Conditions: Multiple Myeloma
Keywords: CAR-T CART CAR T Cell CAR T-Cell Multiple Myeloma BCMA B cell maturation antigen B-cell maturation antigen Descartes-11
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This Phase I study will test the safety and anti-myeloma activity of ascending doses of Descartes-11 (autologous CD8+ T-cells expressing an anti-BCMA chimeric antigen receptor) in eligible patients with active multiple myeloma.

Detailed description:

Arms:
arm 1: Participants were administered Cyclophosphamide and Fludarabine for preconditioning on Days 1,2,3

Participants were administered 10 million cells of Descartes-11 via intravenous catheter on Days 7,14 arm 2: Participants were administered Cyclophosphamide and Fludarabine for preconditioning on Days 1,2,3

Participants were administered 32 million cells of Descartes-11 via intravenous catheter on Days 7,14 arm 3: Participants were administered Cyclophosphamide and Fludarabine for preconditioning on Days 1,2,3

Participants were administered 100 million cells of Descartes-11 via intravenous catheter on Days 7,14 arm 4: Participants were administered Cyclophosphamide and Fludarabine for preconditioning on Days 1,2,3

Participants were administered 150 million cells of Descartes-11 via intravenous catheter on Days 7,14,21 arm 5: Participants were administered Cyclophosphamide and Fludarabine for preconditioning on Days 1,2,3

Participants were administered 150 million cells of Descartes-11 via intravenous catheter on Days 7,10,14,21 arm 6: Participants were not administered Cyclophosphamide and Fludarabine for preconditioning on Days 1,2,3

Participants were administered 150 million cells of Descartes-11 via intravenous catheter on Days 1,4, 7,10,14,21

Interventions: intervention 1: Descartes-11 intervention 2: Fludarabine intervention 3: Cyclophosphamide
Intervention descriptions: intervention 1: CAR T-Cells intervention 2: Pre-conditioning chemotherapy intervention 3: Pre-conditioning therapy

Protocol document:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
TITLE: Phase I safety study of Descartes-11 in patients with relapsed/refractory multiple 
myeloma 
 
Protocol number: 
DC11A 
IND number: 
19050 
Investigators:  
Multi-center 
Sponsor: 
Cartesian Therapeutics, Inc. 
Address:  
704 Quince Orchard Rd., Suite 210A 
Gaithersburg, MD 20878 
Phone: 
+1-301-348-8698 
Website:  
www.cartesiantherapeutics.com 
e-mail:  
metin.kurtoglu@cartesiantx.com 
Study Product: 
Descartes-11 
Original Protocol Date: 
May 14, 2019 
Amendment Revision No: 
Amendment Date: 
Version 1.6 
5 October, 2020  
 
 
 


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SPONSOR SIGNATURE PAGE 
 
 
 
 
 
 
 
 
5-OCT-2020 
___________________________ 
______________________ 
Company/Sponsor signatory 
Date 
Metin Kurtoglu, MD, PhD 
Cartesian Therapeutics, Inc. 
704 Quince Orchard Rd. Suite 210A  
Gaithersburg, MD 20878 
Tel 301-348-6898 
 
 


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INVESTIGATOR’S AGREEMENT 
I have received and read the investigator’s brochure for Descartes-11. I have read protocol and 
agree to conduct the study as outlined and in conformance with Good Clinical Practices (GCPs) 
and applicable regulatory requirements. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
Printed Name of Investigator 
 
 
Signature of Investigator 
 
___________________________________ 
Date 
 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ..............................................................................................2 
INVESTIGATOR’S AGREEMENT .........................................................................................3 
ABBREVIATIONS AND DICTIONARY OF TERMS ...........................................................9 
1 INTRODUCTION .............................................................................................................11 
1.1 
Study Objectives ....................................................................................................11 
1.1.1 
Primary Objectives .....................................................................................11 
1.1.2 
Secondary Objective ..................................................................................11 
1.1.3 
Exploratory Objectives ..............................................................................11 
1.2 
Background and Rationale .....................................................................................11 
1.2.1 
Epidemiology of Multiple Myeloma .........................................................11 
1.2.2 
Treatment of Relapsed/Refractory Multiple Myeloma ..............................11 
1.2.3 
Engineering of CAR T-cells ......................................................................12 
1.2.4 
CAR-T Therapy in Multiple Myeloma ......................................................12 
1.2.5 
Summary of CAR T-cell Related Adverse Events ....................................13 
1.2.6 
Rationale for Current Protocol ...................................................................15 
1.2.7 
Rationale Behind Preconditioning Chemotherapy .....................................15 
1.2.8 
Preface to Protocol Version 1.5 .................................................................16 
1.2.9 
Preface to Protocol Version 1.6 .................................................................16 
1.3 
Study Drug .............................................................................................................16 
1.3.1 
Description .................................................................................................16 
1.3.2 
Route of Administration and Dosing Regimen ..........................................16 
1.3.3 
Preclinical Data ..........................................................................................17 
2 ELIGIBILITY AND ENROLLMENT ..............................................................................18 
2.1 
Eligibility Criteria ..................................................................................................18 
2.1.1 
Inclusion Criteria .......................................................................................18 
2.1.2 
Exclusion Criteria ......................................................................................19 
2.2 
Screening, Evaluation and Enrollment ..................................................................20 
2.2.1 
Recruitment of Patients ..............................................................................20 
2.2.2 
Screening Evaluation .................................................................................20 
2.2.3 
Enrollment ..................................................................................................21 
2.2.4 
Early Withdrawal of Subjects ....................................................................21 
2.2.5 
Data Collection and Follow-Up of Early Withdrawals ..............................21 
3 STUDY DESIGN...............................................................................................................22 
3.1 
Study Schema .........................................................................................................22 
3.2 
Study Implementation ............................................................................................22 


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3.2.1 
Overall treatment design ............................................................................22 
3.2.2 
Dose Levels ................................................................................................23 
3.2.3 
Dose Escalation / Stopping Rules ..............................................................24 
3.2.4 
Delay of Cell Infusion ................................................................................25 
3.3 
Drug Administration ..............................................................................................25 
3.3.1 
Leukapheresis ............................................................................................25 
3.3.2 
Administration of Cyclophosphamide and Fludarabine ............................26 
3.3.3 
Preparation and Administration of Study Drug .........................................26 
3.3.4 
Return or Destruction of Study Drug .........................................................27 
3.3.5 
Post-Infusion Observation .........................................................................27 
3.3.6 
Management of Toxicities .........................................................................27 
3.3.7 
Concomitant Medications ..........................................................................28 
4 PROTOCOL EVALUATION AND BIOSPECIMEN COLLECTION ............................30 
4.1 
Study Procedures ...................................................................................................30 
4.1.1 
Baseline Evaluation (Day -60 to Day -8) ...................................................30 
4.1.2 
Leukapheresis (Day -59 to Day -7) ............................................................31 
4.1.3 
First day of Pre-conditioning chemotherapy (Day 1 (± 1 d) of Cycle 1) ...31 
4.1.4 
Second and Third day of Preconditioning chemotherapy (Day 2 to Day 3 
of Cycle 1) ..................................................................................................32 
4.1.5 
Descartes-11 infusion .................................................................................32 
4.1.6 
Safety Review and Response Assessment Visit (Day 21+3 days) ............33 
4.1.7 
Follow-up Months 3, 6, 9, 12 (+ 2 weeks) .................................................34 
4.2 
Study Calendar .......................................................................................................35 
4.3 
Biospecimen Collection for Exploratory Studies ..................................................37 
4.3.1 
Explanation of Research Blood Assays .....................................................37 
4.3.2 
Future Studies ............................................................................................37 
4.3.3 
Research Blood Sample and Remaining Study Drug Destruction Upon 
Protocol Completion ..................................................................................38 
4.4 
Treatment Response Assessment ...........................................................................38 
4.5 
Criteria for Removal from Protocol Therapy and Off-Study Criteria ...................40 
4.5.1 
Criteria for Removal from Descartes-11 Therapy .....................................40 
4.5.2 
Criteria for Off-Study ................................................................................40 
5 SAFETY, ADVERSE EVENTS, PROTOCOL DEVIATION AND STOPPING 
RULES ...............................................................................................................................41 
5.1 
Definitions ..............................................................................................................41 
5.1.1 
Adverse Events (AE) .................................................................................41 
5.1.2 
Suspected Adverse Reaction ......................................................................41 


