Protocol H125001: An Open-Label Phase 1/2 Study of JCARH125, BCMA-targeted Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Juno Therapeutics, a Subsidiary of Celgene

Official Title of Study: 
Protocol H125001: An Open-Label Phase 1/2 Study of JCARH125, BCMA-targeted Chimeric Antigen 
Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory Multiple Myeloma 
 
 
NCT Number: NCT03430011 
Document Date (Date in which document was last revised): February 10, 2020 

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
1
H125001 Amendment 6 Final: 10 Feb 2020
TITLE PAGE
PROTOCOL H125001: AN OPEN-LABEL PHASE 1/2 
STUDY OF JCARH125, BCMA-TARGETED CHIMERIC 
ANTIGEN RECEPTOR (CAR) T CELLS, IN SUBJECTS 
WITH RELAPSED AND/OR REFRACTORY MULTIPLE 
MYELOMA
Protocol Number:
H125001
Study ID:
EVOLVE
NCT Number:
NCT03430011
Date:
10 Feb 2020
Regulatory Sponsor:
Juno Therapeutics, Inc., a wholly-owned subsidiary of Celgene Corporation
400 Dexter Ave North, Suite 1200
Seattle, WA 98109
Phone:
Medical Director:
Sr. Medical Director
Juno Therapeutics, Inc.
Mobile: 
E-mail: 
Statistician:
Director, Biostatistics
Juno Therapeutics, Inc.
Phone: 
E-mail: 
Study Manager:
Sr. Clinical Trial Manager
Juno Therapeutics, Inc.
Mobile:
 
E-mail:
Safety Reporting:
CONFIDENTIAL
The information herein is proprietary and confidential and is not to be disclosed without written consent of Juno 
Therapeutics, Inc., except to the extent that disclosure would be required by law and for the purpose of 
conducting a clinical study. The contents of this protocol are only to be disclosed to the Institutional Review 
Board and relevant clinical study personnel.
This trial will be conducted in compliance with the protocol, International Council for Harmonisation Good 
Clinical Practice (ICH GCP), and applicable state, local, and federal regulatory requirements.
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
2
H125001 Amendment 6 Final: 10 Feb 2020
SIGNATURE PAGE
Protocol H125001: An Open-Label Phase 1/2 Study of JCARH125, BCMA-targeted 
Chimeric Antigen Receptor (CAR) T Cells, in Subjects with Relapsed and/or Refractory 
Multiple Myeloma
We, the undersigned, have read this protocol and agree that it contains all necessary information required to 
conduct the study.
Sponsor Signatures:
Date:
__________________________
_________________________
Sr. Medical Director
_________________________
__________________________
Director, Biostatistics
_________________________
__________________________
Sr. Clinical Trial Manager
I have read this protocol and agree to conduct the study as outlined herein, in accordance with the Declaration of 
Helsinki, the International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice, US FDA 
regulations, Institutional Review Board regulations, and all national, state, and local laws and/or requirements of 
the pertinent regulatory authorities.
_____________________________
Date
Investigator Printed Name
_____________________________
__________________________
Investigator Signature
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
3
H125001 Amendment 6 Final: 10 Feb 2020
PROTOCOL SYNOPSIS
Protocol Number: H125001
Product Name: JCARH125
Protocol Title:
Protocol H125001: An Open-Label Phase 1/2 Study of JCARH125, BCMA-targeted Chimeric Antigen Receptor 
(CAR) T Cells, in Subjects with Relapsed and/or Refractory Multiple Myeloma
Sponsor: Juno Therapeutics, Inc., a wholly owned
subsidiary of Celgene Corporation
Study Phase: Phase 1/2
Study Rationale:
Substantial progress in the treatment of multiple myeloma (MM) has been made over the past 2 decades with the 
development of proteasome inhibitors (eg, bortezomib and carfilzomib), immunomodulator drugs (IMiDs) 
(eg, lenalidomide, pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab). However, MM
remains incurable and nearly all patients eventually relapse with disease that becomes increasingly resistant to 
treatment with each additional line of therapy. High-dose therapy followed by autologous stem cell transplant 
performed either at the time of initial diagnosis or at relapse, is considered the standard of care for younger 
patients (less than 70 years of age) with newly diagnosed MM. Although high-dose therapy with ASCT is not 
curative, event-free survival and overall survival are prolonged compared to treatment with standard-dose 
myeloma treatments alone.
Autologous T cells transduced with a recombinant chimeric antigen receptor (CAR) are engineered to bind to a 
tumor-specific antigen. BCMA is an ideal target for CAR T cell therapy since its expression is highly restricted to 
MM cells and plasma cells, and therefore, the toxic effect of anti-BCMA CAR T cells on normal cells is minimal. 
Adoptive cellular therapy using CAR T cells targeting specifically expressed antigen on tumor cells has become 
one of the exciting breakthroughs in MM immunotherapy.
Study Objectives:
Phase 1 Dose-Escalation
Primary:

To evaluate the safety and tolerability of JCARH125 in subjects with relapsed/refractory (R/R) MM

To determine the recommended Phase 2 dose(s) (RP2D) of JCARH125 in subjects with R/R MM
Secondary:

To evaluate the expansion and persistence (ie, pharmacokinetics [PK]) of JCARH125 in peripheral 
blood 

To assess preliminary antitumor activity of JCARH125, as determined by the overall response rate 
(ORR) and complete response (CR)/stringent complete response (sCR) rate according to the 
International Myeloma Working Group (IMWG) Uniform Response Criteria
Phase 1 Anakinra Cohort - Prophylactic Treatment with Anakinra 
Primary

To evaluate the safety and tolerability of JCARH125 at the dose level 3 and/or dose level 3a and to 
explore the incidence and onset of Grade ≥2 cytokine release syndrome (CRS) in subjects with R/R 
MM who receive prophylactic treatment with anakinra
Secondary

To evaluate the expansion and persistence (ie, PK) of JCARH125 in subjects who receive prophylactic 
treatment with anakinra in peripheral blood 
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
4
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125

To assess preliminary antitumor activity of JCARH125 in subjects who receive prophylactic treatment 
with anakinra, as determined by the ORR and CR/sCR rate according to the IMWG Uniform Response 
Criteria 
Phase 2 Expansion
Primary:

To evaluate the antitumor activity of JCARH125, as determined by the ORR according to the IMWG 
criteria, at the RP2D(s) in subjects with R/R MM
Secondary:

To evaluate the CR/sCR rate assessed according to the IMWG criteria

To assess the duration of response (DOR) following treatment with JCARH125

To evaluate the safety and tolerability of JCARH125 in subjects with R/R MM

To evaluate overall survival (OS) and progression -free survival (PFS)

To assess time to response to JCARH125

To evaluate expansion and persistence (ie, PK) of JCARH125 in peripheral blood 

To assess health -related quality of life (HRQoL) and health economics and outcomes research (HEOR)
Phase 2a Prior BCMA-directed Anti-myeloma Therapy Cohort
Primary:

To evaluate the antitumor activity of JCARH125 at the RP2D(s) in subjects with R/R MM who have 
relapsed following prior treatment with a BCMA-directed anti-myeloma therapy, including T-cell 
engager (TCE), antibody-drug conjugate (ADC), or CAR T-cell therapy
Secondary:

To evaluate the CR/sCR rate assessed according to IMWG criteria 

To assess the duration of response (DOR) following treatment with JCARH125

To evaluate the safety and tolerability of JCARH125 in subjects with R/R MM

To evaluate overall survival (OS) and progression free survival (PFS)

To assess time to response to JCARH125

To evaluate expansion and persistence (ie, PK) of JCARH125 in peripheral blood 
Additional Exploratory Objectives 
 
 
Additional Exploratory Objectives in Phase 1 Anakinra Only

Study Design:
This is an open-label, multicenter, Phase 1/2 study to determine the safety, PK, and antitumor activity of 
JCARH125 in adult subjects with R/R MM. The Phase 1 dose-escalation portion of the study will evaluate the 
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
5
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
safety and tolerability of increasing dose levels of JCARH125 to identify the RP2D. The Phase 2 expansion 
portion of the study will further evaluate the safety, PK, and antitumor activity of JCARH125 at the RP2D(s).
An additional phase 2 cohort will evaluate the safety and tolerability of JCARH125 at the RP2D(s) in subjects 
with R/R MM who have relapsed following prior treatment with a BCMA-directed anti-myeloma therapy 
including TCE, ADC, or CAR T-cell therapy.
The Phase 1 anakinra cohort will evaluate the safety and tolerability of JCARH125 at the dose level 3 and/or dose 
level 3a following prophylactic use of anakinra.
Phase 1 Dose Escalation:
The JCARH125 dose levels planned to be evaluated in Phase 1 are provided in the table below. Dose-
escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm with a target 
dose-limiting toxicity (DLT) rate of 30% and an equivalence interval of 25% to 35%. Dose-escalation may be 
halted once a dose level with acceptable safety and satisfactory antitumor activity has been selected for
evaluation in Phase 2. A maximum tolerated dose (MTD) may not be defined in this study.
Dose Level
JCARH125 Dose (CD3+CAR+ cells)
-1
25 × 106
1
50 × 106
2
150 × 106
2aa
300 × 106
3
450 × 106
3ab
600 × 106
4
800 × 106
a Introduced with Protocol Amendment 4 (10 September 2018) as a part of safety measures. 
b Introduced with Protocol Amendment 5 (31 May 2019) as a possible intermediate dose level. 
Note: Additional intermediate dose levels may be evaluated based on ongoing safety and efficacy data.
For a dose level to be considered safe, at least 3 DLT-evaluable subjects must have completed the 21-day DLT 
evaluation period and the level estimated to be safe per the mTPI-2 algorithm. The decision to open a dose level 
for enrollment will be made by the Sponsor based on results from the mTPI-2 algorithm after consultations with 
the Principal Investigators at each site as appropriate.
The first 3 subjects treated in the study will be treated with JCARH125 at Dose Level 1 (50×106 CD3+CAR+ 
cells). Within the first dose cohort, treatment of the first 3 subjects will be staggered by a minimum of 14 days. 
At each higher dose level, treatment of the first 3 subjects within the dose cohort will be staggered by a minimum 
of 7 days. Staggering of subjects in a dose cohort may be lifted after a minimum of 3 subjects have been treated 
in that dose cohort, have completed the 21-day DLT evaluation period, and the dose level is determined to be safe 
according to the mTPI-2 algorithm.
A maximum of 3 subjects will initially be treated at a dose level. If none of these 3 subjects experience a DLT, 
the dose may be escalated to the next higher dose level. If 1 of 3 subjects experiences a DLT at a dose level, then 
additional subjects will be enrolled at this dose level and dose-escalation/de-escalation decisions will be made per 
the mTPI-2 algorithm after the DLT data for these additional subjects are available. If 2 of 3 subjects experience 
a DLT at a dose level, then the dose will be de-escalated to the next lower dose level. If all 3 subjects experience 
a DLT at a dose level, the dose will be de-escalated and this dose and all higher doses will be removed from 
further evaluation in the trial.
To be considered evaluable for DLT, a subject must have received the conforming JCARH125 cell product at the 
assigned dose of JCARH125 and completed the 21-day evaluation period or experienced a DLT prior to 
completing the 21-day evaluation. Subjects who are not evaluable for DLT will be replaced.
Based on the cumulative safety and antitumor activity data from subjects treated in Phase 1, one or more dose 
levels will be selected for further evaluation in the Phase 2 portion of the trial (the RP2D); this dose level(s) will 
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
6
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
be selected by the Sponsor in collaboration with the Investigators. It is not necessary for the MTD to be 
determined per the mTPI algorithm in order to select the dose level(s) to be evaluated in Phase 2.
Phase 1 Anakinra Cohort - Prophylactic Treatment with Anakinra
Up to 14 subjects will be treated at the dose level 3 and/or dose level 3a with the addition of the prophylactic 
treatment with anakinra. The purpose is to investigate the potential benefit of prophylactic treatment with
anakinra on the onset, incidence and severity of CRS.
All subjects who receive conforming JCARH125 product and receive at least 1 dose of prophylactic anakinra will 
be evaluated for safety and tolerability of JCARH125 following prophylactic treatment with anakinra. Subjects 
will receive 2 doses of 100 mg anakinra administered subcutaneously (SC) prior to JCARH125 infusion, one the 
night before and one 3 hours before JCARH125 infusion. Subjects will continue with anakinra for 5 consecutive 
days at a dose of 100 mg SC. In the case of CRS onset, anakinra 100 mg SC should be administered twice daily 
until CRS resolution. The anakinra dose should be administered at approximately the same time every day. In the 
case of worsening of CRS and/or in case of onset of neurological toxicity, the toxicity guidelines from the 
protocol should be followed. 
If prophylactic treatment with anakinra reduces the incidence, severity or delays the time to onset of CRS, 
prophylactic treatment with anakinra may be implemented in the Phase 2 portion of the trial.
Phase 2 Expansion
In the Phase 2 portion of the study, subjects will be treated at the RP2D(s) identified in Phase 1. The primary 
analysis population for evaluation of JCARH125 efficacy (ie, the efficacy analysis set) will include all subjects 
treated at the RP2D(s) in Phase 2 expansion, subjects treated at the RP2D(s) in Phase 1 dose escalation, and 
subjects treated at the RP2D(s) in the Phase 1 anakinra cohort who have measurable disease as determined by the 
central laboratory at the last disease assessment prior to JCARH125 infusion and receive conforming product.
The efficacy analysis set will include at least 75 subjects who are evaluable for both safety and efficacy.
Phase 2a – Prior BCMA-directed Anti-Myeloma Therapy Cohort
In the Phase 2a portion of the study, 3 separate cohorts of subjects with exposure to prior BCMA-directed anti-
myeloma therapy cohort including TCE, ADC or CAR T-cell therapies will be treated at the RP2D(s) identified 
in Phase 1. All subjects who receive conforming JCARH125 product will be evaluated for safety and tolerability 
of JCARH125. 
Cohort 1: 14 subjects who have been exposed to prior BCMA-directed CAR T-cell therapy
Cohort 2: 14 subjects who have been exposed to prior BCMA-directed TCE
Cohort 3: 14 subjects who have been exposed to prior BCMA-directed ADC therapy
Study Procedures and Evaluations for Subjects in Phase 1 dose escalation, Phase 1 anakinra cohort, Phase 
2, and Phase 2a prior BCMA-directed anti-myeloma therapy cohort
A tumor biopsy sample (bone marrow biopsy, bone marrow aspirate and plasmacytoma biopsy if applicable) will 
be obtained from all subjects during initial screening. Subjects who meet all eligibility criteria will be enrolled 
and will undergo leukapheresis to enable JCARH125 product generation. Subjects may receive bridging therapy, 
excluding experimental and biological agents (daratumumab, eg), after leukapheresis and before lymphodepleting 
chemotherapy if deemed necessary by the treating physician for disease control during JCARH125 
manufacturing. Bridging therapies must be discontinued at least 14 days prior to initiation of lymphodepletion 
and subjects must continue to meet eligibility criteria pertaining to measurable disease, adequate organ function, 
active infections, pregnancy, and washout of prior therapy before initiation of lymphodepleting chemotherapy. If 
JCARH125 cannot be made from the first leukapheresis product, additional leukapheresis may be allowed after 
consultation with the Sponsor.
Following successful JCARH125 product generation, subjects will enter the treatment phase and will receive one 
cycle of JCARH125 treatment. A treatment cycle will include lymphodepleting chemotherapy with fludarabine 
(30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) for 3 days followed by a single dose of JCARH125 
administered intravenously (IV) on Day 1. JCARH125 will be administered 2 to 7 days after completion of 
lymphodepleting chemotherapy unless clinical or logistical circumstances require modification of this timing.
Dose adjustments or changes to the lymphodepleting chemotherapy regimen may be indicated due to the 
subject’s creatinine clearance.
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
7
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
Follow-Up Period
Subjects will be followed under this protocol for 2 years after JCARH125 administration for safety, disease 
status, additional anticancer therapies, and survival. If disease progression occurs during this 2-year timeframe, 
subjects should still be followed per the Schedule of Evaluations outlined in Appendix A. The number of 
JCARH125 cells in peripheral blood and bone marrow will be assessed by quantitative polymerase chain reaction 
(qPCR) from the time of JCARH125 administration until the end of the study. Disease assessments will be 
performed approximately every 4 weeks following JCARH125 administration for the first 6 months, and then 
every 3 months until 2 years after JCARH125 administration or until disease progression, whichever comes first.
Bone marrow biopsy, bone marrow aspirate and plasmacytoma biopsy if applicable will be performed for all 
subjects for disease response evaluations, PK, and/or research assessments at Day 15, Day 29, Month 3, Month 6, 
Month 12, Month 18, Month 24, for confirmation of CR, and in the event of disease progression. Response to 
JCARH125 will be assessed according to IMWG criteria. All subjects will have their response to JCARH125 
assessed by the Investigator. In addition, all subjects treated at the RP2D, will have their responses assessed by
the Investigator and by an Independent Review Committee (IRC). Evaluation of the primary efficacy endpoint of 
ORR in Phase 2 will be based on IRC assessment.
All subjects who receive JCARH125 will be asked to enroll in a separate Celgene-sponsored long-term follow-up 
(LTFU) study at the time of completion or discontinuation from this study. Subjects who enroll in the LTFU 
protocol will sign a separate informed consent form and may be followed per current FDA guidelines for up to 
15 years after JCARH125 administration for long-term JCAR-related safety and efficacy.
Oversight Committees:
Data Safety Monitoring Board
An independent Data Safety Monitoring Board (DSMB) will review cumulative study data approximately 
quarterly over the course of the study to evaluate safety, protocol conduct, and scientific validity and integrity of 
the trial. In addition, in the event of a toxicity that meets the protocol-defined criteria for pausing the study, the 
DSMB will be convened to evaluate the comprehensive safety data and to make a recommendation for study 
continuation, modification, or termination. The DSMB has been assembled under a dedicated charter specifically 
developed for safety oversight of Juno-sponsored studies.
Independent Review Committee
An IRC will determine response and progression status for all subjects treated in the Phase 2 expansion portion of 
the study, as well as subjects in the Phase 1 dose escalation portion of the study, the Phase 1 anakinra cohort, and 
the Phase 2a prior BCMA-directed anti-myeloma therapy cohort who were treated with JCARH125 at the 
RP2D(s), for the purpose of the primary efficacy analysis.
Study Population:
The target study population consists of subjects with R/R MM who meet all of the following inclusion criteria 
and none of the exclusion criteria:
Inclusion Criteria:
Subjects must meet all of the following criteria to be enrolled in this study:
1.
Age ≥18 years at the time of consent.
2.
Signed informed consent form.
3.
Diagnosis of multiple myeloma (MM) with relapsed and/or refractory disease. Subjects must have 
received at least 3 prior anti-myeloma treatment regimens (note: induction with or without bone marrow 
transplant and with or without maintenance therapy is considered one regimen). Subjects must be 
refractory to the last anti-myeloma treatment regimen prior to entering the study. Refractory myeloma is 
defined as non-responsiveness (best response of ≤ stable disease) to last anti-myeloma treatment 
regimen or documented progressive disease during or within 60 days (measured from the last dose) of 
completing treatment with the last anti-myeloma treatment regimen before study entry. Subjects must 
have previously received all of the following therapies:
a.
Autologous stem cell transplant.
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
8
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
b.
A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide, 
pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), either alone or 
in combination. Subjects must have undergone at least 2 consecutive cycles of treatment for each 
regimen unless progressive disease was the best response to the regimen.
c.
Anti-CD38 (eg, daratumumab) as part of a combination regimen or as a monotherapy.
Subjects who have received prior allogeneic stem cell transplant or donor lymphocyte infusion (DLI) at 
least 100 days before enrollment with no signs of acute or chronic graft-versus-host disease (GVHD) will 
be considered eligible.
Subjects who were not candidates to receive one or more of the above treatments (ie, contraindicated) 
are eligible; the reason for not receiving treatment must be clearly documented in the case report form.
4.
Subjects must have measurable disease as determined by the central laboratory defined as meeting at 
least one of the criteria below:
a.
Serum M-protein ≥1 g/dL.
b.
Urine M-protein ≥200 mg/24 hour.
c.
Involved serum free light chain (sFLC) level ≥10 mg/dL with abnormal κ/λ ratio (light chain 
disease is acceptable only for subjects without measurable disease in the serum or urine).
5.
Subject must be willing to provide a fresh bone marrow biopsy sample during Screening (and at 
Pre-treatment Screening, if required).
6.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
7.
Adequate organ function, defined as:
a.
Adequate renal function, defined as calculated creatinine clearance (Cockcroft-Gault) ≥60 mL/min
without the assistance of hydration.  
i.
Subjects must not have received IV rehydration within 3 days of renal function assessment.
b.
Adequate bone marrow function, defined as absolute neutrophil count (ANC) ≥1000 cells/mm3, 
hemoglobin (Hb) ≥8 g/dL, and platelet count ≥50,000/mm3. Transfusions and growth factors must 
not be used to meet these requirements at initial Screening.
i.
Subjects must not have received growth factors within 14 days of initial Screening.
ii.
Subjects must not have received red blood cell (RBC) transfusions within 21 days of initial 
Screening.
iii.
Subjects must not have received platelet transfusions within 7 days of initial Screening.
c.
Adequate hepatic function, defined as:
i.
Alanine aminotransferase (ALT) ≤3×ULN.
ii.
Aspartate aminotransferase (AST) ≤3×ULN.
iii.
Total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with documented Gilbert’s syndrome).
iv.
International ratio (INR) or partial thromboplastin time (PTT) ≤1.5×ULN.
d.
Adequate pulmonary function, defined as saturated oxygen (SaO2) ≥92% on room air.
e.
Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥40% as assessed 
by echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 
8 weeks prior to initial Screening.
8.
Subject either currently has central vascular access or is a candidate to receive central vascular access or 
peripheral vascular access for leukapheresis procedure.
9.
Subjects must be at least 100 days since autologous stem cell transplant (ie, Day 0, receipt of 
hematopoietic stem cells) at the time of initial Screening, if performed.
10. Recovery to ≤Grade 1 or baseline of any non-hematological toxicities due to previous therapy, except 
alopecia and peripheral neuropathy.
11. Females of reproductive potential (defined as all females physiologically capable of becoming pregnant) 
must agree to use one highly effective method of contraception from screening until at least 12 months 
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
9
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
following lymphodepleting chemotherapy. There are insufficient exposure data to provide any 
recommendation concerning the duration of contraception following treatment with JCARH125. Any 
decision regarding contraception after JCARH125 infusion should be discussed with the treating 
physician.
12. Females of reproductive potential must have 2 negative pregnancy tests as verified by the Investigator 
(one negative serum beta-human chorionic gonadotropin [ß-hCG] pregnancy test result at screening, and 
within 7 days prior to the first dose of lymphodepleting chemotherapy). This applies even if the subject 
practices true abstinence* from heterosexual contact.
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In 
contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.
13. Males who have partners of childbearing potential must agree to use an effective barrier contraceptive 
method from initiation of lymphodepleting chemotherapy and for at least 12 months after and should not 
donate semen or sperm during the entire study period and for at least 12 months following 
lymphodepleting chemotherapy.
14. Phase 2a prior BCMA-directed anti-myeloma therapy cohort only – Subjects with R/R MM who have 
been previously treated with prior BCMA-directed anti-myeloma therapy, achieved at least a partial 
response (PR) per IMWG response criteria and subsequently progressed on the following treatment:
a.
Subjects who have received prior BCMA-directed CAR T-cell therapy. The last CAR T-cell therapy 
must have been received at least 6 months prior to JCARH125 study enrollment (screening).
b.
Subjects who have received prior BCMA-directed TCE therapy.
c.
Subjects who have received prior BCMA-directed ADC therapy.
Subjects with prior BCMA-directed anti-myeloma therapy are not required to have received at least 3 
prior anti-myeloma treatment regimens and do not have to be refractory to the last anti-myeloma 
regimen to be eligible for this trial.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from participation in this study:
1.
Subjects with known active or history of central nervous system (CNS) involvement by malignancy.
2.
Subjects with solitary plasmacytoma; active or history of plasma cell leukemia (PCL); Waldenstrom's 
macroglobulinemia; POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal 
plasmaproliferative disorder, Skin changes); or symptomatic amyloidosis.
3.
Subjects who are considered eligible to receive and have refused an autologous stem cell transplant.
4.
History of another primary malignancy that has not been in remission for at least 3 years. The following 
are exempt from the 3-year limit: non-melanoma skin cancer, curatively treated localized prostate 
cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in 
situ breast cancer that has been completely resected.
5.
Require systemic immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate, 
mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-interleukin 6 [IL-6]
or anti-interleukin 6 receptor [IL-6R]).
6.
Prior CAR T-cell or other genetically-modified T-cell therapy (not applicable to Phase 2a cohorts).
7.
Prior treatment with a BCMA-directed therapy (not applicable to Phase 2a cohorts).
8.
Human immunodeficiency virus (HIV) infection positive subjects
9.
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as indicated by positive serology or 
nucleic acid testing. Subjects who are solely hepatitis B surface antibody (HBsAb)-positive are eligible.
10. Untreated or active infection at the time of initial Screening, at the time of leukapheresis, within 
72 hours before lymphodepletion, or 5 days before JCARH125 infusion. Subjects with ongoing use of 
prophylactic antibiotics, antifungals, or antivirals are eligible if no evidence of active infection.
11. History of any one of the following cardiovascular conditions within the 6 months prior to initial 
Screening: Class III or IV heart failure as defined by the New York Heart Association (NYHA), 
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
10
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmias, any ventricular 
arrhythmias, or other clinically significant cardiac disease.
12. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, aphasia, stroke, 
severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or 
psychosis.
13. History of ≥ Grade 2 hemorrhage within 30 days or requirement for ongoing treatment with chronic, 
therapeutic doses of anticoagulants (eg, warfarin, low molecular weight heparin, or Factor Xa 
inhibitors).
14. Pregnant or nursing (lactating) women.
15. Treatment with the following therapies within the specified time period:
a.
Monoclonal antibodies (anti-CD38 and anti-SLAMF7 antibody) within 4 weeks prior to 
leukapheresis.
b.
Any other systemic therapy approved for the treatment of MM within 14 days before leukapheresis
or within 14 days before lymphodepleting chemotherapy.
c.
Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small molecules) before 
leukapheresis.
d.
Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 
14 days before leukapheresis. Physiologic replacement, topical, and inhaled steroids are permitted.
e.
Radiation to a single lesion within 14 days before leukapheresis.
f.
Radiation that includes a large bone marrow field such as the pelvis or sternum within 6 weeks 
before leukapheresis.
16. Plasmapheresis within 14 days before leukapheresis.
17. Any medical, psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol, as judged by the Investigator; medical or psychiatric conditions or 
laboratory abnormalities that could jeopardize subject safety, as judged by the Investigator or Sponsor 
Medical Monitor; or unwillingness or inability to follow the procedures required in the protocol.
18. Use of any live vaccines against infectious diseases within 8 weeks before JCARH125 infusion.
19. Subjects with known hypersensitivity to Escherichia coli (E. coli)-derived proteins (only applicable for 
subjects getting prophylactic anakinra).
20. History of severe immediate hypersensitivity reaction to any of the protocol-mandated and 
recommended agents used in this study.
Investigational Product, Dose, and Mode of Administration:
The JCARH125 investigational drug product is composed of autologous CD4+ and CD8+ T cells that express a 
BCMA-specific CAR. The drug product is provided as a combined CD8+ and CD4+ frozen T-cell suspension in 
a medium containing dimethyl sulfoxide (DMSO) for IV administration.
JCARH125 will be administered as a single IV dose on Day 1 (between 2 to 7 days after completion of 
lymphodepleting chemotherapy).
Rationale for Starting Dose of JCARH125 in Phase 1 dose escalation:
The starting dose level for JCARH125 in Phase 1 is 50×106 CD3+ CAR+ T cells. The starting dose for this 
first-in-human Phase 1 trial with the JCARH125 investigational agent was selected based upon the clinical 
experience of other investigational CAR T cell agents in hematological malignancies of the B-cell lineage, 
including MM, including CAR T cells targeting BCMA. Subjects with chronic lymphocytic leukemia (CLL), 
non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), and MM have been treated with doses 
ranging from 107 to 109 CAR+ T cells. As of May 2017, in a clinical trial testing BCMA-specific CAR T cells in 
a population similar to those to be enrolled in this trial, subjects had been treated with up to 800×106 CAR+ 
T cells with no DLTs, and there had been no reports of Grade 3 or 4 neurotoxicity.
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
11
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
Study Duration:
The enrollment period is expected to take approximately 36 months and the follow-up period for each subject is 
approximately 24 months after JCARH125 administration. Thus, the total duration of the study is expected to be 
approximately 60 months.
Duration of Subject Participation:
The expected duration of participation for each subject in this treatment protocol will be approximately 
26 months.
Study Sites:
It is planned to enroll subjects at approximately 20 sites in the United States.
Efficacy Assessments:
Disease response will be assessed according to the IMWG Uniform Response Criteria. The following 
assessments are used to assess disease status: measurement of M protein in blood and urine by electrophoresis
and immunofixation, quantification of sFLC (κ and λ) in blood, skeletal survey, and imaging by positron 
emission tomography (PET)/computed tomography (CT) or diffusion-weighted magnetic resonance imaging 
(DW-MRI) in subjects with extramedullary disease. In addition, all subjects who achieve a CR must have a bone 
marrow evaluation, radiological assessment (for subjects with a history of extramedullary disease) for 
confirmation of CR per the IMWG criteria and must have a sample evaluated for MRD status if applicable.
Safety Assessments:
Adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities (type, frequency, and 
severity) will be collected. Adverse events of special interest (AESIs) will include infusion reactions, cytokine 
release syndrome (CRS), neurologic toxicity, macrophage activation syndrome (MAS), tumor lysis syndrome 
(TLS), severe infections, and severe prolonged cytopenias; the list of AESIs may be updated during the course of 
the study based on observed safety signals.
Replication-competent lentivirus (RCL) and viral vector sequence testing will be performed at specified time 
points during the study using polymerase chain reaction (PCR)-based assays.
DLT Definition:
DLTs are AEs that occur within 21 days following JCARH125 infusion and meet any of the following criteria:

Treatment-emergent ≥ Grade 3 allergic reactions related to JCARH125

Treatment-emergent Grade 3 seizures, regardless of attribution, that do not resolve to ≤ Grade 2 within 3 
days in subjects who have no evidence of CNS involvement of MM or other CNS pathology

Treatment-emergent autoimmune toxicity ≥ Grade 3, regardless of attribution (excluding B-cell aplasia) 

Treatment-emergent Grade 3 CRS that does not resolve to ≤ Grade 2 within 72 hours

Any other treatment-emergent Grade 3 AE related to JCARH125 that does not resolve to ≤ Grade 2 
within 7 days (see exceptions listed below)

Any treatment-emergent Grade 4 AE related to JCARH125 that does not resolve to ≤ Grade 2 within 
7 days (see exceptions listed below)

Treatment-emergent Grade 4 CRS of any duration

Any treatment-emergent Grade 5 toxicity not due to the underlying malignancy
The following will not be considered DLTs:

Non-hematologic AEs:

Grade 4 infusional toxicities that are reversible to Grade ≤ 2 within 8 hours 

Grade 3 fatigue lasting ≤ 7 days

Fever of any grade, including febrile neutropenia

Grade 4 increase in transaminases for ≤ 7 days
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
12
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125

Grade 3 TLS for ≤ 2 weeks or Grade 4 TLS for ≤ 7 days

Grade 4 hypotension (without other CRS symptoms) requiring a single vasopressor for support that 
resolves to Grade < 3 in ≤ 72 hours

Grade 3 or 4 CRS with hypotension alone requiring a low dose of a single vasopressor (as defined 
by Lee et al (Lee, 2014)) for support (not requiring intubation) that resolves to Grade < 3 in 
≤72 hours

Grade 3 chills 

Grade 3 or 4 asymptomatic, non-hematological clinical laboratory abnormalities that return to 
Grade ≤2 within 7 days or electrolyte abnormalities that resolve with replacement

Grade 3 diarrhea lasting ≤ 72 hours

Grade 3 nausea/vomiting lasting ≤ 72 hours

Hematologic AEs:

Grade 3 neutropenia of any duration or Grade 4 neutropenia lasting ≤28 days

Grade 3 or 4 lymphopenia of any duration 

Grade 3 or 4 leukopenia of any duration

Grade 3 thrombocytopenia of any duration or Grade 4 thrombocytopenia lasting ≤ 28 days

Grade 3 anemia of any duration or Grade 4 anemia lasting ≤ 28 days
The timing and severity of AEs will be reviewed continuously with study Investigators and on a regular basis 
with the DSMB. In the event that AEs meeting DLT criteria occur beyond the DLT evaluation period, the DLT 
window may be extended following discussion with the Investigators.
Criteria for Pausing the Study during Phase 1 Dose Escalation, Phase 1 Anakinra Cohort, or Phase 2a:
Further enrollment or treatment of subjects in any or all appropriate cohorts will be paused pending notification 
of the DSMB and appropriate regulatory authorities if any subject experiences any of the following events within 
30 days of a JCARH125 infusion:

Life-threatening (Grade 4) toxicity attributable to JCARH125 that is unexpected and unrelated to 
chemotherapy
Expected toxicities that would not lead to study interruption include Grade 4 CRS, neurotoxicity (eg, 
confusion, aphasia, seizures, convulsions, lethargy, and/or altered mental status), fever, hypotension, 
hypoxia, TLS, and disseminated intravascular coagulation. In addition, intensive care unit (ICU)
admission, the need for dialysis, and/or the need for mechanical ventilation are also expected. These
expected toxicities may also result in secondary toxicities of Grade 4 renal toxicity, hepatic toxicity, or 
other organ involvement. Any Grade 4 toxicity that is not considered to be a DLT (refer to listed 
exceptions) will not lead to study interruption.

An unacceptably high incidence, across multiple dose levels or after at least 10 subjects have been 
treated at the RP2D, of expected Grade 4 toxicities, including Grade 4 CRS (> 40%), Grade 4 
neurotoxicity (> 30%), Grade 4 renal toxicity not associated with disease progression (> 30%), and 
Grade 4 hepatotoxicity (> 30%), attributable to JCARH125 or chemotherapy

Death related to JCARH125 therapy
Criteria for Terminating the Study (or Cohort) Prematurely:
Further enrollment or treatment of subjects in any or all appropriate cohorts will be terminated for the following 
reasons:

Any subject develops confirmed RCL during the study

The Sponsor, Institutional Review Board/Independent Ethics Committee, or DSMB decides that subject 
safety may be compromised by continuing the study (or cohort)

The Sponsor decides to discontinue the development of JCARH125 entirely (or for the indications under 
evaluation in a given cohort)
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
13
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
Other Assessments:
The following assessments will be performed at specified time points:
PK assessments: Assessment of JCARH125 expansion and persistence will be determined by qPCR to detect the 
JCARH125 transgene. JCARH125 PK will be assessed from the time of the JCARH125 infusion until the end of 
study.
 
 
 
 
Health-related quality of life (HRQoL) assessments: HRQoL will be assessed using the EORTC QLQ-C30 
questionnaire including the QLQ-MY20 MM module, as well as the EuroQol instrument EQ-5D-5L.
Statistical Methods:
Phase 1 Dose-Escalation Cohorts
Statistical analyses of the primary, secondary, and exploratory endpoints will be primarily descriptive for the 
Phase 1 dose-escalation portion of the trial; summaries will be provided by dose level and overall. The incidence 
of DLTs, the incidence and severity of AEs, and the incidence and severity of laboratory abnormalities will be 
described and summarized.
Phase 1 Anakinra Cohort - Prophylactic Treatment with Anakinra
Data from the Phase 1 anakinra cohort will be summarized separately but subjects treated in this cohort at the 
RP2D(s) will also be pooled with subjects treated at the RP2D(s) in Phase 1 dose escalation and Phase 2 
expansion for the primary analyses. Statistical analyses of the primary, secondary, and exploratory endpoints will 
be primarily descriptive for this cohort. The incidence and severity of AEs and the incidence and severity of 
laboratory abnormalities will be described and summarized.  The number and percentage of subjects developing 
Grade ≥2 CRS, as well as an upper 1-sided 80% confidence interval (CI) will be provided and benchmarked 
against the observed rate from dose levels 3 and/or 3a from the dose escalation portion of the trial.  A similar 
analysis will be provided for the number and percentage of subjects with no CRS occurring on study days 1, 2, or 
3.  The onset of Grade ≥2 CRS will be summarized descriptively and will be referenced to onset of Grade ≥ 2 
CRS in subjects treated at the RP2D(s) in the Phase 1 dose escalation portion of the trial.
Phase 2 Expansion Cohort
The efficacy analysis set for formal statistical hypothesis testing consists of all subjects across Phase 1 dose 
escalation, the Phase 1 anakinra cohort, and Phase 2 expansion who have measurable disease at the last disease 
assessment prior to JCARH125 infusion and who receive conforming product at the RP2D(s).
The primary endpoint for Phase 2 is ORR, defined as the rate of sCR + CR + very good partial response (VGPR)
+ partial response (PR), as assessed by the IRC. A key secondary endpoint for Phase 2 is CR rate, defined as the 
rate of sCR + CR as assessed by the IRC. Disease response will be assessed until disease progression, end of 
study, death, or the start of another anticancer therapy or hematopoietic stem cell transplant (HSCT). Subjects 
without any reported disease response assessments will be considered non-responders. Formal statistical 
hypothesis testing of ORR and CR will be based on the IRC.
Exact binomial tests at the 1-sided 0.025 significance level will be used to evaluate the statistical hypotheses to be 
formally tested and an exact 2-sided 95% confidence interval for ORR and CR will be provided for each analysis 
set using the Clopper-Pearson procedure.
A gatekeeping approach will be used to control the overall type 1 error rate for the analyses of the primary 
endpoint and the CR endpoint. The CR endpoint will only be tested for statistical significance if the primary 
endpoint is significant at the 1-sided 0.025 significance level.
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
14
H125001 Amendment 6 Final: 10 Feb 2020
Protocol Number: H125001
Product Name: JCARH125
Phase 2a Prior BCMA-directed Anti-Myeloma Therapy Cohort
Each Phase 2a cohort will be analyzed separately from the Phase 1 dose-escalation cohorts and the Phase 2
expansion cohort.  Statistical analyses of the primary, secondary, and exploratory endpoints will be primarily 
descriptive for the Phase 2a portion of the trial. The ORR and CR will be summarized.  The incidence and 
severity of adverse events (AEs) and the incidence and severity of laboratory abnormalities will be described and 
summarized. 
Timing of Analyses
The primary analysis for ORR is planned after at least 75 subjects in the efficacy analysis set have been evaluated 
for response. The exact timing of the analysis will be determined after discussions with regulatory agencies.
An interim analysis may be performed after at least 20 subjects have been treated at the RP2D(s) pooled across
Phase 1 dose escalation, the Phase 1 anakinra cohort, and Phase 2 expansion and are evaluable for response (ie, 
have had at least 1 post-treatment disease assessment and all objective responses confirmed). The purpose of the 
interim analysis is to inform the development program for JCARH125. There are no intentions to stop the trial 
early for positive efficacy; therefore, no adjustment to the alpha level will be made for the final analysis.
Sample Size
A sample size of approximately 75 treated subjects at the RP2D(s) is planned for the primary efficacy evaluation.  
A sample size of up to 120 subjects is planned for Phase 1 dose escalation with up to approximately 106 subjects 
potentially evaluated in Phase 1 dose escalation at dose levels not at the RP2D(s). The Phase 1 anakinra cohort 
will be comprised of up to 14 subjects and is planned to be included in the primary efficacy evaluation for 
subjects treated at the RP2D(s).  Phase 2a will be comprised of up to 42 subjects (up to 14 subjects per cohort).
Assuming approximately 5% to 10% of subjects may not be evaluable for the primary endpoint due to reasons 
such as not being evaluable for DLT assessment, receiving non-conforming product, or not having measurable 
disease after receiving bridging chemotherapy, a total sample size of 245 subjects is planned for this Phase 1/2 
study.
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
15
H125001 Amendment 6 Final: 10 Feb 2020
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
SIGNATURE PAGE...................................................................................................................2
PROTOCOL SYNOPSIS............................................................................................................3
LIST OF ABBREVIATIONS....................................................................................................23
1.
INTRODUCTION..................................................................................................28
1.1.
Multiple Myeloma ..................................................................................................28
1.2.
BCMA as a Therapeutic Target...............................................................................28
1.3.
BCMA-targeted Therapies......................................................................................29
1.3.1.
BCMA-targeted CAR T Cells.................................................................................29
1.3.2.
BCMA-targeted Antibody Drug Conjugate.............................................................31
1.3.3.
BCMA-targeted TCE..............................................................................................32
1.4.
JCARH125 Investigational Drug Product ...............................................................33
1.5.
Potential Risks of BCMA-Targeted CAR T Cells ...................................................33
2.
STUDY PURPOSE AND RATIONALE ................................................................35
2.1.
JCARH125 Dose Rationale ....................................................................................35
2.2.
Rationale for Lymphodepletion Chemotherapy.......................................................36
2.3.
Rationale for Prophylactic Treatment with Anakinra...............................................36
2.4.
Rationale for Study Design.....................................................................................37
2.5.
Justification of Endpoints .......................................................................................37
3.
STUDY OBJECTIVES AND ENDPOINTS...........................................................38
4.
STUDY DESIGN AND INVESTIGATIONAL PLAN ...........................................42
4.1.
Overall Study Design..............................................................................................42
4.2.
Phase 1 Dose-Escalation.........................................................................................43
4.3.
Dose-Limiting Toxicities........................................................................................45
4.4.
Phase 1 Anakinra Cohort ........................................................................................46
4.5.
Phase 2a – Subjects with Prior BCMA-directed Anti-myeloma Therapy 
Cohort ....................................................................................................................47
4.6.
Phase 2 Expansion..................................................................................................47
4.7.
Study Duration and Duration of Subject Participation.............................................47
4.8.
Criteria for Pausing the Study During Phase 1 Dose Escalation, Phase 1 
Anakinra Cohort, and Phase 2a prior BCMA-directed Anti-myeloma 
Therapy Cohort.......................................................................................................48
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
16
H125001 Amendment 6 Final: 10 Feb 2020
4.9.
Criteria for Terminating the Study Prematurely ......................................................48
4.10.
Study Completion...................................................................................................48
4.11.
Study Oversight......................................................................................................49
4.11.1.
Data Safety Monitoring Board................................................................................49
4.11.2.
Independent Review Committee .............................................................................49
4.12.
Suspension or Early Termination of the Study ........................................................49
5.
STUDY POPULATION.........................................................................................50
5.1.
Inclusion Criteria....................................................................................................50
5.2.
Exclusion Criteria...................................................................................................52
5.3.
Childbearing Potential and Contraception Requirements.........................................54
5.4.
Removal of Subjects from Treatment or Study........................................................55
5.4.1.
Screen Failures .......................................................................................................55
5.4.2.
Subject Withdrawal from Study..............................................................................55
5.4.3.
Replacement of Study Subjects...............................................................................56
6.
STUDY TREATMENTS........................................................................................56
6.1.
Therapy for Disease Control during JCARH125 Manufacturing .............................56
6.2.
Lymphodepleting Chemotherapy............................................................................56
6.3.
Anakinra (for Subjects Treated with Prophylactic Anakinra) ..................................57
6.4.
Investigational Product: JCARH125 .......................................................................57
6.4.1.
Dose and Schedule..................................................................................................58
6.4.2.
Pre-medication........................................................................................................58
6.4.3.
JCARH125 Preparation and Administration............................................................58
6.4.4.
Overdose ................................................................................................................58
6.5.
Avoidance of Bias ..................................................................................................58
6.6.
Recommended Supportive Care, Additional Treatment, and Monitoring.................59
6.7.
Concomitant Medications .......................................................................................60
6.7.1.
Reporting Periods ...................................................................................................60
6.7.2.
Concomitant Medications during Hospitalizations ..................................................60
6.8.
Prohibited Medications, Devices, and Procedures...................................................61
7.
MANAGEMENT OF TOXICITIES ASSOCIATED WITH JCARH125 ................62
7.1.
Cytokine Release Syndrome ...................................................................................62
7.2.
Fever ......................................................................................................................62
7.3.
Cytopenias..............................................................................................................63
Approved
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v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
17
H125001 Amendment 6 Final: 10 Feb 2020
7.4.
Infections................................................................................................................63
7.5.
Neurologic Toxicities .............................................................................................63
7.6.
Macrophage Activation Syndrome (MAS) / Hemophagocytic Lympho-
histiocytosis (HLH) ................................................................................................64
7.7.
Infusion Reactions ..................................................................................................64
7.8.
Tumor Lysis Syndrome ..........................................................................................64
7.9.
B-cell Aplasia.........................................................................................................65
7.10.
Uncontrolled T-cell Proliferation ............................................................................65
7.11.
Replication-Competent Lentivirus, Clonality, and Insertional Oncogenesis.............65
7.12.
Adverse Reactions to Excipients.............................................................................66
7.13.
Autoimmune Reactions...........................................................................................66
7.14.
Risks Associated with Anakinra treatment ..............................................................66
7.15.
Risks Associated with Lymphodepleting Chemotherapy.........................................66
8.
STUDY ASSESSMENTS AND PROCEDURES ...................................................66
8.1.
Schedule of Evaluations..........................................................................................66
8.2.
Screening................................................................................................................67
8.3.
Leukapheresis.........................................................................................................68
8.4.
Anticancer Treatments between Leukapheresis and JCARH125 Production............69
8.5.
Study Visits ............................................................................................................69
8.5.1.
Pre-treatment Screening and Baseline Evaluations..................................................69
8.5.2.
Lymphodepleting Chemotherapy............................................................................70
8.5.3.
Criteria for JCARH125 Infusion (Day -1)...............................................................70
8.5.3.1.
Phase 1 Anakinra Cohort (JCARH125 Infusion [Day -1]).......................................71
8.5.4.
JCARH125 Administration (Day 1)........................................................................71
8.5.5.
Day 2 through Day 29.............................................................................................71
8.5.6.
Follow-up Period: Month 2 through Month 24........................................................71
8.6.
Unscheduled Evaluations........................................................................................72
8.7.
Assessments to be Performed in the Event of Death................................................72
8.8.
Assessments to be Performed upon Disease Progression or Relapse........................73
8.9.
Assessments to be Performed in the Event of a new Second Primary 
Malignancy.............................................................................................................73
8.10.
Early Withdrawal....................................................................................................73
8.11.
Long-Term Follow-Up ...........................................................................................73
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
18
H125001 Amendment 6 Final: 10 Feb 2020
8.12.
Study Assessments .................................................................................................73
8.12.1.
Disease Assessments ..............................................................................................74
8.12.2.
Physical Examination, Neurologic Examination, and MMSE..................................74
8.12.3.
Vital Signs..............................................................................................................75
8.12.4.
Electrocardiogram ..................................................................................................75
8.12.5.
Echocardiogram and Multigated Acquisition ..........................................................75
8.12.6.
Local Laboratory Evaluations .................................................................................75
8.12.7.
CSF Examination and CNS Symptom Assessment..................................................76
8.12.8.
Pharmacokinetics, Vector Sequence Testing, and Exploratory Research 
Evaluations.............................................................................................................76
8.12.9.
Pharmacokinetic Assessments.................................................................................76
8.12.9.1.
Viral Vector Sequence Testing ...............................................................................76
77
77
8.12.10.
RCL Testing...........................................................................................................78
8.12.11.
Health-Related Quality of Life................................................................................78
8.12.12.
Health Economics and Outcomes Research.............................................................79
9.
ASSESSMENT OF SAFETY.................................................................................79
9.1.
Definitions..............................................................................................................79
9.1.1.
Adverse Event ........................................................................................................79
9.1.2.
Serious Adverse Event............................................................................................80
9.2.
Grading and Intensity of Adverse Events ................................................................81
9.3.
Relationship to Study Drug.....................................................................................81
9.4.
Recording Adverse Events......................................................................................82
9.4.1.
Recording a Diagnosis versus Signs and Symptoms................................................82
9.4.2.
Clinical Laboratory Abnormalities and Other Abnormal Assessments ....................82
9.4.3.
Recording Serious Adverse Events .........................................................................83
9.4.4.
Death Reports.........................................................................................................83
9.4.5.
Pregnancy...............................................................................................................83
9.5.
Reporting Adverse Events to the Sponsor ...............................................................84
9.5.1.
Reporting Periods for AEs and SAEs......................................................................84
9.5.2.
Reporting Timelines for SAEs................................................................................85
10.
STATISTICAL METHODS...................................................................................85
Approved
3.0
v
Approved
1.0
v

EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
19
H125001 Amendment 6 Final: 10 Feb 2020
10.1.
General Considerations...........................................................................................85
10.2.
Analysis Sets ..........................................................................................................86
10.2.1.
Analysis Sets for Phase 1 Dose Escalation..............................................................86
10.2.1.1.
Screened Analysis Set.............................................................................................86
10.2.1.2.
Leukapheresed Analysis Set ...................................................................................86
10.2.1.3.
Safety Analysis Set.................................................................................................86
10.2.1.4.
DLT-evaluable Analysis Set ...................................................................................86
10.2.1.5.
Efficacy Analysis Set..............................................................................................86
10.2.1.6.
Pharmacokinetic Analysis Set.................................................................................86
10.2.2.
Analysis Sets for the Phase 1 Anakinra Cohort .......................................................87
10.2.2.1.
Safety Analysis Set.................................................................................................87
10.2.2.2.
Efficacy Analysis Set..............................................................................................87
10.2.2.3.
Additional Analysis Sets.........................................................................................87
10.2.3.
Primary Analysis Sets.............................................................................................87
10.2.3.1.
Efficacy Analysis Set..............................................................................................87
10.2.3.2.
Safety Analysis Set.................................................................................................87
10.2.3.3.
Additional Analysis Sets.........................................................................................87
10.2.4.
Analysis Sets for the Phase 2a Prior BCMA-Directed Anti-Myeloma 
Therapy Cohorts.....................................................................................................87
10.2.4.1.
Safety Analysis Set.................................................................................................87
10.2.4.2.
Efficacy Analysis Set..............................................................................................88
10.2.4.3.
Additional Analysis Sets.........................................................................................88
10.3.
Planned Analyses....................................................................................................88
10.3.1.
Subject Disposition and Baseline Characteristics ....................................................88
10.3.2.
Primary Endpoints in Phase 1 Dose Escalation .......................................................88
10.3.3.
Secondary Endpoints in Phase 1 Dose Escalation....................................................88
10.3.4.
Primary Endpoints for the Phase 1 Anakinra Cohort ...............................................89
10.3.5.
Secondary Endpoints for the Phase 1 Anakinra Cohort ...........................................89
10.3.6.
Primary Endpoint for Phase 2 .................................................................................89
10.3.7.
Secondary Endpoints for Phase 2............................................................................90
10.3.7.1.
Efficacy Subgroup Analyses...................................................................................91
10.3.8.
Other Secondary Endpoints for Phase 2 ..................................................................91
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10.3.9.
Primary Endpoint for the Phase 2a Prior-BCMA Directed Anti-Myeloma 
Therapy Cohort.......................................................................................................92
10.3.10.
Secondary Endpoints the Phase 2a Prior-BCMA Directed Anti-Myeloma 
Therapy Cohorts.....................................................................................................92
10.3.11.
Safety Analyses ......................................................................................................93
10.3.11.1. Adverse Events.......................................................................................................93
10.3.11.2. Laboratory Data......................................................................................................93
94
10.3.11.4. Other Safety Analyses ............................................................................................94
10.3.11.5. Safety Subgroup Analyses ......................................................................................94
10.3.12.
Concomitant Medications .......................................................................................94
10.3.13.
Pharmacokinetic Analyses ......................................................................................95
10.3.13.1. Pharmacokinetic Subgroup Analyses ......................................................................95
10.3.14.
Health-Related Quality of Life................................................................................95
10.3.15.
Health Economics and Outcomes Research.............................................................96
10.3.16.
Exploratory Endpoints............................................................................................96
10.4.
Multiplicity.............................................................................................................96
10.5.
Sample Size Considerations....................................................................................96
10.6.
Timing of Analyses ................................................................................................98
10.6.1.
Interim Analyses.....................................................................................................98
10.6.2.
Primary Analyses....................................................................................................98
10.6.3.
Final Analysis.........................................................................................................98
11.
DATA MANAGEMENT........................................................................................98
11.1.
Data Collection System ..........................................................................................98
11.2.
Data Quality ...........................................................................................................98
12.
STUDY ADMINISTRATION................................................................................99
12.1.
Regulatory and Ethical Considerations....................................................................99
12.1.1.
Regulatory Authority Review .................................................................................99
12.1.2.
Institutional Review Board/Independent Ethics Committee Approval.....................99
12.1.3.
Institutional Biosafety Committee Approvals..........................................................99
12.1.4.
Subject Informed Consent.......................................................................................99
12.2.
Investigator Obligations........................................................................................100
12.2.1.
Investigator Responsibilities .................................................................................100
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12.2.2.
Investigator Reporting Requirements....................................................................100
12.2.3.
Product Quality Complaint ...................................................................................100
12.3.
Access to Information for Monitoring...................................................................101
12.4.
Site Audits and Regulatory Inspections.................................................................101
12.5.
Protocol Deviations ..............................................................................................101
12.6.
Quality Assurance and Quality Control.................................................................101
12.7.
Public Notification of Study Conduct....................................................................102
12.8.
Study Completion.................................................................................................102
12.9.
Site Termination...................................................................................................102
12.10.
Records Retention ................................................................................................102
12.11.
Confidentiality of Information ..............................................................................103
12.12.
Future Use of Stored Specimens and Data ............................................................103
12.13.
Publication Plan....................................................................................................103
12.14.
Conflict of Interest................................................................................................103
13.
REFERENCES.....................................................................................................104
14.
APPENDICES......................................................................................................112
APPENDIX A.
SCHEDULES OF EVALUATIONS............................................................113
APPENDIX B.
IMWG UNIFORM RESPONSE CRITERIA FOR MULTIPLE 
MYELOMA .........................................................................................................127
APPENDIX C.
COCKCROFT-GAULT EQUATION FOR CALCULATING 
ESTIMATED CREATININE CLEARANCE .......................................................129
APPENDIX D.
MANAGEMENT OF TOXICITIES ASSOCIATED WITH
JCARH125 ...........................................................................................................130
APPENDIX E.
MINI MENTAL STATE EXAMINATION..................................................141
145
146
148
150
APPENDIX J.
MODIFIED TOXICITY PROBABILITY INTERVAL DECISION 
TABLE (PHASE 1)..............................................................................................152
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LIST OF TABLES
Table 1:
Study Objectives and Endpoints..............................................................................38
Table 2:
Planned JCARH125 Dose Levels............................................................................44
Table 3:
Reporting Periods for Concomitant Medications.....................................................60
Table 4:
Analytes for Local Laboratory Evaluations.............................................................75
Table 5:
Definitions of Serious Adverse Events....................................................................80
Table 6:
Special Considerations for SAE Reporting..............................................................80
Table 7:
Reporting Periods for AEs and SAEs......................................................................84
Table 8:
Grading Criteria for Cytokine Release Syndrome .................................................132
Table 9:
High-dose Vasopressors (all doses required for ≥ 3 hours)....................................132
Table 10:
Differential Diagnoses of CRS-related MAS/HLH................................................135
LIST OF FIGURES
Figure 1:
H125001 Study Schema..........................................................................................43
Figure 2:
Cytokine Release Syndrome Treatment Algorithm ...............................................134
Figure 3:
Neurotoxicity Treatment Algorithm......................................................................140
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LIST OF ABBREVIATIONS
Abbreviation or Term
Definition/Explanation
ADC
antibody-drug conjugate
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALL
acute lymphoblastic leukemia
ALT 
alanine aminotransferase 
ANC
absolute neutrophil count
APRIL
a proliferation-inducing ligand
aPTT
activated partial thromboplastin time
AST 
aspartate aminotransferase 
ASTCT
American Society for Transplantation and Cellular Therapy
AUC
area under the curve
ß-hCG
beta human chorionic gonadotropin
BAFF
B-cell activation factor
BBB
blood-brain barrier
BCMA
B-cell maturation antigen
BiTE
bispecific T-cell engager 
BUN
blood urea nitrogen
CAR
chimeric antigen receptor
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
Cmax
maximum concentration
CMV
cytomegalovirus
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRA
Clinical Research Associate
CrCl
creatinine clearance
CRF
case report form
CRP
C-reactive protein
CRS
cytokine release syndrome
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Abbreviation or Term
Definition/Explanation
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLI
donor lymphocyte infusion
DLT
dose-limiting toxicity
DMSO
dimethyl sulfoxide
DOCR
duration of complete response
DOR
duration of response
DSMB
Data Safety Monitoring Board
DW-MRI
diffusion-weighted magnetic resonance imaging
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC 
electronic data capture
EEG
electroencephalogram
EGFR
epidermal growth factor receptor
EGFRt
truncated epidermal growth factor receptor
EORTC
European Organization for Research and Treatment of Cancer
EOS
end of study
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FHCRC
Fred Hutchinson Cancer Research Center
G-CSF
granulocyte colony-stimulating factor
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GM-CSF
granulocyte macrophage colony-stimulating factor
GVHD
graft-versus-host disease
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HEOR
health economics and outcomes research
HIPAA
Health Information Portability and Accountability Act of 1996
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
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Abbreviation or Term
Definition/Explanation
HSCT
hematopoietic stem cell transplant
IB
Investigator’s Brochure
IBC
Institutional Biosafety Committee
ICF
informed consent form
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committee
IFN
interferon
IFN-g
interferon-gamma
IHC
Immunohistochemistry
IL-6
interleukin 6
IL-6R
interleukin 6 receptor
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group
IND
Investigational New Drug Application
INR
international normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IUD
intrauterine device
IV
intravenous(ly)
IVIG
intravenous immunoglobulin
LDH
lactate dehydrogenase
LTFU
long-term follow-up
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAS
macrophage activation syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MMSE
Mini Mental State Examination
MR
minimal response
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
MUGA
multiple uptake gated acquisition
NCI 
National Cancer Institute
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Abbreviation or Term
Definition/Explanation
NDA
no data available
NGS
next-generation sequencing 
NHL
non-Hodgkin lymphoma
NK
natural killer
NT
neurologic toxicity
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCL
plasma cell leukemia
PCP
pneumocystis pneumonia
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PN
polyneuropathy
PO
per oral
POEMS
Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasmaproliferative 
disorder, Skin changes
PR
partial response
PRES
posterior reversible encephalopathy syndrome
qPCR
quantitative polymerase chain reaction
RA
rheumatoid arthritis
RCL
replication-competent lentivirus
RP2D
recommended Phase 2 dose
R/R
relapsed and/or refractory
SAE
serious adverse event
SaO2
saturated oxygen
SAP
statistical analysis plan
SC
subcutaneous(ly)
scFv
single chain variable fragment
SCID
severe combined immunodeficiency
sCR
stringent complete response
sCRS
severe cytokine release syndrome
SCT
stem cell transplant
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Abbreviation or Term
Definition/Explanation
SD
stable disease
sFLC
serum free light chain
SNP
single nucleotide polymorphism
SOC
system organ class
SPEP
serum protein electrophoresis
SPM
second primary malignancy
TCE
T-cell engager
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
Tmax
time to maximum concentration
TMG
toxicity management guidelines
TNF
tumor necrosis factor
TNF-α
tumor necrosis factor-alpha
TTCR
time to complete response
TTR
time to response
ULN
upper limit of normal
UPenn 
University of Pennsylvania
UPEP
urine protein electrophoresis
US
United States
VGPR
very good partial response
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1.
INTRODUCTION
1.1.
Multiple Myeloma
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation 
of plasma cells in the bone marrow. Clinical features of symptomatic disease are summarized by 
the so-called “CRAB criteria,” which consist of hypercalcemia, renal impairment, anemia, and 
bone lesions (Palumbo, 2011; Gerecke, 2016; Naymagon, 2016).
It is estimated that there will be approximately 32,110 new cases diagnosed and 12,960 deaths 
from MM in the United States (US) in 2019 (Siegel, 2019). Myeloma primarily affects older 
individuals; the median age at diagnosis is 69 and less than 15% of those newly diagnosed are 
under the age of 55 (Howlader, 2016).
Although MM remains incurable, significant progress has been made over the past 20 years with 
the development of proteasome inhibitors (eg, bortezomib and carfilzomib), immunomodulators 
(IMiDs) (eg, lenalidomide, pomalidomide), and monoclonal antibodies (elotuzumab and 
daratumumab). Newly diagnosed patients who are medically fit commonly receive induction 
therapy prior to autologous stem cell transplant (SCT) with a triplet combination regimen 
consisting of a proteasome inhibitor and dexamethasone, together with lenalidomide, 
cyclophosphamide, or thalidomide (Raza, 2017). For older or medically unfit patients, first-line 
treatment may consist of lenalidomide with low-dose dexamethasone, a melphalan-containing 
regimen, or a dose-adjusted triplet regimen without SCT. The availability of these newer agents 
has extended median survival from 3 to 4 years to more than 7 years after initial diagnosis 
(Anderson, 2011). 
Depth of response has been shown to correlate with improved overall survival in multiple 
myeloma. Multiple studies have shown that patients with MM who achieve a complete response 
(CR) following therapy with or without transplant had prolonged overall survival compared with
patients achieving less than CR (van de Velde, 2007; Lahuerta, 2008; Gay, 2011). Assessment 
for minimal residual disease (MRD) by both flow cytometry and deep sequencing demonstrates a 
correlation between achieving an MRD-negative status and increased overall survival
(Martinez-Lopez, 2014; Rawstron, 2015).
Despite improvements in the treatment of newly diagnosed MM, nearly all patients relapse and 
become increasingly resistant to treatment which may be attributed, at least in part, to genetic 
heterogeneity of myeloma cells and clonal evolution during treatment (Cornell, 2016; Chung, 
2017). Treatment of R/R disease remains challenging. Patients refractory to both IMiDs and 
proteasome inhibitors have a median overall survival of only 9 months (Kumar, 2012). The 
development of the monoclonal antibodies elotuzumab and daratumumab has expanded 
treatment options for patients with relapsed disease; however, agents with a novel mechanism of 
action are still urgently needed to combat development of resistance to existing therapies.
1.2.
BCMA as a Therapeutic Target
B-cell maturation antigen (BCMA), a member of the tumor necrosis factor (TNF) receptor 
superfamily, is a cell surface protein expressed on normal and malignant plasma cells that is 
involved in regulating the maturation of B cells and differentiation into plasma cells. It is 
induced during differentiation of plasma cells in parallel with the loss of expression of a related 
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receptor for B-cell activation factor (BAFF-R). Binding of BCMA to its ligands, B-cell 
activation factor (BAFF) and a proliferation-inducing ligand (APRIL), leads to survival of 
plasma cells, resulting in enhanced humoral immunity. BCMA is highly expressed on MM cell 
lines and on cells from patients with MM, and expression appears to increase with progression of 
the disease (Tai, 2015). Importantly, BCMA protein is not expressed by hematopoietic stem 
cells, naïve B cells, or normal non-hematopoietic cells (Carpenter, 2013; Tai, 2015). Thus, with 
the exception of possible B-cell aplasia, which is easily managed, toxicity associated with 
on-target/off-tumor interactions is not expected to be a concern with agents targeting BCMA.
1.3.
BCMA-targeted Therapies
Three therapeutic modalities to target BCMA expressing myeloma cells have entered clinical 
trials: CAR T cells, antibody drug conjugates, and T cell engagers. The reasons for lack of 
response or relapse following these therapies is not well understood. Cross resistance across 
modalities has not been rigorously tested. Differences in mechanism of action or the design of 
CAR T constructs suggest that these agents may be potentially active when administered in 
sequence.
1.3.1.
BCMA-targeted CAR T Cells
One therapeutic strategy that has demonstrated particular promise in hematologic cancers has 
been the development of chimeric antigen receptors (CARs) targeting the CD19 antigen for the 
treatment of CD19-positive B-cell malignancies. CARs are artificial single-transmembrane 
domain receptors typically composed of an extracellular antigen-specific binding domain linked 
to native T-cell receptor signaling domains, typically CD3ζ in tandem with either the CD28 or 
4-1BB costimulatory domain. The antigen-binding domain may be generated using a 
single-chain variable fragment (scFv) from an antibody with appropriate antigen specificity.
Antitumor activity against malignant B cells expressing the CD19 antigen is achieved via 
transduction of a patient’s T cells with a retroviral or lentiviral vector containing the 
CD19-specific CAR and re-infusion into the patient. Engagement of the CAR T cells with 
CD19-expressing B cells elicits an immune response resulting in the targeted killing of the 
malignant cells. CR rates as high as approximately 90% have been reported in patients with acute 
lymphoblastic leukemia (ALL), and overall response rates (ORRs) of approximately 80% and 
approximately 90% have been reported in patients with non-Hodgkin lymphoma (NHL) and 
chronic lymphocytic leukemia (CLL), respectively (Park, 2016a; Turtle, 2016a; Abramson, 
2017). 
Based on the encouraging activity of CD19-targeted CAR T cells in B-cell malignancies, 
BCMA-directed CAR T cells are being evaluated for treatment of MM. In preclinical studies, 
T cells transduced with anti-BCMA CAR produced cytokines (eg, interferon gamma [IFN-γ]) 
and proliferated upon stimulation with BCMA-expressing target cells (Carpenter, 2013). In 
addition, anti-BCMA CAR T cells killed BCMA-expressing multiple myeloma cells and 
eradicated BCMA-expressing tumors in mouse xenograft models (Carpenter, 2013).
Several Phase 1 clinical trials evaluating different anti-BCMA CAR T cell-products are ongoing.
Early results from a Phase 1 clinical trial (NCT02215967) by the National Cancer Institute (NCI) 
evaluating anti-BCMA CAR T cells in patients with MM appear promising:
2 treatment-refractory patients treated at the highest dose level (9×106 CAR T cells/kg) were 
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reported to achieve a response (one with a complete remission of 17 weeks before relapse and 
the second with a partial remission that was ongoing at the time of publication) (Ali, 2016).
Toxicity reported for both patients treated at this dose level included symptoms associated with 
cytokine release syndrome (CRS) (fever, hypotension, dyspnea) and prolonged cytopenias.
In a Phase 1 CRB-401 study (NCT02658929), as of 29 March 2018, 43 subjects with R/R MM in 
dose-escalation (n = 21) and dose-expansion (n = 22) cohorts were treated at 4 dose levels of 
idecabtagene autoleucel (an investigational BCMA-targeted CAR T cell product). No dose-
limiting toxicities (DLTs) were observed at any dose level studied. Subjects enrolled in the 
optimal dose levels (>150 × 106 CAR+ T cells) had received a median of 8 prior regimens (range 
3 to 23). Cytokine release syndrome (CRS) occurred in 63% of subjects, mostly Grade 1 or 2 in 
severity and manageable. Responses were achieved by 95.5% of subjects at the optimal dose 
levels. The percentage of subjects with complete response (CR) or better (CR and stringent CR) 
was 50%, and 36.4% of subjects had a very good partial response (VGPR). Median progression-
free survival (PFS) was 11.8 months in all subjects and 17.7 months in subjects who were MRD-
negative (Raje, 2018). The pivotal Phase 2 KarMMa study of bb2121 further confirmed an 
overall response of 73% with a 31% CR rate. Safety results were consistent with the CRB-401 
study data. Cytokine release syndrome occurred in 84% of subjects and neurotoxicity of any 
grade occurred in 15% of subjects. Grade 3 or higher CRS and neurologic toxicity (NT) were 
only observed in <6% of subjects (BMS, 2019).
One CAR construct employing a human BCMA-binding domain is currently undergoing 
evaluation by the University of Pennsylvania (UPenn) (NCT02546167). A total of 25 subjects 
with R/R MM received treatment with the UPenn CAR T cell product in one of 3 dose cohorts (9 
subjects in cohort 1, 1 × 108 to 5 × 108 CART-BCMA cells alone; 5 subjects in cohort 2, 
cyclophosphamide [Cy] 1.5 g/m2 plus 1 × 107 to 5 × 107 CART-BCMA cells; 11 subjects in 
cohort 3, Cy 1.5 g/m2 plus 1 × 108 to 5 × 108 CART-BCMA cells). Clinical activity was reported 
for 17 subjects, including 1 stringent complete response (sCR), 1 complete response (CR), 
5 VGPR, 5 partial response (PR), and 5 minimal response (MR). Overall response rate was 48%
(12 out of 25). CRS was reported for 22 of the 25 subjects (88%), with Grade 3 CRS in 
8 subjects and Grade 4 CRS in 3 subjects. A DLT of Grade 4 posterior reversible encephalopathy 
syndrome (PRES) was reported for 1 subject and Grade 3 cardiomyopathy and Grade 4 
spontaneous hemothorax for 1 subject (Cohen, 2019).
Data from a fourth Phase 1 study conducted in China (sponsored by Nanjing Legend) with a data 
cutoff date of 31 Dec 2018, revealed an ORR of 88% among 57 subjects with R/R MM who 
received treatment with the BCMA-targeted CAR T cell product LCAR-B38M. Forty-two of the 
57 subjects (74%) were reported to experience a CR, 2 subjects (4%) had VGPR, and 6 subjects 
(11%) had PR. Cytokine release syndrome was reported in 90% of subjects; only 4 subjects (7%) 
were reported to have Grade 3 CRS. Neurotoxicity was reported in 1 subject (Wang, 2019).
Another BCMA CAR T cell therapy with the same construct as BMCA CAR T cells investigated 
in China by Nanjing Legend Pharmaceutical is JNJ-68284528 (JNJ-4528). This BCMA CAR T
cell construct contains two BCMA-targeting single-domain antibodies designed to confer 
avidity. As of the June 24, 2019 data cut, 21 patients that were evaluable for response had an 
overall response of 91% with a median follow up of 3 months. Four patients achieved sCR, 2 
achieved CR, 7 achieved VGPR, and 6 achieved PR. Patients were treated with a single dose of 
JNJ-4528 at a targeted dose of 0.75 x 106 CAR+ cells/kg (target range 0.5-1.0 x 106). The 
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median age was 61 years (range 50–75). Patients had received a median of 5 (range 3–16) prior 
lines of treatment. A total of 88% were triple refractory to a PI, IMiD, and anti-CD38 antibody, 
72% were penta-exposed, and 36% were penta-refractory. The median administered dose was 
0.73x106 CAR+ cells/kg (range 0.5–0.9x106). Additionally, 80% (20/25) of subjects treated with 
JNJ-4528 suffered from Grade 1 or Grade 2 CRS. One subject had a Grade 3 CRS event, while 
another had a Grade 5 event. Three subjects also had CAR-T neurotoxicity of Grade 1 (2
subjects) and Grade 3 (1 subject) (Madduri, 2019).
bb21217 is an investigational BCMA-targeted CAR T cell therapy that uses the bb2121 construct 
with a modified manufacturing process designed to improve CAR T cell functional persistence. 
The phosphoinositide 3-kinase inhibitor bb007 is used during ex vivo culture to enrich the drug 
product for T cells with a memory-like phenotype. As of 20 April 2019, 22 subjects (median age 
63 years old) have received bb21217 (12 at 150, 6 at 300 and 4 at 450 ×106 CAR T cells). Eleven 
had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Subjects had a 
median of 7 prior lines of therapy and 18 of 22 had prior autologous stem cell transplant; 7 of 22 
had high-risk cytogenetics. Of the 22 subjects, 19 received prior daratumumab and 13 received 
prior bortezomib/lenalidomide/carfilzomib/pomalidomide/daratumumab. Median follow-up after 
bb21217 infusion was 23 weeks. As of the data cutoff, 13 of the 22 (59%) subjects had 
developed CRS (5 with maximum CRS severity of Grade 1, 7 with maximum severity of Grade 
2, and 1 with maximum severity of Grade 3) and responded to supportive care, tocilizumab,
and/or corticosteroids. Five (23%) subjects developed neurotoxicity [1 Grade 1, 2 Grade 2, 1 
Grade 3 (vertigo/dizziness), 1 Grade 4 (encephalopathy, previously reported)]. For the 1 patient 
with Grade 4 neurotoxicity, Grade 3 CRS was also reported; both events have resolved. A total 
of 18 subjects were evaluable for response with ≥ 2 months of follow-up or PD within 2 months. 
Fifteen (83%) subjects demonstrated clinical response per International Myeloma Working 
Group (IMWG) criteria. Six (27%) of these subjects subsequently progressed. Nine (41%) 
subjects remained in response, including 2 subjects with ongoing response at Months 15 and 18. 
MRD-negative results at 10-5 nucleated cells or better were obtained by next-generation 
sequencing (NGS) in 10 of 10 evaluable responders at Month 1. Overall, 6 of 8 subjects 
evaluable at 6 months and 2 of 2 subjects evaluable at 12 months had detectable CAR T cells in 
peripheral blood (Berdeja, 2019).
1.3.2.
BCMA-targeted Antibody Drug Conjugate
Antibody–drug conjugates, composed of recombinant monoclonal antibodies (mAbs) covalently 
bound to cytotoxic chemicals via synthetic chemical linkers, represent the fast-growing class of 
cancer therapeutics (McCombs, 2015). The antibody-drug conjugate (ADC) first identifies and 
binds to the antigen on the surface of tumor cells via the mAb, and then is absorbed or 
internalized. After the ADC is internalized, the cytotoxic chemicals are released in the lysosomes 
and transported to cytosol to kill the tumor cells. 
Belantamab mafodotin is a humanized, IgG1 mAb with high affinity to BCMA (Kd of ~0.5 nM) 
(Tai, 2014), synthesized with a non-cleavable linker, maleimidocaproyl, and a new class of 
antimitotic agents, monomethyl auristatin F. This structure is characterized by high stability and 
high antitumor potency.
Belantamab mafodotin binds to all CD138+ and BCMA+ MM cell lines and patient MM cells
and inhibits proliferation of myeloma cells. Belantamab mafodotin also triggers antibody-
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dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular-mediated 
phagocytosis against patient MM cells. (Tai, 2014).
Belantamab mafodotin was evaluated in DREAMM-2, an open-label, 2-arm trial that recruited 
patients with R/R MM who have received at least 3 lines of anti-myeloma therapy. Patients were 
randomized to receive 2 separate doses of the agent, either 2.5 mg/kg or 3.4 mg/kg, via 
intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or 
unacceptable toxicity. The overall response rate in each group exceeded 30%, with 31% of 
patients receiving 2.5 mg/kg (n = 97) and 34% of patients receiving 3.4 mg/kg (n = 99) achieving 
a response. Corresponding rates of very good partial response or better were 19% and 20% 
(Trudel, 2019). Two additional anti-BCMA ADCs, MEDI2228 and AMG 224, are in ongoing 
Phase 1 trials for R/R MM—NCT03489525 and NCT02561962, respectively. In the former, 
BCMA is conjugated via a protease-cleavable pyrrolobenzodiazepine warhead linker, while 
AMG 224 is comprised of an antitumor maytansine derivative connected to antibody lysine 
residues via the non-cleavable 4-(N-maleimidomethyl) cyclohexane-1-carboxylate linker.
1.3.3.
BCMA-targeted TCE 
T-cell engagers (TCE) are antibodies which bind simultaneously to a surface tumor cell antigen 
and a component of the T-cell receptor (TCR) complex to induce T cell–mediated killing of 
tumor cells harboring the target surface antigen. After formation of a cytolytic synapse, the T 
cells release perforin and granzyme B, finally leading to apoptosis of the tumor cells
(Brischwein, 2006). Activation of T cells leads to transient release of cytokines, which engages 
other immune cells and broadens the immune response against the tumor tissue and ultimately 
leads to proliferation of T cells and serial killing of tumor cells (Hoffmann, 2005; Gruen, 2004;
Baeuerle, 2009). Bispecific T-cell engager (BiTE) antibody constructs are highly potent and 
efficacious molecules but have a short half-life due to their small size (55kDa). BLINCYTO is 
the first anti-CD19 BiTE approved by the FDA for the treatment of adults and children with 
relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor 
acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual 
disease (MRD) greater than or equal to 0.1%. (BLINCYTO prescribing information, 2019).
Two BiTEs directed against BCMA are currently in Phase 1 development, including AMG 420 
and AMG 701, a bispecific TCE targeting BCMA and CD3. No clinical data have been 
published for AMG 701; however, the predecessor compound, AMG 420, demonstrated a 
response rate of 70% among 10 subjects with R/R MM who were treated at the highest dose 
level. From 42 patients who have received AMG 420, 2 patients died due to adverse events
(AEs) (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus 
infection); neither were treatment related. Serious adverse events occurring in >1 patient were 
infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 
PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients (Topp, 2019).
CC-93269 is another BCMA TCE. Results from a phase 1 dose escalation trial with data cutoff 
of 24 May 2019 showed an ORR of 53% (10/19) subjects. Cytokine release syndrome occurred 
in 90% of subjects, with only 1 grade 3 CRS (6%) was reported (Costa, 2019). 
Approved
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Juno Therapeutics
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A Celgene Company
Confidential and Proprietary
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1.4.
JCARH125 Investigational Drug Product
The JCARH125 investigational drug product comprises autologous CD4+ and CD8+ T cells that 
have been transduced using a replication-incompetent, self-inactivating lentiviral vector 
encoding a CAR directed to BCMA. The drug product is provided as a combined CD8+ and 
CD4+ frozen T-cell suspension in a formulation containing dimethyl sulfoxide (DMSO).
JCARH125 is administered by intravenous (IV) infusion.
The BCMA-specific CAR comprises a binding domain isolated from a human scFv phage 
display library, an 
 hinge region, 
 transmembrane domain, and 4-1BB and 
CD3ζ signaling domains.
 
In vitro pharmacology proof-of-concept studies have demonstrated the ability of JCARH125 to 
proliferate, secrete pro-inflammatory cytokines, and kill BCMA-expressing cells. This activity is 
minimally affected by the addition of increasing amounts of soluble BCMA. Studies conducted 
in tumor xenograft models in mice bearing BCMA-positive multiple myeloma tumor cells 
demonstrated tumor clearance and improved survival following JCARH125 administration.
Additional details are provided in the JCARH125 Investigator’s Brochure.
1.5.
Potential Risks of BCMA-Targeted CAR T Cells 
The CAR T cell products furthest along in clinical development target the CD19 B-cell antigen 
that is expressed by most B-cell malignancies. Across CD19 CAR T cell programs, the most 
concerning safety issues have been CRS and neurotoxicity. CRS is a potentially life-threatening 
condition associated with the release of pro-inflammatory cytokines that occurs following 
activation of the CAR T cells upon antigen engagement. Symptoms may be evident as early as 
1 day after CAR T cell infusion and can include high fever, fatigue, nausea, headache, dyspnea, 
tachycardia, rigors, hypotension, hypoxia, myalgia, arthralgia, and/or anorexia. The risk of 
severe CRS (sCRS) in patients with B-cell malignancies appears to be correlated with burden of 
disease at initiation of treatment (Geyer, 2016; Park, 2016b; Hay, 2017; Kymriah 
(tisagenlecleucel) prescribing information, 2018). Corticosteroids, interleukin-6 receptor 
inhibitor such as tocilizumab, or interleukin-6 inhibitor such as siltuximab are most commonly 
used to treat severe symptoms of CRS.
Neurotoxicity, which may manifest as altered mental status, aphasia, altered level of 
consciousness, encephalopathy, and/or seizures, can occur in the context of CRS symptoms, 
before or after onset of CRS, or in the absence of CRS. Several fatal cases of cerebral edema 
have been reported following administration of different CD19-directed CAR T cell products
(Hu, 2016; Turtle, 2016b; Harris, 2017; Turtle, 2017). The pathogenesis of CAR T cell-induced 
neurotoxicity and optimal treatment regimens for reversing symptoms have yet to be determined.
Based on the data available from ongoing BCMA CAR T cell trials (see Section 1.3), CAR 
T cells targeted against the BCMA antigen appear to display some similar toxicities. CRS was 
commonly observed; symptoms of CRS were generally Grade 1 or 2 in severity. Grade 3 CRS 
was reported for 2 of 33 subjects (6%) treated with bb2121 (one each at dose levels of 450×106
and 800×106 CAR+ T cells) (Raje, 2019). The most common adverse events observed in subjects 
treated with LCAR-B38M CAR T cells was CRS (100%; Grade 1/2 [n=10]; Grade 3 [n=6]; 
Grade 5 [n=1]) (Chen, 2019). In the UPenn study, CRS Grade 3 and 4 on the Penn grading scale 
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
34
H125001 Amendment 6 Final: 10 Feb 2020
was reported in 8 (32%) subjects, all of whom were treated at the 1 × 108 to 5 × 108 dose (Cohen,
2019). Severe neurotoxicity was less commonly observed with the BCMA CAR T cell products
compared with CD19-directed CAR T cell therapies. In the UPenn study, neurotoxicity with 
transient confusion and/or aphasia was seen in 8 of 25 subjects (32%) and was mild (Grade 1–2) 
in 5 subjects. Three (12%) had Grade 3–4 encephalopathy including 1 subject with posterior 
reversible encephalopathy syndrome (PRES) with severe obtundation, recurrent seizures, and 
mild cerebral edema on MRI that fully resolved after treatment with high-dose
methylprednisolone and cyclophosphamide. All 3 subjects with severe neurotoxicity had high 
tumor burden (2 with extramedullary disease), had received a dose of 5 × 108 CART-BCMA 
cells, and had Grade 3 or 4 CRS (Cohen, 2019). Neurotoxicity was reported for 14 of 33 subjects 
(42%) treated with bb2121 with Grade 1 or 2 reported in 13 subjects (39%). One subject (3%) 
with a high tumor burden had a Grade 4 neurotoxicity starting 11 days after the infusion; this 
effect resolved within 1 month. One subject reported a Grade 3 headache during CRS in the 
absence of other signs of neurotoxicity (Raje, 2019). No Grade 3 or 4 neurotoxicity has been 
reported with LCAR-B38M to date (Chen, 2019).
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
35
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2.
STUDY PURPOSE AND RATIONALE
The purpose of the study is to evaluate the safety, antitumor activity, and pharmacokinetics (PK)
of JCARH125 in subjects with R/R MM.
2.1.
JCARH125 Dose Rationale
The starting dose level for JCARH125 is 50 × 106 CD3+ CAR+ T cells with 4 additional dose 
levels of 150 × 106, 300 × 106, 450 × 106, and 600 × 106 CAR+ T cells being explored to date.
The starting dose for this first-in-human Phase 1 trial with the JCARH125 investigational agent
was selected based upon the clinical experience of other investigational CAR T cell agents in 
hematological malignancies of the B-cell lineage, including MM. Subjects with CLL, NHL, 
ALL, and MM have been treated with doses ranging from 107 to 109 CAR+ T cells (Maude, 
2014b; Kochenderfer, 2015; Abramson, 2017; Berdeja, 2017). As of May 2017, subjects with 
MM had received doses of bb2121 up to 800 × 106 CAR+ T cells on the CRB-401 trial with no
DLTs, and there had been no reports of Grade 3 or 4 neurotoxicity. As previously described in 
Section 1.3, Grade 3 CRS had been reported for 2 of 21 subjects (10%) in that study (1 each at 
dose levels of 450 × 106 and 800 × 106 CAR+ T cells) (Berdeja, 2017). At a dose of 150 × 106 
CAR+ T cells, CRS had been reported for 2 subjects and were Grades 1 and 2 (Berdeja, 2017).
At the starting dose in the CRB-401 trial (50 × 106 CAR+ T cells), 1 subject was reported to 
experience Grade 1 CRS and dramatically less antitumor activity was observed; only 1 subject 
out of 3 was reported to experience a PR, which lasted less than 8 weeks before the subject’s 
disease progressed. In contrast, a response of PR or better was reported for all subjects who 
received doses of ≥150 × 106 CAR T cells and, as of May 2017, it was reported that none of 
these subjects had progression of their disease (Berdeja, 2017). Another BCMA-directed CAR T
cell product, LCAR-B38M, has also reported only 2 events of Grade 3 CRS among 35 subjects 
treated (5.7%) (Fan, 2017). However, dose levels for LCAR-B38M have not been clearly 
described.
In general, the dose of CAR T cells varies by different products, indications and protocols; 
optimal cell doses, number of doses, and infusion timing that provide maximal efficacy with 
minimal toxicity are areas of active investigation. Two CAR T cell products have been approved 
so far, Kymriah and YESCARTA, both anti-CD19 CAR T cell products. Kymriah has a dose 
range for adult patients of 0.6 to 6 × 108 CAR + T cells. YESCARTA target dose is 2 × 106 CAR 
+ T cells per kg body weight, with a maximum of 2 × 108 CAR + T cells. A different anti-
BCMA CAR T cell product, bb2121 (Raje, 2019) explores a dose range from 50 × 106 to 800 × 
106 BCMA CAR T cells, while at the University of Pennsylvania (Cohen, 2019), a dose range of 
1 × 108 to 5 × 108 BCMA CAR T cells given over 3 days as split-dose intravenous infusions 
(10% of dose given on day 0, 30% on day 1, and 60% on day 2) has been explored.  BCMA 
CAR T cells given over 3 days as split-dose intravenous infusions (10% of dose given on day 0, 
30% on day 1, and 60% on day 2) has been explored. 
In this study, more than one dose level of JCARH125 could be explored in the Phase 1 anakinra 
cohort, Phase 2 expansion and Phase 2a portions of study if there is consistent efficacy and 
acceptable tolerability at multiple dose levels.
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
36
H125001 Amendment 6 Final: 10 Feb 2020
2.2.
Rationale for Lymphodepletion Chemotherapy
It is widely believed that lymphodepleting chemotherapy improves engraftment and activity of 
CAR T cells. However, the mechanism by which T-cell engraftment is facilitated by 
lymphodepleting chemotherapy is not fully understood. The rationale for combining adoptive 
T-cell immunotherapy with lymphodepleting therapy is multifold. First, lymphodepleting 
chemotherapy may enhance adoptively transferred tumor-specific T cells to proliferate in vivo 
through homeostatic proliferation (Grossman, 2004; Stachel, 2004). Second, chemotherapy may 
reduce or eliminate CD4+CD25+ regulatory T cells, which can suppress the function of 
tumor-targeted adoptively transferred T cells (Turk, 2004). Third, lymphodepleting 
chemotherapy prior to adoptive T-cell therapy may enhance the expression of stromal 
cell-derived factor 1 (SDF-1) in the bone marrow, enhancing the homing of modified T cells to 
the primary tumor site through binding of SDF-1 with CXCR-4 expressed on the T-cell surface 
(Pinthus, 2004). Finally, lymphodepleting chemotherapy may further reduce the subject’s tumor 
burden and potentially lower the risk and severity of CRS.
In this study, lymphodepleting chemotherapy will consist of 30 mg/m2 fludarabine and 
300 mg/m2 cyclophosphamide administered daily for 3 days with reduced dose for subjects with 
decreased renal function (Section 6.2). The combination of fludarabine and cyclophosphamide 
has been used for lymphodepletion in other CAR T cell trials with demonstrable CAR T cell 
expansion, persistence, and antitumor activity and acceptable safety (Kochenderfer, 2015; Turtle, 
2016b; Abramson, 2017).
2.3.
Rationale for Prophylactic Treatment with Anakinra
The toxicity caused by CAR T cells vary from fever as an only CRS symptom to neurotoxicity, 
macrophage activating syndrome (MAS) and other post-CAR T cells toxicities. The tocilizumab 
(Actemra) indication was expanded from its original designation of rheumatoid arthritis (RA) 
treatment to treating CRS in patients undergoing CAR T treatment. Tocilizumab works by 
blocking interleukin-6 (IL-6), an inflammatory cytokine. Even though this inhibitor has been 
quite effective in treatment of CRS in patients receiving CAR T treatment, it doesn’t always 
provide relief from symptoms. CRS may respond to IL-6 receptor blockade but can require 
further treatment with high dose corticosteroids to curb potentially lethal severity (Maude,
2014a; Park, 2018; Barrett, 2014; Brudno, 2016; Neelapu, 2018).
The pathophysiology of CRS and neurotoxicity suggest that macrophage-produced IL-1 plays a 
major role in triggering CRS. CRS may also be associated with disseminated intravascular 
coagulation and it may cause a clinical and pathological picture that is similar to macrophage 
activating syndrome (MAS) (Hay, 2018; Wolf, 2019).
One of the selective interleukin-1 (IL-1) receptor antagonists (IL-1Ra) is anakinra. Anakinra was 
approved by the FDA for subjects with moderate to severe active rheumatoid arthritis (RA), in 
patients 18 years of age or older. IL-1 blockade through IL-1Ra can demonstrably prevent severe 
CRS while maintaining intact antitumor efficacy (Giavridis, 2018). The benefits of an IL-1 
blockade through IL-1Ra are especially intriguing given the latter’s ability to cross the blood–
brain barrier and therefore reduce the severity of CAR T cell related neurotoxicity (Gutierrez, 
1994), unlike tocilizumab (Neelapu, 2018). Anakinra has been proposed in a recent publication 
for treatment of refractory CRS and also in the setting of MAS/HLH (Shimabukuro-Vornhagen, 
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
37
H125001 Amendment 6 Final: 10 Feb 2020
2018). As of now, subjects in this clinical trial treated with anakinra had no adverse events 
attributable to the use of anakinra in this setting. 
The potential benefit of prophylactic treatment of anakinra on the onset, incidence and severity 
of CRS will be investigated.
2.4.
Rationale for Study Design
The Phase 1 dose escalation part of this study will utilize a modified toxicity probability interval 
(mTPI) design (Ji, 2010; Guo, 2017) to determine the safety and tolerability of various 
JCARH125 dose levels in subjects with R/R MM. The mTPI design uses a Bayesian statistical 
framework and a beta/binomial hierarchic model to compute the posterior probabilities of three
intervals that reflect the relative distance between the toxicity rate of each dose level to help 
identify an optimally safe dose range with the lowest number of treated subjects possible. The 
mTPI design has been demonstrated to more frequently select the true MTD for an 
investigational drug than the traditional 3+3 design (Ji, 2013).
2.5.
Justification of Endpoints
The primary objective of the Phase 1 dose escalation portion of the study will be to establish the 
safety and tolerability of one or more dose levels for JCARH125 in subjects with R/R MM. This 
will be determined by the incidence and severity of all AEs, including DLTs.
The primary objective for the Phase 1 anakinra cohort will be to evaluate the safety and 
tolerability of JCARH125 at the at the dose level 3 and/or dose level 3a following prophylactic 
treatment with anakinra.
The primary endpoint of the Phase 2 portion of the study is ORR, defined as the rate of sCR + 
CR + VGPR + PR as assessed by an Independent Review Committee (IRC). A key secondary 
endpoint of Phase 2 is the CR rate, defined as the rate of sCR + CR as assessed by the IRC.
Treatment response will be assessed according to the International Myeloma Working Group 
(IMWG) Uniform Response Criteria (Kumar, 2016). These response criteria are well accepted 
for use in assessing efficacy in this population.
The primary objective of the Phase 2a portion of the study will be to evaluate the efficacy of 
JCARH125 at the RP2D(s) in subjects with R/R MM who have relapsed following prior BCMA-
directed therapy.
Approved
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Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
38
H125001 Amendment 6 Final: 10 Feb 2020
3.
STUDY OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints for the study are presented in Table 1.
Table 1:
Study Objectives and Endpoints
Objective
Endpoints
Phase 1 Dose-Escalation
Primary 

