very unlikely because it has never happened 
in the hundreds of patients who have received genetically-modified T cells.   
Many patients have received similar cell infusions that are aimed at targets other than BCMA.  In 
the studies that are most similar to this anti-BCMA T-cell study, patients have experienced a 
variety of side-effects.  Most of these patients have developed fever and fatigue that can last for 
up to 2 weeks after cell infusion.  Some patients that have received similar treatments have 
developed low blood pressure.  In a minority of patients developing low blood pressure, a 
temporary decrease in kidney function also occurred.  Several patients developed temporary 
confusion, headaches, or weakness.  One patient developed severe, but temporary, muscle 
twitching.  Three patients developed a temporary inability to speak, which resolved completely 
after a few days.  One patient developed a temporary decrease in heart function.  His heart function 
subsequently returned to normal levels.  One patient developed tumor lysis syndrome, which is a 
release of toxic substances from tumor cells that are being destroyed.  This tumor lysis syndrome 
was successfully treated and caused no long-term problems for the patient.  Patients at risk of 
tumor lysis syndrome on the anti-BCMA T-cell study will receive medication to prevent this 
complication. Chemotherapy is part of this protocol.  The chemotherapy part of this study can 
cause decreased blood count, nausea, and hair loss.  The decreased blood counts due to 
chemotherapy can lead to infections and bleeding. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 9 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Potential risks of anti-BCMA T cells infusion include: 
Likely: 
Less Likely: 
Rare:
x
Fever
x
Chills  
x
Fatigue
x
Low
immunoglobulin
levels
x
Headache 
x
General feeling of being unwell (malaise) 
x
Temporary decreased kidney function 
x
Temporary weakness or difficulty 
speaking 
x
Low blood pressure 
x Tumor lysis syndrome (rapid breakdown 
of tumor that can cause side-effects) 
o
Possible intensive care unit 
admission 
o
Fast heart rate 
o
Possible kidney damage that will 
most likely be temporary 
o
Possible breathing problems that 
might in rare cases require 
mechanical ventilation (breathing 
machine) 
x Cytokine release syndrome (release of 
substances from T cells that can cause 
many side-effects) including 
o
Fever
o
Fast heart rate 
o
Low Blood Pressure 
o
Possible intensive care unit 
admission 
o
Rare cases, death. 
x
Decreased cardiac function
x
Prolonged (a month or more) low blood 
counts including low white blood cells and 
platelets 
x
Muscle pain, 
twitching
x
Death
x
Permanent kidney 
damage
x
Other neurologic 
problems
x
Coma 
x
Temporary liver 
damage
x
Extreme 
weakness of the 
arms and legs
x
Muscle damage
x
Long-term 
debilitation


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 10 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
There are no data available at this time to guide us in how humans might respond to this type of 
cell infusion.  As this is a new experimental therapy, side effects that we do not anticipate that may 
cause your condition to worsen may be encountered.  
You will be treated on this gene transfer protocol with a viral vector that was manufactured at the 
NCI Surgery Branch Vector Production Facility before May 2016.   An internal review of the 
facility that made the vector for this protocol determined that the facility needed to be closed due 
to manufacturing issues.  We know of no additional risks related to the previously produced vector 
for patients who have received cells with vectors made in this facility as the vectors were 
extensively tested by outside experts.  Therefore, the IRB has determined that the potential benefit 
to you outweighs the potential risks.