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5.1.3 
Serious Unexpected Adverse Reaction (SUSAR) .....................................41 
5.1.4 
Serious Adverse Event (SAE) ....................................................................42 
5.1.5 
Dose Limiting Toxicity (DLT) ..................................................................42 
5.1.6 
Protocol Deviation .....................................................................................43 
5.2 
Recording of Adverse Events ................................................................................43 
5.2.1 
Adverse Event Recording Period ...............................................................43 
5.2.2 
Hospitalization, Prolonged Hospitalization or Surgery .............................43 
5.2.3 
Pregnancies ................................................................................................43 
5.2.4 
Recording of Adverse Events ....................................................................44 
5.2.5 
SAE and SUSAR Reporting ......................................................................45 
5.3 
Medical Monitor ....................................................................................................47 
5.4 
Recording of Protocol Deviations ..........................................................................47 
5.5 
Stopping Rules and Study Termination .................................................................47 
6 STATISTICAL CONSIDERATIONS...............................................................................49 
6.1 
Primary Endpoints .................................................................................................49 
6.1.1 
Safety and Tolerance ..................................................................................49 
6.1.2 
Feasibility ...................................................................................................49 
6.2 
Secondary Endpoints .............................................................................................49 
6.2.1 
Efficacy ......................................................................................................49 
6.3 
Exploratory Endpoints ...........................................................................................49 
6.3.1 
Descartes-11 Biology .................................................................................49 
6.3.2 
Immunogenicity Assessment .....................................................................49 
7 ETHICAL CONSIDERATIONS .......................................................................................50 
7.1 
General Issues ........................................................................................................50 
7.2 
Rationale for Subject Selection ..............................................................................50 
7.3 
Evaluation of Benefits and Risks ...........................................................................50 
7.4 
Recordkeeping .......................................................................................................51 
7.4.1 
Source Data ................................................................................................51 
7.4.2 
Case Report Forms .....................................................................................51 
7.4.3 
Confidentiality ...........................................................................................51 
7.4.4 
Records Retention ......................................................................................51 
8 PHARMACEUTICAL INFORMATION ..........................................................................52 
9 REFERENCES ..................................................................................................................53 
10 APPENDIX 1 MANAGEMENT GUIDELINES FOR CAR T-CELL-RELATED 
TOXICITIES ......................................................................................................................59 
 


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List of In-Text Tables 
Table 1. 
CRS Grading Scale .............................................................................................14 
Table 2. 
Dose Levels and Infusion Schedule per Cycle ...................................................23 
Table 3. 
Dose Escalation Rules ........................................................................................25 
Table 4. 
IMWG response criteria82 ...................................................................................38 
Table 5. 
Relapse from sCR or MRD-negative Criteria .....................................................39 
 
List of In-Text Figures 
Figure 1. 
Study Schema .....................................................................................................22 
 


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ABBREVIATIONS AND DICTIONARY OF TERMS 
AE 
Adverse Event 
ALL 
Acute Lymphoblastic Leukemia 
ALT 
Alanine aminotransferase 
ASCT 
Autologous stem cell transplant 
ASH 
American Society of Hematology 
AST 
Aspartyl aminotransferase 
AUC 
Area Under the (time-concentration) Curve 
BCMA 
B-Cell Maturation Antigen 
BSC 
Biological Safety Cabinet 
CAR 
Chimeric Antigen Receptor 
CBC 
Complete blood count 
CDR 
Complementarity-Determining Regions 
CLL 
Chronic Lymphocytic Leukemia 
CMC 
Chemistry, Manufacturing, and Controls 
CNS 
Central Nervous System 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRS 
Cytokine Release Syndrome 
CSF 
Cerebrospinal fluid 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMF 
Drug Master File 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
FHCRC 
Fred Hutchinson Cancer Research Center  
FLC 
Free light chain 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte-Macrophage colony-stimulating factor 
GMP 
Good Manufacturing Practice 
GVHD 
Graft-versus-host disease 
HAMA 
Human anti-mouse antibody 
HAS 
Human Serum Albumin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
HPLC 
High Performance Liquid Chromatography 
HR 
Hazard Ratio 
IFN-g 
Interferon-gamma 
IL 
Interleukin 


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IMID 
Immunomodulatory drug 
IMWG 
International Myeloma Working Group 
IND 
Investigational New Drug (application) 
IV 
Intravenous(ly) 
MFC 
Multi-parameter flow cytometry 
MHC 
Major histocompatibility complex 
MM 
Multiple Myeloma 
MOI 
Multiplicity of infection 
MRD 
Minimal Residual Disease 
MTD 
Maximal Tolerated Dose 
NCI 
National Cancer Institute 
NGS 
Next Generation Sequencing 
NOAEL 
No Observed Adverse Effect Level 
NSAID 
Non-steroidal anti-inflammatory drug 
MRSD 
Maximum Recommended Starting Dose 
MSSD 
Maximum Safe Starting Dose 
NDA 
New Drug Application 
ODD 
Orphan Drug Designation (application) 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PI 
Proteasome inhibitor 
PK 
Pharmacokinetic 
PR 
Partial Response 
PRBC 
Packed Red Blood Cells 
PRES 
Posterior Reversible Encephalopathy Syndrome 
SAE 
Serious Adverse Event 
sCR 
Stringent Complete Response 
SEM 
Standard Error of the Mean 
SIFE 
Serum immunofixation electrophoresis 
SM 
Starting Materials 
SPEP 
Serum protein electrophoresis 
SPD 
Sum of the Products of the Maximal Perpendicular Diameters 
TK 
Toxicokinetic(s) 
TLS 
Tumor Lysis Syndrome 
TNF α 
Tumor-necrosis factor alpha 
UIFE 
Urine immunofixation electrophoresis 
UPEP 
Urine protein electrophoresis 
VGPR 
Very Good Partial Response 
 
 


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1 Introduction 
1.1 Study Objectives 
1.1.1 
Primary Objectives 
1. Determine the safety of Descartes-11 in patients with relapsed/refractory multiple myeloma 
(MM) 
2. Determine the feasibility of manufacturing Descartes-11 from apheresis products of patients 
with relapsed/refractory MM 
 