To evaluate the safety and tolerability of 
JCARH125 in subjects with R/R MM 

To determine the RP2D(s) of JCARH125 in 
subjects with R/R MM

Incidence of DLTs

Incidence and severity of AEs

Incidence and severity of clinically significant 
laboratory abnormalities
Secondary 

To evaluate the expansion and persistence 
(ie, PK) of JCARH125 in peripheral blood 

Cmax, tmax, and AUC of JCARH125 CAR T cells in the 
blood

Duration of persistence of JCARH125 CAR T cells in 
the blood 

To assess preliminary antitumor activity of 
JCARH125

Overall response rate (defined as sCR, CR, VGPR, or 
PR) assessed according to IMWG criteria

Complete response rate (defined as sCR or CR) assessed 
according to IMWG criteria
Phase 1 Anakinra Cohort
Primary

To evaluate the safety and tolerability of 
JCARH125 at the dose level 3 and/or dose 
level 3a and to explore the incidence and 
onset of Grade ≥2 CRS in subjects with R/R 
MM who receive prophylactic treatment with 
anakinra 

Incidence and severity of AEs

Incidence of Grade ≥2 CRS in subjects receiving 
prophylactic anakinra relative to incidence of Grade ≥2 
CRS in subjects treated at the RP2D(s) in the Phase 1 
dose escalation portion of the trial 

Onset of Grade ≥2 CRS in subjects receiving 
prophylactic anakinra relative to onset of Grade ≥ 2 CRS 
in subjects treated at the RP2D(s) in the Phase 1 dose 
escalation portion of the trial 

The number and percentage of subjects with no CRS 
occurring on study days 1, 2, or 3

Incidence and severity of clinically significant 
laboratory abnormalities
Secondary

To evaluate the expansion and persistence 
(ie, PK) of JCARH125 in subjects who 
receive prophylactic treatment with anakinra 
in peripheral blood

Cmax, tmax, and AUC of JCARH125 CAR T cells in the 
blood

Duration of persistence of JCARH125 CAR T cells in 
the blood 
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
39
H125001 Amendment 6 Final: 10 Feb 2020
Table 1:
Study Objectives and Endpoints (Continued)
Objective
Endpoints

To assess preliminary antitumor activity of 
JCARH125 in subjects who receive 
prophylactic treatment with anakinra

Overall response rate (defined as sCR, CR, VGPR, or 
PR) assessed according to IMWG criteria

Complete response rate (defined as sCR or CR) assessed 
according to IMWG criteria
Phase 2 Single-Agent Expansion
Primary

To evaluate the antitumor activity of 
JCARH125 at the RP2D(s) in subjects with 
R/R MM 

Overall response rate (defined as sCR, CR, VGPR, or 
PR) assessed according to the IMWG criteria in the 
efficacy analysis set
Secondary

To evaluate the CR/sCR rate assessed 
according to IMWG criteria 

Complete response rate (defined as sCR or CR) as 
assessed according to IMWG criteria in the efficacy 
analysis set

To assess DOR following treatment with 
JCARH125

DOR, defined as the time from first response (sCR, CR, 
VGPR, or PR) to the earlier date of PD or death due to 
any cause

DOCR, defined as the time from first sCR or CR to the 
earlier date of PD or death due to any cause

To evaluate the safety and tolerability of 
JCARH125 in subjects with R/R MM

Incidence and severity of AEs

Incidence and severity of clinically significant 
laboratory abnormalities

To evaluate OS and PFS 

OS, defined as the time from the JCARH125 infusion 
until death

PFS, as assessed by IMWG criteria, defined as the time 
from the JCARH125 infusion until the earliest of date of 
death or disease progression

To assess time to response to JCARH125

TTR, defined as the interval from JCARH125 infusion 
to the first documentation of sCR, CR, VGPR, or PR

TTCR, defined as the interval from JCARH125 
treatment to the first documentation of sCR or CR

To evaluate expansion and persistence (ie, 
PK) of JCARH125 in peripheral blood 

Cmax, tmax, and AUC of JCARH125 CAR T cells in the 
blood

Duration of persistence of JCARH125 CAR T cells in 
the blood 

To assess HRQoL and HEOR

Measurement of HRQoL changes as assessed using the 
EORTC QLQ-C30 and its MM-specific module 
QLQ-MY20, as well as the EuroQol instrument 
EQ-5D-5L

Numbers of ICU inpatient days and non-ICU inpatient 
days and reasons for hospitalization
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
40
H125001 Amendment 6 Final: 10 Feb 2020
Table 1:
Study Objectives and Endpoints (Continued)
Objective
Endpoints
Phase 2a Prior BCMA-directed Anti-myeloma Therapy Cohort
Primary

To evaluate the antitumor activity of 
JCARH125 at the RP2D(s) in subjects with 
R/R MM who had relapsed after prior 
BCMA-directed therapy 

Overall response rate (defined as sCR, CR, VGPR, or 
PR) assessed according to the IMWG criteria in the 
efficacy analysis set
Secondary

To evaluate the CR/sCR rate assessed 
according to IMWG criteria 

Complete response rate (defined as sCR or CR) as 
assessed according to IMWG criteria in the efficacy 
analysis set

To assess DOR following treatment with 
JCARH125

DOR, defined as the time from first response (sCR, CR, 
VGPR, or PR) to the earlier date of PD or death due to 
any cause

DOCR, defined as the time from first sCR or CR to the 
earlier date of PD or death due to any cause

To evaluate the safety and tolerability of 
JCARH125 in subjects with R/R MM

Incidence and severity of AEs

Incidence and severity of clinically significant 
laboratory abnormalities

To evaluate OS and PFS 

OS, defined as the time from the JCARH125 infusion 
until death

PFS, as assessed by IMWG criteria, defined as the time 
from the JCARH125 infusion until the earliest of date of 
death or disease progression

To assess time to response to JCARH125

TTR, defined as the interval from JCARH125 infusion 
to the first documentation of sCR, CR, VGPR, or PR

TTCR, defined as the interval from JCARH125 
treatment to the first documentation of sCR or CR

To evaluate expansion and persistence (ie, 
PK) of JCARH125 in peripheral blood 

Cmax, tmax, and AUC of JCARH125 CAR T cells in the 
blood

Duration of persistence of JCARH125 CAR T cells in 
the blood 
Additional Exploratory Objectives in Phase 1, Phase 1 Anakinra Cohort, Phase 2, and Phase 2a
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
41
H125001 Amendment 6 Final: 10 Feb 2020
Table 1:
Study Objectives and Endpoints (Continued)
Objective
Endpoints
AE = adverse event; 
; AUC = area under the curve; BCMA = B-cell maturation antigen; Cmax = 
maximum concentration; CR = complete response; CRS = cytokine release syndrome; DLT = dose-limiting toxicity; DOCR = 
duration of complete response; DOR = duration of response; EORTC = European Organization for Research and Treatment of 
Cancer; HEOR = health economics and outcomes research; HRQoL = health-related quality of life; ICU = intensive care unit; 
IMWG = International Myeloma Working Group; MM = multiple myeloma; MRD = minimal residual disease; ORR = overall 
response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetics; PR = 
partial response; RP2D = recommended Phase 2 dose; R/R = relapsed and/or refractory; sCR = stringent complete response; tmax
= time to maximum concentration; TTR = time to response; VGPR = very good partial response.
Approved
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
42
H125001 Amendment 6 Final: 10 Feb 2020
4.
STUDY DESIGN AND INVESTIGATIONAL PLAN
4.1.
Overall Study Design
This is an open-label, multicenter, Phase 1/2 study to determine the safety, PK, and antitumor 
activity of JCARH125 in adult subjects with R/R MM. The Phase 1 dose-escalation portion of 
the study will evaluate the safety and tolerability of increasing dose levels of JCARH125 in order 
to identify RP2D(s). The Phase 2a portion of the study will evaluate the antitumor activity of 
JCARH125 at the RP2D(s) in subjects who have been previously treated with BCMA-directed 
therapy. The Phase 1 anakinra cohort will evaluate the safety and tolerability of JCARH125 at 
the dose level 3 and/or dose level 3a in subjects who receive prophylactic treatment with
anakinra. The Phase 2 expansion portion of the study will further evaluate the safety, PK, and 
antitumor activity of JCARH125 at the RP2D(s).
A tumor biopsy sample (bone marrow biopsy, bone marrow aspirate) will be obtained from all 
subjects during initial screening. A plasmacytoma biopsy sample will also be obtained at 
screening if feasible (see the H125001 Central Laboratory Manual).
Subjects who meet all eligibility criteria will be enrolled and will undergo leukapheresis to 
enable JCARH125 product generation. Subjects may receive bridging therapy, excluding 
experimental and biological agents (eg, daratumumab), after leukapheresis and before 
lymphodepleting chemotherapy if deemed necessary by the treating physician for disease control 
during JCARH125 manufacturing (see Section 8.4 for allowed therapies). Bridging therapies 
must be discontinued at least 14 days prior to initiation of lymphodepletion and subjects must 
continue to meet eligibility criteria pertaining to adequate organ function, active infections, 
pregnancy, measurable disease, and washout of prior therapy before initiation of 
lymphodepleting chemotherapy. If JCARH125 cannot be made from the first leukapheresis 
product, additional leukapheresis may be allowed after consultation with the Sponsor.
Following successful JCARH125 product generation, subjects will enter the treatment phase and 
will receive lymphodepletion followed by JCARH125 infusion. Eligibility criteria and disease 
assessments will be confirmed prior to initiation of lymphodepletion and JCARH125 infusion
(see Section 8.5.1). A treatment cycle will include lymphodepleting chemotherapy with
fludarabine and cyclophosphamide (see Section 6.2 for regimen), followed by a single dose of 
JCARH125 administered IV on Day 1. JCARH125 will be administered 2 to 7 days after 
completion of lymphodepleting chemotherapy unless clinical or logistical circumstances require 
modification of this timing. Dose adjustments or changes to the lymphodepleting chemotherapy 
regimen may be indicated due to the subject’s creatinine clearance (CrCl) as described in 
Section 6.2. The sequence of events is depicted in Figure 1.
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A Celgene Company
Confidential and Proprietary
43
H125001 Amendment 6 Final: 10 Feb 2020
Figure 1:
H125001 Study Schema
Subjects will be followed under this protocol for 2 years after JCARH125 administration for 
safety, disease status, additional anticancer therapies, and survival. If disease progression occurs 
during this 2-year timeframe, subject should still be followed per the Schedule of Evaluations 
outlined in Appendix A. The number of JCARH125 cells in both peripheral blood and bone 
marrow samples will be assessed by quantitative polymerase chain reaction (qPCR) from the 
time of JCARH125 administration until the end of the study. Disease assessments will be 
performed prior to study treatment, approximately every 4 weeks following JCARH125
administration for the first 6 months, and then every 3 months until 2 years after JCARH125
administration or until disease progression has been confirmed, whichever comes first. Bone 
marrow biopsy and aspirate will be performed for all subjects for disease response evaluations, 
PK, and/or research assessments at Day 15, Day 29, Month 3, Month 6, Month 12, Month 18, 
and Month 24 for confirmation of CR, and in the event of disease progression. Response to
JCARH125 will be assessed according to the 2016 IMWG criteria (Appendix B). In Phase 1 and 
Phase 2a, response to JCARH125 will be assessed by the Investigator. In Phase 2 and for 
subjects treated in Phase 1 and the Phase 1 anakinra cohort at the RP2D(s), response will be 
assessed by the Investigator and confirmed by an Independent Review Committee (IRC).
Evaluation of the primary efficacy endpoint of ORR in Phase 2 will be based on IRC assessment.
All subjects who receive JCARH125 will be asked to enroll in a separate Celgene-sponsored 
long-term follow-up (LTFU) study at the time of completion or discontinuation from this study.
Subjects who enroll in the LTFU protocol will sign a separate informed consent form and may be 
followed for up to 15 years after JCARH125 administration as per current FDA guidelines (Food 
and Drug Administration, 2006a) for long-term JCARH125-related safety and efficacy.
4.2.
Phase 1 Dose-Escalation
The JCARH125 dose levels to be evaluated in Phase 1 are provided in Table 2. Dose-
escalation/de-escalation will follow a modified toxicity probability interval (mTPI-2) algorithm 
(Guo, 2017) with a target DLT rate of 30% and an equivalence interval of 25% to 35%. The table 
in Appendix J provides the dose-escalation and de-escalation guidelines based on the number of 
subjects treated at a dose level who experience a DLT. Dose-escalation may be halted once one 
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Protocol H125001
A Celgene Company
Confidential and Proprietary
44
H125001 Amendment 6 Final: 10 Feb 2020
or more dose levels with acceptable safety and satisfactory antitumor activity has been selected 
for evaluation in Phase 2 expansion and Phase 2a. A maximum tolerated dose (MTD) may not be 
defined in this study.
For a dose level to be considered safe, at least 3 DLT-evaluable subjects must have completed 
the 21-day DLT evaluation period and the level is estimated to be safe per the mTPI-2 algorithm.
The decision to open a dose level for enrollment will be made by the Sponsor based on results 
from the mTPI-2 algorithm after consultations with the Principal Investigators at each site as 
appropriate.
Table 2:
Planned JCARH125 Dose Levels
Dose Level
JCARH125 Dose (CD3+CAR+ cells)
-1
25 × 106
1
50 × 106
2
150 × 106
2aa
300 × 106
3
450 × 106
3ab
600 × 106
4
800 × 106
a Introduced with Protocol Amendment 4 (10 September 2018) as a part of safety measures.
b Introduced with Protocol Amendment 5 (31 May 2019) as a possible intermediate dose level.
Note: Intermediate dose levels may be evaluated based on ongoing safety and efficacy data.
The first 3 subjects treated in the Phase 1 dose escalation portion of the study will be treated with 
JCARH125 at Dose Level 1 (50×106 CD3+CAR+ cells). Within the first dose cohort, treatment 
of the first 3 subjects will be staggered by a minimum of 14 days. At each higher dose level, 
treatment of the first 3 subjects within the dose cohort will be staggered by a minimum of 7 days.
Staggering of subjects in a dose cohort may be lifted after a minimum of 3 subjects have been 
treated in that dose cohort, have completed the 21-day DLT evaluation period, and the dose level 
is determined to be safe according to the mTPI-2 algorithm.
A maximum of 3 subjects will initially be treated at a dose level. If none of these 3 subjects 
experience a DLT, the dose may be escalated to the next higher dose level. If 1 of 3 subjects 
experiences a DLT at a dose level, then additional subjects will be enrolled at this dose level and 
dose-escalation/de-escalation decisions will be made per the mTPI-2 algorithm after the DLT 
data for these additional subjects are available. If 2 of 3 subjects experience a DLT at a dose 
level, then the dose will be de-escalated to the next lower dose level. If all 3 subjects experience 
a DLT at a dose level, the dose will be de-escalated and this dose and all higher doses will be 
removed from further evaluation in the trial. The mTPI-2 decision table is provided in
Appendix J.
To be considered evaluable for DLT, a subject must have received the conforming JCARH125 
cell product at the assigned dose of JCARH125 and completed the 21-day evaluation period or 
experienced a DLT prior to completing the 21-day evaluation. Subjects who are not evaluable for 
DLT will be replaced.
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A Celgene Company
Confidential and Proprietary
45
H125001 Amendment 6 Final: 10 Feb 2020
Based on the cumulative safety and antitumor activity data from subjects treated in Phase 1, one 
or more dose levels may be selected for further evaluation in the Phase 2 expansion and Phase 2a
portions of the trial (the RP2D). The RP2D(s) will be selected by the Sponsor in collaboration 
with the Investigators. It is not necessary for the MTD to be determined per the mTPI algorithm 
to select the dose level(s) to be evaluated in Phase 2.
If a dose level is deemed to be safe (ie, ‘S’ to stay at the same dose or ‘E’ to escalate to the next 
higher dose level) per the mTPI-2 algorithm, the dose level can be expanded to treat a maximum 
number of 30 subjects. A sample size of 14 to 30 subjects at a dose level will provide a high 
probability of excluding an overly toxic dose level from RP2D consideration. Dose expansion at 
a dose level may also be stopped for lack of efficacy, defined as the lower 80% 1-sided 
confidence interval for ORR less than 30% based on a minimum of 10 efficacy-evaluable 
subjects. 
4.3.
Dose-Limiting Toxicities
Dose-limiting toxicities in this study are defined as AEs that occur within 21 days following
JCARH125 infusion and meet any of the following criteria:

Treatment-emergent Grade ≥3 allergic reactions related to JCARH125

Treatment-emergent Grade 3 seizures, regardless of attribution, that do not resolve to 
Grade ≤2 within 3 days in subjects who have no evidence of central nervous system 
(CNS) involvement of MM or other CNS pathology

Treatment-emergent autoimmune toxicity Grade ≥3, regardless of attribution 
(excluding B-cell aplasia) 

Treatment-emergent Grade 3 CRS that does not resolve to Grade ≤2 within 72 hours

Any other treatment-emergent Grade 3 AE related to JCARH125 that does not 
resolve to Grade ≤2 within 7 days (see exceptions listed below) 

Any treatment-emergent Grade 4 AE related to JCARH125 that does not resolve to 
Grade ≤2 within 7 days (see exceptions listed below)

Treatment-emergent Grade 4 CRS of any duration

Any treatment-emergent Grade 5 toxicity not due to the underlying malignancy
The following will not be considered DLTs:

Non-hematologic AEs:

Grade 4 infusional toxicities that are reversible to Grade ≤2 within 8 hours 

Grade 3 fatigue lasting ≤7 days

Fever of any grade, including febrile neutropenia

Grade 4 increase in transaminases for ≤7 days

Grade 3 tumor lysis syndrome (TLS) for ≤2 weeks or Grade 4 TLS for ≤7 days
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
46
H125001 Amendment 6 Final: 10 Feb 2020

Grade 4 hypotension (without other CRS symptoms) requiring a single 
vasopressor for support that resolves to Grade < 3 in ≤72 hours

Grade 3 or 4 CRS with hypotension alone requiring a low dose of a single 
vasopressor (as defined by Lee et al [Lee, 2014]) for support (not requiring 
intubation) that resolves to Grade < 3 in ≤72 hours

Grade 3 chills

Grade 3 or 4 asymptomatic, non-hematological clinical laboratory abnormalities 
that return to Grade ≤2 within 7 days or electrolyte abnormalities that resolve 
with replacement

Grade 3 diarrhea lasting ≤72 hours

Grade 3 nausea/vomiting lasting ≤72 hours

Hematologic AEs:

Grade 3 neutropenia of any duration or Grade 4 neutropenia lasting ≤28 days

Grade 3 or 4 lymphopenia of any duration 

Grade 3 or 4 leukopenia of any duration

Grade 3 thrombocytopenia of any duration or Grade 4 thrombocytopenia lasting 
≤28 days

Grade 3 anemia of any duration or Grade 4 anemia lasting ≤28 days
The timing and severity of AEs will be reviewed continuously with study Investigators and on a 
regular basis with the Data Safety Monitoring Board (DSMB). In the event that AEs meeting 
DLT criteria occur beyond the DLT evaluation period, the DLT window may be extended 
following discussion with the Investigators.
4.4.
Phase 1 Anakinra Cohort
The primary objective of the Phase 1 anakinra cohort will evaluate the safety and tolerability of 
JCARH125 at the dose level 3 and/or dose level 3a in subjects with R/R MM who received a 
prophylactic treatment with anakinra. The potential benefit of prophylactic treatment with
anakinra on the onset, incidence and severity of CRS will be investigated.
Subjects will receive 2 doses of 100 mg anakinra administered subcutaneously (SC), one the 
night before and one in the morning, 3 hours before JCARH125 infusion. Subjects will continue 
with anakinra treatment for 5 consecutive days at a dose of 100 mg SC. In the case of CRS (any 
grade) onset, 100 mg anakinra SC should be administered twice daily until CRS resolution. 
Anakinra should be administered at approximately the same time every day. In the case of CRS 
worsening and/or in case of onset of neurological toxicity, the toxicity management guidelines 
from the protocol should be followed (see Appendix D). 
If prophylactic administration of anakinra shows a positive effect on the onset, incidence and 
severity of CRS, prophylactic treatment with anakinra may be subsequently implemented in the 
Phase 2 dose expansion portion of the trial. 
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EDMS Doc. Number: 24465987 - 24356973
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
47
H125001 Amendment 6 Final: 10 Feb 2020
4.5.
Phase 2a – Subjects with Prior BCMA-directed Anti-myeloma 
Therapy Cohort
The Phase 2a cohorts will evaluate the safety and tolerability of JCARH125 administered at the 
RP2D(s) in subjects who have been previously treated with BCMA-directed anti-myeloma 
therapy. The primary objective of these cohorts is to determine the efficacy of JCARH125 at the 
RP2D(s) in this particular population of patients.
In the Phase 2a portion of the study, 3 separate cohorts of subjects with exposure to prior 
BCMA-directed anti-myeloma therapy including TCE, ADC, or CAR T-cell therapies will be 
treated at the RP2D(s) identified in Phase 1. 
Cohort 1: 14 subjects who have been exposed to prior BCMA-directed CAR T-cell therapy
Cohort 2: 14 subjects who have been exposed to prior BCMA-directed TCE therapy
Cohort 3: 14 subjects who have been exposed to prior BCMA-directed ADC therapy
4.6.
Phase 2 Expansion
Phase 2 is an expansion stage to further evaluate safety, PK, and antitumor activity of 
JCARH125 administered at the RP2D(s). The primary objective of this part of the study is to 
evaluate the efficacy of JCARH125 administered at the RP2D(s).
In the Phase 2 part of the study, subjects will be treated at the RP2D(s) identified in Phase 1. The 
primary analysis population for evaluation of JCARH125 efficacy (ie, the efficacy analysis set) 
will include all subjects treated at the RP2D(s) in Phase 2 expansion, as well as subjects treated 
at the RP2D(s) in Phase 1 dose escalation and in the Phase 1 anakinra cohort, who have 
measurable disease as determined by the central laboratory at the last disease assessment prior to 
JCARH125 infusion and receive conforming JCARH125 product. The efficacy analysis set will 
include at least 75 subjects who are evaluable for both safety and efficacy (as defined in 
Section 10.2.3.1).
4.7.
Study Duration and Duration of Subject Participation
The enrollment period is expected to take approximately 36 months and the follow-up period for 
each subject is approximately 24 months after JCARH125 administration. Thus, the total 
duration of the study is expected to be approximately 60 months.
The expected duration of participation for subjects who complete the study will be 
approximately 26 months. All subjects who receive JCARH125 will be eligible to enroll in a 
separate Celgene-sponsored LTFU protocol after completion of this study or earlier 
discontinuation, per health authority regulatory guidelines, currently up to 15 years after 
JCARH125 administration.
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Protocol H125001
A Celgene Company
Confidential and Proprietary
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4.8.
Criteria for Pausing the Study During Phase 1 Dose Escalation, 
Phase 1 Anakinra Cohort, and Phase 2a prior BCMA-directed Anti-
myeloma Therapy Cohort
Further enrollment or treatment of the subjects in any or all appropriate cohorts will be paused 
pending notification of the DSMB and appropriate regulatory authorities if any subject 
experiences any of the following events within 30 days of a JCARH125 infusion:

Life-threatening (Grade 4) toxicity attributable to JCARH125 that is unexpected and 
unrelated to chemotherapy

Expected toxicities that would not lead to study interruption include Grade 4 CRS, 
neurotoxicity (eg, confusion, aphasia, seizures, convulsions, lethargy, and/or altered 
mental status), fever, hypotension, hypoxia, TLS, and disseminated intravascular 
coagulation. In addition, ICU admission, the need for dialysis, and/or the need for 
mechanical ventilation are also expected. These expected toxicities may also result in 
secondary toxicities of Grade 4 renal toxicity, hepatic toxicity, or other organ 
involvement, each of which also would not lead to study interruption. A Grade 4 
toxicity that is not considered to be a DLT (refer to listed exceptions in Section 4.3) 
will not lead to study interruption.

An unacceptably high incidence, across multiple dose levels or after at least 
10 subjects have been treated at the RP2D(s), of expected Grade 4 toxicities, 
including Grade 4 CRS (> 40%), Grade 4 neurotoxicity (> 30%), Grade 4 renal 
toxicity not associated with disease progression (> 30%), and Grade 4 hepatotoxicity 
(> 30%), attributable to JCARH125 or chemotherapy

Death related to JCARH125 therapy
4.9.
Criteria for Terminating the Study Prematurely
Further enrollment or treatment of subjects in any or all appropriate cohorts will be terminated 
for any of the following reasons:

Any subject develops confirmed replication-competent lentivirus (RCL) during the 
study

The Sponsor, Institutional Review Board (IRB)/Independent Ethics Committee (IEC),
or DSMB decides that subject safety may be compromised by continuing the study

The Sponsor decides to discontinue the development of JCARH125 entirely (or for 
the indications under evaluation in a given cohort)
4.10.
Study Completion
A subject is considered to have completed the study if he/she has completed the last scheduled 
visit shown in the Schedule of Evaluations (Appendix A).
The end of the study is defined as the date of the last scheduled assessment shown in the 
Schedule of Evaluations for the last subject in the trial.
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Protocol H125001
A Celgene Company
Confidential and Proprietary
49
H125001 Amendment 6 Final: 10 Feb 2020
4.11.
Study Oversight
4.11.1.
Data Safety Monitoring Board
An independent DSMB will review cumulative study data approximately quarterly over the 
course of the study to evaluate safety, protocol conduct, and scientific validity and integrity of 
the trial. In addition, in the event of a toxicity that meets the criteria for pausing the study (see 
Section 4.8), the DSMB will be convened to evaluate the comprehensive safety data and to make 
a recommendation for study continuation, modification, or termination. The DSMB has been 
assembled under a dedicated charter specifically developed for safety oversight of 
Juno-sponsored studies. 
Subject safety will be evaluated as specified in the DSMB charter. The DSMB will provide 
advice to the Sponsor and study investigators as outlined in the DSMB charter. Juno will provide 
a DSMB review summary to the study investigators for submission to the site’s IRB/IEC within 
10 working days of receipt of the statement.
4.11.2.
Independent Review Committee
An IRC will determine response and progression status for all subjects treated in the Phase 2
expansion portion of the study, as well as subjects in the Phase 1 dose escalation, Phase 1 
anakinra cohort and Phase 2a portion of the study who were treated with JCARH125 at the 
RP2D(s). The IRC will include qualified physicians; the details of the review processes and 
methods will be described in a charter developed by Juno. 
Clinical management of study subjects will be based upon Investigator assessment. The findings 
of the IRC will serve as the basis for the primary analyses of ORR, CR, DOR, and other
endpoints based on IMWG criteria in the Phase 2 portion of the study.
4.12.
Suspension or Early Termination of the Study
The study can be suspended or terminated at any time by the Sponsor, the Food and Drug 
Administration (FDA), the DSMB, or an IRB/IEC for any reason. Circumstances that may 
warrant suspension or termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to subjects (see 
Section 4.8 and Section 4.9 for criteria for pausing and stopping the study, 
respectively)

Determination of futility 

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable
If the study is suspended or terminated for safety reasons, Juno will promptly inform the 
Investigator, and will also inform the regulatory authorities of the suspension or termination of 
the study and the reasons for the action. The Investigator may be informed of additional 
procedures to be followed to ensure adequate protection of subjects. The Investigator will be 
responsible for promptly informing IRBs/IECs, other applicable regulatory committees, and 
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
50
H125001 Amendment 6 Final: 10 Feb 2020
study subjects of the suspension or early termination of the trial, including the reasons for 
suspension or termination and any other regulatory committee as applicable.
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed to the satisfaction of the Sponsor, IRB, and/or FDA.
5.
STUDY POPULATION
5.1.
Inclusion Criteria
Subjects must meet all of the following criteria to be enrolled into this study: 
1. Age ≥18 years at the time of consent
2. Signed informed consent form
3. Diagnosis of multiple myeloma (MM) with relapsed and/or refractory disease. Subjects 
must have received at least 3 prior anti-myeloma treatment regimens (note: induction 
with or without bone marrow transplant and with or without maintenance therapy is 
considered one regimen). Subjects must be refractory to the last anti-myeloma treatment 
regimen prior to entering the study. Refractory myeloma is defined as non-responsiveness 
(best response of ≤ stable disease) to last anti-myeloma treatment regimen or documented 
progressive disease during or within 60 days (measured from the last dose) of completing 
treatment with the last anti-myeloma treatment regimen before study entry. Subjects must 
have previously received all of the following therapies:
a.
Autologous stem cell transplant.
b. A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide, 
pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), 
either alone or in combination. Subjects must have undergone at least 2 consecutive 
cycles of treatment for each regimen unless progressive disease was the best response 
to the regimen.
c.
Anti-CD38 (eg, daratumumab) as part of a combination regimen or as a monotherapy.
Subjects who have received prior allogeneic stem cell transplant or donor lymphocyte 
infusion (DLI) at least 100 days before enrollment with no signs of acute or chronic graft-
versus-host disease (GVHD) will be considered eligible.
Subjects who were not candidates to receive one or more of the above treatments 
(ie, contraindicated) are eligible; the reason for not receiving treatment must be clearly 
documented in the case report form (CRF).
4. Subjects must have measurable disease as determined by the central laboratory defined as 
meeting at least one of the criteria below:
a.
Serum M-protein ≥1 g/dL
b. Urine M-protein ≥200 mg/24 hour
c.
Involved serum free light chain (sFLC) level ≥10 mg/dL with abnormal κ/λ ratio
(light chain disease is acceptable only for subjects without measurable disease in the 
serum or urine)
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A Celgene Company
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5. Subject must be willing to provide a fresh bone marrow biopsy sample during Screening 
(and at Pre-treatment Screening, if required).
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix F).
7. Adequate organ function, defined as:
a.
Adequate renal function, defined as calculated creatinine clearance (Cockcroft-Gault) 
≥60 mL/min without the assistance of hydration
i. Subjects must not have received IV rehydration within 3 days of renal function 
assessment.
b. Adequate bone marrow function, defined as absolute neutrophil count (ANC) 
≥1000 cells/mm3, hemoglobin (Hb) ≥8 g/dL, and platelet count ≥50,000/mm3. 
Transfusions and growth factors must not be used to meet these requirements at initial 
Screening.
i.
Subjects must not have received growth factors within 14 days of initial 
Screening
ii.
Subjects must not have received red blood cell (RBC) transfusions within 
21 days of initial Screening
iii.
Subjects must not have received platelet transfusions within 7 days of initial 
Screening
c.
Adequate hepatic function, defined as:
i.
Alanine aminotransferase (ALT) ≤3 × ULN 
ii.
Aspartate aminotransferase (AST) ≤3 × ULN
iii.
Total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with documented 
Gilbert’s syndrome)
iv.
International ratio (INR) or partial thromboplastin time (PTT) ≤1.5 × ULN
d. Adequate pulmonary function, defined as saturated oxygen (SaO2) ≥92% on room air
e.
Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥40% 
as assessed by echocardiogram (ECHO) or multiple uptake gated acquisition 
(MUGA) scan performed within 8 weeks prior to initial Screening
8. Subject either currently has central vascular access or is a candidate to receive central 
vascular access or peripheral vascular access for leukapheresis procedure
9. Subjects must be at least 100 days since autologous stem cell transplant (ie, Day 0, 
receipt of hematopoietic stem cells) at the time of initial Screening, if performed.
10. Recovery to Grade ≤1 or baseline of any non-hematological toxicities due to previous 
therapy, except alopecia and peripheral neuropathy
11. Females of reproductive potential (defined as all females physiologically capable of 
becoming pregnant) must agree to use one highly effective method of contraception from 
screening until at least 12 months following lymphodepleting chemotherapy. There are
insufficient exposure data to provide any recommendation concerning the duration of 
contraception following treatment with JCARH125. Any decision regarding 
contraception after JCARH125 infusion should be discussed with the treating physician.
(see Section 5.3)
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12. Females of reproductive potential must have 2 negative pregnancy tests as verified by the 
Investigator (one negative serum beta-human chorionic gonadotropin [ß-hCG] pregnancy 
test result at screening, and within 7 days prior to the first dose of lymphodepleting 
chemotherapy). This applies even if the subject practices true abstinence* (see 
Section 5.3 for details) from heterosexual contact.
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle 
of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
13. Males who have partners of childbearing potential must agree to use an effective barrier 
contraceptive method from initiation of lymphodepleting chemotherapy and for at least 
12 months and should not donate semen or sperm during the entire study period and for at 
least 12 months following lymphodepleting chemotherapy (see Section 5.3).
14. Phase 2a prior BCMA-directed anti-myeloma therapy cohort only – Subjects with R/R 
MM who have been previously treated with prior BCMA-directed anti-myeloma therapy, 
achieved at least a partial response (PR) per IMWG response criteria and subsequently 
progressed on the following treatment:
a.
Subjects who have received prior BCMA-directed CAR T-cell therapy. The last CAR 
T-cell therapy must have been received at least 6 months prior to JCARH125 study 
enrollment (screening).
b. Subjects who have received prior BCMA-directed TCE therapy.
c.
Subjects who have received prior BCMA-directed ADC therapy.
Subjects with prior BCMA-directed anti-myeloma therapy are not required to have 
received at least 3 prior anti-myeloma treatment regimens and do not have to be 
refractory to the last anti-myeloma regimen to be eligible for this trial.
5.2.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from participation in this study:
1. Subjects with known active or history of CNS involvement by malignancy
2. Subjects with solitary plasmacytoma; active or history of plasma cell leukemia (PCL);
Waldenstrom's macroglobulinemia; POEMS syndrome (Polyneuropathy, Organomegaly, 
Endocrinopathy, Monoclonal plasmaproliferative disorder, Skin changes); or 
symptomatic amyloidosis
3. Subjects who are considered eligible to receive and have refused an autologous stem cell 
transplant 
4. History of another primary malignancy that has not been in remission for at least 3 years.
The following are exempt from the 3-year limit: non-melanoma skin cancer, curatively 
treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous 
intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely 
resected.
5. Require systemic immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate, 
mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-IL-6
or anti-IL-6 receptor [IL-6R])
Approved
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EDMS Doc. Number: 24465987 - 24356973
JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
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6. Prior CAR T cell or other genetically-modified T-cell therapy (not applicable to Phase 2a 
cohorts)
7. Prior treatment with a BCMA-directed agent (not applicable to Phase 2a cohorts)
8. Human immunodeficiency virus (HIV) infection positive subjects
9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as indicated by positive 
serology or nucleic acid testing. Subjects who are solely hepatitis B surface antibody 
(HBsAb)-positive are eligible.
10. Untreated or active infection at the time of initial Screening, at the time of leukapheresis,
or within 72 hours before lymphodepletion, or 5 days before JCARH125 infusion.
Subjects with ongoing use of prophylactic antibiotics, antifungals, or antivirals are 
eligible if no evidence of active infection.
11. History of any one of the following cardiovascular conditions within the 6 months prior 
to initial Screening: Class III or IV heart failure as defined by the New York Heart 
Association (NYHA), myocardial infarction, unstable angina, uncontrolled or 
symptomatic atrial arrhythmias, any ventricular arrhythmias, or other clinically 
significant cardiac disease
12. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, 
aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, 
organic brain syndrome, or psychosis.
13. History of Grade ≥2 hemorrhage within 30 days or requirement for treatment with 
chronic, therapeutic doses of anticoagulants (eg, warfarin, low molecular weight heparin, 
or Factor Xa inhibitors)
14. Pregnant or nursing (lactating) women
15. Treatment with the following therapies within the specified time period:
a.
Monoclonal antibodies (anti-CD38 and anti-SLAMF7 antibody) within 4 weeks prior 
to leukapheresis
b. Any other systemic therapy approved for the treatment of MM within 14 days before 
leukapheresis or within 14 days before lymphodepleting chemotherapy
c.
Any experimental therapy within 8 weeks (for biologics) or 5 half-lives (for small 
molecules) before leukapheresis
d. Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or 
equivalent) within 14 days before leukapheresis. Physiologic replacement, topical, 
and inhaled steroids are permitted.
e.
Radiation to a single lesion within 14 days before leukapheresis.
f.
Radiation that includes a large bone marrow field such as the pelvis or sternum within 
6 weeks before leukapheresis
16. Plasmapheresis within 14 days before leukapheresis
17. Any medical psychological, familial, sociological, or geographical conditions that do not 
permit compliance with the protocol, as judged by the Investigator; any medical or 
psychiatric conditions or laboratory abnormalities that could jeopardize subject safety, as 
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judged by the Investigator or Sponsor Medical Monitor; or unwillingness or inability to 
follow the procedures required in the protocol
18. Use of any live vaccines against infectious diseases within 8 weeks before JCARH125 
infusion
19. Subjects with known hypersensitivity to E. coli-derived proteins (only applicable for
subjects getting prophylactic anakinra)
20. History of severe immediate hypersensitivity reaction to any of the protocol-mandated 
and recommended agents used in this study
5.3.
Childbearing Potential and Contraception Requirements
Any woman who does not meet at least one of the following criteria will be considered to have 
reproductive potential:
1. Achieved menarche at some point, or
2. Has not undergone a hysterectomy or bilateral oophorectomy, or
3. Has not been naturally post-menopausal (amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 12 consecutive months (ie, has had menses at 
any time in the preceding 12 consecutive months).
Female study participants of reproductive potential must have 2 negative pregnancy tests as 
verified by the Investigator (one negative serum beta-human chorionic gonadotropin [ß-hCG] 
pregnancy test result at screening, and within 7 days prior to the first dose of lymphodepleting 
chemotherapy). This applies even if the subject practices true abstinence* from heterosexual 
contact.
Female subjects with reproductive potential who are not sexually abstinent must agree to use one 
highly effective method of contraception from screening until at least 12 months following 
lymphodepleting chemotherapy. There are insufficient exposure data to provide any 
recommendation concerning the duration of contraception following treatment with JCARH125. 
Any decision regarding contraception after JCARH125 infusion should be discussed with the 
treating physician. 
Male subjects who have partners of childbearing potential must agree to use an effective barrier 
contraceptive method from initiation of lymphodepleting chemotherapy and for at least 12 
months after and should not donate semen or sperm during the entire study period and for at least 
12 months after lymphodepleting chemotherapy.
Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% 
per year) when used consistently and correctly. Below is a list of highly effective methods of 
contraception:

Intrauterine device (IUD)

Hormonal (birth control pill, injections, implants)

Tubal ligation

Partner's vasectomy
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5.4.
Removal of Subjects from Treatment or Study
At the time of consent, subjects will be advised that they are free to withdraw from the study at 
any time for any reason; however, all subjects who have received treatment with JCARH125 will 
be encouraged to continue all study evaluations through the End-of-Study (EOS) visit and to 
participate in the LTFU study. The Sponsor must be notified if a subject is withdrawn from the 
study, and the reason(s) for withdrawal must be documented.
5.4.1.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
determined not to meet all eligibility criteria required to participate in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
reason for screen failure, and, if applicable, any serious AEs (SAEs). Biopsy samples obtained 
during Screening for subjects who are determined to be screen failures may be used by the 
Sponsor for exploratory research. 
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened. 
5.4.2.
Subject Withdrawal from Study
A subject may be withdrawn from the study for any of the following reasons:

Subject did not receive JCARH125 due to disease-related complications

Subject did not receive JCARH125 due to interim treatment-related toxicities

Subject no longer meets eligibility criteria for other reasons (not related to disease or 
interim treatment)

JCARH125 could not be manufactured

Subject withdrawal of consent

Study termination by Sponsor, an IRB/IEC, a regulatory authority or based on a 
determination by the DSMB 

Lost to follow up

Death

Other (specified on CRF)
If a subject is withdrawn prematurely from the study, the reason for study discontinuation must 
be recorded in the CRF and the Principal Investigator should ask the subject to participate in the 
Celgene-sponsored LTFU protocol. The discussion between the subject and the Investigator must 
be documented in the subject source documents.
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5.4.3.
Replacement of Study Subjects
Subjects in Phase 1 who sign the informed consent form but do not receive JCARH125 may be 
replaced. The reason(s) for not receiving JCARH125 must be recorded in the CRF. Subjects in 
Phase 1 who are not evaluable for DLT (see Section 10.2.1.4 for criteria for inclusion in the 
DLT-evaluable analysis set) may also be replaced. Subject numbers will not be re-used. Efficacy 
classification of subjects who undergo leukapheresis but do not receive JCARH125 is described 
in Section 10.3.6.
6.
STUDY TREATMENTS
6.1.
Therapy for Disease Control during JCARH125 Manufacturing
At the Investigator’s discretion, subjects may receive bridging therapy for disease control while 
their JCARH125 product is being manufactured (see Section 8.4 for allowed therapies).
6.2.
Lymphodepleting Chemotherapy
Lymphodepleting chemotherapy will consist of 3 days of fludarabine (30 mg/m2) and 
cyclophosphamide (300 mg/m2) and must be completed between 2 days (≥48 hours) and 7 days
prior to the JCARH125 infusion. The recommended order and timing of administration is as 
follows: 
1. The IV hydration is 1 L of 0.9% NaCl given at 500 mL/h starting 2 hours prior to 
cyclophosphamide 
2. Fludarabine 30 mg/m2 IV over 30 minutes or per institutional standard
3. Cyclophosphamide 300 mg/m2 IV over 60 minutes 
4. Additional 1 L of 0.9% NaCl given at 500 mL/h
Lymphodepleting chemotherapy should be withheld if the calculated CrCl (Cockcroft-Gault;
Appendix D) is < 60 mL/min or radioisotope glomerular filtration rate (GFR) is <60 
mL/min/1.73 m2. Delay of lymphodepleting chemotherapy by more than 14 days from the Pre-
treatment screening start date requires discussion with the Sponsor and may require rescreening.
If lymphodepleting chemotherapy had to be delayed for reasons previously discussed with the 
Sponsor Medical Monitor, and if the delay was not longer than 14 days, please refer to 
Appendix A for which safety assessments have to be repeated. Disease assessments do not need 
to be repeated unless there is clinical evidence of progression. Safety assessments should be 
conducted per the Schedule of Evaluations in Appendix A.
Subjects who cannot receive lymphodepletion within 8 weeks after leukapheresis must be 
rescreened and safety and efficacy assessments must be repeated. Disease assessments as part of 
pre-treatment screening may be reduced for those subjects following discussion with the Sponsor 
Medical Monitor. 
Subjects with CrCl between 60 and 70 mL/min should have a 20% reduction of fludarabine.
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Antiemetic therapy, except dexamethasone or other steroids, may be given prior to 
lymphodepleting chemotherapy per institutional practice. Mesna may be used for subjects with a 
history of hemorrhagic cystitis per institutional practice.
Refer to the most recent package inserts for further details on administration of these agents.
6.3.
Anakinra (for Subjects Treated with Prophylactic Anakinra)
Anakinra is an interleukin-1 receptor antagonist indicated for the reduction in signs and 
symptoms and slowing the progression of rheumatoid arthritis (RA) in patients 18 years of age or 
older at the recommended dose of 100 mg/day administered daily by SC injection. Anakinra is 
also indicated for cryopyrin-associated periodic syndromes (CAPS), with a phenotype of 
neonatal-onset multisystem inflammatory disease (NOMID).
The potential benefit of prophylactic treatment with anakinra on the onset, incidence and severity 
of CRS will be investigated.
Subjects will receive 2 doses of 100 mg anakinra SC, one the night before and one 3 hours 
before JCARH125 infusion. Subjects will continue with anakinra treatment for 5 consecutive 
days at a dose of 100 mg SC. In the event of CRS onset, 100 mg anakinra SC should be 
administered twice daily until CRS resolution. Anakinra should be administered at 
approximately the same time every day. In the event of worsening CRS and/or in case of onset of 
neurological toxicity, the toxicity management guidelines from the protocol should be followed
(see Appendix D). If prophylactic treatment with anakinra shows a positive effect on the onset, 
incidence and severity of CRS, prophylactic anakinra may be implemented in the Phase 2 portion 
of the trial.
Anakinra has been associated with an increased incidence of serious infections (2%) vs. placebo 
(< 1%) in clinical trials in rheumatoid arthritis. Treatment with anakinra should not be initiated in 
patients with severe active infections. The safety and efficacy of anakinra in immunosuppressed 
patients or in patients with chronic infections have not been evaluated.
Drugs that affect the immune system by blocking tumor necrosis factor (TNF) have been 
associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that 
taking drugs such as anakinra that blocks IL-1 increases the risk of TB or other atypical or 
opportunistic infections. The most common side effects include mild to moderate swelling, 
redness, or pain at the injection site. Rare and/or serious side effects include allergic reaction, 
serious infections, and decrease in white blood cell counts. Refer to the package insert for further
details on administration of this agent.
6.4.
Investigational Product: JCARH125
JCARH125 is a CAR T cell product composed of autologous CD4+ and CD8+ T-cell 
populations that have been transduced with a genetically-engineered, replication-incompetent, 
self-inactivating lentiviral vector to express a BCMA-specific CAR comprising a human 
BCMA-specific scFv, an 
 hinge region, 
 transmembrane domain, a 
CD137 (4-1BB) costimulatory domain, and a CD3ζ signaling domain.
 
 
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The drug product is provided as a combined CD8+ and CD4+ frozen T-cell suspension in a 
formulation containing DMSO for IV administration. Additional details of product formulation, 
packaging, labeling, tracking, accountability, preparation, administration, disposal, and 
destruction are provided in the JCARH125 Product Administration Manual.
6.4.1.
Dose and Schedule
JCARH125 will be administered as an IV infusion at the dose level to which the subject is 
assigned 2 to 7 days after completion of lymphodepleting chemotherapy. The list of planned 
JCARH125 dose levels to be investigated is provided in Section 4.2.
6.4.2.
Pre-medication
All subjects will receive the following pre-medications approximately 30 to 60 minutes prior to 
JCARH125 infusion: acetaminophen (650 mg orally [PO]) or diphenhydramine (25 to 50 mg PO 
or IV), or both at the discretion of the Investigator. These medications may be repeated every 
6 hours as needed based on the Investigator’s assessment of symptoms. Pre-medication with 
steroids is not allowed (see Section 6.8).
6.4.3.
JCARH125 Preparation and Administration
Each JCARH125 dose consists of CD3+ CAR+ T cells. The subject must be continuously 
monitored during IV administration of JCARH125. Assessments performed on the day of 
administration are described in Section 8.5.3 and Appendix A.
Additional information is provided in the JCARH125 Product Administration Manual.
6.4.4.
Overdose
Overdose, as defined for this protocol, refers to lymphodepleting chemotherapy with 
fludarabine/cyclophosphamide (Flu/Cy), anakinra or JCARH125. On a per-dose basis, an 
overdose is defined as the following amount over the protocol-specified dose of these drug(s) 
assigned to a given subject, regardless of any associated AEs or sequelae:

PO: any amount over the protocol-specified dose

IV: 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol-required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the CRF. See Section 9 for the 
reporting of AEs associated with overdose.
6.5.
Avoidance of Bias
This is an open-label study. Potential bias will be reduced by the use of an IRC (described in 
Section 4.11.2) for centralized review of efficacy assessments as per the IRC charter for all 
subjects in Phase 2 and for subjects treated in Phase 1 and in the Phase 1 anakinra cohort with 
JCARH125 at the RP2D(s).
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6.6.
Recommended Supportive Care, Additional Treatment, and 
Monitoring
Because of the risk of CRS, subjects treated on this protocol should initially remain within 
approximately 60 minutes of the participating institution for 21 days after infusion with 
JCARH125. The Sponsor may decide to remove the proximity restriction based upon cumulative 
safety data.

Acute infusion reactions may occur with administration of JCARH125. Guidelines 
for the treatment of acute T-cell infusion reactions are provided in Section 7.7.

TLS treatment and TLS prophylaxis are strongly recommended for subjects at risk 
for TLS, per institutional or clinical standards. Guidelines for the treatment of TLS 
are provided in Section 7.8.

CRS management and supportive care are detailed in Appendix D

Infections should be ruled out when a subject develops fever and/or if laboratory 
findings indicate possible ongoing infection. In those cases, the subject should be 
monitored as per institutional or standard clinical practice. The use of prophylactic or 
empiric anti-infective agents (eg, trimethoprim/sulfamethoxazole for pneumocystis 
pneumonia [PCP] prophylaxis, broad-spectrum antibiotics, antifungal agents, or 
antiviral agents for febrile neutropenia) is recommended per institutional or standard 
clinical practice. The use of prophylactic or empiric anti-infective agents is especially 
recommended in subjects presenting with prolonged and/or recurrent cytopenias, 
especially in conjunction with hypogammaglobulinemia, CD4 T-cell count of < 
200/μL, and/or recent use of corticosteroids, and subjects with a history of repetitive 
and/or recent infections. Guidelines for fever and infection assessments, and infection 
prophylaxis are provided in Section 7.2 and Section 7.4, respectively.

Neurologic toxicities (NT) Levetiracetam or alternative anti-seizure medication 
should be considered for seizure prophylaxis. Management of neurologic events and 
prophylactic treatment measures are detailed in Appendix D and Section 7.5.

Macrophage activation syndrome (MAS) may occur with clinical manifestations 
and laboratory findings that can considerably overlap with CRS. Subjects treated with 
JCARH125 should be monitored for MAS. More information including 
considerations for treatment are provided in Section 7.6.

Granulocyte colony-stimulating factor (G-CSF) and transfusions of blood and 
blood products The use of red blood cells and platelet transfusions, and/or 
colony-stimulating factors is permitted after determination of eligibility at initial 
Screening, per institutional or clinical standards. However, a short-acting G-CSF, eg,
filgrastim, is prohibited starting 7 days prior to JCARH125 infusion to 7 days after 
the infusion. A long-acting G-CSF (eg, pegfilgrastim) is prohibited starting 11 days 
prior to JCARH125 infusion to 7 days after the infusion. Prophylaxis may be 
provided for lymphopenia and/or neutropenia.

IV rehydration is prohibited within 3 days prior to renal function assessment at the 
time of eligibility determination at initial Screening.
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Hospitalization is required for all subjects in Phase 1 and Phase 1 anakinra cohort after treatment 
with JCARH125 for monitoring or management of any treatment associated-toxicities. For 
subjects in Phase 2, and Phase 2a who do not have accommodation within an approximately 30-
minute drive from the hospital or do not have reliable transportation to the clinic for scheduled 
evaluation or emergencies should be considered for hospitalization for the at least first 7 days 
after JCARH125 treatment.
6.7.
Concomitant Medications
6.7.1.
Reporting Periods 
Reporting periods for concomitant medications are summarized in Table 3.
Table 3:
Reporting Periods for Concomitant Medications
Reporting Period
What to Record/Report
Informed consent to leukapheresis
Any ongoing medications at the time of informed consent and
any newly started concomitant medications or transfusions 
during this period
Leukapheresis to start of lymphodepleting 
chemotherapy
Any newly started medications or transfusions during this 
period
From start of lymphodepleting chemotherapy 
to 90 days following the dose of JCARH125, 
or to EOS visit, whichever is earlier
All medications must be recorded/reported
From 91 days following the dose of 
JCARH125 until EOS visit
The following medications must be recorded/reported:

G-CSF (until start of new MM therapy)

Transfusions (until start of new MM therapy)

IVIG (until start of new MM therapy)

Anticancer therapies

Medications used to treat Grade ≥3 AEs/SAEs related to 
JCARH125 
AE = adverse event; EOS = end of study; G-CSF = granulocyte colony-stimulating factor; IVIG = intravenous immunoglobulin; 
MM = multiple myeloma; SAE = serious adverse event.
6.7.2.
Concomitant Medications during Hospitalizations
Due to the large amount of data generated during hospitalizations, a reduced concomitant 
medication collection approach will be utilized for the CRF during hospital stays. Therefore, the 
following medications should not be entered on the Concomitant Medication CRF during 
inpatient and ICU stays:

IV fluids (except boluses used to treat impaired renal function or CRS, and hydration 
of subjects prior to JCARH125 infusion, both of which should be recorded)

Heparin flushes

Stool softeners

Vitamins, minerals, health supplements

Saline
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
Lotions
The following treatments should be reported during inpatient and ICU stays:

Vasopressors

Oxygen use

Antibiotics/antifungals/antivirals

Growth factors

Transfusions

Systemic anticoagulants
6.8.
Prohibited Medications, Devices, and Procedures 
The following medications are prohibited until disease progression, 1 year following JCARH125 
treatment, or loss of detectable JCARH125 cells, whichever comes first:

Steroids: Pre-medication with steroids for JCARH125 administration is not allowed. 
Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or 
equivalent) must not be administered within 72 hours before JCARH125 
administration. After JCARH125 infusion, administration of therapeutic doses of 
corticosteroids is not permitted unless used for treatment of Grade ≥2 CRS or any 
grade of neurotoxicity. Therapeutic doses may be used in life-threatening situations 
and for other medical conditions when indicated, or after loss of detectable 
JCARH125 cells. Pre-treatment containing steroids may be given for necessary 
medications (eg, IV immunoglobulin) after discussion with the Sponsor. Physiologic 
replacement dosing of steroids (≤12 mg/m2/day hydrocortisone or equivalent 
[≤3 mg/m2/day prednisone or ≤0.45 mg/m2/day dexamethasone]) is allowed. Topical 
steroids and inhaled steroids are permitted.
As noted in Section 6.6, filgrastim (G-CSF) is prohibited starting 7 days and pegfilgrastim 
starting 11 days prior to JCARH125 infusion to 7 days after the infusion.
Use of any live vaccines is prohibited within 8 weeks before JCARH125 infusion.
Plasmapheresis is prohibited at any time between screening and JCARH125 infusion.
A re-infusion of autologous peripheral blood stem cells (stem cell boost) preceded by bridging 
chemotherapy is not permitted.  
Inferior vena cava (IVC) filter utilization is prohibited for treatment of deep vein thrombosis at 
any time between screening and JCARH125 infusion.
The following medications are prohibited during the treatment and follow-up periods until
disease progression or discontinuation from the study:

Non-protocol-specified anticancer agents. Lympholytic cytotoxic chemotherapy may 
be administered as an extraordinary measure to treat AEs of uncontrolled JCARH125 
proliferation or CRS or neurotoxicity unresponsive to other therapeutic interventions.

Any anti-epidermal growth factor receptor (EGFR) treatments
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
Experimental agents

Curative radiation (palliative radiation for pain management is permitted)
7.
MANAGEMENT OF TOXICITIES ASSOCIATED WITH 
JCARH125
Cytokine release syndrome and neurologic toxicities (NT) are associated with CAR T cell 
therapies. Celgene has developed specific toxicity management guidelines (TMG) for CRS and 
NT associated with Celgene cellular products based on current clinical experience across the 
clinical development programs adapted for each indication based on disease specific safety 
observations (Appendix D). These recommendations are based on the CRS revised grading 
system (Lee, 2014) and the Common Toxicity Criteria for Adverse Events (CTCAE) and need to 
be used for grading of CRS and NT to guide management in this trial.
If available and adopted as per site standard practice, CRS and NT grading according to the 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading 
System (Lee, 2019) should also be recorded in the electronic case report form (eCRF) to inform 
future modifications of the management guidelines.
A complete discussion of identified and potential risks associated with JCARH125 is available in 
the current version of the JCARH125 Investigator’s Brochure (IB).
7.1.
Cytokine Release Syndrome
Administration of CAR T cells, such as JCARH125, is associated with CRS. CRS is 
characterized by high fever, fatigue, nausea, headache, dyspnea, tachycardia, rigors, hypotension, 
hypoxia, myalgia/arthralgia, and/or anorexia. Clinical symptoms and severity of CRS are highly 
variable (Lee, 2014), and management can be complicated by concurrent conditions. CRS 
symptoms typically appear a few hours to a few days following administration of CAR T cells 
and may be severe and life-threatening. Refer to Appendix D for a detailed description of CRS 
and for grading and treatment recommendations. Fever ≥38.5°C or ≥101.3°F is a commonly 
observed hallmark of CRS, and many features of CRS mimic infection. Hence, infection must be 
considered in all subjects presenting with CRS symptoms, and appropriate cultures must be
obtained and empiric antibiotic therapy initiated per institution standard of care.
Less common symptoms associated with CRS include cardiac dysfunction, adult respiratory 
distress syndrome, renal and/or hepatic failure, coagulopathies, disseminated intravascular 
coagulation, and capillary leak syndrome. 
Neurologic toxicity has been observed concurrently with CRS.
With other CAR T cell products, CRS has been reported to be associated with findings of 
macrophage activation syndrome/hemophagocytic lympho-histiocytosis (MAS/HLH), and the 
physiology of the syndromes may overlap (Section 7.6). 
7.2.
Fever
Subjects who develop a fever (temperature ≥38.5ºC) should be evaluated for infection and 
treated with antibiotics, fluids, and other supportive care as per institutional or standard clinical 
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practice, and as determined by the Investigator or treating physician. Neutropenic fever should 
be evaluated promptly (eg, blood cultures obtained, imaging as clinically required for 
identification of potential source of infection) and managed medically per institutional or 
standard clinical practice. 
The possibility of CRS should be considered for all subjects with fever following JCARH125 
infusion. Any onset of fever (≥38.0°C/100.4°F) within the first 2 weeks after JCARH125 
infusion should be further investigated and subjects admitted for observation. Febrile subjects 
should be monitored closely for hemodynamic instability and changing neurologic status.
7.3.
Cytopenias
Severe (Grade ≥3) and prolonged cytopenias, including anemia, leukopenia, neutropenia, and 
thrombocytopenia, may occur with both lymphodepleting chemotherapy and JCARH125.
Complete blood counts (CBCs) should be monitored both prior to and after JCARH125 
infusions. Institutional guidelines should be followed in the event of Grade ≥3 cytopenias.
7.4.
Infections
Life-threatening and fatal infections associated with CAR T cell therapy, including JCARH125
have been observed. Severe infections may include bacterial, fungal (including pneumocystis 
jirovecii), and viral infections (including cytomegalovirus (CMV), HBV, and other respiratory 
viruses). Subjects with prolonged and/or recurrent cytopenias, especially in conjunction with 
hypogammaglobulinemia, CD4 T-cell count of < 200 μL, and/or recent use of corticosteroids are 
at increased risk of viral reactivation and serious opportunistic infections. In these settings, 
prophylactic, pre-emptive, or symptomatic treatment with antimicrobial, antifungal, anti-
pneumocystic, and/or antiviral therapies is recommended per local institutional guidelines or 
standard clinical practice.
Antiviral therapy with appropriate antiviral agent for HBV is recommended for subjects with 
positive hepatitis B surface antigen, HBcAb, and/or measurable viral load. 
Subjects with a CD4 T-cell count of < 200 μL should be maintained on pneumocystis 
prophylaxis with trimethoprim-sulfamethoxazole. If subjects cannot tolerate 
trimethoprim/sulfamethoxazole, an alternative pneumocystis prophylaxis should be used.
7.5.
Neurologic Toxicities
CAR T cell therapy is associated with unique neurologic toxicities. Neurologic symptoms may 
include altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like 
activity. Neurologic symptoms may begin 2 to 14 days after CAR T cell infusion and in severe 
cases may require admission to the ICU for frequent monitoring, respiratory support, or 
intubation for airway protection (Davila, 2014; Maude, 2014a; Kochenderfer, 2015; Gardner, 
2016; Turtle, 2016a). The symptoms are variable and generally occur as CRS is resolving or 
after CRS resolution.
Refer to Appendix D for a detailed description of neurologic toxicities and for grading and 
treatment recommendations.
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7.6.
Macrophage Activation Syndrome (MAS) / Hemophagocytic 
Lympho-histiocytosis (HLH)
Macrophage activation syndrome (MAS) is a serious disorder potentially associated with 
uncontrolled activation and proliferation of CAR T cells and subsequent activation of 
macrophages. Macrophage activation syndrome is typically characterized by high-grade, non-
remitting fever, cytopenias, and hepatosplenomegaly. Laboratory abnormalities found in MAS 
include elevated inflammatory cytokine levels, serum ferritin, soluble IL-2 receptor (sCD25), 
triglycerides, and decreased circulating natural killer (NK) cells. Other findings may include 
elevated levels of transaminases, signs of acute liver failure, coagulopathy, and disseminated 
intravascular coagulopathy. There are no definitive diagnostic criteria for MAS; it is typically 
diagnosed using published criteria for hemophagocytic lympho-histiocytosis (Schulert, 2015). 
While there is considerable overlap in clinical manifestations and laboratory findings between 
MAS and CRS, other distinguishing MAS physical findings such as hepatosplenomegaly and 
lymphadenopathy are not common in adult subjects treated with activated T-cell therapies. 
Subjects treated with JCARH125 should be monitored for MAS, and in case of MAS occurrence, 
cytokine-directed therapy with an IL-1 receptor antagonist therapy anakinra, eg, should be 
considered as clinically indicated. Refer to Appendix D for a detailed description of MAS and 
treatment recommendations.
7.7.
Infusion Reactions
Administration of JCARH125 may cause infusion reactions, including fever, rigors, rash, 
urticaria, dyspnea, hypotension, and/or nausea. To minimize the risk of infusion reactions, all 
subjects should be pre-medicated with acetaminophen and/or diphenhydramine (see 
Section 6.4.2). Mild infusion reactions should be managed expectantly with antipyretics, 
antihistamines, and anti-emetics. Corticosteroids should be avoided because of the potential 
impact on efficacy of infused JCARH125 cells. Rigors may be treated with meperidine.
The following guidelines should be followed for infusion reactions:

Grade 1: administer symptomatic treatment, continue JCARH125 administration at 
the same dose and rate

Grade 2: stop administration of JCARH125, administer symptomatic treatment,
resume JCARH125 administration at a reduced rate only after symptoms resolve

Grade 3: stop administration of JCARH125, administer symptomatic treatment, and 
resume JCARH125 administration at a reduced rate of administration only after 
symptoms resolve. If Grade 3 reaction recurs, discontinue JCARH125; no further 
JCARH125 should be administered

Grade 4: discontinue administration of JCARH125 and administer symptomatic 
treatment as necessary; no further JCARH125 should be administered
7.8.
Tumor Lysis Syndrome 
Both the lymphodepleting chemotherapy employed in this protocol and JCARH125 therapy may 
cause TLS in subjects with high disease burden. Subjects should be closely monitored for 
laboratory evidence of TLS (hyperuricemia, hyperkalemia, hyperphosphatemia, and 
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hypocalcemia) and subjects at high risk for developing TLS, such as those with high disease 
burden and high cell turnover, should receive prophylactic treatment, including administration of 
allopurinol and hydration, as per standard clinical practice. 
7.9.
B-cell Aplasia
This toxicity may be managed by monitoring serum immunoglobulin levels, and infusion of 
intravenous immunoglobulin (IVIG) for hypogammaglobulinemic subjects (serum IgG 
< 400 mg/dL) should be considered. 
7.10.
Uncontrolled T-cell Proliferation
CAR T cells, including JCARH125, could theoretically proliferate out of control. If uncontrolled 
JCARH125 T-cell proliferation occurs, subjects may be treated with high-dose steroids (eg, 
methylprednisolone 1 to 3 mg/kg/day, tapered over 7 days) or lymphodepleting doses of 
cyclophosphamide (1-3 g/m2 IV). If an Investigator suspects uncontrolled JCARH125 
proliferation, the Sponsor should be contacted immediately.
7.11.
Replication-Competent Lentivirus, Clonality, and Insertional 
Oncogenesis 
Lentiviral vectors used in gene transfer are engineered to be replication-defective; however, 
generation of replication-competent lentiviruses (RCL) during manufacturing is still a 
possibility. Modern vector production systems have been improved to reduce the risk of RCL 
generation. To date, there have been no reports of RCL generated during lentiviral vector 
manufacturing, which may be due, at least in part, to the use of self-inactivating vectors such as 
the lentiviral vector used in the production of JCARH125 (Rothe, 2013).
Concerns for possible vector integration into the host genome have arisen due to preclinical 
studies that have shown retrovirus-mediated malignant transformation in mice (Li, 2002; 
Modlich, 2005) and monkeys (Donahue, 1992), and a single clinical study reporting 
development of leukemia in subjects with X-linked severe combined immunodeficiency (SCID) 
who received retroviral-modified CD34+ hematopoietic stem cells (Hacein-Bey-Abina, 2003), 
including 1 subject who died (Couzin, 2005). Of note, no instances of RCL generation during 
production or lentivirus-mediated malignant transformation in animals or subjects have been 
reported to date.
Data have recently been published on the integration sites of retroviral and lentiviral vectors used 
for T-cell modification in clinical trials (Wang, 2009; Scholler, 2012; McGarrity, 2013). No 
clonality of integration sites was observed. In addition, there did not appear to be enrichment of 
integration sites near genes involved in clonal expansion or persistence.
Per the FDA Recombinant DNA Advisory Committee guidelines (Food and Drug 
Administration, 2006b; Food and Drug Administration, 2006a), all subjects treated with 
JCARH125 will be followed for RCL and vector sequences for up to 15 years following 
JCARH125 administration as part of a LTFU protocol. All subjects will be monitored for 
evidence of unexpected JCARH125 expansion and the emergence of a new malignancy, 
particularly one of T-cell origin. Investigators should contact the Sponsor immediately if a new 
malignancy arises. 
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7.12.
Adverse Reactions to Excipients
Because JCARH125 is a cryopreserved autologous cell product containing DMSO, subjects may 
notice a garlic-like taste and odor and/or experience other side effects associated with DMSO, 
including tachycardia, bradycardia, hypertension, hypotension, chest tightness, dyspnea, 
pulmonary edema, abdominal cramping, diarrhea, shivering, and restlessness. 
7.13.
Autoimmune Reactions
Because JCARH125 cells are activated immune cells, it is theoretically possible that the 
JCARH125 cells could attack normal cells in the skin, liver, kidney, bone marrow, and joints.
Additionally, cytokines released from genetically modified T cells could trigger other T cells in 
the body to attack normal tissue, resulting in an autoimmune reaction.
7.14.
Risks Associated with Anakinra treatment
For subjects who receive prophylactic treatment with anakinra, refer to the local package insert 
for specific details regarding the risks of anakinra.
7.15.
Risks Associated with Lymphodepleting Chemotherapy
Subjects will receive fludarabine and cyclophosphamide prior to treatment with JCARH125 to 
facilitate lymphodepletion and CAR T cell engraftment. Refer to the local package inserts for 
specific details surrounding the risks of fludarabine and cyclophosphamide.
8.
STUDY ASSESSMENTS AND PROCEDURES
A schedule of evaluations is provided in Appendix A. Specific visits are described in Section 8.2
through Section 8.5 and descriptions of study assessments are presented in Section 8.12.
All procedures and clinical laboratory assessments on days that lymphodepleting chemotherapy 
or JCARH125 is administered must be performed pre-dose unless otherwise specified. With the 
exception of CrCl, which must be measured on the first day of lymphodepleting chemotherapy 
(see Section 6.2), clinical laboratory assessments may be performed within 1 day prior to start of 
lymphodepleting chemotherapy or JCARH125 administration. Results from the clinical 
laboratory assessments must be reviewed prior to initiation of lymphodepleting chemotherapy or 
JCARH125 administration.
8.1.
Schedule of Evaluations
The study schedule is divided into 3 parts: Pre-treatment, Treatment, and Post-treatment periods.
The Pre-treatment period includes:
1. Screening, to determine initial eligibility for study participation
2. Apheresis, for all subjects who meet all initial eligibility criteria at Screening
3. Pre-treatment Screening, to confirm that subjects meet eligibility criteria at the time of 
study treatment initiation (both prior to lymphodepleting chemotherapy and prior to 
JCARH125 infusion)
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Eligibility will be assessed by the Sponsor at the following time points:
1. Prior to leukapheresis following site’s completion of all screening assessments
2. Prior to lymphodepleting chemotherapy
3. Prior to JCARH125 infusion
The treatment period includes lymphodepleting chemotherapy (Section 6.2) and JCARH125 
administration (Section 6.4), as well as follow-up through Day 29. The Post-treatment period 
continues through Month 24 unless the subject discontinues early or is lost to follow-up. All 
subjects will be assessed for response in accordance with the IMWG criteria at the times noted in
Appendix A.
The Post-treatment period includes follow-up visits for evaluation of safety and disease status at 
indicated times. The 24-month visit will be the EOS visit, unless a subject discontinues early.
Subjects who experience disease progression or relapse should complete the PD visit and will be 
encouraged to continue all study evaluations through the EOS visit, as well as participate in the 
LTFU study (Section 8.11). For subjects who withdraw from the study before the 24-month visit, 
the EOS visit should be completed at the time of study withdrawal.
8.2.
Screening
The standard screening process begins when the subject signs the IRB/IEC-approved informed 
consent form for participation in the study and continues until the subject is determined to be 
eligible and is enrolled or is determined to be a screen failure.
The following assessments will be performed during Screening (may be performed up to 4 weeks 
following informed consent):

Assess eligibility per inclusion/exclusion criteria. All eligibility criteria must be met 
for subjects to continue in the study.

Obtain clinically significant medical history, including disease diagnosis and history,
HSCT history, and chemotherapy, radiation, and surgical history. May include history 
of toxicities related to prior treatments and allergies

ECOG performance status assessment (see Appendix F)

Physical examination, including routine neurologic examination, vital signs, height,
and weight

Brain magnetic resonance imaging (MRI) (may be performed within 8 weeks prior to 
Screening)

12-Lead electrocardiogram (ECG) (may be performed up to 8 weeks prior to 
Screening)

Cardiac ECHO or MUGA scan (may be performed up to 8 weeks prior to Screening)

Collection of peripheral blood samples for local clinical laboratory evaluations 
(hematology, coagulation, chemistry, viral serology) and serum pregnancy test (see 
Section 8.12.6). Hematology, chemistry, coagulation, and inflammatory markers 
results should not be older than 5 days.
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
Lumbar puncture (only required in subjects with signs/symptoms of potential CNS 
involvement) 

Bone marrow aspirate, bone marrow biopsy, and plasmacytoma biopsy (if accessible) 
sampling for morphology, MRD-clonotype analysis, PK, analysis of BCMA 
expression, and research evaluations

Serum and urine M-protein (serum protein electrophoresis [SPEP] and 24-hour urine 
protein electrophoresis [UPEP])

Serum and urine immunofixation

sFLC

Quantitative immunoglobulins

Positron emission tomography (PET)/computed tomography (CT) or 
diffusion-weighted magnetic resonance imaging (DW-MRI) (Note: the same imaging 
modality should be used for all assessments of extramedullary disease during the 
study follow-up period).

Skeletal survey; PET/CT or DW-MRI may be used in place of standard X-ray skeletal 
survey if the same imaging modality is used to evaluate for bone lesions for all 
assessments

β2-microglobulin

Record all AEs/SAEs related to protocol-mandated procedures and concomitant 
medications taken at that time
8.3.
Leukapheresis
Following enrollment on the study, a leukapheresis collection will be performed on each subject 
to obtain a sufficient quantity of peripheral blood mononuclear cells (PBMCs) for the production 
of the JCARH125 investigational product (see exclusion criteria in Section 5.2 for timing of 
leukapheresis in relationship to previous therapies). If a technical issue arises during the 
procedure or in the immediate processing of the product such that it cannot be used for 
JCARH125 production, the subject may have additional leukapheresis procedures performed.
Leukapheresis should be scheduled as soon as possible after the subject meets eligibility 
requirements, in coordination with the Sponsor. Venous access is required for leukapheresis and 
should be determined according to institutional practice. 
The following assessments will be conducted on the day of leukapheresis:

Collection of peripheral blood samples for local clinical laboratory evaluations, 
including:

Hematology (complete blood count [CBC] with differential)
Note: Hematology results must be evaluated prior to leukapheresis; in order to ensure results are 
available, sample may be collected up to 24 hours prior to leukapheresis.

Vital signs (before leukapheresis)
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
Record all AEs related to protocol-mandated procedures, all SAEs, and concomitant 
medications taken at that time
8.4.
Anticancer Treatments between Leukapheresis and JCARH125 
Production
The manufacturing and quality testing of JCARH125 may take several weeks following 
leukapheresis. During this time, subjects may receive short term (≤4 weeks) bridging therapy 
with one of the following recommended regimens: 

Dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) 

Bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and 
etoposide (VD-PACE)

Cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD)

Pulsed dexamethasone
An alternate bridging therapy regimen that is institutional standard may be used, following 
discussion with the Sponsor’s Medical Monitor. Anti-CD38 agents such as daratumumab, or 
other monoclonal antibodies (eg, elotuzumab) are not permitted as bridging therapy. A re-
infusion of autologous peripheral blood stem cells (stem cell boost) preceded by bridging 
chemotherapy is not permitted.  Experimental agents are not permitted. Duration of bridging 
therapy is limited to a maximum of 4 weeks. All therapies (including steroids) must be
discontinued at least 14 days prior to initiation of lymphodepletion and the time period from 
leukapheresis to lymphodepletion cannot exceed 8 weeks. Subjects must have recovered from 
bridging therapy-related toxicities to Grade ≤2 (except for alopecia) prior to initiation of 
lymphodepletion. Subjects who cannot receive lymphodepletion within 8 weeks after 
leukapheresis must be rescreened and must complete all screening assessments.
Palliative radiation is permitted but must be discussed with the Sponsor’s Medical Monitor in 
advance.
If bridging anticancer therapy is necessary, appropriate disease measurements (eg, bone marrow 
evaluation, serum and urine M-protein, serum and urine immunofixation, sFLC, quantitative 
immunoglobulins, and a PET/CT or DW-MRI) must be repeated prior to lymphodepletion and 
all subjects must have measurable disease prior to initiating lymphodepletion. Subjects who did
not have extramedullary disease at screening and who do not have evidence of disease 
progression do not have to repeat a PET/CT or DW-MRI after bridging therapy. Subjects who 
respond to bridging chemotherapy and who no longer have measurable disease must wait until 
their disease becomes measurable to be considered for JCARH125 treatment.
8.5.
Study Visits
8.5.1.
Pre-treatment Screening and Baseline Evaluations
The subject must continue to meet eligibility criteria pertaining to adequate organ function, 
active infections, pregnancy, measurable disease, and washout of prior therapy before initiation 
of lymphodepleting chemotherapy (see Section 5.1 and Section 5.2). Growth factors and 
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transfusions may be administered for subjects who do not meet the minimum ANC, hemoglobin,
and platelet count requirements at the Pre-treatment Screening evaluation.
Subjects whose disease becomes non-measurable following bridging chemotherapy will not 
receive lymphodepleting chemotherapy or JCARH125. These subjects may be treated with the 
study regimen when their disease becomes measurable; rescreening is required.
Pre-treatment Screening evaluations must occur within 14 days (+3 days) prior to initiation of 
lymphodepleting chemotherapy and must occur after the completion of any bridging 
chemotherapy. For subjects who receive bridging chemotherapy with potentially cardiotoxic 
drugs, a repeat MUGA/ECHO must be performed within 7 days prior to initiation of 
lymphodepleting chemotherapy. Evaluations will be performed as indicated in the Schedule of 
Evaluations (see Appendix A).
Subjects should have a hemoglobin level of ≥8 g/dL and a platelet count of ≥50,000/mm3 prior 
to lymphodepletion; RBC transfusions and other supportive measures may be used. If 
lymphodepleting chemotherapy had to be delayed for reasons previously discussed with the
Sponsor Medical Monitor, and if the delay was not longer than 14 days, only safety assessments 
have to be repeated. Disease assessments do not need to be repeated unless there is clinical 
evidence of disease progression.
8.5.2.
Lymphodepleting Chemotherapy
Upon notification from the Sponsor that JCARH125 will be available, lymphodepleting 
chemotherapy should be initiated (see Section 6.2 for details and timing of the lymphodepleting 
regimen and criteria for withholding or adjusting treatment based on reduced CrCl; see 
Section 8.5.3 for criteria for initiating treatment).
The following assessments will be performed on each day of lymphodepleting chemotherapy, 
prior to administration of lymphodepleting chemotherapy:

Physical examination, including routine neurologic examination, vital signs, and 
weight

ECOG performance status assessment (first day of lymphodepleting chemotherapy 
only) (see Appendix F)

Local laboratory assessments, including hematology, coagulation, and chemistries 

Record all AEs and concomitant medications
8.5.3.
Criteria for JCARH125 Infusion (Day -1)
Subjects should not experience a significant worsening in clinical status compared to initial 
eligibility criteria that would, in the opinion of the treating physician, increase the risk of adverse 
events associated with JCARH125 infusion. Subjects who meet at least one of the following 
criteria within 24 hours prior to the scheduled JCARH125 infusion should have JCARH125 
administration delayed:

Suspected or active systemic infection 5 days before JCARH125 infusion

All cultures must be negative if subject had a recent infection
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
Onset of fever ≥38.0°C/100.4°F, not related to underlying disease

Platelet count < 50,000/mm3

Calculated creatinine clearance (Cockcroft Gault) < 60 mL/min

Presence of progressive radiographic abnormalities on chest x-ray, or requirement for 
supplemental oxygen to keep saturation greater than 91%

Cardiac arrhythmia not controlled with medical management

Hypotension requiring vasopressor support

New-onset or worsening of other non-hematologic organ dysfunction Grade ≥3

Taking any of the prohibited medications as described in Section 6.8
In the event that a subject experiences any of the above, the Sponsor must be contacted and 
discussion regarding delay of treatment must occur. Subjects with active infection must have 
JCARH125 infusion postponed until the active infection has resolved (subjects with 
suspected/active infection must have negative culture for at least 24 hours on appropriate 
antibiotics or negative rapid viral panel). Subjects with organ toxicities may not receive 
JCARH125 until the organ toxicities have recovered to Grade ≤2. In case of delayed infusion, 
lymphodepleting chemotherapy may need to be repeated after discussion with the Sponsor (see 
Section 6.2).
8.5.3.1.
Phase 1 Anakinra Cohort (JCARH125 Infusion [Day -1])
Subjects receiving prophylactic treatment with anakinra and who do not meet any of criteria 
listed above will receive 1 dose of 100 mg anakinra SC the night before JCARH125 infusion.
8.5.4.
JCARH125 Administration (Day 1)
JCARH125 will be administered as described in Section 6.4. Evaluations will be performed as 
indicated in the Schedule of Evaluations (see Appendix A). Additionally, vital signs (see 
Section 8.12.3) will be measured within approximately 15 minutes (±5 min) before and 
15 minutes (±5 min) after infusion, then approximately every 15 minutes thereafter for the first 
hour and hourly (±15 min) for the next 3 hours. Thereafter, vital signs should continue to be 
monitored until stable and as clinically indicated.
8.5.5.
Day 2 through Day 29
Evaluations will be performed as indicated in the Schedule of Evaluations (see Appendix A).
Subjects in the Phase 1 anakinra cohort will continue with anakinra treatment for 5 consecutive 
days at a dose of 100 mg SC. In the event of CRS onset, 100 mg anakinra SC should be 
administered twice daily until CRS resolution. Anakinra should be administered at 
approximately the same time every day.
8.5.6.
Follow-up Period: Month 2 through Month 24
All subjects, including subjects with PD, will be asked to complete the Post-treatment follow-up 
visits at Months 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, and 24 after administration of JCARH125 for
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disease status and survival. Evaluations will be performed as indicated in the Schedule of 
Evaluations (see Appendix A).
8.6.
Unscheduled Evaluations
If the Investigator feels that a subject needs to be evaluated at a time other than a 
protocol-specified visit, the subject may be asked to come in to the clinic for an unscheduled 
evaluation. The following assessments may be performed as clinically indicated, and results 
reported into the clinical database:

Physical examination

Vital signs 

ECOG performance status assessment 

Clinical laboratory evaluations (eg, hematology, coagulation, chemistries)

Note: If peripheral blood samples are obtained for clinical laboratory evaluations, 
samples should also be collected and submitted to the Sponsor for exploratory 
research.