Potential risks of cyclophosphamide: 
Likely: 
Less Likely: 
Rare:
x
Low blood counts
x Nausea and vomiting  
x Painful and bloody urination
x Sterility
x Water retention
x Hair Loss
x Heart damage  
x Secondary leukemia (a
different type of cancer)
x Skin rash 
x Bleeding 
Potential risks fludarabine: 
Likely: 
Less Likely: 
Rare:
x Low blood counts 
x Long-term reduction of 
lymphocyte counts which 
could increase the risk of 
infection. 
x Infection 
x Damage to the nervous 
system  
x Causing seizures, coma 
and even death
x Inflammation in the lungs
x Kidney damage


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 11 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Gene Therapy Risk of Cancer and Other Diseases:
The risks of gene therapy causing new disease are unknown.  It is possible that the gene therapy 
may cause an immune system, blood, or neurological disorder, or cause a new cancer in your blood 
cells to develop.  It is unknown if you will develop any of these disorders, but you need to be aware 
of this possible risk.  Children in France and England received gene therapy for a particular disease 
of the immune system.   In these children, stem cells were genetically modified, in contrast, during 
the research being offered to you, T cells will be genetically modified.  Most of the children were 
cured, but 5 out of 22 children developed leukemia and one died.  Experts who examined this case 
thought that the gene therapy caused the leukemia in these children.  To monitor you for this risk 
we will be testing your blood as previously described.   
Procedure Risks 
Blood draws: Side effects of drawing blood include pain and bruising in the area where the blood 
was drawn, lightheadedness, or rarely fainting due to transient lowering of blood pressure. If you 
feel dizzy, you should lie down for a few minutes to avoid hurting yourself if you fall. Infection at 
the blood-drawing site could also occur.
Intravenous Catheter: In order to receive this treatment, you will need to have a central venous 
catheter.  This catheter is placed under the skin of the chest wall and enters a major vein in the 
chest.  There are several types of catheters including those which must be removed after each cycle 
of chemotherapy (temporary type) and those which may be kept for the duration of therapy 
(permanent type).  These options will be discussed with you.  The risks associated with placing 
some catheters include pain, bleeding, infection and collapsed lung.  The long term risks of the 
catheter include infection, and clotting of your veins.  If these occur, it may be necessary to remove 
the catheter.  These risks will be explained to you in more detail at the time of insertion. 
Bone marrow aspiration and biopsy: A bone marrow biopsy is performed by inserting a needle 
into a bone of the hip.  In the aspiration part of the procedure, a small amount of liquid bone 
marrow is removed, and in the biopsy part, a tiny solid piece of bone marrow is removed.  You 
may feel a pressure sensation when the needle is being inserted and a pulling sensation and brief 
pain as the marrow is withdrawn. The amount of marrow taken is very small and will not change 
your body's ability to form blood cells. Potential complications of this procedure are local bleeding, 
pain at the site, and infection. Both of these are very rare. Bleeding can be stopped by applying 
local pressure and an infection can be treated with antibiotics. 
Non-physical risks of genetic research 
Psychological or Social Risks Associated with Return of Incidental or Secondary Findings 
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. Although your genomic information is unique to you, you share 
some genomic similarities with your children, parents, brothers, sisters, and other blood relatives. 
Therefore, learning your research results could mean something about your family members and 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 12 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
their risk for certain illnesses. Before joining the study, it may be beneficial to talk with your 
family members about whether and how they want you to share your results with them.  
Privacy Risks Associated with Return of Incidental or Secondary Findings 
Your privacy is very important to us and we will use many safety measures to protect your 
privacy. However, in spite of all of the safety measures that we will use, we cannot guarantee 
that your identity will never become known. While neither the public nor the controlled-access 
databases developed for this project will have information such as your name, address, telephone 
number, or social security number, it may be possible to identify you based on the information in 
these databases and other public information (including information you tell people or post about 
yourself).  The risk of this happening is currently very low.
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. Consequently, it may be 
possible that genetic information from them could be used to help identify you.  Similarly, it may 
be possible that genetic information from you could be used to help identify them.  Patterns of 
genetic variation also can be used by law enforcement agencies to identify a person or his/her 
blood relatives.
It is possible also that someone could get unauthorized access or break into the system that stores 
information about you.  Every precaution will be taken to minimize this risk.  There also may be 
other privacy risks that we have not foreseen. 