1.1.2 
Secondary Objective 
1. Describe anti-myeloma responses after Descartes-11 infusion 
a. Determine best response according to the IMWG response criteria 
b. Determine progression-free survival (PFS) after Descartes-11 infusion 
 
1.1.3 
Exploratory Objectives 
1. Characterize Descartes-11 persistence, homing, phenotype, and function in patients with MM 
2. Determine impact of Descartes-11 on systemic soluble immune factors and BCMA levels 
3. Test for immunogenicity of Descartes-11 
 
1.2 Background and Rationale 
1.2.1 
Epidemiology of Multiple Myeloma 
In 2018, there were over 30,000 new cases of multiple myeloma (MM) and over 10,000 deaths 
from this disease.1 MM is the second most common hematological malignancy in adults after 
lymphoma. and median survival after diagnosis is around five years.2  MM is still considered an 
incurable disease, as almost all patients eventually relapse after each line of treatment.    
1.2.2 
Treatment of Relapsed/Refractory Multiple Myeloma 
First-line therapy of MM with autologous stem cell transplant (ASCT), a proteasome inhibitor 
(PI), and immunomodulatory agent (IMID) has extended the time to relapse of disease progression. 
However, until recently, limited treatment options existed when the disease became resistant to 
both PI and IMID, with a median survival of 13 months after documentation of symptomatic 
progression.3 In the past decade, discovery of several new myeloma-specific pathways and 
antigens has changed this paradigm by providing several potent options for second-line treatment. 
Newly approved agents for myeloma include carfilzomib,4,5 ixazomib,6 daratumumab,7,8 
elotuzumab,9 panobinostat10 and pomalidomide11.  These agents are used in combination with 
either dexamethasone, bortezomib-dexamethasone, or lenalidomide-dexamethasone for patients 
who are refractory to, or relapsed after, first-line treatment. While these combinations are highly 
effective in achieving deep responses when given as second-line therapy, disease almost always 


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relapses, leaving patients with limited approved options for third-line therapies and beyond. 
Among various experimental options for advanced MM, Chimeric Antigen Receptor (CAR) T-
cell therapy has drawn significant attention due to its unprecedented activity in patients who have 
relapsed after multiple lines of therapy. The concept and reported clinical activity of CAR T-cell 
treatment are summarized below. 
1.2.3 
Engineering of CAR T-cells 
Chimeric antigen receptors (CARs) are fusion proteins that include an extracellular antigen-
recognition domain linked to an intracellular signaling domain.12  When the CAR is expressed in 
a T-cell, the cell recognizes a specific antigen and subsequently stimulates T-cell proliferation, 
cytolysis, and cytokine secretion to eliminate the target cell. Autologous T-cells carry negligible 
risk of graft-versus-host disease (GVHD).  The process theoretically allows any specific surface 
antigen to be targeted by T-cells in a manner unrestricted by the major histocompatibility complex 
(MHC). 
1.2.4 
CAR-T Therapy in Multiple Myeloma 
B-cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily 
member 17 (TNFRSF17) or CD269, is consistently and selectively expressed on normal plasma 
and myeloma cells.13  For this reason, it is considered the most promising target antigen for CAR 
immunotherapy of MM. Upon engagement by its ligands, i.e., TNFSF13 (APRIL: a proliferation-
inducing ligand; CD256) and TNFSF13B (BAFF: B cell-activating factor; also known as BLYS 
or CD257), BCMA supports survival of plasma cells.14 
A CAR construct against BCMA was originally developed at the National Cancer Institute (NCI). 
The scFv portion of this CAR was derived from a mouse anti-human-BCMA monoclonal 
antibody. 13  The construct also contains the hinge and transmembrane regions of the CD8-alpha 
molecule, the signaling moiety of CD28, and the signaling domains of CD3-zeta. T-cells virally 
transduced with the anti-BCMA CAR produced large amounts of IFN-g when cultured overnight 
with the BCMA-expressing cell lines BCMA-K562 and RPMI8226. Furthermore, when one dose 
of anti-BCMA CAR T-cells was administered to immunodeficient mice implanted with the human 
myeloma cell line RPMI8226, tumor eradication was evident in 10/10 animals. Following these 
remarkable preclinical results, a Phase I single ascending dose trial was initiated at NCI. The trial 
enrolled MM patients who had relapsed or remained refractory after 3 or more lines of therapy.15 
The results of the trial were updated recently, and at the maximum tolerated dose (MTD) of 9x106 
cells/kg, 63% of the patients achieved very good partial response (VGPR) or better. 16 
Given the promising efficacy of the virally transduced anti-BCMA CAR T-cells, several other 
groups created anti-BCMA CAR T-cells now in clinical testing. Bluebird Bio’s anti-BCMA-CAR 
T-cell construct is currently in Phase II clinical trials, with approximately 45% of the patients 
achieving complete response (CR).17,18 The CAR developed by the University of Pennsylvania has 
published results of their first cohort that received 1-5x108 cells without any chemotherapy and 2 
out of 6 patients achieved VPGR or better.19  Poseida developed an anti-BCMA CAR T-cell 
product, which expresses a non-antibody based target binding domain in a highly enriched stem 
cell memory T-cell population and 83% of the patients treated above Dose Level 1 achieved a 
clinically meaningful result.20 Finally, LCAR-38M from Nanjing Legend Biotech resulted in 
VGPR or better response rate in 88% of the patients tested.21  In addition to these reported phase I 


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trials, several other anti-BCMA CAR constructs have been synthesized and are undergoing human 
testing in the United States (NCT03549442, NCT03338972, NCT03288493, NCT03070327, 
NCT03502577, NCT03602612, NCT03287804, NCT03548207, NCT03318861, NCT03274219) 
as well as several more in China.  To our knowledge, all of these trials use permanently modified 
CAR T-cell products that are engineered by gene transfer, usually through viral transduction. The 
published results of the permanently modified CAR T-cell products demonstrate their 
effectiveness as an anti-myeloma therapy; however, the therapies show significant toxicity 
(summarized in Section 1.2.5), which unfortunately appears to correlate with antitumor response.  
1.2.5 
Summary of CAR T-cell Related Adverse Events 
The potency of virally transduced CAR therapies comes with significant risks.  All clinical trials 
of virally transduced CAR T-cells have recorded serious instances of cytokine release syndrome 
(CRS) and neurological toxicity. 
1.2.5.1 
Cytokine Release Syndrome 
In the recent American Society of Blood and Marrow Transplant (ASBMT) consensus meeting, 
CRS was defined as “a supraphysiologic response following any immune therapy that results in 
the activation or engagement of endogenous or infused T cells and/or other immune effector cells. 
Symptoms can be progressive, must include fever at the onset, and may include hypotension, 
capillary leak (hypoxia) and end organ dysfunction.”22 CRS is a prototypical systemic 
inflammatory response syndrome that occurs hours to days after CAR T-cell infusion.  Signs and 
symptoms include fever, myalgia, malaise, and, in more severe cases, a capillary leak syndrome 
associated with hypoxia, hypotension, and occasionally renal dysfunction and coagulopathy. Peak 
CAR T-cells as a result of in vivo proliferation has been strongly associated with the severity of 
CRS in many CAR T-cell studies.23-32 The proliferation of CAR T-cells upon engagement with 
target antigen drives them to secrete cytokines that initiates a cascade of systemic inflammatory 
events. It has been shown that severe CRS (requiring vasopressors) was associated with elevated 
C-reactive protein, ferritin, interleukin-6 (IL-6), interferon gamma (IFN-g) and soluble interleukin-
2 (IL-2) receptor. 25,26,33-35 and an on-going research effort is to design a panel of cytokines that 
can predict severe CRS before it occurs. 33 Among all cytokines elevated during CRS, IL-6 plays 
a central role as neutralization of this cytokine quickly and effectively reverses clinical 
deterioration in most cases.  
The first presenting symptom of CRS is usually fever associated with mild constitutional 
symptoms. 25,26,28,36 In a number of patients, the initial mild symptoms progress over the course of 
hours to days and turn into a systemic inflammatory syndrome characterized by sinus tachycardia, 
hypotension and hypoxia. In severe cases, patients may require mechanical ventilation and 
vasopressors. CRS can start as early as the day of CAR T-cell infusion and in most cases it occurs 
within the first 14 days following the infusion. Severe cases appear to occur closer to the time of 
infusion and the severity of CRS was reported to correlate with peak CAR T-cell levels as 
mentioned above as well as disease burden 
15,16 and addition of preconditioning 
chemotherapy.25,28,32,37 As there is gradual progression of signs and symptoms, prompt diagnosis 
and supportive treatment together with close monitoring are key steps in the management of CRS. 
Tocilizumab is an anti-IL6 antibody that is approved for the treatment of CRS.38 Upon 
administration, in many cases hemodynamic instability resolves rapidly and patients recover 
within 24-48 hours. Thus, it is important to administer it before patient requires mechanical 