Bone marrow or plasmacytoma biopsy

Note: If bone marrow or plasmacytoma samples are obtained, samples should also be 
collected and submitted to the Sponsor for exploratory research.

Other tissue assessments (eg, CSF, SPM) 

Note: If tissue or fluid samples are obtained, samples should also be collected and 
submitted to the Sponsor for exploratory research.

CNS imaging (CT and/or MRI)

Note: If scans are obtained as part of a neurologic examination, results should be 
reported.

Disease assessments as needed to confirm a response (eg, SPEP, 24-hour UPEP, 
serum and urine immunofixation, sFLC, quantitative immunoglobulins, PET/CT, 
DW-MRI scan or skeletal survey)

If collected, samples for SPEP, 24-hour UPEP, serum and urine immunofixation, and 
sFLC must be submitted to the central laboratory.

MMSE (see Appendix E) 

Subjects who develop neurologic symptoms suspicious of and/or diagnosed as 
neurologic toxicity will have daily MMSEs until resolution of symptoms, unless the 
subject is medically incapacitated and/or medically unable to complete the MMSE.
8.7.
Assessments to be Performed in the Event of Death
In the event of a subject’s death, autopsy may be requested. If an autopsy is performed, tissue 
samples may be requested and sent to the Sponsor for evaluation of the presence of JCARH125 
cells in brain, liver, kidney, lungs, bone marrow, blood, heart, reproductive organs, and any sites 
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of disease (see the H125001 Central Laboratory Manual). Every effort will be made to assay for 
RCL in a sample of the pertinent autopsy tissue.
8.8.
Assessments to be Performed upon Disease Progression or Relapse
The assessments listed in the Schedule of Evaluations for PD or relapse (Appendix A) will be 
performed as soon as possible after disease progression/relapse is suspected. These subjects 
should be encouraged to continue to be followed as per the Schedule of Evaluations Table A-4
through Month 24.
8.9.
Assessments to be Performed in the Event of a new Second Primary 
Malignancy
Second primary malignancies (SPMs) will be monitored as events of interest and must be 
reported as SAEs regardless of treatment subject is receiving (see Section 9.1.2). Events of SPM
are to be reported using the SAE Report Form and must be considered “Important Medical 
Events” if no other serious criteria apply; these events must also be documented in the 
appropriate page(s) of the eCRF and subject’s source documents. Documentation on the 
diagnosis of SPM must be provided at the time of SAE reporting (eg, any confirmatory histology 
or cytology results, x-rays, CT scans).
If subject develops a new malignancy, the sponsor will request a tumor sample (refer to 
laboratory manual) and blood samples (Section 8.12.9.1 and Section 8.12.10).
8.10.
Early Withdrawal
If a subject withdraws prematurely from the study, an EOS visit will be scheduled as soon as 
possible and all of the assessments listed for the EOS visit will be performed. The reason for 
early withdrawal will be captured in the CRF.
8.11.
Long-Term Follow-Up
Because this protocol involves gene transfer, follow up for lentiviral vector safety, disease status, 
and long-term survival will continue on this protocol until 24 months after JCARH125
administration, regardless of disease status, and under a separate Celgene-sponsored LTFU 
protocol for up to 15 years after JCARH125 administration. 
All subjects treated with JCARH125 who either complete the primary follow-up period specified 
in this protocol or who prematurely withdraw after at least one dose of JCARH125 will be asked 
to enroll in the Celgene-sponsored LTFU protocol at the EOS visit or at the time of withdrawal, 
respectively. A separate informed consent form will be provided for the Celgene-sponsored 
LTFU protocol. Subjects who do not consent to participate in the Celgene-sponsored LTFU 
protocol or who are lost to follow-up will be followed for survival through public record.
8.12.
Study Assessments
All study assessments should be performed at the times indicated in the Schedule of Evaluations 
in Appendix A.
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8.12.1.
Disease Assessments
Response to JCARH125 will be assessed according to the IMWG criteria (Kumar, 2016) (see
Appendix B). In Phase 2, and for subjects in Phase 1 and the Phase 1 anakinra cohort who 
receive JCARH125 at the RP2D(s), response will be assessed by an IRC in addition to the 
Investigator assessment, as described in Section 4.11.2.
Some or all of the following are required for the assessment of disease status:

SPEP and 24-hour UPEP (central laboratory)

For subjects with disease that is only detectable in the serum, a 24-hour UPEP is only 
required at Screening, for confirmation of CR, as clinically indicated, and at EOS.

Serum/urine immunofixation (central laboratory)

Quantitative sFLC (central laboratory)

Quantitative immunoglobulins (central laboratory)

Bone marrow assessment for plasma cell percentage (central pathology review)

Bone marrow evaluations are required for all subjects at Screening, Day 15, Day 29, 
Month 3, Month 6, Month 12, Month 18, Month 24/EOS, for confirmation of CR, and 
in the event of PD. In addition, subjects for whom inadequate or insufficient samples 
were available at Screening and subjects who receive bridging chemotherapy will 
also have bone marrow evaluations at Pre-treatment Screening.

Skeletal survey

The skeletal survey is required at Screening and will only be performed as clinically 
indicated thereafter. At the Investigator’s discretion, a PET/CT or DW-MRI may be 
performed in lieu of the skeletal survey to evaluate for bone lesions at Screening, 
provided that the same imaging modality is used for all future assessments.

Imaging by PET/CT or DW-MRI in subjects with extramedullary disease or if a new 
extramedullary lesion is suspected. 

MRD assessment by next-generation sequencing and/or flow cytometry evaluation of 
bone marrow aspirate samples collected at Screening (clone identification), Day 29, 
Month 3, Month 6, Month 12, Month 18, Month 24/EOS, and if otherwise collected 
to confirm CR.
8.12.2.
Physical Examination, Neurologic Examination, and MMSE
Physical examinations must include, at a minimum, neurologic, cardiovascular, pulmonary, 
abdominal, and extremity examinations. In addition, symptom-directed exams should be 
performed as appropriate. Height and weight will be measured at visits specified in Appendix A.
The neurologic examination should include, at minimum, a physical examination to assess 
cranial nerves, motor and sensory skills, coordination, and balance, as well as an MMSE.
The MMSE (see Appendix E) may be administered by an appropriately trained provider (eg,
physician, nurse); a neurologist is not required. Efforts should be made to have the same provider 
perform the MMSE on a given subject to maintain consistency of these assessments.
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Subjects who develop neurologic symptoms suspicious of and/or diagnosed as neurologic
toxicity will have daily MMSEs performed per Appendix E until resolution of symptoms, unless 
the subject is medically incapacitated and/or medically unable to complete the MMSE.
8.12.3.
Vital Signs
Vital signs include temperature, respiratory rate, heart rate, blood pressure, and SaO2 by pulse 
oximetry.
8.12.4.
Electrocardiogram
An ECG will be performed at Screening to assess eligibility to participate in the study.  
Additional ECGs may be required as clinically indicated by the Investigator in order to support 
diagnosis and monitoring of any cardiac-associated adverse events.
8.12.5.
Echocardiogram and Multigated Acquisition
A cardiac ECHO or MUGA scan will be performed at Screening to assess eligibility to 
participate in the study. Subjects who receive bridging chemotherapy with potentially cardiotoxic 
drugs must have a repeat ECHO or MUGA within 7 days prior to initiation of lymphodepleting 
chemotherapy.
8.12.6.
Local Laboratory Evaluations
Screening and other laboratory evaluations (see Table 4) will be performed at study visits 
indicated in Appendix A. Additional assessments should be performed between scheduled study 
visits as clinically required in order to diagnose and monitor AEs or expected events.
Requirements for reporting laboratory abnormalities are provided in Section 9.4.2.
Table 4:
Analytes for Local Laboratory Evaluations
Laboratory Panel
Analytes
Hematology
CBC with differential; absolute lymphocyte count (ALC) required within 24 hours 
prior to leukapheresis, CD4 T-cell count (or ALC if CD4 T-cell count is not available) 
is required at Pre-treatment Screening and as clinically indicated 
Chemistry
Glucose, BUN, serum creatininea, sodium, potassium, chloride, calcium, total protein, 
albumin, total and direct bilirubin, alkaline phosphatase, ALT, AST, magnesium, 
phosphate, bicarbonate, LDH, uric acid, triglycerides, beta-2-microglobulinb
Coagulation
Prothrombin time/ aPTT, INR, fibrinogen, and D-dimer
Viral serology 
HIV-1 and HIV-2
Hepatitis B (HBsAb, HBsAg, and HBcAb)
Hepatitis C (Hep C Ab and HCV RNA)
Serum pregnancy
Serum ß-hCG pregnancy test
Inflammatory markers
CRP, ferritin
CSF (if clinically 
indicated)
Protein, cell counts
Bone marrow
Cytogenetics (at screening visit if recent analysis not available)
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ALC = absolute lymphocyte count; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; ß-hCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; CBC 
= complete blood count; CRP = C-reactive protein; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B 
surface antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; Hep C Ab = hepatitis C antibody; 
HIV = human immunodeficiency virus; INR = international normalized ratio; LDH = lactate dehydrogenase.
a Serum creatinine, used to calculate creatinine clearance prior to initiation of lymphodepleting chemotherapy (see 
Section 6.2 and Appendix C).
b Beta-2-microglobulin is only required at the time points indicated in Appendix A.
8.12.7.
CSF Examination and CNS Symptom Assessment
CSF assessments and CNS imaging should be performed after JCARH125 administration as 
clinically indicated (eg, if new CNS symptoms occur, or if clinical signs or suspicion of CNS 
involvement by MM). If CT and/or MRI scans are obtained as part of a neurologic examination, 
results should be reported. If CSF fluid is collected, a sample should be submitted to the central 
laboratory to evaluate for the presence of JCARH125 (see the H125001 Central Laboratory 
Manual for instructions on sending a sample for JCARH125 testing). 
8.12.8.
Pharmacokinetics, Vector Sequence Testing, and Exploratory Research 
Evaluations
Testing and analysis of samples will generally follow the Schedule of Evaluations in
Appendix A. Allocation of samples to specific testing may be modified where sample material is 
limited; however, the total volume and type of material collected will not be modified beyond 
what is described in the H125001 Central Laboratory Manual. Instances where specimens are not 
collected at the required study visit due to insufficient sample volume or subject refusal will not 
be reported as a protocol deviation.
Detailed information regarding the collection, handling, and shipment of samples for PK, 
 and exploratory research assessments is provided in the H125001 
Central Laboratory Manual.
8.12.9.
Pharmacokinetic Assessments
Assessment of JCARH125 expansion and persistence (PK) in blood 
 
 will be determined by qPCR to detect the JCARH125 transgene.
8.12.9.1.
Viral Vector Sequence Testing
In accordance with the FDA guideline for evaluating delayed adverse events (Food and Drug 
Administration, 2006a), if more than 1% of cells in test samples collected at the Month 12 visit 
or later test positive for the JCARH125 transgene (as determined using the qPCR PK assay), the 
pattern of vector integration sites will be analyzed. If a predominant integration site is detected, 
then the subject will be asked to provide another blood draw 3 months later for follow-up testing.
If a subject develops disease recurrence or a new malignancy, the Sponsor will request a tumor 
sample and blood sample at time of new malignancy for assessment of viral vector sequence 
testing.
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8.12.10.
RCL Testing
Details regarding sample collection and processing are provided in the H125001 Central 
Laboratory Manual. RCL testing will be performed using an analytically validated polymerase 
chain reaction (PCR)-based assay to detect viral envelope sequence in peripheral blood. If all 
samples collected within the first year after the final dose of JCARH125 are negative, subsequent 
samples will be archived at a central laboratory. However, if any of the samples are positive, 
additional testing will be performed on PBMCs to confirm the result. If the repeat test is also 
positive, further analysis of the RCL will be undertaken to ascertain the nature of the RCL and 
potential effects. Any confirmed positive result from RCL testing will be reported as an adverse 
experience in the form of an Investigational New Drug (IND) safety report.
If a subject develops a new or recurrent neoplasm, the Sponsor will request a blood sample for 
assessment of RCL.
8.12.11.
Health-Related Quality of Life 
Health-related quality of life outcomes will be assessed using the EORTC QLQ-C30 and its 
MM-specific module QLQ-MY20, as well as the EuroQol instrument EQ-5D-5L. 
The EORTC QLQ-C30 is a 30-item scale composed of both multi-item scales and single-item 
measures. All of the scales and single-item measures range in score from 0 to 100. A higher scale 
score represents a higher level of well-being and better ability of daily functioning. A 10-point 
change in the scoring is considered to be a meaningful change in HRQoL. Thus, a high score for 
a functional scale represents a high/healthy level of functioning; a high score for the global 
health status/HRQoL represents a high HRQoL, but a high score for a symptom scale/item 
represents a high level of symptomatic problem. A copy of a sample QLQ-C30 questionnaire is 
presented in Appendix G.
QLQ-MY20 is composed of questions that address various domains of HRQoL important in 
MM. It was developed using the EORTC recommended guidelines, with additional patient 
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interviews based on a grounded theory approach. A copy of a sample QLQ-MY20 questionnaire 
is presented in Appendix H.
Subjects should complete the questionnaires at the study visit, prior to any procedure or clinical 
evaluation. For subjects who do not complete the questionnaire, the reason for not completing 
the questionnaires(s) will be recorded (eg, too sick/unable to complete, administration error, 
subject refusal). If the subject withdraws from the study prematurely, all attempts should be 
made to obtain final quality-of-life questionnaires prior to subject discontinuation.
8.12.12.
Health Economics and Outcomes Research
Health utility scores will be measured by the EuroQol instrument EQ-5D-5L. EQ-5D is a 
standardized measure of health status developed by the EuroQol Group in order to provide a 
simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of 
the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive 
system comprises dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression). Each dimension has 5 levels. A copy of a sample EQ-5D-5L questionnaire 
is presented in Appendix I.
Subjects should complete the questionnaires at the study visit, prior to any procedure or clinical 
evaluation. For subjects that do not complete the questionnaire, the reason for not completing the 
questionnaires(s) will be recorded (eg, too sick/unable to complete, administration error, subject 
refusal). If the subject withdraws from the study prematurely, all attempts should be made to 
obtain final quality-of-life questionnaires prior to subject discontinuation.
Hospital resource utilization will be assessed based on the numbers of ICU inpatient days and 
non-ICU inpatient days. Dates of admission and discharge to the hospital and to the ICU will be 
collected on the appropriate CRF.
9.
ASSESSMENT OF SAFETY
9.1.
Definitions
9.1.1.
Adverse Event
In accordance with the International Conference on Harmonisation (ICH) E2A guideline and 21 
CFR §312.32, an AE is defined as any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which does not necessarily have a causal relationship 
with this treatment.
Abuse, withdrawal, sensitivity, or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the Study Drug Administration CRF (see Section 6.4.4 for the definition of 
overdose). Any sequela of an accidental or intentional overdose of an investigational product 
should be reported as an AE on the AE CRF. If the sequela of an overdose is an SAE, then the 
sequela must be reported on an SAE report form and on the AE CRF. The overdose resulting in 
the SAE should be identified as the cause of the event on the SAE report form and CRF but 
should not be reported as an SAE itself.
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In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for JCARH125 or 
fludarabine/cyclophosphamide overdose. Actual treatment should depend on the severity of the 
clinical situation and the judgment and experience of the treating physician.
9.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that, at any dose, meets any of the criteria 
in Table 5. Special considerations for SAE reporting, including events that should always be 
reported as SAEs in this study, are presented in Table 6.
Table 5:
Definitions of Serious Adverse Events
Criteria
Description
Fatal
The AE resulted in death.
Life-threatening
The AE placed the subject at immediate risk of death. (This classification 
does not apply to an AE that hypothetically might have caused death if it 
had been more severe).
Hospitalization/prolongati
on of hospitalization
The AE resulted in hospitalization or prolongation of hospitalization (see
Table 6).
Disability/incapacity
The AE resulted in a disability, significant incapacity, or substantial 
disruption of the subject’s ability to conduct normal life functions
Congenital anomaly/birth 
defect
The AE was an adverse outcome in a child or fetus of a subject exposed 
to the study treatment regimen before conception or during pregnancy
Medically important
The AE was a medically important event that did not meet any of the 
above criteria, but may have jeopardized the subject and may have 
required medical or surgical intervention to prevent one of the outcomes 
listed above (examples include allergic bronchospasm that required 
treatment in an emergency room, seizures that do not result in 
hospitalization, or blood dyscrasias)
Table 6:
Special Considerations for SAE Reporting
Criteria
Description
Other events that should 
always be reported as SAEs 
through the EOS visit (per 
the FDA’s Guidance for 
Industry; Gene Therapy 
Clinical Trials – Observing 
Subjects for Delayed 
Adverse Events)
New/secondary malignancies
New onset or exacerbation of a pre-existing neurologic disorder
New onset or exacerbation of rheumatologic or other autoimmune 
disorder
New onset hematologic disorder
Rare and unexpected disorders with and unknown etiology 
(eg, Guillain-Barre, Stevens-Johnson’s syndrome)
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Table 6:
Special Considerations for SAE Reporting (Continued)
Criteria
Description
Hospitalization/
prolongation of 
hospitalization
Note: Complications 
and/or prolonged 
admissions for 
routine treatment or 
procedure do require 
SAE reporting.
This classification does not apply for the following hospitalizations:

Admissions for social or situational reasons (eg, no place to stay, live too 
far away to come for hospital visits) in the absence of any clinical AE

Admissions at the discretion of the Investigator for administration of 
lymphodepleting chemotherapy or JCARH125

Admissions for elective or pre-planned treatment or procedure for a 
pre-existing condition that is unrelated to the condition under study and has 
not worsened since providing informed consent

Admissions for routine treatment (eg, platelet transfusion) or monitoring of 
the condition under study that is not associated with any deterioration in 
condition. 

Admissions for routine procedures (eg, bone marrow aspiration) associated 
with the disease under study 

Emergency outpatient treatment or observation that does not result in 
admission, unless fulfilling other seriousness criteria above
9.2.
Grading and Intensity of Adverse Events
Adverse events, with the exception of CRS, will be graded using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03. 
CRS will be graded according to the grading scale adapted from Lee et al (Lee, 2014), which is 
provided in Table 8 in Appendix D.
The reported verbatim term should be the most descriptive medical diagnosis and does not have 
to be found in CTCAE.
AE severity and seriousness will be assessed independently. ‘Severity’ refers to the intensity of 
an AE, while ‘serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations.
9.3.
Relationship to Study Drug
The assessment of the relationship (related or not related) of an AE to lymphodepleting 
chemotherapy or JCARH125 is a clinical decision based on all available information and the 
following considerations:
Related:
There is a reasonable possibility and/or evidence to suggest a causal relationship 
between study drug and the AE and no other more likely alternative cause 
(concomitant drugs, therapies, disease complications, etc.) is suspected.
Not related: There is no reasonable possibility and/or evidence to suggest a causal relationship 
between study drug and the AE and another more likely alternative cause 
(concomitant drugs or therapies, disease complications, etc.) is suspected.
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9.4.
Recording Adverse Events
AEs/SAEs are recorded on the CRF in accordance with the reporting criteria for different time 
periods as defined in Section 9.5. Each AE/SAE is to be evaluated for:

Duration (onset and resolution dates) 

Severity, including Grade changes as per the CRF completion guidelines (see 
Section 9.2)

Outcome 

Seriousness (see Section 9.1.2)

Causal relationship with protocol-mandated procedures, lymphodepleting 
chemotherapy, or JCARH125 (see Section 9.3)
9.4.1.
Recording a Diagnosis versus Signs and Symptoms
Whenever possible, a unifying diagnosis should be reported as opposed to a listing of individual 
symptoms. However, symptoms should be grouped into a diagnosis only if each sign or symptom 
is a medically confirmed component of that diagnosis as evidenced by current standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
the individual symptom should be reported as a separate AE.
One exception to reporting a diagnosis as opposed to symptoms is the event of CRS. If a subject 
experiences an event of CRS, a diagnosis of CRS and any Grade changes for the event of CRS 
should be reported as an AE. Individual signs and symptoms of CRS, and maximum Grade for 
those signs and symptoms, should be entered as CRS symptoms on a separate CRF.
When manifestations of neurologic toxicities appear in the presence of CRS, those 
manifestations should be reported as separate AEs.
9.4.2.
Clinical Laboratory Abnormalities and Other Abnormal Assessments
Any laboratory abnormality (eg, clinical chemistry or hematology) or other abnormal assessment 
findings (eg, ECG or vital signs) that meets any of the following criteria should be recorded as an 
AE or SAE:

Requires medical or surgical intervention 

Leads to product discontinuation, delay, or interruption

Associated with clinical signs and/or symptoms

Otherwise clinically significant as determined by the Investigator
Whenever possible, the clinical diagnosis, rather than the laboratory result, should be reported by 
the Investigator (eg, anemia versus low hematocrit). 
Clinically significant abnormal laboratory values occurring during the study will be followed 
until repeat tests return to normal, stabilize, or are no longer clinically significant.
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9.4.3.
Recording Serious Adverse Events
The following should be considered when recording SAEs:

Death is an outcome of an event. The event that resulted in death should be recorded 
in the CRF and reported on the SAE report form.

For hospitalizations or surgical or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness.

Events related to disease progression must be reported as SAEs if they meet serious 
criteria. When reporting an SAE of progression of the disease under investigation, 
specific manifestations of the progression (eg, “new bone pain,” “worsening anemia 
and renal failure”) should be reported, rather than the general term “disease 
progression.”
9.4.4.
Death Reports
Deaths must be reported as an SAE on the Death CRF per the reporting periods described in
Table 7.
Progressive disease is considered a study endpoint; however, death due to disease progression 
must be reported as an SAE if it occurs from the start of leukapheresis to within 90 days of 
JCARH125 administration. Deaths that occur more than 90 days after JCARH125 infusion will 
be captured on the Death CRF and reported as an SAE only if considered related to any 
protocol-mandated procedure or JCARH125.
9.4.5.
Pregnancy
To ensure subject safety, each pregnancy occurring in a female subject or in the female partner 
of a male subject from the time of informed consent until the end of study must be reported to 
the Sponsor within 24 hours of learning of its occurrence. If the pregnancy is discovered 
following initiation of lymphodepleting chemotherapy treatment, the pregnancy should be 
followed to determine outcome. All pregnancies or suspected pregnancies occurring at any time 
after receipt of JCARH125, in either a female subject of childbearing potential or partner of 
childbearing potential of a male subject, are immediately reportable events.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
Investigator to the Sponsor. Pregnancy follow-up should be recorded on the same form and 
should be submitted to the Sponsor within 24 hours of awareness. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. Abortion, whether accidental, therapeutic, 
or spontaneous, should be reported as an SAE. Congenital anomalies or birth defects, as defined 
by the “seriousness criteria” in Section 9.1.2, should be reported as SAEs.
All pregnancies should be monitored for the full duration, and all perinatal and neonatal 
outcomes should be reported.
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9.5.
Reporting Adverse Events to the Sponsor
9.5.1.
Reporting Periods for AEs and SAEs
Reporting periods for AEs and SAEs are summarized in Table 7.
Table 7:
Reporting Periods for AEs and SAEs
Time Period
Events to Record
Informed consent to leukapheresis
Only AEs/SAEs related to protocol-mandated 
procedures
Leukapheresis to start of lymphodepleting 
chemotherapy

AEs related to protocol-mandated procedures

All SAEs

AEs associated with any signs/symptoms/diagnosis 
of opportunistic infections
From start of lymphodepleting chemotherapy 
to 90 days following the dose of JCARH125
(or to 30 days after the last dose of Flu/Cy 
for subjects who are discontinued from the 
study prior to JCARH125 administration)
All AEs/SAEs (note that this includes complications 
that arise from any procedure, whether or not the 
procedure was considered protocol-mandated) must be 
recorded/reported
For subjects starting a subsequent 
non-chemotherapy-containing anticancer 
therapy (eg, checkpoint inhibitors, IMiDs) 
prior to 90 days following the dose of 
JCARH125
All AE/SAEs will be collected after initiation of the 
subsequent therapy for 90 days following final 
JCARH125 infusion or 30 days following subsequent 
therapy, whichever is longer.
For subjects starting a subsequent 
chemotherapy-containing anticancer therapy 
prior to 90 days following the dose of 
JCARH125
Only AEs and SAEs related to JCARH125 or a 
protocol-mandated procedure must be 
recorded/reported after initiation of subsequent therapy
From 91 days following the dose of 
JCARH125 to end of study
Only AEs and SAEs related to JCARH125 or a 
protocol-mandated procedure must be 
recorded/reported
Other events that should always be reported 
as SAEs through the EOS visit (per the 
FDA’s Guidance for Industry; Gene Therapy 
Clinical Trials – Observing Subjects for 
Delayed Adverse Events)

New/second primary malignancies

New onset or exacerbation of a pre-existing 
neurologic disorder

New onset or exacerbation of rheumatologic or 
other autoimmune disorder

New onset hematologic disorder

Rare and unexpected disorders with and unknown 
etiology (eg, Guillain-Barre, Stevens-Johnson’s 
syndrome)
SAEs will be followed until they resolve or return to baseline, the event stabilizes or is no longer 
considered clinically significant by the Investigator, the subject dies or withdraws consent, or the 
study is closed. All non-serious AEs will be followed through the safety reporting period
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described in Table 7. Certain non-serious AEs, as requested by the Sponsor, may be followed 
until resolution, return to baseline, or study closure.
9.5.2.
Reporting Timelines for SAEs
All SAEs must be reported within 24 hours of awareness. An SAE Report Form may be 
submitted and should also include supporting documentation (eg, hospital admission notes, test 
results).
For initial SAE reports, the following minimum criteria must be reported on the SAE form:

Subject number

Date of event onset

Description of event

Study treatment

Relationship to study treatment
The completed SAE Report Form and supporting documentation should be sent according to the 
instructions on the SAE Report Form.
Relevant follow-up information is to be submitted to the Sponsor as soon as it becomes 
available.
10.
STATISTICAL METHODS
10.1.
General Considerations
All analyses will be separated by dose level unless otherwise specified. In the Phase 1 dose 
escalation portion of the trial, summaries will be prepared by dose level and overall. Data from 
Phase 1 dose escalation at the RP2D(s), data from the Phase 1 anakinra cohort at the RP2D(s),
and data from Phase 2 expansion will be pooled for analysis. If more than 1 dose level is selected 
as the RP2D, then analyses pooled across the RP2D levels in Phase 1 dose escalation, the Phase 
1 anakinra cohort, and Phase 2 expansion will be considered as the primary analyses, with 
analyses by dose level being considered as supplementary. The Phase 2 efficacy analysis may be 
refined in a detailed statistical analysis plan (SAP), following further discussion with regulatory 
authorities.  Data from the Phase 1 anakinra cohort will be summarized separately but subjects 
treated in this cohort at the RP2D(s) will also be pooled with subjects treated at the RP2D(s) in 
Phase 1 dose escalation and Phase 2 expansion for the primary analyses.  Data from the Phase 2a 
prior BCMA-directed anti-myeloma therapy cohorts will be analyzed separately from Phase 1 
and Phase 2 expansion.  Supplementary analyses pooling across all subjects treated at the 
RP2D(s) across all cohorts may be performed if deemed warranted.
By-subject listings will be provided. Summary tables for continuous variables will contain the 
following statistics: N (number in population), n (number with data), mean, standard deviation, 
95% confidence intervals (CIs) on the mean as appropriate, median, minimum, and maximum. 
Summary tables for categorical variables will include: N, n, percentage, and 95% CIs on the 
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percentage as appropriate. Unless otherwise indicated, 95% CIs for binary variables will be 
calculated using the binomial distribution (exact method) and will be 2-sided. 
Unless otherwise specified, all statistical hypothesis testing will be 2-sided at the 0.05 level of 
significance.
Subjects who do not receive JCARH125 will be included in by-subject listings but will not be 
included in data summaries unless otherwise specified.
Subjects who receive non-conforming product of JCARH125 will be analyzed separately. 
10.2.
Analysis Sets
10.2.1.
Analysis Sets for Phase 1 Dose Escalation
10.2.1.1.
Screened Analysis Set
The Screened Analysis Set includes all subjects who have signed informed consent.
10.2.1.2.
Leukapheresed Analysis Set
The Leukapheresed Analysis Set includes all subjects who have signed informed consent and 
who undergo leukapheresis.
10.2.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who receive JCARH125.
10.2.1.4.
DLT-evaluable Analysis Set
The DLT-evaluable Analysis Set includes all subjects who have received the conforming 
JCARH125 cell product at the assigned dose level, and who have either experienced a DLT or 
were followed for the full DLT evaluation period. This analysis set will be used for the 
determination of the MTD. The DLT-evaluable period is defined as Days 1 to 22, for a total 
evaluation period of 21 days following JCARH125 infusion.
10.2.1.5.
Efficacy Analysis Set
The Efficacy Analysis Set in Phase 1 includes all subjects who have received conforming 
JCARH125 cell product, have measurable disease at the last disease assessment prior to 
receiving JCARH125 infusion, and who have at least 1 post-infusion disease response 
assessment.
10.2.1.6.
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set includes subjects in the safety analysis set who have the 
necessary PK measurements to provide interpretable results for the specific parameters of 
interest.
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10.2.2.
Analysis Sets for the Phase 1 Anakinra Cohort
10.2.2.1.
Safety Analysis Set
The Safety Analysis Set for the Phase 1 anakinra cohort includes all subjects who receive 
JCARH125 and at least one dose of anakinra as prophylactic intervention.
10.2.2.2.
Efficacy Analysis Set
The Efficacy Analysis Set for the Phase 1 anakinra cohort includes all subjects who have 
received conforming JCARH125 cell product at the dose level 3 and/or dose level 3a, received at 
least one dose of anakinra as prophylactic intervention, have measurable disease at the last 
disease assessment prior to receiving JCARH125 infusion, and who have at least 1 post-infusion 
disease response assessment.  All efficacy endpoints will be analyzed using this analysis set.
10.2.2.3.
Additional Analysis Sets
The Screened Set, Leukapheresed Analysis Set, and PK Analysis Set for the Phase 1 anakinra 
cohort will follow the same definition as in Phase 1 dose escalation.
10.2.3.
Primary Analysis Sets
Data from Phase 1 dose escalation at the RP2D(s), data from the Phase 1 anakinra cohort at the 
RP2D(s), and data from Phase 2 expansion will be pooled for the primary analyses of the study.
10.2.3.1.
Efficacy Analysis Set
The Efficacy Analysis Set includes all subjects across Phase 1 dose escalation, the Phase 1 
anakinra cohort, and Phase 2 expansion of the trial who have measurable disease at the last 
disease assessment prior to JCARH125 infusion and who receive conforming product at the 
RP2D(s). All efficacy endpoints will be analyzed using this analysis set.
10.2.3.2.
Safety Analysis Set
The Safety Analysis Set includes all subjects who receive JCARH125. This analysis set will be 
used in the analyses of safety endpoints.  
10.2.3.3.
Additional Analysis Sets
The Screened Set, Leukapheresed Analysis Set, and PK Analysis Set for the primary analyses 
will follow the same definition as in Phase 1 dose escalation. Additional analysis sets may be 
defined in the SAP.
10.2.4.
Analysis Sets for the Phase 2a Prior BCMA-Directed Anti-Myeloma Therapy 
Cohorts
Each prior BCMA-directed anti-myeloma therapy cohort will have separate analysis datasets.
10.2.4.1.
Safety Analysis Set
The Safety Analysis Set for each prior BCMA-directed anti-myeloma therapy cohort includes all 
subjects who receive JCARH125.
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10.2.4.2.
Efficacy Analysis Set
The Efficacy Analysis Set for each prior BCMA-directed anti-myeloma therapy cohort includes 
all subjects who have received conforming JCARH125 cell product at the RP2D(s) and have 
measurable disease at the last disease assessment prior to receiving JCARH125 infusion.  All 
efficacy endpoints will be analyzed using this analysis set.
10.2.4.3.
Additional Analysis Sets
The Screened Set, Leukapheresed Analysis Set, and PK Analysis Set for each prior BCMA-
directed anti-myeloma therapy cohort will follow the same definition as in Phase 1 dose 
escalation.
10.3.
Planned Analyses
10.3.1.
Subject Disposition and Baseline Characteristics
Descriptive summaries of demographics, baseline characteristics, and subject disposition will be 
provided for each analysis set.
10.3.2.
Primary Endpoints in Phase 1 Dose Escalation
The following are primary endpoints in Phase 1 dose escalation:

Incidence of DLTs
The type and incidence of DLTs will be summarized by dose level and total. The 
rates of DLT at each dose level and the MTD will be estimated using isotonic 
regression as described in (Ji, 2010)

Type, frequency, and severity of AEs

Incidence and severity of clinically significant laboratory abnormalities
All AEs will be listed and summarized (see Section 10.3.11.110.3.11.1 for details).
10.3.3.
Secondary Endpoints in Phase 1 Dose Escalation 
Secondary endpoints in Phase 1 dose escalation are:

Cmax, tmax, and AUC of JCARH125 CAR T cells in the blood
Determination of these parameters will be based on data obtained after the 
JCARH125 infusion through the Day 29 visit. Cmax is the maximal concentration after 
infusion; tmax is the first study day the Cmax is reached. AUC will be calculated using 
the trapezoid rule. 

Duration of persistence of JCARH125 CAR T cells in the blood 
Persistence will be defined as the time between the first measurement above the limit 
of detection until the last measurement above the limit of detection.

Overall response rate (defined as sCR, CR, VGPR, or PR) assessed according to 
IMWG criteria
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
Complete response rate (defined as sCR or CR) assessed according to IMWG criteria
Analysis of PK endpoints is discussed in Section 10.3.13.
10.3.4.
Primary Endpoints for the Phase 1 Anakinra Cohort 
The following are primary endpoints in the Phase 1 anakinra cohort:

Incidence and severity of AEs

Incidence of Grade ≥2 CRS in subjects receiving prophylactic anakinra relative to 
incidence of Grade ≥2 CRS in subjects treated at the RP2D(s) in the Phase 1 dose 
escalation portion of the trial 

Onset of Grade ≥2 CRS in subjects receiving prophylactic anakinra relative to onset 
of Grade ≥ 2 CRS in subjects treated at the RP2D(s) in the Phase 1 dose escalation 
portion of the trial 

The number and percentage of subjects with no CRS occurring on study days 1, 2, 
or 3

Incidence and severity of clinically significant laboratory abnormalities
All AEs will be listed and summarized (see Section 10.3.11.1 for details).
The number and percentage of subjects developing Grade ≥2 CRS, as well as an upper 1-sided 
80% CI will be provided and benchmarked against the observed rate from dose levels 3 and/or 3a 
from the dose escalation portion of the trial.  A similar analysis will be provided for the number 
and percentage of subjects with no CRS occurring on study days 1, 2, or 3.  The onset of Grade 
≥2 CRS will be summarized descriptively and will be referenced to onset of Grade ≥ 2 CRS in 
subjects treated at the RP2D(s) in the Phase 1 dose escalation portion of the trial.
10.3.5.
Secondary Endpoints for the Phase 1 Anakinra Cohort
The following are secondary endpoints in the Phase 1 anakinra cohort:

Cmax, tmax, and AUC of JCARH125 CAR T cells in the blood

Duration of persistence of JCARH125 CAR T cells in the blood 

Overall response rate (defined as sCR, CR, VGPR, or PR) assessed according to 
IMWG criteria

Complete response rate (defined as sCR or CR) assessed according to IMWG criteria
Analysis of PK endpoints is discussed in Section 10.3.13.
10.3.6.
Primary Endpoint for Phase 2
ORR (defined as sCR, CR, VGPR, or PR), as assessed by the IRC according to IMWG criteria, 
is the primary endpoint for Phase 2.
The ORR is the best overall response recorded from the time of the JCARH125 infusion until 
disease progression, end of study, or the start of another anticancer therapy or stem cell 
transplant. Subjects without any reported disease response assessments will be considered 
non-responders.
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The primary analysis of the primary endpoint will be conducted in the Efficacy Analysis Set as 
defined in Section 10.2.3.1. The primary efficacy analysis in Phase 2 will test the null hypothesis 
of ORR ≤30% against the alternative hypothesis that the ORR > 30% at a 1-sided 0.025 level of 
significance based on the exact binomial test, ie,
H0: ORR ≤ 30% vs Ha: ORR > 30%
In addition, an exact 2-sided 95% CI for ORR will be provided for the primary analysis.
Data will be presented for both Investigators' assessments and IRC assessments. The findings of 
the IRC will be considered primary for analysis of ORR. Concordance between IRC and 
Investigator assessments will be summarized by the percent agreement for ORR. 
A sensitivity analysis including all subjects in the leukapheresed analysis set will be conducted 
for the primary endpoint based on IRC assessment. Subjects who underwent leukapheresis but 
did not have any reported disease assessments by the IRC will be considered as non-responders 
for the sensitivity analysis.
10.3.7.
Secondary Endpoints for Phase 2
Secondary efficacy endpoints in Phase 2 include the following:
1. CR rate, defined as CR or sCR, as assessed by the IRC according to IMWG criteria.
Subjects without any reported disease response assessments will be considered 
non-responders.
2. Duration of response, defined as the time from first objective response (sCR, CR, VGPR, 
or PR) as assessed by the IRC until the earliest date of PD or death from any cause
3. Duration of complete response, defined as the time from first complete response (sCR, 
CR) as assessed by the IRC according to IMWG criteria until the earliest date of PD or 
death from any cause
4. Incidence and severity of AEs
5. Incidence and severity of clinically significant laboratory abnormalities
6. Time to response, defined as the time from JCARH125 infusion until first objective 
response (sCR, CR, VGPR, or PR) as assessed by the IRC according to IMWG criteria
7. Time to complete response, defined as the time from JCARH125 infusion until first 
complete response (sCR, CR) as assessed by the IRC according to IMWG criteria
8. OS, defined as the time from JCARH125 infusion until death from any cause
9. PFS, as assessed by the IRC according to IMWG criteria, defined as the time from the 
JCARH125 infusion until the earliest date of disease progression or death from any cause
10. Cmax, Tmax, and AUC of JCARH125 CAR T cells in the blood
11. Duration of persistence of JCARH125 CAR T cells in the blood 
12. Measurement of HRQoL changes as assessed using the EORTC QLQ-C30 and its 
MM-specific module QLQ-MY20, as well as the EuroQol instrument EQ-5D-5L
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13. Numbers of ICU inpatient days and nonICU inpatient days and reasons for 
hospitalization
A key secondary efficacy analysis in Phase 2 will test the null hypothesis of CR ≤5% against the 
alternative hypothesis that the CR > 5% at a 1-sided 0.025 level of significance using the exact 
binomial test based on the Efficacy Analysis Set. In addition, an exact 2-sided 95% CI for CR 
will be provided. To preserve the type I error rate, a gatekeeping approach will be used as 
discussed in Section 10.4.
The Kaplan-Meier method will be used to summarize time-to-event endpoints, and the median 
time to event and associated 95% CI will be provided.
Duration of response will be summarized using the Kaplan-Meier method on the set of subjects 
that achieved sCR, CR, VGPR, or PR as assessed by the IRC according to IMWG criteria.
Subjects that do not progress or die will be censored at the last disease response assessment.
Subjects will also be censored at the last disease response assessment prior to receiving a new 
anticancer agent. Duration of CR will be summarized in a similar manner on the set of subjects 
that achieved sCR or CR as assessed by the IRC according to IMWG criteria.
Time to response and time to complete response will be summarized using descriptive statistics.
OS will be summarized using the Kaplan-Meier method. Subjects that do not die will be 
censored at the last known date alive.
PFS will be summarized using the Kaplan-Meier method. Subjects that do not progress or die 
will be censored at the last disease response assessment. Subjects will also be censored at the last 
disease response assessment prior to receiving a new anticancer agent.
10.3.7.1.
Efficacy Subgroup Analyses
Efficacy subgroup analysis will be performed on the following variables: 

Age: < 65 versus ≥65 years at the time of the JCARH125 infusion 

Sex: male versus female

Ethnicity: Hispanic or Latino versus not Hispanic or Latino

Race: White versus other races

Prior autologous stem cell transplant status: yes versus no

Prophylactic anakinra usage:  yes versus no
Subgroup analyses will be performed for the primary and secondary efficacy endpoints and will 
only be performed if there are at least 5 subjects in each subgroup. Other subgroup analyses will 
also be performed if deemed appropriate.
10.3.8.
Other Secondary Endpoints for Phase 2
Other secondary endpoints for Phase 2 are:

Type, frequency, and severity of AEs
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
Type, frequency, and severity of clinically significant laboratory abnormalities as 
recorded on the adverse event page

Cmax, tmax, and AUC of JCARH125 CAR T cells in the blood

Duration of persistence of JCARH125 CAR T cells in the blood 

HRQoL change from baseline

Days hospitalized in ICU and days hospitalized in non-ICU
All AEs will be listed and summarized (see Section 10.3.11.1 for details).
Details regarding analysis of pharmacokinetic data are provided in Section 10.3.13.
10.3.9.
Primary Endpoint for the Phase 2a Prior-BCMA Directed Anti-Myeloma 
Therapy Cohort
ORR (defined as sCR, CR, VGPR, or PR) as assessed by the IRC according to IMWG criteria, is 
the primary endpoint for the Prior-BCMA Directed Anti-Myeloma cohorts.
The ORR is the best overall response recorded from the time of the JCARH125 infusion until 
disease progression, end of study, or the start of another anticancer therapy or stem cell 
transplant. 
The primary efficacy analysis in Phase 2a will test for each cohort separately the null hypothesis 
of ORR ≤10% against the alternative hypothesis that the ORR > 10% at a 1-sided 0.20 level of 
significance based on the exact binomial test, ie,
H0: ORR ≤ 10% vs Ha: ORR > 10%
In addition, exact lower 1-sided 80% and exact 2-sided 95% CI for ORR will be provided for the 
primary analysis.  If the lower 1-sided confidence limit for ORR exceeds the 10% null 
hypothesis threshold (for example, 3 or more responders out of 14 subjects), then this would be 
considered a preliminary positive signal.
A 2-stage approach is planned for each cohort in the Phase 2a portion of the study with a futility 
analysis for each cohort planned after 6 subjects have been evaluated for response and stopping 
for futility if no responses have been observed.
Analyses pooling across all cohorts in Phase 2a will also be provided.
10.3.10.
Secondary Endpoints the Phase 2a Prior-BCMA Directed Anti-Myeloma 
Therapy Cohorts
The following are secondary endpoints in Phase 2a:

Complete response rate as assessed by the IRC according to IMWG criteria

Incidence and severity of AEs

Incidence and severity of clinically significant laboratory abnormalities

Cmax, tmax, and AUC of JCARH125 CAR T cells in the blood

Duration of persistence of JCARH125 CAR T cells in the blood 
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
Duration of response as assessed by the IRC according to IMWG criteria

Duration of CR as assessed by the IRC according to IMWG criteria

Time to response as assessed by the IRC according to IMWG criteria

Time to complete response as assessed by the IRC according to IMWG criteria

OS

PFS as assessed by the IRC according to IMWG criteria
Analysis of secondary efficacy endpoints in Phase 2a will be produced separately for each cohort 
and will be based on the methods outlined in Section 10.3.6.  No formal statistical hypothesis 
testing is planned for the complete response endpoint in Phase 2a, however exact 80% and 95% 
CIs will be generated for the complete response rate for each cohort in Phase 2a.  
Details regarding analysis of pharmacokinetic data are provided in Section 10.3.13.
10.3.11.
Safety Analyses
Safety analyses will be based on the Safety Analysis Set.
10.3.11.1. Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs 
(TEAEs). A TEAE is defined as an AE that starts any time from initiation of JCARH125 
administration through and including 90 days following the JCARH125 infusion. Any AE 
occurring after the initiation of another anticancer treatment will not be considered a TEAE.
Reporting of AEs will be based on the Medical Dictionary for Regulatory Activities (MedDRA) 
and CTCAE version 4.03. TEAEs will be summarized by System Organ Class (SOC), Preferred 
Term, and severity. A subject who reports multiple occurrence of TEAEs within the same SOC 
and Preferred Term is counted only once using the maximum severity grade for summaries.
10.3.11.2. Laboratory Data
All laboratory data will be listed. The focus of laboratory data summarization (including 
hematology, chemistry) will be on treatment-emergent laboratory abnormalities. A 
treatment-emergent laboratory abnormality is defined as an abnormality that, compared with
baseline, worsens by at least one grade within 90 days following the JCARH125 infusion. The 
baseline value is defined as the last available recorded value on or prior to the date of the 
JCARH125 infusion.
If baseline data are missing, then any graded abnormality (ie, an abnormality that is Grade ≥1 in 
severity) will be considered treatment-emergent. Hematological and chemistry data will be 
graded according to CTCAE version 4.03 when applicable. Grade 0 includes all non-missing 
values that do not meet the criteria for an abnormality of at least Grade 1. Grade 5 will not be 
used. Some laboratory tests have criteria for both increased and decreased levels; analyses for 
each direction (ie, increased, decreased) will be presented separately. 
The following summaries will be presented for selected analytes:
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
Raw values and changes from baseline will be summarized by visit for numerical lab 
results in conventional units

Number of subjects by CTCAE severity grade, with corresponding percentages at 
each visit, and maximum post-baseline severity grade

Number and percentage of subjects with a treatment-emergent CTCAE Grade 3 or 4 
laboratory abnormality
Shift tables showing the change in CTCAE severity grade from baseline to the maximum 
severity grade post baseline; for laboratory tests where CTCAE grade does not exist, the shift 
table will present the low/normal/high shift.
 