Certificate of Confidentiality 
We have obtained a Certificate of Confidentiality from the Department of Health and Human 
Services.  The Certificate is designed to prevent us from being forced to disclose identifying 
information for use in any federal, state, or local civil, criminal, administrative, legislative, or other 
court proceeding, even if faced with a court subpoena.  You should understand, however, that a 
Certificate of Confidentiality does not prevent you or a member of your family from voluntarily 
releasing information about yourself or your involvement in this research.  We may not withhold 
information if you give your insurer or employer or a law enforcement agency permission to 
receive information about your participation in this project.  This means that you and your family 
must also actively protect your own privacy. 
The Certificate does not prevent us from taking steps, including reporting to authorities, to prevent 
serious harm to yourself or others. We will also share information as described in item 1 on page 
16.
Potential Benefits of Participation 
It is unknown at this time whether anti-BCMA T cell infusions will improve survival or have any 
benefit for patients with multiple myeloma. If accepted by your body, the cell infusion may 
decrease the amount of your cancer.  Your participation in this experimental treatment may also 
help us advance the understanding and treatment of multiple myeloma.


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 13 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
x
Getting care for your cancer without being in a study such as other forms of chemotherapy, 
radiation,  stem cell or bone marrow transplantation, or immune therapies.
x
Taking part in another study 
x
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
You should discuss with your referring doctor and the NIH doctors whether any of these treatments 
might represent a reasonable treatment option for your disease. 
Research Subject’s Rights 
What are the costs of taking part in this study?
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
x
You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, NIH if 
the study related treatment is not available at the NIH.
x
There are limited funds available to cover some travel expenses for travel to appointments 
required by this clinical trial. 
x
There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs if they are not covered 
by your insurance company. 
x
Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH. 
x
Once you have completed taking part in the study, medical care will no longer be provided by 
the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include: 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 14 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
x
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
x
National Cancer Institute Institutional Review Board
x
The study Sponsor or his agent(s) 
Controlled access databases: 
Your individual genomic data and health information will be put in a controlled-access database.  
This means that only researchers who apply for and get permission to use the information for a 
specific research project will be able to access the information.  Your genomic data and health 
information will not be labeled with your name or other information that could be used to identify 
you.  Researchers approved to access information in the database have agreed not to attempt to 
identify you. 
Stopping Therapy
Your doctor may decide to stop your therapy for the following reasons: 
x
if he/she believes that it is in your best interest 
x
if your disease progresses or comes back after a remission 
x
if you have side effects from the treatment that your doctor thinks are too severe 
x
if new information shows that another treatment would be better for you.  
x
if the study doctor decides to end the study 
x
if you become pregnant 
In this case, you will be informed of the reason therapy is being stopped. 
You may stop your participation in the study at any time. However, if you decide to stop taking 
part in the study, we would like you to talk to the study doctor and your regular doctor first 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Center for Cancer 
Research, NCI or designated representatives. If you withdraw your consent and leave the trial, any 
samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request.  However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 15 of 17 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Conflict of Interest  
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide . You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.
Use of Specimens and Data for Future Research
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. .We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that it may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 16 of 17 pages 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided by 
the National Institutes of Health, the Clinical Center, or the Federal Government.  However, you 
have the right to pursue legal remedy if you believe that your injury justifies such action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Jim Kochenderfer, M.D., Building 10, Room 12C121, Telephone:  240-760-6062. 
You may also call the Clinical Center Patient Representative at 301-496-2626. If you have any 
questions about the use of your specimens or data for future research studies, you may also contact 
the Office of the Clinical Director, Telephone:  240-760-6070. 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 14-C-0168 
CONTINUATION: page 17 of 17 pages 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby 
consent to take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ 
Guardian 
Date
Print Name 
Print Name 
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM DECEMBER 17, 2018 THROUGH JANUARY 7, 2020. 
Signature of Investigator 
Date 
Signature of Witness 
Date 
Print Name 
Print Name