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ventilation for best outcome. See Section 3.3.6.4 for more details of management of CRS. While 
Tocilizumab became an important medication to reverse CRS, there are some reservations against 
its use as tocilizumab has been to shown to increase risk of cytopenia and infection 39 and a small 
theoretical risk of inhibiting CAR T-cell function exists. Thus, its use should be limited only to 
patients with severe CRS. Taken together, CRS is the main toxicity of CAR T-cell treatment and 
its management requires inpatient monitoring, limiting the scope of clinics that are equipped to 
administer a CAR T-cell based product. 
1.2.5.2 
Neurotoxicity 
Neurotoxicity associated with CAR T-cell treatment, now named “Immune effector cell-associated 
neurotoxicity syndrome” (ICANS) in the ASBMT consensus panel document, is described as “a 
disorder characterized by a pathologic process involving the central nervous system following any 
immune therapy that results in the activation or engagement of endogenous or infused T cells 
and/or other immune effector cells. Reported neurologic toxicities include headaches, confusion, 
alterations in wakefulness, hallucinations, dysphasia, ataxia, apraxia, facial nerve palsy, tremor, 
dysmetria, and seizures 25,26,29,30,34,35,37,40,41. Neurotoxicity has been reported in several anti-CD19 
CAR T-cell trials and severe cerebral edema lead to death in a small number of patients27,42. 
However, it has not been reported as frequently in anti-BCMA CAR T-cell trials16,43. Factors that 
underlie CRS like peak CAR T-cell levels25,27,28,44 or cytokine levels29,30,37,45 are also associated 
with neurotoxicity. See Section 3.3.6.5 for management of neurotoxicity.  
1.2.5.3 
CAR T-cell related CRS grading 
Several grading systems have been developed for CAR T-cell-related CRS and this protocol uses 
grading developed by Lee et al.46  In the clinical study report, CRS and neurotoxicity will also be 
analyzed retrospectively by ASBMT consensus criteria.22 
Table 1. 
CRS Grading Scale 
Grade 
Toxicity 
Grade 1 
Symptoms are not life threatening and require symptomatic treatment only. e.g., fever, 
nausea, fatigue, headache, myalgias, malaise  
Grade 2 
Symptoms require and respond to moderate intervention 
Oxygen requirement less than 40% or 
Hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ 
toxicity  
Grade 3 
Symptoms require and respond to aggressive intervention Oxygen requirement equal or 
more than 40% or Hypotension requiring high dose or multiple vasopressors or Grade 3 
organ toxicity or grade 4 transaminitis  
Grade 4 
Life-threatening symptoms 
Requirement for ventilator support or 
Grade 4 organ toxicity (excluding transaminitis)  
Grade 5 
Death 


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The definition of high dose vasopressors is: 
• Norepinephrine monotherapy>20 mcg/min 
• Dopamine monotherapy>10 mcg/kg/min 
• Phenylephrine monotherapy>200 mcg/min  
• Epinephrine monotherapy>10 mcg/min 
• If on vasopressin> 10 mcg/min norepinephrine equivalent [norepinephrine 
(mcg/min)+dopamine (mcg/kg/min)/2]+[epinephrine (mcg/min)]+[phenylephrine 
(mcg/min)/10]  
If on combination vasopressors without vasopressin then norepinephrine>20 mcg/min  
1.2.6 
Rationale for Current Protocol 
Severe CRS and neurotoxicity have only been observed in the context of CAR T-cells that are 
permanently modified by gene transfer.  Under conditions of genomic modification, once CAR T-
cells are engrafted, they proliferate exponentially and generate very high numbers of cells without 
need for a repeat infusion. While this may provide long-time control of the disease, the sudden, 
exponential CAR T-cell proliferation also can cause severe toxicity. In contrast, in CAR T-cells 
transfected with mRNA, the CAR T-cell’s mRNA and CAR protein is halved with each T-cell 
division, effectively limiting the proliferative capacity and total circulating numbers of CAR T-
cells.  In theory, this should limit the potential for severe CRS and neurotoxicity. Furthermore, 
because the mRNA has an inherent rate of degradation, CAR expression gradually declines to zero 
even in the absence of target antigen. These pharmacological properties resemble conventional 
drugs with respect to predictable pharmacokinetics (PK) and pharmacodynamics (PD), properties 
that would be difficult or impossible to obtain with genomically modified CAR T-cells.47 More 
predictable PK in mRNA-transfected CAR T-cell activity affords the opportunity for systematic 
repeat dosing to maintain or, as needed, intensify anti-tumor activity. In preclinical studies, repeat 
dosing of mRNA-transfected CAR T-cells has shown efficacy in ALL48, AML49, breast cancer50, 
neuroblastoma51, mesothelin-expressing cancers52 and EGFR-expressing cancers.53 
Cartesian is currently conducting a Phase I/IIa clinical trial for Descartes-08, an mRNA-transfected 
CAR T-cell product targeting BCMA, in patients with relapsed/refractory multiple myeloma.  The 
product is currently enrolling patients in a classic 3+3 dose-escalation design. In that protocol, 
Descartes-08 is infused on Days 0, 3 and 7 to obtain about 2 weeks of CAR T-cell exposure, which 
was shown to be an adequate time for eliminating myeloma cells using the same CAR protein in 
the original NCI trial16 To date, Descartes-08 has been well tolerated. 
The current protocol is designed to test a derivative of Descartes-08, named Descartes-11, where 
the scFv of the CAR has been humanized to display low immunogenicity.54  Descartes-11 will be 
administered for up to three 21-day Cycles. Each Cycle will start with preconditioning 
chemotherapy (except for Dose Level 4C).  This will be  followed by a dose of Descartes-11 
(administered as a split dose, in 2 to 6  equal infusions, according the schedule shown in Section 
3.2).  After Cycle 1, if a patient does not meet removal from treatment criteria as set forth in Section 
4.5.1, he/she may receive up to two more cycles of treatment. 
1.2.7 
Rationale Behind Preconditioning Chemotherapy 
The use of non-myeloablative conditioning to support adoptive cell therapies was developed in the 
studies using tumor-infiltrating lymphocytes (TILs) in the late 1980s55 Cytotoxic chemotherapy 