 
 
 
10.3.11.4. Other Safety Analyses
Vital signs and the MMSEs will be summarized using descriptive statistics and listed. All other 
safety data will be listed.
10.3.11.5. Safety Subgroup Analyses
In the safety analysis set, safety subgroup analyses will be performed for key safety summaries
and will only be performed if there are at least 5 subjects in each subgroup. Other subgroup 
analyses will also be performed if deemed appropriate.
Subgroup analysis will be performed for key safety summaries based on the following variables:

Age: < 65 versus ≥65 years at the time of the JCARH125 infusion

Sex: male versus female

Ethnicity: Hispanic or Latino versus not Hispanic or Latino

Race: White versus other races

Prophylactic anakinra usage:  yes versus no
10.3.12.
Concomitant Medications
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary (WHO-DD) and listed. All concomitant medications and blood product transfusions 
administered after the JCARH125 infusion will be summarized.
Specific treatments for CRS (eg, corticosteroids, tocilizumab) will be summarized, as will 
specific treatments for neurotoxicity.
Anticancer interventions will be summarized.
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10.3.13.
Pharmacokinetic Analyses
Assessment of JCARH125 expansion and persistence (PK) in blood 
 
 will be determined by qPCR to detect the JCARH125 transgene. 
For all subjects in the PK analysis set, the in vivo PK profile of JCARH125 cells in target tissues 
(blood,
 and CSF if collected) will be characterized, including Cmax, tmax, AUC, and 
other relevant PK parameters. The maximum extent of expansion of JCARH125 in the blood will 
be determined by Cmax, along with the persistence of JCARH125 in the blood 
 
based on the qPCR assay (time above lower limit of detection).
The following PK parameters will be displayed graphically where possible: qPCR-based 
JCARH125 concentration versus time in peripheral blood 
The following PK parameters, along with other relevant PK parameters, will be estimated from 
the individual concentration-time profiles using a non-compartmental analysis approach: AUC, 
Cmax, tmax, and time above lower limit of detection. Cmax is the maximal concentration after 
infusion. tmax is the first study day the Cmax is reached. AUC will be calculated using the 
trapezoid rule. Determination of AUC, Cmax, and tmax will be based on data obtained after the 
JCARH125 infusion through the Study Day 29 visit. All concentrations below the limit of 
detection or quantitation, or missing data, will be labeled as such in the concentration data 
listings.
Persistence will be defined as the time between the first measurement above the limit of 
detection until the last measurement above the limit of detection.
Descriptive statistics for PK parameters will be categorized by key efficacy and safety measures 
and will include mean, standard deviation, coefficient of variation, minimum, and maximum.
 
10.3.13.1. Pharmacokinetic Subgroup Analyses
Subgroup analyses will be based on the PK analysis set and performed for key PK summaries 
based on the following variables:

Age: < 65 versus ≥65 years at the time of the JCARH125 infusion 

Sex: male versus female

Cellular and/or humoral immunogenicity: present (positive) or absent (negative)

Ethnicity: Hispanic or Latino versus not Hispanic or Latino

Race: White versus other races

Prophylactic anakinra usage:  yes versus no
10.3.14.
Health-Related Quality of Life 
In the absence of a more specific hypothesis, the global score will be used as the primary 
HRQoL outcome and the physical functional score and fatigue item will be used as secondary 
outcomes. 
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The EORTC QLQ-C30 and QLQ-MY20 will be analyzed according to the functional scores and 
the recommendations in the scoring manual. Scores will be descriptively tabulated (number, 
mean, standard deviation, median, 95% CI) at each time point with change from baseline and 
summarized over time with graphical displays by cohort and for all subjects. Single items will be 
also described in terms of number and frequency. Details will be given in the HRQoL SAP.
10.3.15.
Health Economics and Outcomes Research
The EQ-5D-5L will be analyzed according to the recommendations in the scoring manual. 
Hospital resource utilization will be assessed based on the numbers of ICU inpatient days and 
non-ICU inpatient days. Descriptive statistics of ICU inpatient days and non-ICU inpatient days 
will be provided.
Details will be given in a separate HEOR SAP. 
10.3.16.
Exploratory Endpoints
The exploratory endpoints for the study are listed in Section 3. Details of the exploratory 
analyses are provided in the SAP.
10.4.
Multiplicity
The overall type 1 error rate will be strongly controlled at the 1-sided 2.5% level.
The statistical hypotheses planned to be tested are:
1. H0 ORR ≤30%, Ha ORR > 30% in the Efficacy Analysis Set
2. H0 CR ≤5%, Ha CR > 5% in the Efficacy Analysis Set
A gatekeeping approach will be used to control the type 1 error rate at the 1-sided 2.5% 
significance level for evaluations of the primary endpoint and the CR endpoint. Hypothesis 2) 
will only be tested at the 1-sided 0.025 significance level if hypothesis 1) is rejected at the 
1-sided 0.025 significance level.
10.5.
Sample Size Considerations
Subjects in Phase 1 who are not evaluable for DLT will be replaced. A sample size of 
approximately 75 treated subjects at the RP2D(s) is planned for the primary efficacy evaluation.  
A sample size of up to 120 subjects is planned for Phase 1 dose escalation with up to 
approximately 106 subjects potentially evaluated in Phase 1 dose escalation at dose levels not at 
the RP2D(s). The Phase 1 anakinra cohort will be comprised of up to 14 subjects and is planned 
to be included in the primary efficacy evaluation.  Phase 2a will be comprised of up to 42 
subjects (up to 14 subjects per cohort).  Assuming approximately 5% to 10% of subjects may not 
be evaluable for the primary endpoint due to reasons such as not being evaluable for DLT 
assessment, receiving non-conforming product, or not having measurable disease after receiving 
bridging chemotherapy, a total sample size of 245 subjects is planned for this Phase 1/2 study.
Upon completion of the Phase 1 dose-escalation portion of the study, additional subjects will be 
enrolled such that at least 75 subjects will be included in the Efficacy Analysis Set. The 
appropriate sample size per dose level will be based on discussions with regulatory agencies if 
more than 1 dose level is selected as the RP2D(s).
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Based on the cumulative safety and antitumor activity data from subjects treated in Phase 1 dose 
escalation, one or more dose levels will be selected for further evaluation in the Phase 2
expansion and Phase 2a portions of the trial (the RP2D(s)). It is anticipated that 14-30 subjects 
will be treated at a dose level in Phase 1 dose escalation prior to determination of a RP2D(s). A 
sample size of 14-30 subjects at a dose level will provide a high probability of excluding an 
overly toxic dose level from RP2D(s) consideration. For example, if the true DLT rate for a dose 
level is 45%, then the probability of excluding this dose level from RP2D(s) consideration per 
the mTPI-2 table is ≥74% for all sample sizes in the range of 14-30 subjects. The standard error 
of the ORR point estimate based on 14 or 30 subjects will be <13.4% or 9.2%, respectively, 
providing reasonable precision for decision making regarding the determination of the RP2D(s).
For the primary efficacy endpoint of ORR in the Efficacy Analysis Set, a sample size of 
75 subjects will allow for approximately 90% power or higher based on the null hypothesis of 
ORR ≤30% assuming an effect size of ORR ≥49% using a 1-sided exact test at the 0.025 level.
For the key secondary endpoint of CR in the Efficacy Analysis Set, a sample size of 75 subjects 
will allow for approximately 80% power or higher based on the null hypothesis of CR ≤5% 
assuming an effect size of CR ≥15%.
The reference ORR of 30% is based on results from a daratumumab monotherapy study (Lonial, 
2016) evaluated in 106 subjects with R/R MM who had received at least 3 prior lines of therapy 
including a proteasome inhibitor and an immunomodulatory agent or who were 
double-refractory to a proteasome inhibitor and an immunomodulatory agent. The ORR and CR 
rate were 29.2% (95% CI: 20.8, 38.9) and 2.8% (95% CI: 0.6, 8.0), respectively, in the 
daratumumab monotherapy study.
A sample size of up to 14 subjects per cohort as a proof of concept in the Phase 2a prior-BCMA 
directed anti-myeloma therapy portion of the study allows for approximately 80% power or 
greater using a 1-sided exact test at the 0.20 level based on the null hypothesis of ORR ≤10% 
assuming an effect size of ORR ≥30%. A 2-stage approach is planned for each cohort in the 
Phase 2a portion of the study with a futility analysis for each cohort planned after 6 subjects have 
been evaluated for response and stopping for futility if no responses have been observed.  
A sample size of 14 subjects is planned for the Phase 1 anakinra cohort.  An objective of this 
cohort is to investigate if prophylactic use of anakinra in subjects treated at the RP2D(s) with 
JCARH125 will reduce the onset, incidence and severity of CRS relative to subjects treated with 
JCARH125 at the RP2D(s) in Phase 1.  The following hypothesis will be tested in this cohort as 
an evaluation of the potential merits of prophylactic intervention with anakinra:  
H0 P ≥P0, Ha P < P0 where P denotes the true Grade 2 or higher CRS TEAE incidence rate when 
JCARH125 is administered at the dose level 3 and/or dose level 3a with prophylactic use of 
anakinra and P0 denotes the observed Grade 2 or higher TEAE CRS incidence rate for the 
subjects in Phase 1 of this trial treated at the dose level 3 and/or dose level 3a. A 1-sided test at 
the 0.20 significance level using a normal approximation to the binomial distribution will be 
used for this hypothesis test.  A sample size of 14 subjects will provide at least 80% power for 
this hypothesis test assuming P0 is at least 40% and assuming an effect size of at least a 50% or 
more reduction in P0 if subjects are treated with JCARH125 at the dose level 3 and/or dose level 
3a with prophylactic anakinra. 
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10.6.
Timing of Analyses
10.6.1.
Interim Analyses
An interim analysis may be performed after at least 20 subjects have been treated at the RP2D(s)
pooled across Phase 1 dose escalation, the Phase 1 anakinra cohort and Phase 2 expansion and 
are evaluable for response (ie, have had at least 1 post-treatment disease assessment and all 
objective responses confirmed). The purpose of the interim analysis is to inform the development 
program for JCARH125. There are no intentions to stop the trial early for positive efficacy;
therefore, no adjustment to the alpha level will be made for the final analysis.
10.6.2.
Primary Analyses
The primary analysis for ORR is planned after at least 75 subjects in the Efficacy Analysis Set 
have been evaluated for response. The exact timing of the analysis will be determined after 
discussions with regulatory agencies.
10.6.3.
Final Analysis
The final analyses will be carried out after all subjects have completed or discontinued the study 
for any reason. No formal hypothesis testing will be performed at the final analysis.
11.
DATA MANAGEMENT
11.1.
Data Collection System
An electronic data capture (EDC) system provided by Juno will be used for data collection. The 
EDC system is a fully validated, secure system that conforms to 21 CFR Part 11 requirements.
Access to the EDC system is role-based, and login credentials will be provided only after 
completion of the assigned role-based training.
11.2.
Data Quality
Study site personnel will enter data into the CRFs in the EDC system. A Juno Clinical Research 
Associate (CRA) or designee will verify data recorded in the CRFs with the source documents.
To ensure complete and accurate data, automated data validation checks programmed within the 
EDC system will flag missing and non-conformant data during data entry. Data review by the 
Juno project team may result in additional questions. Items flagged by the automated data 
validation checks and by the project team will appear as electronic queries on the applicable CRF 
in the EDC system for a specified user role to resolve. All data entry and subsequent data 
changes are logged in an audit trail in the EDC system. 
The Principal Investigator is responsible for ensuring that the data entered into the CRFs are 
complete and accurate and will electronically sign the CRFs for each subject prior to database 
lock.
Following database lock, an electronic copy of the final subject casebook will be provided to the 
study site for archival.
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12.
STUDY ADMINISTRATION
12.1.
Regulatory and Ethical Considerations
12.1.1.
Regulatory Authority Review
The study will be conducted in accordance with Good Clinical Practice (GCP), the protocol, and 
any other applicable Federal, state, and/or local regulatory requirements.
12.1.2.
Institutional Review Board/Independent Ethics Committee Approval
It is the responsibility of the Investigator to ensure that the appropriate IRB or IEC has reviewed 
and approved this protocol prior to initiating the study. The IRB/IEC must also review and 
approve the investigative site’s Informed Consent Form (ICF), other written information 
provided to the subject, and all subject materials that may be used. 
If the protocol, Investigator’s Brochure, or ICF are amended during the study, per local 
regulations the Investigator is responsible for ensuring that the IRB/IEC has reviewed and 
approved these amended documents. In addition, IRB/IEC approval of the amended documents 
must be obtained before implementation and before new subjects are consented to participate in 
the study using the amended version of the ICF.
12.1.3.
Institutional Biosafety Committee Approvals
JCARH125 is composed of autologous T cells that have been manipulated via genetic 
modification in vitro to express a CAR directed against BCMA. Since neither the subject source 
material nor the final investigational drug product has been tested for the presence of 
communicable diseases in accordance with the provisions in 21 CFR §1271.90(a)(1), the 
JCARH125 investigational drug product should be handled according to institutional procedures 
for materials that may contain infectious materials (eg, BioSafety Level 1 or 2). 
It is the responsibility of the Investigator to ensure that the appropriate Institutional Biosafety 
Committee (IBC) has reviewed and approved this protocol, protocol amendments, and any other 
required materials prior to initiating the study if required per institutional policy. 
Each site will be approved by the IBC in accordance with local procedures and country-specific 
regulatory requirements. Documentation of IBC approval must be in place prior to JCARH125
shipment to the site.
12.1.4.
Subject Informed Consent
Prior to study entry, the Investigator, or a qualified person designated by the Investigator, will be 
responsible for explaining the nature, purpose, benefits, and risks of participation in the study to 
each subject, subject’s legally acceptable representative, or impartial witness. Written informed 
consent must be obtained prior to the subject entering the study (before initiation of any study 
related procedure). Sufficient time will be allowed to discuss any questions raised by the subject.
The Investigator or designated staff will document this process in the study records. The 
Investigator must use the current IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent form will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person conducting the consent 
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discussion, and also by an impartial witness if required by IRB or IEC or local requirements. The 
process of obtaining the informed consent will be in compliance with all federal regulations, ICH 
requirements (ICH E6 4.8) and local laws.
If the ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB/IEC. The investigative site 
must use the amended ICF for all new subjects and, if required per institutional policy, repeat the 
consent process with the amended ICF for any ongoing subjects.
12.2.
Investigator Obligations
12.2.1.
Investigator Responsibilities
The Investigator is responsible for ensuring that all study site personnel, including 
sub-investigators and other responsible study staff members, conduct the study in compliance 
with the Declaration of Helsinki and the ICH E6 Guideline for GCP, including the archiving of 
essential documents.
The Investigator will ensure adherence to the basic principles of GCP, as outlined in 21 CFR 
312, Subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, Part 50 and 21 CFR, 
Part 56.
The Investigator, sub-investigators, and key study staff as listed on FDA Form 1572 will comply 
with 21 CFR, Part 54, providing documentation of any financial conflict of interest. This 
documentation must be provided prior to the Investigator’s (and any sub-investigators’) 
participation in the study. The Investigator and sub-investigator(s) agree to notify Juno of any 
change in reportable interests during the study and for 1 year following study close-out at the 
Investigator’s site. 
If necessary to amend either the protocol or the study ICF, the Investigator will be responsible 
for ensuring that the IRB/ IEC reviews and approves the amended documents, and that subjects 
are informed of applicable changes, and updates.
The Investigator will sign and return to Juno the “Protocol Signature Page” of the original 
protocol and any protocol amendment, provide current medical licenses, curriculum vitae, and 
FDA Form 1572 “Statement of Investigator.” All forms must be updated as applicable 
throughout the study.
12.2.2.
Investigator Reporting Requirements 
In accordance with applicable regulatory requirements, the Investigator is solely obligated to 
inform the IRB/IEC of progress of the study and notify the IRB/IEC of study closure. The 
Investigator must also provide Juno with copies of all IRB/IEC correspondence that relate to 
study approvals, updates, or changes. The Investigator must also forward all IRB/IEC renewals 
to Juno.
12.2.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
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after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the subject.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately.  You can do so by 
emailing 
 or by contacting the Celgene Customer Care Center 
12.3.
Access to Information for Monitoring
Site monitoring is necessary to ensure that the rights and well-being of study subjects are 
protected; that the reported trial data are accurate, complete, and verifiable; and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, 
and with applicable regulatory requirement(s). In accordance with regulations and guidelines, the 
designated Juno CRA must have direct access to the Investigator’s source documentation 
(including medical records, test and procedure results, investigator and study staff notes, etc.) in 
order to verify the accuracy of the data recorded in the CRF.
The CRA is responsible for routine review of the CRFs at regular intervals throughout the study 
to verify adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered on them. The CRA should have access to any subject records needed to verify the 
entries on the CRFs. The Investigator agrees to cooperate with the CRA to ensure that any 
problems detected through any type of monitoring (central, on site) are resolved.
Details regarding site monitoring are provided in the H125001 Study Monitoring Plan.
12.4.
Site Audits and Regulatory Inspections
Representatives of regulatory authorities, Juno, or IRB/IEC may conduct inspections or audits of 
the clinical study. If the Investigator is notified of an inspection by a regulatory authority, the 
Investigator will notify the Juno Study Manager immediately. The Investigator will provide to 
representatives of a regulatory agency or Juno access to records, facilities, and personnel for the 
effective conduct of any inspection or audit.
12.5.
Protocol Deviations
Protocol deviations must be sent to the site’s IRB per their policies. The Investigator is 
responsible for knowing and adhering to the institution’s IRB requirements.
12.6.
Quality Assurance and Quality Control
Juno or its designee will perform quality control and quality assurance checks of all clinical 
studies that it sponsors. Before the enrollment of any subject in this study, Juno personnel will 
review and provide training as needed to the Investigator, sub-investigators, and study site 
personnel regarding the following: protocol, IB, CRFs and procedures for their completion, 
informed consent process, and procedures for reporting SAEs. Site visits will be performed by 
Juno CRAs or designees periodically throughout the study. During these visits, information 
recorded on the CRFs will be verified against source documents, and requests for clarification or 
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correction may be made. The CRFs will be reviewed by the CRA for safety information, 
completeness, accuracy, and logical consistency. Computer programs that identify data 
inconsistencies may be used to help monitor the clinical study. Requests for clarification or 
correction will be sent to Investigators via data queries.
12.7.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Juno will be responsible for ensuring 
that this protocol is listed at the ClinicalTrials.gov website per the US FDA requirement and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study.
12.8.
Study Completion
Upon completion or early termination of the study, the following activities, when applicable, 
must be conducted by the CRA and the Investigator:

Return of all electronic and any non-electronic study data to Juno, if requested

Data clarifications and/or resolutions

Accounting, reconciliation, and final disposition of used and unused study drug

Review of site study records for completeness
In addition, Juno reserves the right to temporarily suspend or prematurely terminate this study 
for any reason (see Section 4.12).
12.9.
Site Termination
Juno has the right to terminate a study site at any time for various reasons. Study termination and 
follow-up will be performed in compliance with the conditions set forth in 21 CFR Parts 312.50 
and 312.56 and local regulation.
12.10.
Records Retention
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. Records of subjects, 
source documents, monitoring visit logs, inventory logs of study investigational product, 
regulatory documents, and other Juno correspondence pertaining to the study must be kept in the 
appropriate study files at the site. Source documents include all recordings and observations or 
notations of clinical activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical study. This includes any electronic records. These records will be 
retained in a secure file for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. Prior to the transfer or 
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destruction of these records, Juno must be notified in writing and be given the opportunity to 
further store such records.
12.11.
Confidentiality of Information
Individual subjects and their research data will be identified by a unique study identification 
number. Subjects’ names will remain confidential and will not be included in the database. This 
confidentiality extends to testing of biological samples and genetic tests in addition to the clinical 
information relating to subjects. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of the 
Sponsor. All study findings will be stored in electronic databases. The Investigator will maintain 
a personal subject identification list (subject numbers with the corresponding subject names) to 
enable records to be identified.
For tracking purposes and product chain of custody, subjects’ name and date of birth will be 
communicated to the study sponsor’s scheduling and manufacturing staff. This information will 
also be listed on the leukapheresis cell collection bag, and other containers throughout the 
JCARH125 manufacturing process. This information will be maintained in a separate 
limited-access database and not together with any other clinical information. Only staff who need 
to use this information will have access to it.
12.12.
Future Use of Stored Specimens and Data
Samples of blood and/or tissue collected during this study may be stored for future research at 
Juno in subjects who provide consent. 
12.13.
Publication Plan
Interim data from this study may be presented at scientific meetings. Juno is responsible for the 
H125001 final clinical study report (CSR) prepared according to ICH guidelines. A final CSR 
will be prepared and will include any subject who has signed informed consent, regardless of 
whether the study is completed or prematurely terminated. If appropriate, an abbreviated report 
may be prepared. The CSR will be in compliance with any applicable regulatory requirements 
and national laws and will be written in English.
12.14.
Conflict of Interest
Any potential conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed in accordance with 21 CFR 
Part 54.
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13.
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14.
APPENDICES
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APPENDIX A. SCHEDULES OF EVALUATIONS
Table A-1: Pre-treatment Period
Procedure (protocol section 
reference)
Study period
Notes
Screening
Apheresis
Pre-treatment 
Screening
(≤14 [+3] days prior 
to lymphodepletion)
Informed consent/HIPAA
X
Eligibility criteria (5.1, 5.2)
X
X
Medical history
X
ECOG (Appendix F)
X
X
Height/weight
X
Physical examination (8.12.2)
X
X
Should include a routine neurologic examination with evaluation of the cranial nerves, 
motor and sensory skills, coordination, and balance, as well as a mental status 
examination
Vital signs (8.12.3)
X
X
X
12-lead ECG (8.12.4)
X
May be performed up to 8 weeks before Screening
MUGA/ECHO
Xa
Xb
a May be performed up to 8 weeks before Screening
b Only required for subjects who receive bridging chemotherapy with potentially 
cardiotoxic drugs; must be conducted within 7 days prior to lymphodepletion
Viral serology (8.12.6)
X
Brain MRI
X
May be performed up to 8 weeks before Screening
CSF assessment (8.12.7)
X
Only required in subjects with signs/symptoms of potential CNS involvement
Serum pregnancy test
X
Xc
Only in females of childbearing potential
c Must be done within 7 days prior to initiation of lymphodepleting chemotherapy
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Table A-1: Pre-treatment Period
Procedure (protocol section 
reference)
Study period
Notes
Screening
Apheresis
Pre-treatment 
Screening
(≤14 [+3] days prior 
to lymphodepletion)
Pregnancy prevention 
counseling
X
X
To be documented in patient source at site.
Hematology (8.12.6)
X
Xd
X
d May be done up to 24 hours prior to leukapheresis
Hematology should be performed within 5 days prior to eligibility verification and 
subject enrollment
Coagulation (8.12.6)
X
X
Coagulation tests should be performed prior to any biopsy procedures
Coagulation tests should be performed within 5 days prior to eligibility verification 
and subject enrollment
Chemistry (8.12.6)
X
X
Chemistry should be performed within 5 days prior to eligibility verification and 
subject enrollment 
Inflammatory markers
X
X
Includes CRP and ferritin
Inflammatory markers should be performed within 5 days prior to eligibility 
verification and subject enrollment
β2-microglobulin
X
X
β2-microglobulin must be performed within 5 days prior to eligibility verification and 
subject enrollment and within 3 days prior to initiation of lymphodepleting 
chemotherapy
MM serum tests
X
X
Includes SPEP, immunofixation, sFLC, quantitative immunoglobulins
MM 24-hour urine tests 
(UPEP and immunofixation)
X
X
Pre-treatment Screening sample is not required for subjects with negative M-protein in 
their urine (by both UPEP and immunofixation) at Screening
Cytogenetics
X
A cytogenetics report is requested if available; a new test is not required
PET/CT or DW-MRI
Xe
Xf
e All subjects must have either a PET/CT or DW-MRI at Screening to evaluate for 
extramedullary plasmacytomas. At the Investigator’s discretion, PET/CT or 
DW-MRI may be used in lieu of the skeletal survey to evaluate for bone lesions 
provided the same imaging modality is used for all future assessments 
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Table A-1: Pre-treatment Period
Procedure (protocol section 
reference)
Study period
Notes
Screening
Apheresis
Pre-treatment 
Screening
(≤14 [+3] days prior 
to lymphodepletion)
f A PET/CT or DW-MRI is required for subjects who had extramedullary lesions at 
Screening, received subsequent bridging therapy after leukapheresis, or who have 
suspicion of a new extramedullary lesion. The same imaging modality should be 
used for all assessments. Subjects who did not have extramedullary disease at 
screening and who do not have an evident proof of disease progression, do not have 
to repeat a PET/CT or DW MRI after bridging therapy.
Skeletal survey
X
At the Investigator’s discretion, PET/CT or DW-MRI may be performed in lieu of the 
skeletal survey to evaluate for bone lesions provided the same imaging modality is 
used for all future assessments
Bone marrow biopsy/aspirate, 
plasmacytoma biopsy for 
disease assessments (8.12.1) 
and PK 
 
8.12.9.3)
Xg
Xh
g Bone marrow samples required for all subjects. 
h Bone marrow samples required only for subjects who had inadequate or insufficient 
bone marrow samples at Screening and for subjects who received bridging 
chemotherapy. Plasmacytoma biopsy samples are also requested for subjects with 
accessible lesions.
Blood sample for PK, 
 
 (8.12.8)
X
Blood sample for RCL 
(8.12.10)
X
HRQoL questionnaires 
(8.12.11)
X
Leukapheresis (8.3)
X
Adverse events (9.5.1)
Xi
Xj
Xj
i Record AEs/SAEs related to protocol-mandated procedures until leukapheresis
j Record AEs related to protocol-mandated procedures and all SAEs 
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Table A-1: Pre-treatment Period
Procedure (protocol section 
reference)
Study period
Notes
Screening
Apheresis
Pre-treatment 
Screening
(≤14 [+3] days prior 
to lymphodepletion)
Concomitant medications (6.7)
Xk
Xl
Xl
k Record all medications taken at the time of AEs/SAEs related to protocol-mandated 
procedures until leukapheresis
l Record all medications taken at the time of AEs related to protocol-mandated 
procedures and at the time of an SAE
MMSE
X
If subjects develop neurologic symptoms suspicious of and/or diagnosed as 
neurologic toxicity, subjects will have daily MMSE exams (see Appendix E) until 
resolution of symptoms, unless the subject is medically incapacitated and/or medically 
unable to complete the MMSE
AE, adverse event; BCMA, B-cell maturation antigen; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; DW-MRI, diffusion-weighted magnetic 
resonance imaging; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HIPAA, Health Insurance Portability and Accountability Act; HRQoL, health-related 
quality of life; MM, multiple myeloma; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; PET/CT, positron emission tomography/computed 
tomography; PK, pharmacokinetics; RCL, replication-competent lentivirus; SAE, serious adverse event; sFLC, serum free light chain; SPEP, serum protein electrophoresis; UPEP, 
urine protein electrophoresis.
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Table A-2: Treatment Period
Lymphodepletion
JCARH125
Notes
Study day
-7 
to -2a 1b
2
3 4-5
8
11 15
22
29
a All evaluations should be performed daily prior to administration of 
Flu/Cy unless otherwise indicated
b All evaluations should be performed prior to JCARH125 administration 
unless otherwise indicated
Month
Visit window (days)
±1 ±1 ±2 ±2
±2
Procedure (protocol section reference)
ECOG (Appendix F)
X
X
First day of lymphodepletion only
Weight
X
First day of lymphodepletion only (may be obtained within the previous 48 
hours)
Physical examination (8.12.2)
X
X
X X
X
X
X
X
X
X
Should include a routine neurologic examination with evaluation of the 
cranial nerves, motor and sensory skills, coordination, and balance, as well 
as a mental status examination
Vital signs (8.12.3)
X
X
X X
X
X
X
X
X
X
ECG
X
Brain MRI
As clinically indicated to assess signs and 
symptoms of neurotoxicity
If CT and/or MRI scans are obtained as part of a neurologic examination, 
results should be reported
CSF assessment (8.12.7)
As clinically indicated to assess signs and 
symptoms of neurotoxicity
If a lumbar puncture is performed, samples should be submitted to the 
central laboratory for evaluation of JCARH125 cells and inflammatory 
markers
Hematology (8.12.6)
Xc
X
X X
X
X
X
X
X
X
c Hematology should be performed within 48 hours prior to the start of 
lymphodepleting chemotherapy
Coagulation (8.12.6)
X
X
X X
X
X
X
X
X
X
Coagulation tests should be performed within 7 days prior to any biopsy 
procedures
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Table A-2: Treatment Period
Lymphodepletion
JCARH125
Notes
Study day
-7 
to -2a 1b
2
3 4-5
8
11 15
22
29
a All evaluations should be performed daily prior to administration of 
Flu/Cy unless otherwise indicated
b All evaluations should be performed prior to JCARH125 administration 
unless otherwise indicated
Month
Visit window (days)
±1 ±1 ±2 ±2
±2
Chemistry (8.12.6)
Xd
X
X X
X
X
X
X
X
X
d Chemistry should be performed within 48 hours prior to the start of 
lymphodepleting chemotherapy, serum creatinine is used to calculate the 
creatinine clearance using the Cockcroft-Gault equation (Appendix D)
Inflammatory markers
X
X X
X
X
X
X
X
X
Includes CRP and ferritin.
Inflammatory markers should be performed within 48 hours prior to the 
start of lymphodepleting chemotherapy.
β2-microglobulin
X
MM serum tests 
X
Includes SPEP, immunofixation, sFLC, quantitative immunoglobulins
MM 24-hour urine tests
X
Day 29 sample is not required for subjects with negative M-protein in their 
urine (by both UPEP and immunofixation) at Screening
PET/CT or DW-MRI
Xe
e Day 29 is only required if clinically indicated to assess rapidly 
progressing MM disease.  The same imaging modality should be used for 
all assessments.
Skeletal survey
As clinically indicated for signs/symptoms 
of new bone lesions
At the Investigator’s discretion, PET/CT or DW-MRI may be performed in 
lieu of the skeletal survey to evaluate for bone lesions provided the same 
imaging modality is used for all assessments
Bone marrow biopsy/aspirate 
(8.12.1), plasmacytoma biopsy 
for disease assessments and PK 
Xf
X
Required for all subjects. 
f Plasmacytoma biopsy at Day 15 is not required.
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Table A-2: Treatment Period
Lymphodepletion
JCARH125
Notes
Study day
-7 
to -2a 1b
2
3 4-5
8
11 15
22
29
a All evaluations should be performed daily prior to administration of 
Flu/Cy unless otherwise indicated
b All evaluations should be performed prior to JCARH125 administration 
unless otherwise indicated
Month
Visit window (days)
±1 ±1 ±2 ±2
±2
and biomarker evaluations 
(8.12.9.3)
Disease response assessment by 
Investigator (8.12.1)
X
Blood sample for PK,
 
(8.12.8)
X
X
X
X
X
X
X
X
HRQoL questionnaires 
(8.12.11)
X
Lymphodepleting chemotherapy 
(6.2)
X
Lymphodepleting chemotherapy should be withheld if the calculated CrCl 
is ≤ 60 mL/min or radioisotope GFR is ≤ 60 mL/min/1.73 m2. Subjects 
with CrCl between 60 and 70 mL/min should have a 20% reduction of 
fludarabine.  
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Table A-2: Treatment Period
Lymphodepletion
JCARH125
Notes
Study day
-7 
to -2a 1b
2
3 4-5
8
11 15
22
29
a All evaluations should be performed daily prior to administration of 
Flu/Cy unless otherwise indicated
b All evaluations should be performed prior to JCARH125 administration 
unless otherwise indicated
Month
Visit window (days)
±1 ±1 ±2 ±2
±2
Anakinra prophylaxis* (6.3)
X
X
X X
X
*For subjects receiving prophylactic intervention of anakinra.
1 dose of 100 mg SC the night before and in the morning, 3 hours before 
JCARH125 infusion.
Continue for d1, d2, d3, d4, d5 at a dose of 100 mg SC.
In the case of CRS onset, anakinra 100 mg SC should be administered 
twice daily until CRS resolution. 
The anakinra dose should be administered at approximately the same time 
every day. 
JCARH125 administration (6.3)
X
AEs (9.5.1)
X
X
X X
X
X
X
X
X
X
Collect all AEs/SAEs from start of lymphodepleting chemotherapy to 90 
days after the dose of JCARH125 (or to 30 days after the last dose of 
Flu/Cy for subjects who are discontinued from the study prior to 
JCARH125 administration)
Concomitant medications (6.7)
X
X
X X
X
X
X
X
X
X
Record all concomitant medications from start of lymphodepleting 
chemotherapy to 90 days after the dose of JCARH125 (or to 30 days after 
the last dose of Flu/Cy for subjects who are discontinued from the study 
prior to JCARH125 administration)
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Table A-2: Treatment Period
Lymphodepletion
JCARH125
Notes
Study day
-7 
to -2a 1b
2
3 4-5
8
11 15
22
29
a All evaluations should be performed daily prior to administration of 
Flu/Cy unless otherwise indicated
b All evaluations should be performed prior to JCARH125 administration 
unless otherwise indicated
Month
Visit window (days)
±1 ±1 ±2 ±2
±2
MMSE
X
X
X
X
X
Subjects who develop neurologic symptoms suspicious of and/or 
diagnosed as neurologic toxicity will have daily MMSE exams (see 
Appendix E) until resolution of symptoms, unless the subject is medically 
incapacitated and/or medically unable to complete the MMSE.
AE, adverse event; CR, complete response; CrCl, creatinine clearance; CRP, C-reactive protein; CSF, cerebrospinal fluid; Cy, cyclophosphamide; ECOG, Eastern Cooperative 
Oncology Group; Flu, fludarabine; GFR, glomerular filtration rate; HRQoL, health-related quality of life; MM, multiple myeloma; MMSE, Mini Mental State Examination; MRI, 
magnetic resonance imaging; PET/CT, positron emission tomography/computed tomography; PK, pharmacokinetics; sFLC, serum free light chain; SC = subcutaneous; SPEP, 
serum protein electrophoresis; UPEP, urine protein electrophoresis.
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Table A-3: Post-treatment Period
Post-treatment
PD or 
relapse
EOS
Notes
Study day
60
90
120
150
180
270
365
Month
2
3
4
5
6
9
12
15
18
21
24
Visit window (days)
±14
±14
±14
±14
±14
±14
±14
±14 ±14
±14
±14
±14
Procedure (protocol section reference)
ECOG (Appendix F)
X
X
X
X
X
X
X
X
X
X
X
X
Weight and vital signs
X
X
Physical examination (8.12.2)
X
X
X
X
X
X
X
X
X
X
X
X
Should include a routine neurological 
examination with evaluation of the cranial 
nerves, motor and sensory skills, coordination, 
and balance, as well as a mental status 
examination
Brain MRI
As clinically indicated to assess signs and symptoms of neurotoxicity
If CT and/or MRI scans are obtained as part of 
a neurological examination, results should be 
reported
CSF assessment (8.12.7)
As clinically indicated to assess signs and symptoms of neurotoxicity
If a lumbar puncture is performed, samples 
should be submitted to the central laboratory 
for evaluation of JCARH125 cells and 
inflammatory markers
Serum pregnancy test
X
X
X
X
Only in females of childbearing potential
Pregnancy prevention 
counseling
X
X
X
X
Hematology (8.12.6)
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (8.12.6)
X
Coagulation tests should be performed prior to any biopsy procedures
Chemistry (8.12.6)
X
X
X
X
X
X
X
X
X
X
X
X
Inflammatory markers
X
X
X
X
X
X
X
X
X
X
X
X
Includes CRP and ferritin
β2-microglobulin
X
X
X
X
X
X
X
X
X
X
X
X
Approved
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Table A-3: Post-treatment Period
Post-treatment
PD or 
relapse
EOS
Notes
Study day
60
90
120
150
180
270
365
Month
2
3
4
5
6
9
12
15
18
21
24
Visit window (days)
±14
±14
±14
±14
±14
±14
±14
±14 ±14
±14
±14
±14
MM serum tests 
X
X
X
X
X
X
X
X
X
X
X
X
Includes SPEP, immunofixation, sFLC, 
quantitative immunoglobulins
MM 24-hour urine test
X
X
X
X
X
X
X
X
X
X
X
X
Subjects who are negative for M-protein in 
their urine (by both UPEP and 
immunofixation) at Screening are only 
required to provide a 24-hour urine sample to 
confirm a CR and at EOS, or as clinically 
indicated
PET/CT or DW-MRI
X
X
X
X
X
X
X
X
X
Required at all disease measurement time 
points for all subjects with extramedullary 
disease at Screening or Pre-treatment 
Screening or if a new extramedullary lesion is 
suspected. Unscheduled assessment is 
required if clinically indicated to assess 
rapidly progressing MM disease.
Skeletal survey
As clinically indicated for signs/symptoms of new bone lesions
At the Investigator’s discretion, PET/CT or
DW-MRI may be performed in lieu of the 
skeletal survey (x-ray) to evaluate for bone 
lesions provided the same imaging modality is 
used for all assessments
Bone marrow biopsy/aspirate 
(8.12.1), plasmacytoma biopsy 
for disease assessments and PK 
 
(8.12.9.3)
X
X
X
X
X
X
Bone marrow samples required at indicated 
time points for all subjects.
Bone marrow samples are also required at 
any time when necessary to confirm a 
CR/sCR response.
When accessible, plasmacytoma biopsy 
samples are also requested for subjects who 
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Table A-3: Post-treatment Period
Post-treatment
PD or 
relapse
EOS
Notes
Study day
60
90
120
150
180
270
365
Month
2
3
4
5
6
9
12
15
18
21
24
Visit window (days)
±14
±14
±14
±14
±14
±14
±14
±14 ±14
±14
±14
±14
are suspected of achieving responses of 
sCR/CR/VGPR, or in case of disease 
progression and occurrence of new 
plasmacytomas.
Disease response assessment by 
Investigator (8.12.1)
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample for PK, 
 
 (8.12.8)
X
X
X
X
X
X
X
X
Blood sample for RCL 
(8.12.10)
X
X
X
X
X
HRQoL questionnaires 
(8.12.11)
X
X
X
X
X
X
MMSE
X
Subjects who develop neurologic symptoms 
suspicious of and/or diagnosed as neurologic 
toxicity will have daily MMSE exams (see 
Appendix E) until resolution of symptoms, 
unless the subject is medically incapacitated 
and/or medically unable to complete the 
MMSE.
Adverse events (9.5.1)
Collect all 
AEs/SAEsd
Collect AEs/SAEs related to JCARH125
d Collect all AEs/SAEs to 90 days after the 
dose of JCARH125 (or to 30 days after the 
last dose of Flu/Cy for subjects who are 
discontinued from the study prior to 
JCARH125 administration)
Concomitant medications (6.7)
Record all 
con medse Record the following medications: 
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Table A-3: Post-treatment Period
Post-treatment
PD or 
relapse
EOS
Notes
Study day
60
90
120
150
180
270
365
Month
2
3
4
5
6
9
12
15
18
21
24
Visit window (days)
±14
±14
±14
±14
±14
±14
±14
±14 ±14
±14
±14
±14

G-CSF (until start of new MM therapy)

Transfusions (until start of new MM therapy)

IVIG (until start of new MM therapy)

Anticancer therapies

Medications used to treat Grade ≥3 AEs/SAEs related to 
JCARH125
e Record all con meds to 90 days after the dose 
of JCARH125 (or to 30 days after the last 
dose of Flu/Cy for subjects who are 
discontinued from the study prior to 
JCARH125 administration)
AE, adverse event; CR, complete response; CRP, C-reactive protein; CSF, cerebrospinal fluid; Cy, cyclophosphamide; ECOG, Eastern Cooperative Oncology Group; EOS, End of 
Study; Flu, fludarabine; GVHD, graft-versus-host disease; HRQoL, health-related quality of life; IVIG, intravenous immunoglobulin; MM, multiple myeloma; MMSE, Mini 
Mental State Examination; MRI, magnetic resonance imaging; PD, progressive disease; PET/CT, positron emission tomography/computed tomography; PK, pharmacokinetics; 
SAE, serious adverse event; sFLC, serum free light chain; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.
Approved
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1.0
v

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Table A-4: Post-PD Period
Post-treatment
EOS
Notes
Study day
60
90
120
150
180
270
365
Month
2
3
4
5
6
9
12
15
18
21
24
Visit window (days)
±14
±14
±14
±14
±14
±14
±14
±14 ±14
±14
±14
Procedure (protocol section reference)
Blood sample for PK, 
 
 (8.12.8)
X
X
X
X
X
X
X
Blood sample for RCL 
(8.12.10)
X
X
X
X
Serum pregnancy test
X
X
X
X
Pregnancy prevention 
counseling
X
X
X
X
Adverse events (9.5.1)
Collect all 
AEs/SAEsd
Collect AEs/SAEs related to JCARH125
d Collect all AEs/SAEs to 90 days after the dose of 
JCARH125 (or to 30 days after the last dose of 
Flu/Cy for subjects who are discontinued from the 
study prior to JCARH125 administration)
Concomitant medications (6.7)
Record all 
con medse Record the following medications: 

Anticancer therapies

Medications used to treat Grade ≥3 AEs/SAEs related to 
JCARH125
e Record all con meds to 90 days after the dose of 
JCARH125 (or to 30 days after the last dose of 
Flu/Cy for subjects who are discontinued from the 
study prior to JCARH125 administration)
AE, adverse event; Cy, cyclophosphamide; EOS, End of Study; Flu, fludarabine; PD, progressive disease; PK, pharmacokinetics; RCL, replication-competent lentivirus; SAE,
serious adverse event.
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APPENDIX B. IMWG UNIFORM RESPONSE CRITERIA FOR 
MULTIPLE MYELOMA
Responsea
Criteria
Sustained 
MRD-negativeb

MRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined 
below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to 
further specify the duration of negativity (eg, MRD-negative at 5 years)
Flow MRD-negativeb

Absence of phenotypically aberrant clonal plasma cells by NGF on bone marrow 
aspirates using the EuroFlow standard operation procedure for MRD detection in 
multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 
10⁵ nucleated cells or higher
Sequencing 
MRD-negativeb

Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of 
a clone is defined as less than two identical sequencing reads obtained after DNA 
sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated 
equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher
Imaging-positive 
MRD-negativeb

MRD negativity as defined by NGF or NGS plus disappearance of every area of 
increased tracer uptake found at baseline or a preceding PET/CT or decrease to less 
mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue
Stringent complete 
response (sCR)

CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow 
biopsy by immunohistochemistry

(κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma 
cells)c
Complete response 
(CR)

Negative immunofixation of serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow aspirates

When the only method to measure disease is by serum FLC levels, CR can be defined 
as a normal FLC ratio of 0.26 to 1.65, in addition to the CR criteria listed previously.
Very good partial 
response (VGPR)

Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
≥90% reduction in serum M-protein level plus urine M-protein level < 100 mg/24 h

When the only method to measure disease is by serum FLC levels, VGPR requires a 
≥90% decrease in the difference between involved and uninvolved FLC levels.
Partial response (PR)

≥50% reduction of serum M-protein plus reduction in 24-hour urinary M-protein by 
≥90% or to < 200 mg/24 h

If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria.