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prior to cell infusion enhances anti-tumor T-cell responses by eradicating regulatory T-cells, 
eliminating other immune cells that may compete for homeostatic cytokines, and enhancing 
antigen-presenting cell activation.56-58 Since the anti-tumor activity of CAR T-cells also depend 
on T-cell activity, similar to TILs, preconditioning chemotherapy was used in almost all of the 
pivotal CAR T-cell studies.23-26,30,31,34,35,40,59-62 Preclinical studies showed the importance of 
cyclophosphamide for CD-19 CAR T-cell engraftment,63 and in a different study this benefit was 
enhanced by addition of fludarabine to preconditioning regimen.64 The clinical proof of this 
concept was shown in an anti-CD19 59 as well as an anti-BCMA CAR T-cell study.19 In other anti-
BCMA CAR T-cell trials, a combination of fludarabine and cyclophosphamide regimen was given 
as preconditioning regimen over 2-4 days. 15-17,20,65-69  
Since the benefit of preconditioning chemotherapy regimen for CAR T-cell activity includes 
enhancing survival of infused T-cells, this protocol will also use a fludarabine/cyclophosphamide 
combination (25mg/m2 fludarabine and 250mg/m2 cyclophosphamide), except for Dose Level 4C, 
which will test Descartes-11 without preconditioning chemotherapy. 
1.2.8 
Preface to Protocol Version 1.5 
This latest amendment of the protocol subdivides Dose Level 4 into three treatment groups:  Dose 
Levels 4A, 4B, and 4C.  Dose levels 4A, 4B, and 4C each administer a total target dose of 150x106 
cells/kg but differ with respect to the administration schedule (see Table 2).  Furthermore, in the 
case of Dose Level 4C, preconditioning chemotherapy is omitted.  The amendment contains 
various other changes, which are mostly administrative in nature. 
1.2.9 
Preface to Protocol Version 1.6 
To date, no Descartes-11-related adverse events have been observed in patients treated with Dose 
Level 4A, 4B or 4C. Two new subcohorts (4D and 4E) will be added to Dose Level 4 to test the 
safety of administering Descartes-11 in patients on a concurrent Immunomodulatory Imide Drug 
(IMiD), such as lenalidomide and pomalidomide. The rationale for this is that IMiDs potentiate 
the activity of CAR T-cells, including mRNA transfected anti-BCMA CAR T-cells (Descartes-
08)70-72. A third subcohort (4F) will administer Descartes-11 by a femoral artery catheter to 
determine if bypassing the pulmonary vasculature may reduce cell trapping and improve anti-
tumor homing of Descartes-11 as demonstrated in a preclinical mouse model.73 Administration of 
tumor-infiltrating T-cells74, lymphokine-activated killer cells75,76 or CAR T-cells77 by intraarterial 
catheter  is safe and may lead to increased penetration of these therapeutic cells into tumor tissue.  
1.3 Study Drug 
1.3.1 
Description 
Descartes-11 is an autologous CD8+ T-cell product modified to express a humanized anti-BCMA 
CAR. 
1.3.2 
Route of Administration and Dosing Regimen 
Descartes-11 is frozen after manufacturing, then thawed at the clinical site immediately prior to 
infusion.  Each dose, provided in one or more vials, will be thawed at 37°C on the day of infusion 
and must be administered within a fixed time after thawing. Please refer to Section 3.3.3.1 and the 


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Descartes-11 Clinic Storage, Handling and Administration Manual for detailed instructions on 
how to prepare and administer the study product. 
1.3.3 
Preclinical Data 
Please refer to Investigator Brochure for a detailed description of nonclinical data. 


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2 Eligibility and Enrollment 
2.1 Eligibility Criteria 
2.1.1 
Inclusion Criteria 
The following inclusion criteria will be applied at Screening, unless another evaluation timepoint 
is specified: 
1. Failure of at least 2 prior lines of therapy. Failure of treatment is defined as: 
a. Progression while on treatment OR 
b. Progression within 60 days after last dose of treatment OR 
c. Intolerability of treatment OR  
d. Increase of 25% from lowest confirmed response value in one or more of the following 
criteria:  
i. 
Serum M-protein (absolute increase must be ≥ 0.5 g/dL); 
ii. 
Serum M-protein increase ≥ 1 g/dL, if the lowest M component was ≥5 g/dL; 
iii. 
Urine M-protein (absolute increase must be ≥ 200 mg/24 h);  
iv. 
In patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL); 
v. 
Bone marrow plasma-cell percentage irrespective of baseline status (absolute increase 
must be ≥ 10%);  
vi. 
Appearance of a new plasmacytoma lesion(s), ≥ 50% increase in size (sum of the 
products of the maximal perpendicular diameters (SPD) of measured lesions) from 
nadir or ≥ 50% increase in the longest diameter of a previous lesion > 1 cm in short 
axis (Plasmacytoma measurements should be taken from the CT portion of the 
PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only 
skin involvement, skin lesions should be measured with a ruler. Measurement of tumor 
size will be determined by the SPD). 
2. Measurable myeloma defined as: 
a. Serum M-protein > 0.5 g/dL OR  
b. Urine M-protein > 200 mg/24 hours OR 
c. An involved serum free light chain (FLC) > 10 mg/dL (provided FLC ratio is abnormal) 
OR 
d. A biopsy-proven plasmacytoma OR 
e. Patients must have greater than 5% bone marrow plasma cells.  
3. Patients with prior ASCT or allotransplant are eligible but must be >100 days post-transplant 
at the time of leukapheresis. 
4. Toxicities from prior therapies must have resolved to Grade 2 or less according to the CTCAE 
5.0 criteria, or to the subject’s pre-therapy baseline at the time of leukapheresis. 
5. Patients must have signed written, informed consent. 


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6. Patients must be 18 years of age or older at the time of enrollment. 
7. Patients must have clinical performance status of ECOG 0-2. 
8. Due to potential teratogenicity of preconditioning chemotherapy: 
a. Women of childbearing potential must have a negative pregnancy test at the time of 
screening. 
b. Patients of both genders must agree to effective contraception from the time of enrollment 
until four months after receiving the last dose of preconditioning chemotherapy. 
9. Patients must be seronegative for HIV.  
10. Patients must be seronegative for hepatitis B (HBV) antigen; or, if the patient is positive for 
the hepatitis B antigen test, he or she must be negative for HBV DNA and must agree to use 
Hepatitis B prophylaxis as per institution guideline and/or principal investigator discretion. 
11. Patients must be seronegative for hepatitis C (HCV) antibody; or, if the hepatitis C antibody 
test is positive, the patient must be tested for the presence of viremia by RT-PCR and must be 
HCV RNA negative.  
12. Patients must have adequate vital organ function as defined by the following criteria:  
• 
Bone marrow function defined by absolute neutrophil count (ANC) >1000 cells/mm3 and 
platelet count >30,000 cells/mm3 
• 
Serum ALT and AST less or equal to 3 times the upper limit of the institutional normal; 
• 
Total bilirubin ≤ 2.0 mg/dL, except in patients with Gilbert’s Syndrome, who must have a 
total bilirubin less than 3.0 mg/dL; 
• 
Normal cardiac ejection fraction (≥ 45% by echocardiography) and no evidence of 
hemodynamically significant pericardial effusion as determined by an echocardiogram 
within 6 months of the start of the leukapheresis; AND 
• 
 Creatinine Clearance (CrCl) ≥ 30 mL/min or 30 mL/min/1.73 m2.  
2.1.2 
Exclusion Criteria 
The following exclusion criteria will be applied at the time of Screening, unless another evaluation 
timepoint is specified: 
1. Patients who are pregnant or lactating.  
2. Patients who have any active and uncontrolled infection. No blood cultures are necessary 
unless clinically indicated.  
3. Use of any of the following: 
a. Therapeutic doses of corticosteroids (defined as > 40 mg/day prednisone or 
equivalent) within 7 days prior to leukapheresis; physiologic replacement, topical, 
and inhaled steroids are allowed. 
b. Standard -of-care anti-myeloma treatment within 7 days of leukapheresis.  Patients 
enrolled in Dose Level 4D and 4E may continue receiving ongoing IMiD therapy. 
c. Experimental agents within 28 days of leukapheresis unless progression is 
documented on therapy and at least 3 half-lives have elapsed prior to leukapheresis 


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4. Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine or systemic steroids 
above 40 mg/day prednisone equivalent)). Topical, inhaled, or intranasal corticosteroids are 
allowed. 
5. Patients who have active central nervous system disease. 
6. Patients with second malignancies in addition to MM are not eligible if the second malignancy 
has required treatment within the past 3 years or is not in complete remission. There are three 
exceptions to this criterion: successfully treated non-metastatic basal cell or squamous cell skin 
carcinoma, or prostate cancer that has not required anticancer therapy.  
7. Active cardiac arrhythmias, active obstructive or restrictive pulmonary disease. If there is a 
history of cardiac or pulmonary morbidities, the principal investigator will judge whether these 
conditions are active or in stable condition.    
8. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease).  
9. History of severe immediate hypersensitivity reaction to any of the agents used in this study. 
10. Subjects who have had a venous thromboembolic event (e.g., pulmonary embolism or deep 
vein thrombosis) requiring anticoagulation and who meet any of the following criteria: 
• Deep venous thrombosis occurred within the past 3 months OR pulmonary embolism 
occurred within the past 6 months 
• If on anticoagulation, based on PI discretion, patient cannot hold the anticoagulation 
during leukapheresis 
• Have had at least Grade 2 hemorrhage in the last 30 days 
• Are experiencing continued symptoms from their venous thromboembolic event 
(e.g. continued dyspnea or oxygen requirement) 
NOTE: Subjects who have had a venous thromboembolic event but do not meet any of the 
above 3 criteria are eligible for participation 
2.2 Screening, Evaluation and Enrollment 
2.2.1 
Recruitment of Patients 
Subjects will be identified through the clinical practices of the investigator or sub-investigators 
and through referrals from outside hospitals and physicians. Patients can be referred any time after 
they meet the criteria for a failure of at least two lines of therapy. Definition for one line of therapy 
will be based on the guideline published by Rajkumar et al. 78 The screening/consent period allows 
consenting patients earlier than the intended Descartes-11 infusion day and provides extra time for 
cell manufacturing and shipment. Therefore, it is recommended that patients be informed of the 
trial as soon as they meet eligibility to facilitate early enrollment. Bridging therapies to control the 
disease are allowed during the waiting period after enrollment (See Section 3.3 for details). 
Patients who are already on or eligible for IMiD therapy may be eligible for subcohorts 4D and 
4E. The IMiDs will be continued concurrently with CAR T-cells.  
2.2.2 
Screening Evaluation 
Please refer to Section 4.1.1 for Screening visit evaluations. 


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2.2.3 
Enrollment 
To enroll a subject on this study, the following documents are required:  
• Copy of signed/dated consent and HIPAA Authorization  
• Source documentation to confirm enrollment/eligibility 
2.2.4 
Early Withdrawal of Subjects 
Patients who do not complete at least one Descartes-11 infusion will be considered to have 
prematurely discontinued the study. The reasons for premature discontinuation (e.g., voluntary 
withdrawal, toxicity, death) must be recorded on the case report form. Final study evaluations will 
be completed at the time of discontinuation. Provided that all protocol requirements are satisfied 
for the trial to continue safely, patients who withdraw early from the study will not be counted 
toward study recruitment limits. 
2.2.5 
Data Collection and Follow-Up of Early Withdrawals 
Patients who withdraw early from the study and who have provided consent for follow-up data 
collection will be eligible for continued data collection for up to one year.  Withdrawn patients 
who are followed at other institutions or practices, because of preference or geographical concerns, 
will confer follow-up via notes from their local physician and/or phone interviews.  Toxicity and 
other clinical assessments will be obtained from the treating physician and recorded into 
appropriate case report form (CRF). In the event a subject fails to complete the follow-up 
requirements, all attempts to contact the subject including: 1) at least three telephone contacts (on 
different days and at different times of the day), and 2) a certified letter will be documented. 


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3 Study Design 
3.1 Study Schema 
Figure 1. Study Schema 
 
3.2 Study Implementation 
3.2.1 
Overall treatment design 
The overall schedule of treatment is illustrated in Figure 1.   
Patients are enrolled between Day -60 and Day -8, with screening and baseline studies conducted 
during this time. Enrollment begins with leukapheresis. Patients meeting eligibility criteria are 
leukapheresed between Day -59 and Day -7. 
Eligible patients participate in up to three, 21-Day Cycles of therapy.  For all cohorts except 4C, 
preconditioning chemotherapy is initiated on Day 1 (+1d) and administered consecutively for 
3 Days. Descartes-11 is administered as a split dose (2-6 equal infusions) on designated Days (see 
Table 2). See Section 3.2.4 for criteria of delaying cell infusion. Safety assessment is on Day 21 
(or at least 14 days after first Descartes-11 infusion if cell infusion is delayed).  Response 
assessment is on Day 21 (or at least 14 days after first Descartes-11 infusion if cell infusion is 
delayed).  At least 21 days must elapse between Day 1 of each Cycle of treatment. Start of a cycle 
can be delayed up to 7 days. 
A DLT will preclude the patient from being eligible to receive another Cycle of treatment.  Patients 
who do not experience a DLT during Cycle 1 are eligible for Cycle 2.  Patients who do not 
experience a DLT during Cycle 2 are eligible for Cycle 3.  Cycles 2 and 3 are administered on the 
same 21-Day schedule as Cycle 1 except for lymphodepletion in Dose Levels 4B and 4D, which 
is not administered in Cycles 2 and 3. Patients are followed up for 12 months after completing 
their final treatment Cycle. 
Day    -60 to -8     -59 to -7                  1 to 3               7 to 21                    21                             
7 to 21               21                                      7 to 21           21                           
Follow-up 
(Post last Dose)
Cycle 1
Cycle 2
Cycle 3
1 to 21                          21                                   1 to 21              21                                  1 to 21                21                           
Dose Levels 1-3, 4A, 4B, 4D
Dose Level 4C, 4E, 4F
Screening/Baseline
Apheresis
Lymphodepletion
Descartes-11 infusions (See Table 2 for schedule)
Primary safety assessment
Response assessment