If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma-cell percentage was ≥30%. 

In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD)d
of soft tissue plasmacytomas is also required
Minimal response 
(MR)

≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein 
by 50%–89%. In addition, if present at baseline, a ≥50% reduction in the size (SPD)d
of soft tissue plasmacytomas is also required
Stable disease (SD)

Not meeting criteria for CR, VGPR, PR, MR, or PD 

Not recommended for use as an indicator of response; stability of disease is best 
described by providing the time-to-progression estimates.
Progressive disease 
(PD)e,f,g
Any one or more of the following criteria:
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Responsea
Criteria

Increase of ≥ 25% from lowest confirmed response value in one or more of the 
following criteria:
Serum M-protein (absolute increase must be ≥0.5 g/dL)
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL
Urine M-protein (absolute increase must be ≥200 mg/24 h)
In subjects without measurable serum and urine M-protein levels at baseline, the 
difference between involved and uninvolved FLC levels (absolute increase must be 
> 10 mg/dL)
In subjects without measurable serum and urine M-protein levels and without 
measurable involved FLC levels at baseline, bone marrow plasma-cell percentage 
irrespective of baseline status (absolute increase must be ≥10%)

Appearance of a new lesion(s), ≥50% increase from nadir in SPDd of > 1 lesion, or 
≥50% increase in the longest diameter of a previous lesion >1 cm in short axis

≥50% increase in circulating plasma cells (minimum of 200 cells/μL) if this is the only 
measure of disease
Relapse (not 
applicable for this 
study)
Clinical relapse requires one or more of the following criteria:

Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) 
related to the underlying clonal plasma-cell proliferative disorder. It is not used in 
calculation of time to progression or progression-free survival but is listed as something 
that can be reported optionally or for use in clinical practice

Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures 
do not constitute progression)

Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPDd of 
the measurable lesion

Hypercalcaemia (> 11 mg/dL)

Decrease in hemoglobin of ≥2 g/dL not related to therapy or other 
non-myeloma-related conditions;

Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma

Hyperviscosity related to serum paraprotein
FLC = free light chain; MRD = minimal residual disease; NGF = next-generation flow; NGS = next-generation sequencing; SPD
= sum of the products of the maximal perpendicular diameters of measured lesions; SUV = standardized uptake value.
a All categories of response and MRD require no known evidence of progressive or new bone lesions if radiographic studies 
were performed. All response categories require two consecutive assessments (confirmatory measurement); however, 
consecutive assessments of bone marrow for CR and MRD is not required. Confirmatory evaluations can be carried out at any 
time following the initial test provided it is before any new/non-protocol therapy.
b IMWG MRD criteria requires a CR
c Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an 
abnormal clone is κ/λ of > 4:1 or < 1:2.
d Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where 
applicable. For subjects with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size 
will be determined by the SPD.
e Positive immunofixation alone in a subject previously classified as achieving a complete response will not be considered 
progression. For purposes of calculating time to progression and progression-free survival, subjects who have achieved a CR 
and are MRD-negative should be evaluated using criteria listed for progressive disease. Criteria for relapse from a CR or 
relapse from MRD should be used only when calculating disease-free survival.
f In the case where a value is felt to be a spurious result per physician discretion (eg, a possible laboratory error), that value will 
not be considered when determining the lowest value.
g All relapse categories require two consecutive assessments made at any time before classification as disease progression and/or 
institution of any new therapy.
Source: (Kumar, 2016).
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APPENDIX C. COCKCROFT-GAULT EQUATION FOR CALCULATING 
ESTIMATED CREATININE CLEARANCE
Serum Creatinine 
Units
Gender
Estimated Creatinine Clearance (mL/min)
mg/dL
Male
(140 subject age [years]) × subject weight (kg)
72 × subject serum creatinine (mg/dL)
Female
(140 subject age [years]) × subject weight (kg) × 0.85
72 × subject serum creatinine (mg/dL)
µmol/L
Male
(140 subject age [years]) × subject weight (kg) × 1.23
Subject serum creatinine (µmol/L)
Female
(140 subject age [years]) × subject weight (kg) × 1.04
Subject serum creatinine (µmol/L)
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APPENDIX D. MANAGEMENT OF TOXICITIES ASSOCIATED WITH
JCARH125
Cytokine release syndrome (CRS) and neurologic toxicities (NT) are associated with chimeric 
antigen receptor (CAR) T cell therapies. Celgene has developed the toxicity management 
guidelines (TMG) for CRS and NT associated with Celgene cellular products used in treatment 
of subjects with relapsed and/or refractory multiple myeloma (R/R MM), based on current 
clinical experience across several clinical development programs. These recommendations are 
based on the CRS revised grading system (Lee, 2014), the Common Toxicity Criteria for 
Adverse Events (CTCAE) and need to be used for grading of CRS and NT to guide management 
in this trial. 
If available and adopted as per site standard practice, CRS and NT grading according to the 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading 
System (Lee, 2019) should also be recorded in the electronic case report form (eCRF) to inform 
future modifications of the management guidelines.
1.
CYTOKINE RELEASE SYNDROME
Administration of cellular products such as CAR-expressing T cells can be associated with 
cytokine-associated toxicity due to systemic production and release of various cytokines into the 
circulation. Cytokine-associated toxicity, also known as CRS, is a toxicity that occurs as a result 
of immune activation (Lee, 2014; Gardner, 2017). 
1.1
Pathophysiology of Cytokine Release Syndrome
The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines. 
Cytokine release syndrome clinically manifests when large numbers of lymphocytes (B-cells, T 
cells, and/or natural killer [NK] cells) and/or myeloid cells (macrophages, dendritic cells, and 
monocytes) become activated and release inflammatory cytokines. Cytokine release syndrome 
has classically been associated with therapeutic monoclonal antibody (mAb) infusions, most 
notably anti-CD3 (OKT3), anti-CD52 (alemtuzumab), anti-CD20 (rituximab), and the CD28 
super-agonist, TGN1412. Cytokine release syndrome is also frequently observed following 
administration of bi-specific T cell engaging antibodies for leukemia, and adoptive cellular 
immunotherapies for cancer, most notably CAR T cells. Incidence, time to onset, and severity of 
CRS due to CAR T cells are at least partially dependent on the infused cell dose and tumor 
burden/antigen density, presumably due to more rapid and higher levels of CAR T cell 
activation. Onset of CRS symptoms typically occurs day(s) to occasionally weeks after the CAR 
T cell infusion, usually preceding maximal in vivo T cell expansion. Cytokine release syndrome 
is associated with elevated interferon gamma (IFN-γ), interleukin (IL)-6, and tumor necrosis 
factor-alpha (TNF-α) levels, and increases in IL-2, granulocyte macrophage colony-stimulating 
factor (GM-CSF), IL-10, IL-8, IL-5, and fractalkine, although the pattern of elevated cytokines 
varies among subjects (Davila, 2014; Hay, 2017). Interleukin 6 has been identified as a central 
mediator of toxicity in CRS. Interleukin 6 is a pleiotropic cytokine with anti-inflammatory and 
proinflammatory properties. High levels of IL-6, present in the context of CRS, likely initiates a 
proinflammatory IL-6-mediated signaling cascade.
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1.2
Clinical Presentation of Cytokine Release Syndrome
Cytokine release syndrome is characterized by high fever, fatigue, nausea, headache, dyspnea, 
tachycardia, rigors, hypotension, hypoxia, myalgia/arthralgia, and/or anorexia. Clinical 
symptoms and severity of CRS are highly variable (Lee, 2014), and management can be 
complicated by concurrent conditions. In multiple myeloma (MM) subjects treated with 
JCARH125, CRS usually occurs within 10 days after infusion (Mailankody, 2018).

Fever, especially high fever (≥38.5°C or ≥101.3°F), is a commonly observed 
hallmark of CRS, and many features of CRS mimic infection. Hence, infection must 
be considered in all subjects presenting with CRS symptoms, appropriate cultures 
must be obtained, and empiric antibiotic therapy initiated per institution standard of 
care.

Less common symptoms associated with CRS include cardiac dysfunction, adult 
respiratory distress syndrome, renal and/or hepatic failure, coagulopathies, 
disseminated intravascular coagulation, and capillary leak syndrome. 

Neurologic toxicity has been observed concurrently with CRS; refer to Appendix D,
Section 3.

CRS has been reported in some cases to be associated with findings of macrophage 
activation syndrome (MAS)/hemophagocytic lympho-histiocytosis (HLH), and the 
physiology of the syndromes may overlap; refer to Appendix D, Section 3.
1.3
Clinical Management of Cytokine Release Syndrome
Across various CAR T cell products, early manifestations of CRS can predict more severe 
toxicity for both CRS and NT. 
CRS has been described to be more severe in subjects with multiple myeloma with higher 
disease burden and is associated with increased serum cytokines including IL-6, IFN-γ, and other 
cytokines together with elevation of inflammatory markers C-reactive protein (CRP) and ferritin 
(Cohen, 2019; Brudno, 2016; Lee, 2015; Davila, 2014). 
It should be noted that, although useful for identifying subjects at higher risk for developing 
CRS, CRP, ferritin, and serum cytokine levels should not be used for CRS clinical 
management/treatment decisions in the absence of other clinical signs and symptoms of CRS; for 
example, a subject with an elevated CRP but no concomitant symptoms may not require 
intervention (Park, 2017). Thus, close observation of these subjects is strongly recommended.
A modification of the CTCAE CRS grading scale has been established to better reflect CAR T 
cell-associated CRS, as detailed in Table 8 (Lee, 2014).
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Table 8:
Grading Criteria for Cytokine Release Syndrome
Symptoms/Signs
CRS Grade 
1 (mild)
CRS Grade 2 
(moderate)
CRS Grade 3 
(severe)
CRS Grade 4 (life-
threatening)
CRS grade is defined by the most severe symptom (excluding 
fever)
Vital 
Signs
Temperature 
≥ 38.5°C/101.3°F
Yes
Yes
Yes
Yes
SBP ≤90 mmHg
N/A
Responds to IV 
fluids or single low-
dose vasopressora
Needs high-dosea or 
multiple vasopressors
Life-threatening
Need for oxygen to 
reach (SaO2) > 90%
N/A
FiO2 < 40%
FiO2 ≥ 40%
Needs ventilator 
support 
Organ 
Toxicity
N/A
Grade 2
Grade 3 or 
transaminitis Grade 4
Grade 4 (excluding 
transaminitis)
CRS = cytokine release syndrome; FiO2 = fraction of inspired oxygen; IV = intravenous; N/A = not applicable; 
SaO2 = oxygen saturation; SBP = systolic blood pressure
a Definition of high-dose vasopressors in Table 9.
Table 9:
High-dose Vasopressors (all doses required for ≥ 3 hours)
Vasopressor
Dose
Norepinephrine monotherapy
≥ 20 μg/min
Dopamine monotherapy
≥ 10 μg/kg/min
Phenylephrine monotherapy
≥ 200 μg/min
Epinephrine monotherapy
≥ 10 μg/min
If on vasopressin
Vasopressin + norepinephrine equivalent of ≥ 10 μg/mina
If on combination vasopressors (not 
vasopressin)
Norepinephrine equivalent of ≥ 20 μg/mina
a VASST Trial Vasopressor Equivalent Equation: Norepinephrine equivalent dose = [norepinephrine (μg/min)] + 
[dopamine (μg/kg/min) ÷ 2] + [epinephrine (μg/min)] + [phenylephrine (μg/min) ÷ 10].
Source:  Adapted from (Lee, 2014).
Detailed CRS management guidelines are shown in Figure 2. Treatment should be individualized 
for each subject’s clinical needs. This guidance emphasizes the importance of early intervention 
for Grade 2 CRS, or in the setting of a rapid onset or rapid progression of CRS symptoms, to 
prevent the development of severe (Grade 3 or greater) CRS and NT.
Tocilizumab, an anti-IL-6R (interleukin 6 receptor)-antibody, may be required in some cases to 
treat toxicities such as severe CRS. Please refer to the currently approved Actemra® prescribing 
information (United States) or RoActemra® Summary of Product Characteristics (Europe). 
Actemra has been approved by the Food and Drug Administration (FDA) for the treatment of 
CAR T cell-induced severe or life-threatening CRS in adults. RoAcetmra has been approved by 
the European Medicines Agency (EMA) for the treatment of CAR T cell-induced severe or life-
threatening CRS in adults. The preferred dose to intervene in adult subjects with CRS is 8 mg/kg 
(maximum 800 mg) intravenously (IV). In the absence of clinical improvement within 24 hours 
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after the first dose or if rapid deterioration should occur, a second dose of tocilizumab should be 
administered and a second-line agent, such as a corticosteroid, should also be introduced 
simultaneously. 
Corticosteroids have been successfully used in the treatment of CRS, as both first- and second-
line treatment. Many times, only short courses of corticosteroids are required (Turtle, 2016; Lee,
2015; Maude, 2014a; Schuster, 2017; Park, 2018). In case of rapid onset of CRS Grade 1 in 
severity or slow onset of CRS starting as Grade 2 in severity following tocilizumab, initiation of 
therapy with dexamethasone should be considered (Figure 2). 
Other anti-IL-6 agents such as siltuximab, if available, should be considered in the event that 
severe CRS is not responding to tocilizumab and corticosteroids. Siltuximab is another 
monoclonal antibody that blocks IL-6 signaling by binding IL-6 itself and preventing it from 
activating immune effector cells. Siltuximab has a higher affinity for IL-6 than tocilizumab has 
for the IL-6R, making it a very effective tool in managing CRS. If a patient does not respond to 
tocilizumab and corticosteroids, then the use of siltuximab is encouraged. Dosing of any other 
anti-IL-6 agent should be per prescribing information. 
Interleukin 1 blockade through IL-1 receptor antagonist (IL-1Ra) could demonstrably prevent 
severe CRS while maintaining intact antitumor efficacy (Giavridis, 2018). The benefits of an 
IL-1 blockade through IL-1Ra are especially intriguing given the latter’s ability to cross the 
blood–brain barrier (BBB) (Gutierrez, 1994), unlike tocilizumab (Neelapu 2018). Human 
microglia activated by IL-1 may produce inducible nitric oxide synthase and proinflammatory 
cytokines (Liu, 1996; Tarassishin, 2014); therefore, blocking IL-1 could potentially not only 
protect from severe CRS but also could reduce the severity of CAR T cell–related neurotoxicity. 
One of the selective IL-1Ra is anakinra.  Anakinra should be considered in the event that severe 
CRS is not responding to tocilizumab and corticosteroids. Anakinra should be given until 
resolution of CRS with a daily dose of 100 mg subcutaneously (SC). In more severe CRS cases, 
especially if combined with MAS/HLH and/or neurotoxicity, anakinra 100 mg twice daily (every 
12 hours) SC should be given until resolution of CRS and other concurrent CAR T cell toxicities,
like neurotoxicity and/or MAS/HLH which could benefit from anakinra treatment. 
In the most unresponsive severe cases, additional treatments should be considered. Recent data 
suggest that monocytes and macrophages contribute to the development of CRS and 
neurotoxicity after CAR T cell therapy. Therefore, neutralization of GM-CSF has been 
investigated as a potential strategy to manage CAR T cell–associated toxicities. Lenzilumab is a 
humanized monoclonal antibody that neutralizes GM-CSF. Pre-clinical and clinical data 
demonstrate that lenzilumab can prevent CRS and significantly reduce serious neurological 
toxicities (Sterner, 2018; Sterner, 2019).
Other possible treatments for persistent or worsening CRS include etanercept and infliximab 
(TNF-α inhibitors), T cell depleting alemtuzumab, anti-thymocyte globulin (ATG), 
cyclophosphamide, ruxolitinib, or ibrutinib (Borrega, 2019). However, if subject is still receiving 
anakinra for management of CAR T cells toxicity, the use of anakinra in combination with TNF 
blocking agents is not recommended.
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Figure 2:
Cytokine Release Syndrome Treatment Algorithm
ANC = absolute neutrophil count; BMA = bone marrow aspirate; CAR = chimeric antigen receptor; CRP = C-reactive protein; CRS = cytokine release 
syndrome; EEG = electroencephalogram; HLH = hemophagocytic lympho-histiocytosis; ICU = intensive care unit; IL-6 = interleukin 6; IL-1Ra = interleukin 1 
receptor antagonist; INR = international normalized ratio; IV = intravenous; MAS = macrophage activation syndrome; NT = neurologic toxicity; PTT = partial 
thromboplastin time; q = every.
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2.
Macrophage Activation Syndrome /Hemophagocytic Lympho-histiocytosis
Macrophage activation syndrome or HLH is a rare, potentially fatal immune-mediated disease, 
which is caused by impaired NK and cytotoxic T cell function. This syndrome has a wide range 
of causes, symptoms, and outcomes, but all lead to a hyperinﬂammatory response with some 
characteristics that overlap with CRS and organ damage (Ramos-Casals, 2014). Pathophysiology 
of MAS/HLH is divided into primary (genetic) and secondary (reactive) forms. Secondary 
MAS/HLH is subclassiﬁed as viral, autoimmune, or tumor related. Macrophage activation 
syndrome/HLH has both infectious and non-infectious triggers (Ramos-Casals, 2014). Viral 
infection is the most frequent trigger, either due to primary infection or after reactivation in 
immunosuppressed patients. Hemophagocytic lympho-histiocytosis can be triggered by viral 
infections, malignancy, autoimmune disease, and acquired immune deficiencies (Usmani, 2013), 
whereas MAS is most often associated with autoimmune and autoinflammatory diseases 
(Ravelli, 2016). Bacterial and fungal infections can also trigger MAS/HLH. Both conditions are 
characterized by a dysregulated immune response resulting in a cytokine storm. Available data 
suggests MAS/HLH emergence as a possible consequence of CRS with CAR T cells being a 
trigger of MAS/HLH (Neelapu, 2017; Borrega, 2019). In many aspects, severe CRS resembles 
MAS/HLH (Borrega, 2019). In clinical and laboratory findings, the cytokine profile and 
myeloid-driven inflammatory responses are closely related between MAS/HLH and severe CRS. 
In patients with CRS-related MAS/HLH-like syndrome (MALS), additional cytokines such as 
IL-18, IL8, IP10, MCP1, MIG, and MIP1β are also elevated (Teachey, 2016). These cytokines 
also have been reported to be elevated in classical MAS/HLH. In addition, IL-6 may also 
promote the development of MAS/HLH in the setting of CRS by inducing dysfunction of 
cytotoxic activity in T and NK cells, which is a hallmark of MAS/HLH (Cifaldi, 2015). 
Consequently, CRS-related MAS/HLH is difficult to distinguish from primary MAS/HLH or 
other conditions that can mimic MAS/HLH such as sepsis. Table 10 summarizes some of the 
factors that help to distinguish CRS-related MAS/HLH from other conditions that present 
similarly.
Table 10:
Differential Diagnoses of CRS-related MAS/HLH 
HLH = hemophagocytic lympho-histiocytosis; IFN-γ = interferon gamma; IL = interleukin; MAS = macrophage 
activation syndrome; NDA = no data available.
Source:  Shimabukuro-Vornhagen, 2018. 
Although in most cases MAS/HLH that develops concurrently with CRS is triggered by CRS, 
other causes of MAS/HLH, such as genetic defects (in pediatric patients), autoimmune disease, 
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infection, or the underlying malignancy itself should be considered. Patients with hematological 
malignancies have a higher risk of developing MAS/HLH. Macrophage activation-like syndrome 
is a distinct entity that leads to early death in septic patients and must be carefully ruled out in 
patients who are prone to develop severe infections, including patients following CAR T cell 
therapy (Karakike, 2019).
2.1
Clinical Presentation and Diagnosis of Macrophage Activation 
Syndrome/Hemophagocytic Lympho-histiocytosis
The presentation of secondary MAS/HLH is heterogeneous and characterized by a panoply of 
clinical signs and symptoms. Cytokine release syndrome shares many pathogenetic and clinical 
similarities with MAS/HLH such as high fever, very high ferritin levels, cytokine profiles, and 
the importance of macrophages in the pathogenesis (Ravelli, 2016). The clinical syndrome can 
be acute or subacute with non-specific symptoms appearing over a few days to 4 weeks (Ramos-
Casals, 2014). The cardinal features are continuous high fever (≥38.5°C) and enlarged 
lymphohematopoietic organs (spleno/hepatomegaly), occasionally accompanied by adenopathy. 
Pulmonary, neurologic, cutaneous, and gastrointestinal involvement may also be present.
Laboratory markers associated with MAS/HLH include pancytopenia, hyperferritinemia, 
hypoﬁbrinogenemia and raised D-dimer levels, hypertriglyceridemia, and abnormalities in liver 
function. 
Detection of any ongoing infection acting as a trigger for MAS/HLH is critical (Figure 2). 
Standard tests should be used to screen for infections caused by the most common viruses such 
as herpes, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Other infectious agents (eg, 
mycobacteria, parasites, and fungi, particularly Candida and Mucor) should be ruled out 
according to speciﬁc clinical or epidemiological features (Ramos-Casals, 2014; Lehmberg, 
2015).
Bone marrow is the preferred anatomical site for investigation of suspected MAS/HLH. Bone 
marrow aspirate can be negative at the initial stage of MAS/HLH and should be repeated during 
the clinical course if there is a high suspicion of MAS/HLH.
The diagnosis of MAS/HLH (according to HLH-2004 consensus criteria, further revised in 2014 
for HLH associated with malignancies) (Lehmberg, 2015) can be established if either of the 
2 criteria below is fulfilled:
1. A molecular diagnosis consistent with MAS/HLH 
2. Diagnostic criteria for MAS/HLH fulfilled (5 out of the 8 criteria below):
a.
high persistent fever (≥ 38.5°C)
b. splenomegaly
c.
cytopenias (affecting 2 of 3 lineages in the peripheral blood): Hemoglobin < 90 g/L, 
platelets < 100 x 109/L, and neutrophils < 1.0 x 109/L
d. triglycerides ≥ 3.0 mmol/L (ie, 265 mg/dL) or fibrinogen ≤ 1.5 g/L
e.
hemophagocytosis in bone marrow, spleen, and/or lymph nodes
f.
low or absent NK-cell activity (according to local laboratory reference range)
g. ferritin ≥ 500 ng/mL
h. soluble CD25 (ie, soluble IL-2 receptor) ≥ 2,400 U/mL
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2.2
Clinical Management of Macrophage Activation Syndrome/Hemophagocytic 
Lympho-histiocytosis
Effective treatment of MAS/HLH requires multiple simultaneous approaches (Ramos-Casals,
2014, Lehmberg, 2015).
1. Supportive care is essential because of frequent life-threatening, severe manifestations 
at presentation. 
2. Appropriate broad-spectrum antiviral, antibacterial, antifungal prophylaxis, and 
treatment must be initiated. The elimination of triggers (particularly infection) is crucial 
to remove the stimuli that initiate the abnormal immune system activation.
3. Suppression of the inﬂammatory response and cell proliferation by immunosuppressive 
and cytotoxic drugs, respectively, is necessary. 
a.
First-line treatment includes IL-6-blockade with tocilizumab unless tocilizumab was 
already administered for the management of CRS. Glucocorticoids are also indicated 
for the initial treatment of MAS/HLH, irrespective of the cause (CRS Grade 4 
treatment recommendations should be followed).
b. Second-line treatment includes interleukin 1 blockade with anakinra. Anakinra 
should be given until resolution of MAS/HLH as a daily dose of 100 mg SC.
c.
In case of rapidly progressing clinical course with ongoing CRS, anakinra should 
be administered as first-line treatment. In more severe MAS/HLH cases, especially if 
combined with CRS and/or neurotoxicity, anakinra 100 mg SC twice daily should be 
given until resolution of MAS/HLH and other concurrent CAR T cell toxicities,
which could benefit from anakinra treatment.  
d. Anti-IL-6 antibody, siltuximab, might be considered as second-line therapy. The use 
of cyclosporin, cyclophosphamide, etoposide, and/or intrathecal methotrexate is not 
generally indicated in patients who develop MAS/HLH after CAR T cell therapy but 
may have to be employed in refractory cases. 
e.
Newer emerging treatments include emapalumab (anti-IFN-γ antibody), which has 
been approved by the FDA for the treatment of primary refractory or recurrent 
MAS/HLH (Benedetti, 2019).
3.
Neurologic Toxicities
CAR T cell therapy is associated with unique neurologic toxicities. Neurologic symptoms may 
include altered mental status, aphasia, altered level of consciousness, and seizures or seizure-like 
activity. The start of neurologic symptoms has been noted with JCARH125 between 3 to 12 days
with median time to onset of 3 days after CAR T cell infusion (Mailankody, 2018). With another 
B-cell maturation antigen (BCMA) CAR T cell therapy, bb2121, the start of neurologic 
symptoms has been noted between 3 to 11 days (median 5 days) after CAR T cell infusion (Raje, 
2019). Severe neurological toxicity cases may require admission to the intensive care unit (ICU) 
for frequent monitoring, respiratory support, or intubation for airway protection. The symptoms 
are variable and generally occur as CRS is resolving or after CRS resolution.
3.1.
Pathophysiology of Neurologic Toxicities
The pathogenesis of neurotoxicity is poorly defined.  The pathophysiology of neurologic 
symptoms in CAR T cell therapy is poorly understood, but the lack of a strict temporal 
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association with CRS indicates that it might be independent from CRS. In addition, IL-6 pathway 
blockade does not seem to be beneficial in the treatment of neurologic symptoms, unlike in CRS, 
indicating a different pathomechanism. The evaluation of larger patient collectives showed that a 
high tumor burden and a more severe CRS lead to a more severe neurotoxicity (Gust, 2017;
Santomasso, 2018). Neurotoxicity has been associated with early onset of CRS and rapid 
elevation of inflammatory cytokines both within the serum and central nervous system (CNS), 
perhaps leading to BBB disruption (Gust, 2017). Analysis of subjects with R/R MM treated with 
CAR T BCMA cells at the University of Pennsylvania, a peak in serum increases of IL-6, IFN-γ, 
and MIP-1α was identified as most associated with neurotoxicity in this study. Interestingly, 
neurotoxicity was also associated with peak fold-increases in IL-1Ra, an endogenous inhibitor of 
the proinflammatory effects of IL-1 alpha (IL-1α) and IL-1 beta (IL-1β), which have been 
implicated in post-CAR T cell neurotoxicity (Giavridis, 2018; Norelli, 2018). This potentially 
suggests that augmenting IL-1 blockade with the recombinant IL-1Ra anakinra in myeloma 
patients with CAR T cell–associated neurotoxicity may have therapeutic benefit, as demonstrated 
in preclinical models (Giavridis, 2018; Norelli 2018).
An analysis showed higher levels for cytokines which are usually associated with a systemic 
inflammation (ie, IL-6, IL-10, and interferon-gamma (IFN-g)) in patients who develop severe 
neurotoxicity indicating a correlation between systemic inflammation and neurologic events 
(Gust, 2017; Turtle, 2017; Santomasso, 2018).Peak levels in CRP are also significantly higher in 
subjects who develop any Grade or Grade 3 or higher neurotoxicity (Turtle, 2016; Heipel, 2017). 
Other organ dysfunction (hepatic and renal), as well as hypoxemia and infection, might also 
contribute to encephalopathy (Neelapu, 2018). In another study, it has been reported that 
evidence for cytokine-mediated endothelial activation causes coagulopathy, capillary leak, and 
BBB disruption, allowing transit of high concentrations of systemic cytokines into the 
cerebrospinal fluid. (Gust, 2017).
3.2
Clinical Management of Neurologic Toxicities
Levetiracetam or alternative anti-seizure medication should be considered for seizure 
prophylaxis. The optimal management of CAR T cell-induced neurotoxicity is unknown at this 
time. These management guidelines below represent the current state of knowledge and 
additional information will be provided to Investigators as it becomes available. A thorough 
neurologic evaluation, including electroencephalogram (EEG), magnetic resonance imaging 
(MRI), or computer tomography (CT) scan of the brain, and diagnostic lumbar puncture and 
frequent monitoring of cognitive function (eg, mini mental status examinations or handwriting 
tests) should be considered. 
Treatable causes of neurologic dysfunction, such as infection or hemorrhage should be ruled out. 
Common manifestations of neurotoxicity (eg, confusion, seizure, and aphasia), can also be seen 
with infection, electrolyte imbalances, metabolic acidosis, uremia, concomitant medication use 
(eg, narcotics), and other medical conditions. Other causes for such symptoms should be 
considered.
Magnetic resonance imaging and CT scans of the brain are usually negative for any anatomical 
pathology that would account for the neurotoxicity symptoms observed in subjects treated with 
CAR T cell therapy, although rare cases of reversible T2/fluid attenuated inversion recovery 
(FLAIR) MRI hyperintensity involving the thalami, dorsal pons, and medulla, and cerebral 
edema have been reported (Neelapu, 2018).
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For subjects who have neurologic toxicity in the presence of CRS, the CRS should be managed 
following the guidelines provided in Figure 3.
Neurotoxicity management guidelines are provided in Figure 3.
First-line treatment includes corticosteroids to be used for severe neurotoxicity, especially in 
the absence of the classic hemodynamic perturbations of CRS. Tocilizumab does not cross the 
BBB and results in transient elevated IL-6 levels in the serum, which is implicated in the 
pathogenesis of neurotoxicity (Nellan, 2018). Thus, tocilizumab is not recommended for the 
primary management of isolated neurotoxicity. For the corticosteroids dosing regimen, please 
refer to Figure 3.
Second-line treatment includes siltuximab which effectively removes active IL-6 from 
circulation and since the siltuximab IL-6 complex is unlikely to cross the BBB, siltuximab 
should have a role in the management of CAR T cell-induced neurotoxicity (Riegler, 2019). 
Anakinra should be considered in the event of neurotoxicity onset with ongoing CRS as well as 
neurotoxicity. It should be given as a daily dose of 100 mg SC or 200 mg SC (100 mg every 12 
hours) depending on the severity of neurotoxicity and other concurrent CAR T cell-related
toxicities. Anakinra should be given until resolution of neurotoxicity and other concurrent CAR 
T cell toxicities which could benefit from anakinra treatment.
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Figure 3:
Neurotoxicity Treatment Algorithm
CAR = chimeric antigen receptor; CRS = cytokine release syndrome; CT = computed tomography; EEG = electroencephalogram; ICU = intensive care unit; 
IL = interleukin 1 receptor antagonist; LP = lumbar puncture; MRI = magnetic resonance imaging; NT = neurologic toxicity; q = every.
Consider IL-1Ra agent
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APPENDIX E. MINI MENTAL STATE EXAMINATION
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APPENDIX J.
MODIFIED TOXICITY PROBABILITY INTERVAL DECISION TABLE (PHASE 1)
Number of Subjects
Number of 
DLTs
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
2
D D D D S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
3
X X D D D D S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
4
X X X D D D D
D
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
5
X X X X X D
D
D
D
D
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
6
X X X X X
X
D
D
D
D
D
D
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
7
X X X X
X
X
X
D
D
D
D
D
D
D
S
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
8
X X X
X
X
X
X
X
X
D
D
D
D
D
D
S
S
S
S
S
S
S
S
S
S
E
E
E
E
9
X X
X
X
X
X
X
X
X
X
X
D
D
D
D
D
D
S
S
S
S
S
S
S
S
S
S
S
10
X
X
X
X
X
X
X
X
X
X
X
X
D
D
D
D
D
D
D
S
S
S
S
S
S
S
S
11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D
D
D
D
D
D
D
S
S
S
S
S
12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D
D
D
D
D
D
D
S
S
13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D
D
D
D
D
D
D
14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D
D
D
D
15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D
16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Note: Table will be applied separately for each dose level. Column indicates number of subjects treated within a given dose level; row indicates number of subjects with DLTs at 
that dose level.
E = Escalate to the next higher dose.
S = Stay at the same dose.
D = De-escalate to the previous lower dose.
X = De-escalate to the previous lower dose and the current dose will never be used again in the trial.
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EDMS Doc. Number: 24465987 - 24356973
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Monday, 10 February 2020, 07:01 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
3
H125001 Amendment 6: 10 Feb 2020
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are to explore anakinra as a toxicity mitigation 
agent and to evaluate the safety and efficacy in subjects who have had prior exposure to other 
therapeutic agents directed against BCMA, and they are summarized below:
Updated Introduction
The introduction was updated to include literature references of recent clinical data with B-cell 
maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR T) cell therapies and 
BCMA directed T cell engager (TCE) and antibody-drug conjugate (ADC) therapies that have 
shown promising activity in multiple myeloma. The potential risks associated with these 
therapies were updated to align with recent published data. These references provide rationale for 
exploration of the prior BCMA directed therapies cohorts.
Ongoing study data to support BCMA-targeted CAR T cells cohort was updated with data from 
current literature or press releases. 
Revised Sections: Section 1.3.1, Section 1.3.2, Section 1.3.3, Section 1.5, Section 2.1
JCARH125 Dose Rationale
Removed clinical data that was used for justifying the addition of the 300M dose level from this 
ongoing trial as it is not in accordance with Celgene standards. 
Revised Section: Section 2.1
Addition of Phase 1 Anakinra Cohort
Interleukin 1 (IL-1) blockade through IL-1 receptor antagonist (IL-1Ra) can demonstrably 
prevent severe cytokine release syndrome (CRS) while maintaining intact antitumor efficacy. 
The benefits of an IL-1 blockade through IL-1Ra are especially intriguing given the latter’s 
ability to cross the blood-brain barrier, unlike tocilizumab. Human microglia activated by IL-1 
may produce inducible nitric oxide synthase and proinflammatory cytokines; therefore blocking 
IL-1 could potentially not only protect from severe CRS but also could reduce the severity of 
CAR T cell–related neurotoxicity. Therefore, anakinra has been included in this trial. 
Furthermore, anakinra has been proposed in recent publication for treatment of refractory CRS 
and in the setting of macrophage activation syndrome (MAS)/ hemophagocytic 
lympho-histiocytosis (HLH).  
Added the primary, secondary and exploratory objectives and endpoints of the Phase 1 anakinra 
cohort. 
Added study design for the Phase 1 anakinra cohort.
Added the rationale for prophylactic treatment with anakinra to align with current literature.
Added Section 6.3 for information and risks about anakinra.
Added the dosing schedule to follow for the Phase 1 anakinra cohort.
Defined the safety analysis set and the efficacy analysis set for the Phase 1 anakinra cohort. 
Revised Sections: Protocol synopsis, Section 2.1, Section 2.3, Section 2.5, Section 3, Table 1, 
Section 4.1, Section 4.4, Section 4.6, Section 4.8, Section 4.11.2, Section 6.3, Section 6.4.4, 
Section 6.5, Section 6.6, Section 7.14, Section 8.5.3.1, Section 8.5.5, Section 8.12.1, Section 
Approved
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Approved
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
4
H125001 Amendment 6: 10 Feb 2020
8.12.9.3, Section 10.1, Section 10.2.2.1, Section 10.2.2.2, Section 10.2.2.3,  Section 10.2.3, 
Section 10.2.3.1, Section 10.3.4, Section 10.3.5, Section 10.3.7.1, Section 10.3.11.5, Section 
10.3.13.1, Section 10.5, Section 10.6.1, Table A-2, Appendix D
Addition of Phase 2a prior BCMA-directed Anti-myeloma Therapy Cohort
Although BCMA-directed CAR T cell therapies have been demonstrated to induce rapid and 
deep responses in almost all subjects, the durability of response remains an issue. Relapse post-
CAR T therapy may be mediated by multiple mechanisms: CAR-intrinsic (loss of functional 
CAR T persistence) or tumor intrinsic (antigen loss), or other mechanisms yet to be determined 
(such as lack of CAR infiltration into suppressive TME in plasmacytomas). Given the potential 
for multiple mechanisms, it may be possible to treat subjects who have relapsed after prior 
BCMA CAR T therapy with JCARH125.
Published data of 4 subjects with relapsed and/or refractory multiple myeloma (R/R MM) treated 
with CT103A, BCMA CAR T cells with human binder, were very encouraging. Patients who 
were previously treated with murine BCMA CAR T cells, after CT103A infusion achieved
excellent responses of complete response (CR) (3 patients) and very good partial response
(VGPR) (1 patient). 
Cohen et al. described 2 patients who progressed after 1 BCMA-targeted therapy and then
responded to a subsequent BCMA-targeted therapy. 
A recent publication describes twenty subjects who were evaluable for BCMA surface 
expression on MM cells by flow cytometry performed on fresh marrow aspirates prior to 
treatment. BCMA intensity was lowest on residual MM cells 1 month after BCMA CAR T cell 
infusion and increased back toward baseline in most. Neither progression-free nor overall 
survival was significantly associated with baseline BCMA expression in this trial.
These cases demonstrate that BCMA targeted therapies may be beneficial in patients previously 
exposed to other BCMA-targeted agents and, therefore, this population has been added to 
explore safety and efficacy in a separate cohort of this trial. BCMA expression will be evaluated 
using the same exploratory methodologies currently in use for the H125001 Phase 1 and pivotal 
cohorts. These assessments will be performed on samples collected at screening to address 
baseline BCMA expression prior to JCARH125 infusion and also on samples collected after 
infusion. IHC will be utilized to measure BCMA expression on CD138+ plasma cells in bone 
marrow biopsies. Flow cytometry will also be used to measure BCMA expression on plasma 
cells in bone marrow aspirates. Results from both assays will be used to evaluate the relationship 
between baseline BCMA expression and JCARH125 activity (safety, efficacy, PK and PD). 
These results will also allow us to address whether subjects who have received prior BCMA-
directed therapies have differential expression of BCMA relative to subjects in the Phase 1
cohort.
Added the primary, secondary and exploratory objectives and endpoints for the Phase 2a portion.
Added study design for the Phase 2a portion.
Defined the safety analysis set and the efficacy analysis set for the Phase 2a portion. 
Revised Sections: Protocol synopsis, Section 1.3, Section 1.3.1, Section 1.3.2, Section 1.3.3, 
Section 2.1, Section 2.5, Section 3, Table 1, Section 4.1, Section 4.2, Section 4.5, Section 4.6, 
Section 4.8, Section 4.11.2, Section 5.1, Section 5.2, Section 6.6, Section 8.12.9.3, Section 10.1, 
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
5
H125001 Amendment 6: 10 Feb 2020
Section 10.2.4, Section 10.2.4.1, Section 10.2.4.2, Section 10.2.4.3, Section 10.3.9, Section 
10.3.10, Section 10.5, Table A-2.
Updated Study Objectives and Endpoints

From the secondary objective in Phase 1 “Duration of persistence of JCARH125 CAR T 
cells in the blood and bone marrow” bone marrow was removed and added as part of the 
exploratory objective and endpoint.
Revised sections: Protocol synopsis, Section 2.5, Section 3, Table 1
Overall Study Design
Added language to the overall study design which now includes the addition of the Phase 1 
anakinra cohort and the Phase 2a portion for patient with prior BCMA targeted therapy.
Changed the primary analysis population for evaluation of JCARH125 efficacy (ie, the efficacy 
analysis set) to include all subjects treated at the RP2D(s) in Phase 2, as well as subjects treated 
at the RP2D(s) in Phase 1 and in the Phase 1 anakinra cohort.
Clarified that a bone marrow biopsy and a plasmacytoma biopsy (if feasible) will also be 
required at screening in order to align with the schedule of events. 
Revised Section: 4.1, Section 4.6
Updated Eligibility Criteria

Clarified inclusion criterion number 3
Refractory myeloma is defined as non-responsiveness (best response of ≤ stable disease) to 
last anti-myeloma treatment regimen or documented progressive disease during or within 60 
days (measured from the last dose) of completing treatment with the last anti-myeloma 
treatment regimen before study entry. 
Clarified that subjects who received prior allogeneic stem cell transplants or donor 
lymphocyte infusion (DLI) at least 100 days before enrollment will be considered eligible. 
This additional editorial change was made to provide further clarification for sites and to 
provide consistency across MM and CAR T-cell programs.
Revised Sections: Protocol Synopsis, Section 5.1

Clarified inclusion criterion number 11
Females of reproductive potential (defined as all females physiologically capable of 
becoming pregnant) must agree to use one highly effective method of contraception from 
screening until at least 12 months following lymphodepleting chemotherapy. There are 
insufficient exposure data to provide any recommendation concerning the duration of 
contraception following treatment with JCARH125. Any decision regarding contraception 
after JCARH125 infusion should be discussed with the treating physician. 
Revised Sections: Protocol Synopsis, Section 5.1, Section 5.3 
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Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
6
H125001 Amendment 6: 10 Feb 2020

Clarified inclusion criterion number 12
Females of reproductive potential must have 2 negative pregnancy tests as verified by the 
Investigator (one negative serum beta-human chorionic gonadotropin [β-hCG] pregnancy test 
result at screening, and within 7 days prior to the first dose of lymphodepleting 
chemotherapy). This applies even if the subject practices true abstinence from heterosexual 
contact. True abstinence was defined and added. 
Revised Sections: Protocol Synopsis, Section 5.1 

Clarified inclusion criterion number 13
Males who have partners of childbearing potential must agree to use an effective barrier 
contraceptive method from initiation of lymphodepleting chemotherapy and for at least 12
months and should not donate semen or sperm during the entire study period and for at least 
12 months following lymphodepleting chemotherapy.
Revised Sections: Protocol Synopsis, Section 5.1, Section 5.3 

Inclusion criterion number 14 was added
Phase 2a prior BCMA-directed anti-myeloma therapy cohort only – Subjects with R/R MM 
who have been previously treated with prior BCMA-directed anti-myeloma therapy, 
achieved at least a partial response (PR) per IMWG response criteria and subsequently 
progressed on the following treatment:
a.
Subjects who have received prior BCMA-directed CAR T-cell therapy. The last CAR 
T-cell therapy must have been received at least 6 months prior to JCARH125 study 
enrollment (screening).
b. Subjects who have received prior BCMA-directed TCE therapy.
c.
Subjects who have received prior BCMA-directed ADC therapy.
Subjects with prior BCMA-directed anti-myeloma therapy are not required to have received
at least 3 prior anti-myeloma treatment regimens and do not have to be refractory to the last 
anti-myeloma regimen to be eligible for this trial.
This additional inclusion criterion was added for subjects enrolled in the Phase 2a cohort 
(prior BCMA-directed anti-myeloma therapy cohort).
Revised Section: Protocol Synopsis, Section 5.1

Exclusion criterion number 19 was added
Subjects with known hypersensitivity to Escherichia coli (E. coli)-derived proteins (only 
applicable for subjects in the Phase 1 anakinra cohort).
Anakinra is produced by recombinant DNA technology using an E. coli bacterial expression 
system and is not recommended for subjects that have a hypersensitivity to E. coli-derived 
proteins. This additional exclusion criterion was added to promote subject safety in the Phase 
1 anakinra cohort. 
Revised Sections: Protocol Synopsis, Section 5.2
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
7
H125001 Amendment 6: 10 Feb 2020

Exclusion criterion number 20 was added
History of severe immediate hypersensitivity reaction to any of the protocol mandated and 
recommended agents used in this study.
Anakinra, tocilizumab, dexamethasone, fludarabine, and cyclophosphamide are amongst 
some of the mandated or recommended agents used in this trial. Therefore, this additional 
exclusion criterion was added to promote subject safety. 
Revised Sections: Protocol Synopsis, Section 5.2
Updated Pregnancy and Contraception Language 
There are insufficient exposure data to provide any recommendation concerning the duration of 
contraception following treatment with JCARH125. Clarification was added to the contraception 
language to better define effective contraception barrier methods and ensure pregnancy testing is 
consistent across the CAR T program.
Added the following language: All pregnancies or suspected pregnancies occurring at any time 
after receipt of JCARH125, in either a female subject of childbearing potential or partner of 
childbearing potential of a male subject, are immediately reportable events. 
Revised Sections: Protocol synopsis, Section 5.1, Section 5.3, Section 9.4.5, Table A-1, Table A-
3, Table A-4
Prohibited Medications
Re-infusion of autologous peripheral blood stem cells (stem cell boost) preceded by bridging 
chemotherapy is not permitted. Inferior vena cava (IVC) filter utilization is prohibited for 
treatment of deep vein thrombosis at any time between screening and JCARH125 infusion.
Revised Sections: Section 6.8, Section 8.4
Toxicity Management – Cytokine Release Syndrome, Lee Criteria 2014

Added clarification to Table 8 that temperature of 38.5◦C or higher is required per Lee 
criteria

Updated Figure 2 to include laboratory monitoring for grade ≥3 CRS to rule out 
MAS/HLH

Added more detailed information about treatment options to consider for rapid onset 
CRS, including tocilizumab and corticosteroids

Addition of treatment options to consider for CRS: siltuximab, anakinra, lenzilumab

Cytokine release syndrome and NT language, table, and figures were updated to align 
with recent literature (Appendix D, Section 1.3, Table 8, and Figure 2, and Appendix D, 
Section 3 and Figure 3, respectively)

Added information about CRS management, tocilizumab, lenzilumab, and corticosteroids 
as treatment for CRS to align with recent literature (Appendix D, Section 1.3 and Table 
8)
Revised sections: Section 7, Appendix D, Appendix D Section 1, Section 1.2, Section 1.3, 
Table 8
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
8
H125001 Amendment 6: 10 Feb 2020
Toxicity Management - Macrophage Activation Syndrome/Hemophagocytic Lympho-
histiocytosis (MAS/HLH)
In Appendix D, Section 2, MAS/HLH was added to include more detailed information about 
MAS diagnosis and treatment from recent clinical data. This additional change was made to 
provide further clarification for sites and to provide consistency across MM and CAR T cell 
programs.