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Once a safe and tolerable dose is identified, up to 12 patients will be enrolled to further characterize 
the safety and preliminary efficacy of the selected dose.  
3.2.2 
Dose Levels 
Doses are expressed as the number of viable CAR+ cells per kg of patient weight up to 100 kg.  
The Dose Levels are summarized in Table 2.  Dose Level 1 is 10 x 106 cells/kg per dose (i.e., 5 x 
106 cells / kg on Day 7, and 5 x 106 cells / kg on Day 14).  Dose Level 2 is 32 x 106 cells/kg per 
dose.  Dose Level 3 is 100 x 106 cells / kg per dose.  Dose Level 4 is 150 x 106 cells / kg per dose. 
The safe and appropriate initial Dose Level 1 (10 x 106 cells/kg) was informed by an ongoing 
clinical trial (NCT 03448978; Descartes-08) for a similar anti-BCMA mRNA CAR T-cell product, 
manufactured under identical conditions to Descartes-11, to treat the same indication 
(i.e., relapsed/refractory MM).  In the referenced Descartes-08 trial, a dose up to 90 x 106 cells / kg 
has resulted in no dose-related AEs to date (please see Descartes-11 Investigator Brochure).  
Preclinical studies also demonstrated that the two products behave similarly and show similar 
BCMA binding, tumor cytotoxicity, and in vivo efficacy.  For example, similar to Descartes-08, 
Descartes-11 showed no CAR-specific off-target binding in a panel of 5528 human plasma 
membrane proteins and human secreted proteins (please see Descartes-11 Investigator Brochure).   
Table 2. 
Dose Levels and Infusion Schedule per Cycle 
Dose Level (Cohort) Total Descartes-11 
Dosea,b 
Flu/Cy Schedule 
(Only Cycle 1) 
Descartes-11 
Schedulec 
Level 1 
10 x 106 cells / kg  
Days 1,2,3 
Days 7,14 
Level 2 
32 x 106 cells / kg  
Days 1,2,3 
Days 7,14 
Level 3 
100 x 106 cells / kg  
Days 1,2,3 
Days 7,14 
Level 4Ad 
150 x 106 cells / kg 
Days 1,2,3 
Days 7,14,21 
Level 4Bd 
150 x 106 cells / kg 
Days 1,2,3 
Days 7,10,14,17 
Level 4Cd 
150 x 106 cells / kg 
None 
Days 1,4,7,10,14,17 
Level 4Dd 
150 x 106 cells / kg 
Days 1,2,3 
Days 7,10,14,17 
Level 4Ed 
150 x 106 cells / kg 
None 
Days 1,4,7,10,14,17 
Level 4Fd,e 
150 x 106 cells / kg 
None 
Days 1,7,14 
a 
 For Dose Levels 1-3, each dose is split into 2 equal infusions, administered 7 days apart, per 21-day Cycle.  
For Dose Level 4A/F, B/D and C/E, each dose is split into 3, 4 or 6 equal infusions, respectively.   
b 
Doses are expressed as viable CAR+ cells per kg of patient weight. 
c 
 ±1 day allowed for each infusion. 
d 
DL4 subgroups may enroll in parallel but each subgroup will independently follow the predetermined dose 
escalation and stopping rules (Section 3.2.2). 
e 
Dose is given by intrafemoral catheter 
 


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The clinic will contact the Sponsor at the time a patient is determined to be eligible.  The Sponsor 
will then assign the patient to the next cohort where space is available. A dose will be considered 
acceptable to administer if it is within ±45% of the dose specified for the applicable Dose Level. 
If it is determined that the patient’s CAR T-cells are insufficient for the assigned Dose Level but 
sufficient for an earlier Dose Level, the Sponsor may (at the discretion of the medical monitor) 
reassign that patient to a lower Dose Level (even if that Dose Level has been completed) or treat 
the patient at an intermediate dose between two Dose Levels. Alternatively, at the discretion of the 
medical monitor, a second attempt may be made to prepare cells for the patient if the patient agrees 
and if the patient still meets eligibility criteria within the specified assessment windows (repeat 
assessments are permitted at the discretion of the medical monitor). 
3.2.3 
Dose Escalation / Stopping Rules 
Prior to any dose escalation, a minimum of 3 patients will be dosed at each Dose Level.  The first 
3 patients from each cohort will be enrolled sequentially.  For the first 3 patients enrolled in the 
study, a minimum of 21 days must elapse between the first dose infusions for successive patients.  
For all other patients, a minimum of 14 days must elapse between the first dose infusions for 
successive patients during dose escalation.  Selection of Day 14 as a threshold is similar to that in 
the reference study (NCT 03448978, Descartes-08) and was based on previous CAR-T trials where 
severe CRS was observed within hours to days after infusion, and mild CRS was observed in the 
first two weeks46.   
The study will not proceed to a higher Dose Level until: 1) at least 3 patients in the previous Dose 
Level have been observed through Day 21 study visit, 2) no study stopping rules have been 
triggered, and 3) the medical monitor has reviewed the cumulative safety data and concluded and 
documented that the next Dose Level may be initiated.  
The medical monitor will apply the following rules to determine if it is safe to proceed to the next 
Dose Level, or if dose escalation should stop (pre-specified rules for pausing or stopping the whole 
study are described in Section 5.5; rules for individual patient withdrawal are described in Section 
4.5.): 
If one of three patients in a Dose Level experiences a DLT within the safety review period AND 
that DLT is assessed as possibly or probably related to Descartes-11 (i.e., Descartes-11-related), 
three more patients will be enrolled and treated at that Dose Level. If only 1/6 of patients at that 
Dose Level has a Descartes-11-related DLT, and if the medical monitor agrees, treatment will 
proceed to the next higher Dose Level.  If two or more out of three to six patients develop a 
Descartes-11-related DLT, no further patients will be dosed at that Dose Level. If the medical 
monitor agrees, up to three additional patients will be treated at the previous (lower) Dose Level 
to provide a total of six patients for that Dose Level and further characterize the safety of the 
maximum tolerated dose. The maximum tolerated dose (MTD) will be defined as the dose at which 
a maximum of one of six patients has a DLT.  Upon determination of the MTD and documented 
approval by the medical monitor, an additional 9 more patients may be treated at the MTD; the 
results of these 9 will not be used to redefine the MTD. 
If the patient’s CAR T-cells are not sufficient to administer the intended dose, the patient may, at 
the medical monitor’s discretion, receive as many cells as possible up to the intended dose. 