Added information about what MAS/HLH is and how it is differentiated from CRS

Added Table 10: Differential diagnosis of CRS-related MAS/HLH

Added detailed information about MAS/HLH diagnosis, occurrence and treatment 
recommendations, including how to establish a diagnosis

Clinical presentation: 
‒
Added information about what MAS/HLH is and how it resembles CRS
‒
Updated to include literature references of recent clinical data on MAS/HLH
‒
Added information about associated laboratory markers
‒
Added Table 10 to define MAS/HLH

Addition of detailed treatment management of MAS/HLH: supportive care, 
elimination of infection (i.e. administer antiviral, antibacterial, antifungal prophylaxis and 
treatment), suppression of the inﬂammatory response and cell proliferation by 
immunosuppressive and cytotoxic drugs. Details were added for first line and second line 
treatment suggestions. Additional treatment suggestions were added for use in refractory 
cases.
Revised Section: Appendix D, Section 2, Table 10, Section 2.1, Section 2.2
Toxicity Management – Neurotoxicity

Changed the start of neurologic symptoms from 2 to 14 day to between 3 to 12 days with 
median time to onset of 3 days after CAR T cell infusion. 

Added information that with another BCMA CAR T cell therapy bb2121, the start of 
neurologic symptoms has been noted between 3 to 11 days (median 5 days) after CAR T 
cell infusion. 

Added additional data based on published information about neurologic toxicities (NTs)

Updated Figure 3 to consider adding an interleukin-1 (IL-1) receptor antagonists (IL-
1Ra) agent as part of second line treatment. 

Added additional information about pathophysiology of neurologic toxicities to align 
with current literature. 

Updated clinical management of neurologic toxicities

Added the following treatment options to consider for NT: Levetiracetam or 
alternative anti-seizure medication, corticosteroids for severe neurotoxicity,
siltuximab, and anakinra.
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
9
H125001 Amendment 6: 10 Feb 2020

Tocilizumab is not recommended for the primary management of isolated 
neurotoxicity as it does not cross the blood brain barrier (BBB) 

Removed: management of NT should be guided per institutional guidelines
Revised Sections: Section 7.5, Appendix D, Section 3, Section 3.1, Section 3.2
The amendment also includes several other minor updates, clarifications and corrections:

Updated the List of Abbreviations to align with updates made throughout the protocol

Provided updated information on other CAR-T cell therapy options including safety and 
efficacy data (Section 1.3)

Updated sample size by dose level to range from 14 to 30. (Section 4.2, Section 10.5)

Updated dose-limiting toxicities (DLT): Rolled Grade 5 CRS into the next bullet defined 
as “any treatment emergent Grade 5 toxicity not due to the underlying malignancy”
(Protocol synopsis, Section 4.3)

Updated the enrollment period of the study from 12 to 36 months and the overall duration 
from 36 to 60 months (Protocol synopsis, Section 4.7)

Added Phase 1, Phase 2a, and Phase 1 anakinra cohort to the title of Section 4.8 and 
made editorial updates to this section (Section 4.8)

Added Phase 1 anakinra cohort and Phase 2a cohort to the Independent Review 
Committee (IRC) review (Section 4.11.2)

Clarified that a fresh biopsy in inclusion criterion 5 is a bone marrow biopsy (Protocol 
synopsis, Section 5.1)

Removed the word ‘not’ from inclusion #3 so it is no longer a double negative. Subjects 
who are considered eligible to receive and have ‘not’ refused an ASCT.

Exclusion criterion number 2 was modified to correctly define the M in POEMS 
syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal 
plasmaproliferative disorder, Skin changes) by changing ‘monoclonal proteins’ to 
‘monoclonal plasmaproliferative disorder (Protocol synopsis, Section 5.2)

Exclusion criterion number 6 clarifies that it is not applicable to Phase 2a. (Protocol 
Synopsis, Section 5.2)

Exclusion criteria number 7 clarifies that it is not applicable to Phase 2a. (Protocol 
Synopsis, Section 5.2)

Exclusion criteria number 15a was modified to include all monoclonal antibodies (anti-
CD38 and anti-SLAMF7) as part of the 4-week washout period. (Protocol synopsis, 
Section 5.2)

Exclusion criteria number 17 was modified to exclude subjects with any condition that 
permits compliance with the protocol and exclude any psychiatric condition that could 
jeopardize subject safety. (Protocol synopsis, Section 5.2)
Approved
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
10
H125001 Amendment 6: 10 Feb 2020

Modified text for withholding lymphodepleting (LD) chemotherapy when calculated 
creatinine clearance (CrCl) or glomerular filtration rate (GFR) from ≤50 to <60mL/min 
and modified text that CrCl between 60 and 70 mL/min would have a 20% reduction in 
fludarabine (Section 6.2, Table A-2)

Updated the avoidance of bias to include Phase 1 and the Phase 1 anakinra cohort
(Section 6.5)

Updated hospitalization requirements for the Phase 1 anakinra cohort and the driving 
distance for the Phase 2 and 2a cohorts from approximately a 60 minute drive to 
approximately a 30 minute drive (Section 6.6)

Updated recommendations and monitoring for infections (Section 6.6)

Updated the hospitalization requirements to include the Phase 2a cohort, the Phase 1 
anakinra cohort, and that subjects should be within approximately 30-minute drive from 
the hospital (Section 6.6)

Additional concomitant medication reporting suggestions are provided in Table 3 of 
Section 6.7.1

Addition of antifungals and antivirals to the concomitant medication reporting 
suggestions during intensive care unit (ICU) stay (Section 6.7.2)

Added devices and new medications to the prohibited medication section (Section 6.8)

Section 7 was updated with current data for management of toxicities (Section 7)

Added the option of collecting American Society for Transplantation and Cellular 
Therapy (ASTCT) score for neurologic toxicities (Section 7, Appendix D)

Clarified that treatment with antivirals is ‘recommended’ rather than ‘should be 
considered’ (Section 7.4)

Moved information about MAS to Appendix D (Section 7.6, Appendix D)

Added associated risks for anakinra (Section 7.14)

Removed collection of archival bone marrow or plasmacytoma from screening 
procedures (Section 8.2)

Clarified that all safety labs should not be older than 5 days at the time of screening 
assessment. (Section 8.2, Table A-1)

Clarified that subjects who did not have extra-medullary plasmacytomas (EMPs) at 
screening would not have to repeat the assessment for positron emission tomography 
(PET)/ computed tomography (CT) or diffusion-weighted magnetic resonance imaging 
(DW-MRI) after bridging therapy (Section 8.4, Table A-1)

Added information about anakinra dosing on Day -1 (Section 8.5.3.1)

Moved the PET/CT, DW-MRI and skeletal survey assessments to part of the unscheduled 
disease assessments (Section 8.6)
Approved
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JCARH125
Juno Therapeutics
Protocol H125001
A Celgene Company
Confidential and Proprietary
11
H125001 Amendment 6: 10 Feb 2020

Removed the clarification that during the treatment period, Day 29 PET/CT or DW/MRI 
is only required if clinically indicated or to assess rapidly progressing MM (Section 
8.12.1)

Clarified that bone marrow exams and MRD assessments are required at Month 24/ EOS 
(Section 8.12.1)

Added CD4 T-Cell count under the hematology lab evaluations and clarified that bone 
marrow for cytogenetics is required at screening if recent analysis is not available
(Section 6.6, Section 8.12.6, Table 4)

Added adverse events (AEs) associated with any signs/symptoms/diagnosis of 
opportunistic infections to the reporting periods for AEs (Section 9.5.1, Table 7)

Updated the general considerations for statistical methods and the analysis sets to include 
the data from Phase 1 anakinra cohort, Phase 1 and Phase 2a portions (Section 10.1, 
Section 10.2.2, Section 10.2.2.1, Section 10.2.2.2, Section 10.2.2.3)

Defined the safety and efficacy analysis sets for all subjects n Phase 1 anakinra cohort 
and Phase 2a cohort (Section 10.2.2, Section 10.2.2.1, Section 10.2.2.2, Section 10.2.2.3, 
Section 10.2.3, Section 10.2.3.1, 10.2.3.3, Section 10.2.4, Section 10.2.4.1, Section 
10.2.4.2, Section 10.2.4.3)

Added all primary and secondary endpoints from Section 3, Table 1 to ensure Section 
10.3.4, 10.3.5 were aligned (Section 10.3.4, Section 10.3.5, Section 10.3.9, Section 
10.3.10)

Added prophylactic anakinra usage (yes vs no) as subgroup analyses for efficacy, safety, 
and pharmacokinetics (Section 10.3.7.1, Section 10.3.11.5, Section 10.3.13.1) 

Updated the sample size consideration to align with the new Phase 2a portion and Phase 
1 anakinra cohort (Protocol Synopsis, Section 10.5)

Updated the interim analysis definitions to include the Phase 1 anakinra cohort (Section 
10.6.1)

Updated References (Section 13)

Added clarification to the Schedule of Evaluations that inflammatory markers should be 
performed within 48 hours prior to the start of lymphodepleting chemotherapy and 
schedule of assessments was updated to add this assessment to the regular visit schedule
(Table A-2, Table A-3)
Approved
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EDMS Doc. Number: 23772190 - 22735700
JCARH125
Summary of Changes H125001
Celgene Corporation
Confidential and Proprietary
3
H125001 Amendment 5 Final: 31 May 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Non-Dose Limiting Toxicities (DLT) adverse events were clarified
The following are updated non-hematologic adverse events:
Fever of any grade, including febrile neutropenia
Grade 4 increase in transaminases for ≤ 7 days
Grade 4 hypotension (without other CRS symptoms) requiring vasopressor for support 
that resolves to <Grade 3 in ≤ 72 hours
The following was removed from the non-hematologic adverse events list:
Grade 3 bone pain due to T cell expansion in marrow compartments for ≤ 2 weeks
The following are updated hematologic adverse events:
Grade 3 neutropenia of any duration or Grade 4 neutropenia lasting ≤ 28 days
Grade 3 or 4 leukopenia of any duration
Grade 3 thrombocytopenia of any duration or Grade 4 thrombocytopenia lasting ≤ 28 
days
Grade 3 anemia of any duration or Grade 4 anemia lasting ≤ 28 days
The following was removed from the hematologic adverse events list:

Grade 3 or 4 B-cell aplasia and hypogammaglobulinemia
These clarifications made to the hematologic and non-hematologic adverse events were created 
to promote consistency across CAR T cell programs.
Revised Sections: Protocol Synopsis, Section 4.3

PK assessment alterations
JCARH125 expansion and persistence will be determined by only qPCR to detect the 
JCARH125 transgene, flow cytometry will no longer be utilized.
This editorial change was made to provide consistency across MM and CAR T-cell programs.
Revised Sections: Protocol Synopsis, Section 8.12.8.1, Section 10.3.9

Evaluation of the depth of response using MRD assessment was removed as a secondary 
objective in Phase 1 and 2 and was added as an exploratory objective in Phase 1 and 
Phase 2
This modification was incorporated to promote consistency across CAR T cell programs.
Revised Sections: Protocol Synopsis, Table 1, Section 10.3.5, Appendix B
Approved
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EDMS Doc. Number: 23772190 - 22735700
JCARH125
Summary of Changes H125001
Celgene Corporation
Confidential and Proprietary
4
H125001 Amendment 5 Final: 31 May 2019

Planned JCARH125 dose levels were modified as follows:
Dose Level
JCARH125 Dose (CD3+CAR+ cells)
-1
25 × 106
1
50 × 106
2
150 × 106
2aa
300 × 106
3
450 × 106
3ab
600 × 106
4
800 × 106
The new dose escalation scheme used in conjunction with the mTPI-2 dosing algorithm will help 
yield a both safe and effective recommended phase 2 dose (RP2D). 
Revised Sections: Protocol Synopsis, Table 2

JCARH125 sample size
Clarified that 20-30 subjects per dose may be treated.
Based on the cumulative safety and antitumor activity data from subjects treated in Phase 1, one 
or more dose levels will be selected for further evaluation in the Phase 2 portion of the trial (the 
RP2D). A sample size of 20-30 subjects at a dose level is used to minimize the probability of 
selecting an overly toxic dose as an RP2D.  
Revised Sections: Section 2.1, Section 4.2, Section 10.5

Eligibility Criteria
Clarified inclusion criterion number 3
Subjects who received prior allogeneic stem cell transplants at least 100 days before 
enrollment with no signs of acute or chronic graft-versus-host disease (GVHD) are now 
eligible in the study.
This additional editorial change was made to provide further clarification for sites and to 
provide consistency across MM and CAR T-cell programs.
Revised Section: Protocol Synopsis, Section 5.1
Clarified inclusion criterion number 7a
Adequate renal function, defined as calculated creatinine clearance (Cockcroft Gault) ≥60 
mL/min without the assistance of hydration. Subjects must not have received IV rehydration 
within 3 days of renal function assessment
An increased incidence of neurotoxicity was noticed in subjects treated with JCARH125 who 
met inclusion criteria with a serum creatinine of ≤ 1.5 x upper limit of normal who also had 
creatinine clearance of less than 60 mL/min.
Revised Section: Protocol Synopsis, Section 5.1
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EDMS Doc. Number: 23772190 - 22735700
JCARH125
Summary of Changes H125001
Celgene Corporation
Confidential and Proprietary
5
H125001 Amendment 5 Final: 31 May 2019
Removed the previously reported exclusion criterion number 8
Prior allogeneic stem cell transplant performed was removed. See Inclusion criterion 3. 
This additional editorial change was made to provide further clarification for sites and to 
provide consistency across MM and CAR T-cell programs.
Revised Section: Protocol Synopsis, Section 5.2
Newly reported exclusion criterion number 8
Human immunodeficiency virus (HIV) infection positive subjects.
Editorial change to highlight HIV as an exclusion criterion.
Revised Section: Protocol Synopsis, Section 5.2
Exclusion criterion number 9 was updated
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as indicated by positive 
serology or nucleic acid testing. Subjects who are solely hepatitis B surface antibody 
(HBsAb)-positive are eligible.
This additional editorial change was made to provide further clarification for sites and to 
provide consistency across MM and CAR T-cell programs.
Revised Section: Protocol Synopsis, Section 5.2
Exclusion criterion number 18 was added
Use of any live vaccines against infectious diseases within 8 weeks before JCARH125 
infusion.
Due to the increased risk of cytopenias and infection caused by CAR T cell products, this 
additional exclusion criterion was added to promote subject safety. Additionally, editorial 
changes were made to provide consistency across MM programs.
Revised Sections: Protocol Synopsis, Section 5.2

Modified the lymphodepleting (LD) chemotherapy creatinine clearance exclusion to ≤ 
50 mL/min. Language was also added explaining that if LD chemotherapy is delayed 
for reasons previously discussed with Sponsor’s Medical Monitor, and if the delay was 
not longer than 14 days, safety assessments have to be repeated per Appendix A.
Lastly, subjects who cannot receive lymphodepletion within 8 weeks after leukapheresis 
must be rescreened and safety and efficacy assessments must be repeated. Modified that 
the reduction of fludarabine/cyclophosphamide (Flu/Cy) will now be when CrCl is 
between 50 and 70 rather than 30 and 49 mL/min. 
Subjects with a creatinine clearance of < 60 mL/min are excluded from receiving JCARH125 
treatment. This additional exclusion will ensure subjects with sufficient renal function 
receive study therapy. Additionally, testing for safety and/or efficacy in the event of LD 
chemotherapy treatment delay was added to ensure subjects continue to meet the inclusion 
and exclusion criteria at the time of LD chemotherapy.
Revised Sections: Section 6.2, Section 8.5.1, Section 8.5.2, Table 4, Table A-2
Approved
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EDMS Doc. Number: 23772190 - 22735700
JCARH125
Summary of Changes H125001
Celgene Corporation
Confidential and Proprietary
6
H125001 Amendment 5 Final: 31 May 2019

Updated prophylaxis recommendations and supportive care monitoring and treatment 
suggestions for tumor lysis syndrome, cytokine release syndrome, infections, 
neurological toxicity, macrophage activation syndrome, granulocyte colony-stimulating 
factors, transfusions, and IV rehydration.
This additional editorial change was made to provide further clarification on the recognition 
and treatment of a variety of conditions subjects could experience while be treated with study 
medications. It also provides consistency across MM and CAR T-cell programs.
Revised Sections: Section 6.6, Section 7.1, Section 7.3, Section 7.4, Section 7.5, Section 7.6, 
Section 7.7, Section 7.8

Additional JCARH125 infusion criteria for Day -1
The additional and/or modified criteria state that JCARH125 infusion should be delayed if 
any of the following are met:

Suspected or active systemic infection 5 days before JCARH125 infusion
o
All cultures must be negative if subject had a recent infection

Platelet count < 50,000/mm3

Calculated creatinine clearance (Cockcroft Gault) < 60 mL/min
These eligibility criteria on the day prior to treatment were added to ensure subject safety and 
eligibility prior to infusion.
Revised Sections: Protocol synopsis, Section 5.2, Section 8.5.3

Added the Mini-Mental State Examination (MMSE) to assess memory and other 
cognitive functions as part of the routine neurological exams done at study visits as well 
as daily during any neurological adverse event that is suspected to be CAR T cell 
associated neurological toxicity
Revised Sections: Section 8.6, Section 8.12.2, Section 10.3.7.4, Table A-1, Table A-2, Table 
A-3, Appendix E

Added assessments for Second Primary Malignancy (SPM) to monitor for and identify 
the potential cause of an SPM
Revised Sections: Section 8.6, Section 8.9, Section 8.12.8.2, Section 8.12.9

Added new Table A-4 to the Schedule of Evaluations to clarify the assessments required 
after a subject has disease progression
Added Table A-4
The amendment also includes several other minor updates, clarifications and corrections:

Added nominal study name to the protocol title

Changed sponsor contact for safety reporting and updated H125001 study team contact 
information.

Updated the Sponsor signature page study team contact information.
Approved
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EDMS Doc. Number: 23772190 - 22735700
JCARH125
Summary of Changes H125001
Celgene Corporation
Confidential and Proprietary
7
H125001 Amendment 5 Final: 31 May 2019

Modified the sponsor name in the protocol synopsis to “Juno Therapeutics, Inc., a wholly 
owned subsidiary of Celgene Corporation.”

Updated the study rationale in the protocol synopsis to include more current data on 
multiple myeloma treatment and BCMA CAR T cell therapy.

Updated the multiple myeloma epidemiology information (Section 1.1)

Provided updated information on other CAR T cell therapy options including safety and 
efficacy data (Section 1.3)

Clarified that when disease progression occurs during the 2-year follow-up timeframe, 
subjects are still followed according to the Schedule of Evaluations. (Protocol Synopsis, 
Section 4.1)

Lines of therapy was replaced with anti-myeloma treatment regimens in inclusion 
criterion number 3 (Protocol Synopsis, Section 5.1)

Added verbiage to inclusion criterion number 4 that clarified subjects must have 
measurable disease as determined by a central laboratory. (Protocol Synopsis, Section 
5.1)

Clarification added to inclusion criterion number 13 that states males who have partners 
of childbearing potential must agree to use an effective barrier contraceptive method from 
initiation of lymphodepleting chemotherapy and for 1 year after the last dose of study 
therapy and should not donate semen or sperm during the entire study period. (Section 
5.1, Section 5.3).

Exclusion criterion number 3 clarifies that subjects who have refused autologous stem 
cell transplant are not eligible for the study. (Protocol Synopsis, Section 5.2)

Exclusion criterion number 4 was modified to exclude subjects with another primary 
malignancy that has not been in remission for at least 3 years. Additionally, subjects with 
completely resected Stage 1 solid tumor with low risk for recurrence was removed from 
the exceptions list. (Protocol Synopsis, Section 5.2)

Verbiage was included that states the Principal Investigator should ask subjects who 
withdraw prematurely from the study to participate in the Celgene sponsored long term 
follow up protocol. (Section 5.4.2)

The statement suggesting bridging therapy must be discontinued at least 14 days prior to 
initiation of lymphodepleting chemotherapy was removed. (Section 6.1)

Added verbiage explaining that administration of JCARH125 may occur 2 to 7 days after 
completion of lymphodepleting chemotherapy. (Protocol Synopsis, Section 4.1, Section 
6.2, Section 6.3.1)

Corrected text in Section 6.3.3 to state that each JCARH125 dose consists of CD3+ 
CAR+ T cells. 

Additional concomitant medication reporting suggestions are provided in Table 3 of 
Section 6.7.1. (Table A-4)
Approved
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EDMS Doc. Number: 23772190 - 22735700
JCARH125
Summary of Changes H125001
Celgene Corporation
Confidential and Proprietary
8
H125001 Amendment 5 Final: 31 May 2019

Plasmapheresis was added as a prohibited procedure between screening and JCARH125 
infusion (Section 6.6, Section 6.8)

The use of live vaccines was added as a prohibited medication within 8 weeks before 
JCARH125 infusion (Section 6.8)

Pegfilgrastim ≤ 11 days prior to JCARH125 infusion or ≤ 7 days after infusion was added 
to the prohibited medications list. (Section 6.8)

Removed the following text: B-cell aplasia is an expected potential off-tumor, on-target 
toxicity, arising from targeted elimination of non-malignant BCMA-positive B cells. The 
main risk of B-cell aplasia is hypogammaglobulinemia, which may increase the risk of 
infection. (Section 7.9)

Revisions to methylprednisolone dose from 2 mg/kg/day to 1 to 3 mg/kg/day and timing 
of taper from 2-3 weeks to 7 days was updated. (Section 7.10)

Verbiage was added to state that eligibility will be assessed by the sponsor prior to 
leukapheresis, prior to lymphodepleting chemotherapy, and prior to JCARH125 infusion.
(Section 8.1)

The option for additional electrocardiograms (ECGs) as clinically indicated was added. 
(Section 8.12.4)

Assessment of health-related quality of life (HRQoL) and health economics and 
outcomes research (HEOR) in subjects were clarified in Phase 2 (Section 8.12.10, 
Section 8.2.11).

Added all primary and secondary endpoints from Table 1 to ensure Section 10.3.2 and 
10.3.5 were aligned (Section 10.3.2, Section 10.3.5)

Clarified that the EQ-5D-5L and will be analyzed according to the recommendations in 
the scoring manual. (Section 10.3.11)

Increased the overall study sample size up to 200 subjects in Phase 1/2 and up to 120 in 
Phase 1 (Protocol Synopsis, Section 10.5).

Added protocol Section 12.2.3 Product Quality Complaint, to align with the Celgene 
protocol template language (Section 12.2.3)

Clarified that unscheduled assessment for PET/CT or DW/MRI is required if clinically 
indicated to assess rapidly progressing MM disease (Table A-3)
Approved
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Protocol H125001 Amendment 4 
10 September 2018 
Juno Therapeutics, Inc. 
Confidential 
Page 2 of 8 
1. 
OVERALL SUMMARY OF CHANGES 
Amendment 4 of Protocol H125001 was prepared to add an intermediate dose level of 300×106 
CD3+CAR+ T cells to the dose levels selected for evaluation.  The rationale for investigating 
this intermediate dose level is based on adverse events that occurred in the first 2 subjects treated 
at Dose Level 3 (450×106 CD3+CAR+ T cells).  Both subjects treated at this dose level 
experienced rapid onset of cytokine release syndrome (CRS) within 8 hours after JCARH125 
infusion and received treatment with tocilizumab. The first subject experienced Grade 2 
neurotoxicity, which completely resolved after treatment with tocilizumab and corticosteroids.  
The second subject developed Grade 4 CRS and Grade 4 neurotoxicity unresponsive to 
corticosteroid therapy, Grade 4 aspartate aminotransferase (AST) increased, Grade 4 acute 
kidney injury, and Grade 5 septic shock. The events experienced by the second subject met dose-
limiting toxicity (DLT) criteria.  Based on the safety results in subjects treated at the 300×106 
CD3+CAR+ cell dose level, the Sponsor, in collaboration with study investigators, will make an 
assessment as to whether it is appropriate to evaluate additional subjects at the 450×106 
CD3+CAR+ cell dose level. 
Accordingly, the following major changes were made to the protocol in this amendment: 
 A dose level of 300×106 CD3+CAR+ T cells was added as Dose Level 2a. 
 The rationale for evaluating the intermediate dose level was provided in Section 2.1. 
The following changes were also made: 
 The requirement to treat only one subject per day after staggering of the first 3 subjects by 
7 days was removed. 
 The recommendation to hospitalize subjects in Phase 1 starting at the time of 
lymphodepleting chemotherapy was removed. 
 The following treatments were added as treatments that should be recorded during 
hospitalizations:  antibiotics, growth factors, transfusions, and systemic anticoagulants. 
 The temperature threshold above which subjects should have JCARH125 administration 
delayed and be hospitalized following JCARH125 infusion was lowered from 38.5°C to 
38.0°C. 
 The requirement to notify the Sponsor and to collect tissue samples for analysis by the 
central laboratory was removed from the instructions to be followed for unscheduled 
evaluations. 
 A mental status evaluation was added to the list of assessments required to be performed as 
part of the neurological examination. 
 The email address for safety reporting was updated to direct reports to Celgene Drug Safety 
rather than Juno Pharmacovigilance. 
In addition, other minor administrative clarifications and typographical corrections were made. 
Approved
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Protocol H125001 Amendment 3 
15 May 2018 
Juno Therapeutics, Inc. 
Confidential 
Page 2 of 24 
1. 
OVERALL SUMMARY OF CHANGES 
Amendment 3 of Protocol H125001 was prepared primarily to further refine the study population 
in order to collect and analyze data on a more homogeneous study population.   
The following major changes were made to the protocol in this amendment: 
 The inclusion criterion regarding required prior treatments was revised to clarify that subjects 
must have had an immunomodulatory agent and a proteasome inhibitor, either in the same 
combination regimen or as separate regimens. 
 The requirement for subjects to be relapsed or refractory was modified to require that 
subjects be refractory to their last prior regimen, defined as disease that is nonresponsive or 
progresses on treatment, or that shows progression within 60 days after the last prior line of 
therapy. 
 Grade 4 lymphopenia lasting more than 14 days will not be considered a dose-limiting 
toxicity (DLT). 
 Separate analyses in the BCMA-high population were removed. 
 Reference to the use of the truncated epidermal growth factor (EGFRt) portion of the 
lentiviral vector encoding the BCMA CAR for the purpose of analytical detection of 
transduced T cells and ablation of CAR T cells in the event of CAR T-cell-related toxicity 
was removed. 
 Language in the management of cytokine release syndrome (CRS) and neurotoxicity sections 
was updated to align with language in the Celgene-approved guidance document; an 
appendix containing an updated algorithm for CRS management and a new algorithm for 
management of neurotoxicity was added. 
 Bone marrow evaluations at Pre-treatment Screening will only be performed in subjects with 
inadequate or insufficient samples at Screening and in subjects who receive bridging 
chemotherapy. 
 Bone marrow evaluations were added at Month 12, Month 18, and Month 24 (end of study 
[EOS]). 
 Minimum renal function (creatinine clearance [CrCl] or glomerular filtration rate [GFR]) 
required for initiating lymphodepleting chemotherapy was decreased from 60 mL/min to 
30 mL/min; instruction to reduce the dose of fludarabine by 40% was added for subjects with 
CrCl between 30 and 49 mL/min. 
 Language in the Safety section (Section 9) was updated to reflect requirements by the 
European Medicines Agency, including defining and requirements for reporting instances of 
overdose, and guidance by the Food and Drug Administration (FDA) for reporting delayed 
adverse events. 
Approved
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Protocol H125001 Amendment 3 
15 May 2018 
Juno Therapeutics, Inc. 
Confidential 
Page 3 of 24 
The following additional changes were also made in this amendment: 
 The normal range for serum creatinine for determination of eligibility will not be adjusted by 
age. 
 Requirements for clotting time were added to inclusion criteria, and an exclusion criterion 
was added for subjects with a history of ≥ Grade 2 hemorrhage or requirement for ongoing 
treatment with chronic, therapeutic doses of anticoagulants. 
 Clarification was made that subjects are required to have recovered from non-hematological 
toxicities due to prior therapy (hematologic requirements are listed in definition of adequate 
bone marrow function in Inclusion Criterion 7b). 
 Subjects with non-secretory disease (ie, those with disease only in the bone marrow and 
those with solitary plasmacytoma) will be excluded. 
 Subjects with a history of central nervous system (CNS) malignancies will be excluded in 
addition to those with active CNS malignancy. 
 Subjects with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin 
changes (POEMS) syndrome and Waldenstrom's macroglobulinemia will be excluded. 
 The exclusion criterion prohibiting untreated or active infection at the time of Screening and 
before leukapheresis was modified to also exclude infection at the time of leukapheresis. 
 An exclusion criterion was added for plasmapheresis within 14 days before leukapheresis. 
 Medical conditions or laboratory abnormalities that, in the judgment of the Investigator, 
could jeopardize subject safety were added to the exclusion criteria. 
 Guidance for recording intravenous (IV) fluids administered during hospitalization for 
treatment of CRS was added. 
 Evaluations of serum chemistry, coagulation parameters, and lymphocyte enumeration on the 
day of apheresis were removed. 
 Clarification was made that only subjects who receive bridging chemotherapy with 
potentially cardiotoxic drugs are required to have a repeat echocardiogram or multiple uptake 
gated acquisition (MUGA) at Pre-Treatment Screening. 
 Language regarding criteria for JCARH125 infusion was modified to align with language in 
other Juno/Celgene protocols. 
 Instruction was added to perform biopsies of any new plasmacytomas when feasible. 
 Guidance to submit samples from serum protein electrophoresis (SPEP), 24-hour urine 
protein electrophoresis (UPEP), serum and urine immunofixation, and/or serum free light 
chain (sFLC) evaluations collected at unscheduled visits was added. 
 An appendix defining a line of therapy was added. 
Other minor clarifications and administrative changes were also made. 
Approved
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Protocol H125001 Amendment 2 
02 January 2018 
Juno Therapeutics, Inc. 
Confidential 
Page 2 of 14 
1. 
OVERALL SUMMARY OF CHANGES 
Amendment 2 of Protocol H125001 was prepared to address FDA feedback following their 
review of Amendment 1 of the protocol 
The following changes were made to the protocol as a result of FDA feedback: 
• Details were added regarding dose escalation/de-escalation decisions based on the first 3 
subjects treated at a dose level. 
• The inclusion criteria pertaining to relapsed or refractory disease were further clarified. 
• Changes were made to the DLT criteria. 
• Replacement of subjects was changed to be limited to Phase 1. 
• Details regarding the recommended management and hospitalization of subjects prior to and 
after JCARH125 administration, including subjects who develop fever following the 
JCARH125 infusion, were added. 
• Guidance for prohibiting filgrastim during the immediate pre-infusion and post-infusion 
periods was added. 
• Changes were made to safety reporting to start collecting all SAEs from the time of 
leukapheresis. 
• The CRS treatment algorithm was updated to reference the Actemra label as indicated for 
managing severe or life-threatening CRS. 
• Details regarding recommended regimens for bridging therapy and maximum allowed 
duration between leukapheresis and initiation of study treatment were added. 
• A repeat MUGA/ECHO scan was added prior to initiation of lymphodepleting chemotherapy 
for subjects that receive bridging therapy during JCARH125 manufacturing. 
• Criteria for receiving JCARH125 infusion were added. 
• Details regarding the specific cytokines to be evaluated in research samples were added. 
• Details regarding reporting of disease progression as SAEs were added. 
• A statement was added indicating the Phase 2 efficacy analysis may be refined in a detailed 
statistical analysis plan (SAP), following further discussion with regulatory authorities. 
• Details regarding the endpoints to be evaluated at the interim analysis were added. 
• Details regarding the timing of the primary analysis were added. 
• Details regarding a sensitivity analysis to be performed in all subjects who undergo 
leukapheresis but who may not receive treatment on study were added. 
• Clarification was made throughout the protocol that only a single dose of JCARH125 will be 
administered in this study, ie, retreatment with a second dose is not an option in this first-in-
human trial. 
Approved
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Protocol H125001 Amendment 2 
02 January 2018 
Juno Therapeutics, Inc. 
Confidential 
Page 3 of 14 
The following additional changes were also made in this amendment: 
• Cytogenetics was removed from research evaluations; information will be obtained through a 
previous report if available. 
• HLA typing and donor chimerism were removed from laboratory evaluations since subjects 
with prior allogeneic transplant are excluded. 
Other minor clarifications and administrative changes were also made. 
 
Approved
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Approved
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Protocol H125001 Amendment 1 
16 October 2017 
Juno Therapeutics, Inc. 
Confidential 
Page 2 of 14 
1. 
OVERALL SUMMARY OF CHANGES 
Amendment 1 of Protocol H125001 was prepared to remove patient selection in Phase 1 based 
on expression of B-cell maturation antigen (BCMA) in tumor biopsy samples.  Data generated at 
Juno Therapeutics from a recent evaluation of BCMA expression in tumor samples from patients 
with multiple myeloma (MM) suggest that more than 90% of MM patients express some level of 
BCMA.  Based on the biological dynamics of BCMA, the heterogeneity of MM, and the 
potential for epitope spreading, there is reason to believe that patients with low BCMA 
expression in a single biopsy sample may benefit from BCMA-directed CAR T-cell therapy.  
This modification allows patients to enroll in Phase 1 at any time, regardless of level of BCMA 
expression; clinical benefit relative to BCMA expression will be explored during the study. 
In addition, the analysis for the primary endpoint of overall response rate (ORR), as well as the 
secondary endpoint of complete response (CR) rate, was redefined to include two analysis 
populations:  (1) all subjects in Phase 1 and Phase 2 who receive treatment with JCARH125 at 
the recommended Phase 2 dose (RP2D) regardless of level of BCMA expression and (2) subjects 
with BCMA expression on > 90% of plasma cells (ie, the BCMA-high population). 
Accordingly, the following changes were made to the protocol: 
• The Pre-Screening visit in Phase 1 for evaluation of BCMA expression in archival samples 
was removed.  Biopsy samples will be collected from all subjects in Phase 1 and Phase 2 
during Screening and Pre-treatment Screening and analyzed for BCMA expression, but 
BCMA expression level will not be used to determine eligibility in either Phase 1 or Phase 2 
of the study.  Archival samples obtained within 1 year prior to Screening will be requested 
from all subjects for whom such samples are available and analyzed for BCMA expression. 
• The statistical method for control of the overall type 1 error rate was updated to reflect that 
analysis of the primary endpoint will be performed in two separate populations, and that 
these analyses are both considered primary. 
• The primary analysis population for efficacy endpoints other than ORR and CR rate, which 
were previously based on subjects expressing BCMA above the pre-defined threshold, will 
now include all evaluable subjects treated at the RP2D in either Phase 1 or Phase 2 of the 
study.  The name of this analysis population was changed from the “primary analysis set” to 
the “efficacy analysis set.” 
• The effect size detectable with 90% power in the BCMA-high population was changed to 
reflect an expectation that 45 subjects determined to be BCMA-high will be included in the 
analyses for this population. 
• The timing of the primary analysis was changed to occur after all subjects in the efficacy 
analysis set have been evaluated for response. 
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Protocol H125001 Amendment 1 
16 October 2017 
Juno Therapeutics, Inc. 
Confidential 
Page 3 of 14 
The following additional changes were also made in this amendment: 
• The inclusion criterion for prior autologous stem cell transplant was deleted and replaced 
with an exclusion criterion excluding subjects eligible for an autologous stem cell transplant. 
• Minimum hemoglobin at Screening was reduced from 9 g/dL to 8 g/dL. 
• Exceptions to exclusion criterion related to toxicities due to previous therapy were modified 
(skin-limited graft-vs-host disease removed as an exception; anemia, thrombocytoypenia, and 
neutropenia added as exceptions). 
• Infection within 72 hours prior to JCARH125 infusion was removed as an exclusion 
criterion. 
• A statement was added indicating that the DLT evaluation period may be extended beyond 
21 days in the event that adverse events meeting DLT criteria are found to occur beyond the 
DLT window. 
• The sample size was increased from approximately 112 subjects to approximately 118 
subjects. 
• Pre-treatment disease assessments and biopsies, previously required only for subjects who 
received bridging chemotherapy during JCARH125 production, will be required for all 
subjects. 
• PET/CT scans at Pre-treatment Screening, previously required for all subjects, will only be 
performed on subjects with extramedullary lesions identified on scans at Screening and on 
subjects with clinical suspicion of new extramedullary lesions. 
• Clarification was made that growth factors and transfusions will be allowed for subjects who 
do not meet the minimum requirements for absolute neutrophil count (ANC), hemoglobin, 
and platelet count requirements at Pre-treatment Screening.  
• Criteria for hemoglobin ≥ 8 g/dL and platelet count ≥ 30,000/mm3 were added prior to 
JCARH125 administration; red blood cell transfusions and other supportive measures may be 
used. 
Other minor clarifications and administrative changes were also made. 
 
Approved
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Approved
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