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If it becomes technically impractical to increase the Dose Level due to cell production constraints 
and an MTD has not been reached, the maximum Dose Level for which at least three patients have 
been treated may be declared the maximum feasible dose. 
Dose escalation will follow the rules outlined in Table 3.  Note that a DLT occurring at given a 
dose level will be considered a DLT for that dose level regardless of whether it occurs after the 
first or second infusion. 
Table 3. 
Dose Escalation Rules 
Number of patients with 
DLT at each dose level 
Dose escalation rule 
0 out of 3 
Proceed to next dose level 
1 out of 3 
Enter up to 3 more patients at this dose level.  
- If 0 of the added 3 patients experience DLT (1 out of 6 overall), 
proceed to the next dose level. 
- Otherwise, see below under “2 or more”  
2 or more 
Dose escalation will be stopped. Administration to other patients in the 
same cohort will be stopped, but patients will remain in the study for 
observation.  This dose level will be declared the Maximum Tolerated 
Dose. Up to 3 additional patients will be treated at the previous 
(immediately lower) Dose Level to reach enrollment of 6 patients in that 
Dose Level. 
Less than 2 out of 6 
This will be the recommended dose for phase 2.  
 
3.2.4 
Delay of Cell Infusion 
Patients experiencing toxicities from their preceding treatments will have their Descartes-11 
infusion schedule delayed until these toxicities have resolved to at least Grade 2 (excluding 
cytopenias), unless in the documented opinion of the medical monitor it is reasonable to proceed. 
During this period, patients will be assessed to record adverse events and decide whether the 
patient meets criteria for cell infusion.  Infusions can also be delayed up to 24 hours due to 
scheduling. Furthermore, prior to study cell infusion, subjects must demonstrate an absence of 
fever, infection and organ dysfunction since eligibility (See Section 3.3.3.2 for details). If patient 
does not meet the infusion criteria, the infusion can be delayed up to 2 weeks. 
3.3 Drug Administration 
3.3.1 
Leukapheresis 
The patient will undergo leukapheresis at least 14 days prior to cell infusion according to 
institutional standard operation procedures. A central or peripheral line will be placed prior to 
leukapheresis.  Five to fifteen liters of blood volume will be processed to collect PBMC and plasma 
that will be used for Descartes-11 manufacturing. The volume of collection will be recommended 
by Sponsor, in consultation with the investigator, based on Dose Level and target cell 


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concentration in peripheral blood. Patients will be cared for and discharged as per institution 
guidelines.  Patients are allowed to receive anti-myeloma treatment (excluding proteasome 
inhibitors and monoclonal antibodies) after enrollment.  Bridging therapy should be stopped at 
least 7 days prior to the start of lymphodepletion chemotherapy.  Corticosteroid-based bridging 
therapy can be stopped up to 3 days prior to the start of lymphodepletion.  
3.3.2 
Administration of Cyclophosphamide and Fludarabine 
On Days 1, 2 and 3 of the first Cycle, patients (except for those in Dose Level 4C) will receive 
250 mg/m2 cyclophosphamide and separately 25 mg/m2 fludarabine. Infusions can be delayed up 
to 24 hours based on PI discretion or scheduling. Each infusion bag will be prepared and 
administered as per institution standards. Dose adjustment is allowed per PI discretion or 
institution standards. It is recommended to give 1000 mL 0.9% normal saline after completing the 
infusion of both agents. Patients will receive anti-emetics as per institution guidelines; however, 
dexamethasone is not allowed. Patients should also be provided with anti-emetics to take at 
home. If the patient is enrolled into Dose Level 4D, IMiD treatment should be paused while patient 
is cytopenic due to chemotherapy and should be resumed when blood counts permit as per 
recommendations in the package insert of the drug.  See below for further discussion of IMiD 
therapy in the context of cytopenia.  
Dose Levels 4C, 4E and 4F do not administer lymphodepletive chemotherapy. 
3.3.3 
Preparation and Administration of Study Drug 
3.3.3.1 
Drug Preparation 
Descartes-11 cells will be prepared at a central manufacturing facility and shipped to the clinical 
site.  Cells will be shipped to arrive no later than one day before the start of lymphodepletive 
chemotherapy.  Upon receipt at the clinical site, the cells should be logged in and stored in a 
secured freezer at -70 to -90 0C until Day 7. On the day of infusion, before thawing Descartes-
11, study staff must verify that patient identifiers shown on the labels positively match the 
intended patient. Detailed instructions for thawing the cells and preparing for administration are 
written in the Descartes-11 Clinic Storage, Handling and Administration Manual.  
3.3.3.2 
Drug Administration 
Refer to Table 2 for schedule of infusions.  Prior to each infusion, patients must meet the following 
criteria: 
1. Temperature is less than 37.9oC; 
2. There are no signs of an active infection; 
3. If patient is taking corticosteroids, the dose has been reduced to 40 mg/day prednisone or 
equivalent and the dose is held for at least 12 hours prior to infusion; 
4. Other than a cytopenia, there are no ongoing Grade 2 toxicities from prior treatment precluding 
cell infusion;  
5. Pre-infusion clinical assessment does not suggest organ dysfunction and/or rapid disease 
progression since enrollment. 
 


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See Section 3.2.4 for conditions to delay cell infusion.  Premedication for the cell infusion will be 
given within 15 to 120 minutes prior to the infusion. The medications are acetaminophen 500-1000 
mg orally and diphenhydramine 25-50 mg intravenously or by mouth.   Prior to infusion, the cell 
product identity label is double-checked by two authorized staff (MD or RN), and 
identification of the product and documentation of administration are entered in the 
patient's chart as is done for blood banking protocols. Please see detailed infusion instructions 
in the Descartes-11 Clinic Storage, Handling and Administration Manual. 
3.3.4 
Return or Destruction of Study Drug 
The remaining thawed material should be discarded as per institution’s biohazard waste removal 
procedures. Frozen Descartes-11 cells may require return to the Sponsor for a variety of reasons, 
including but not limited to: 1) condition of patient prohibits infusion/injection or 2) subject refuses 
infusion/injection or 3) extra product remains after completion of treatment. Sponsor will perform 
ongoing reconciliation of drug shipped, drug consumed, and drug remaining.  Drug destroyed on 
site will be documented in the study files. 
3.3.5 
Post-Infusion Observation 
Emergency medical equipment (i.e., emergency cart) will be available during the infusion in case 
the subject has an allergic response, or severe hypotensive crisis, or any other reaction to the 
infusion. Vital signs (temperature, respiration rate, pulse, blood pressure and oxygen saturation by 
pulse oximetry) will be measured prior to the infusion, within 10 minutes post infusion, then every 
30 minutes (±5 minutes) for two hours. If the vital signs are not satisfactory and not stable two 
hours post-infusion, vital signs will continue to be monitored at a minimum of every hour or as 
clinically indicated until stable. Following the 2-hour mandatory observation, the investigator will 
decide whether it is safe to discharge the patient.  Patients should remain within 90 minutes of 
driving distance for possible daily assessment of toxicities until Primary Safety Review (Day 21, 
Cycle 1). Patients will be required to monitor their temperature daily and report to the study team 
if it is > 37.9°C. Follow-up assessments should include vital signs and a focused physical exam. 
At minimum, the following should be documented: ECOG performance status, cardiovascular 
exam, pulmonary exam and brief neurological exam. If clinically indicated, a more comprehensive 
evaluation should be added and documented in detail. 
3.3.6 
Management of Toxicities 
For CAR T-cells, significant toxicities, if any, typically occur within one week of administration 
and include infusion reactions, CRS and neurotoxicity. 
The guidelines below are recommendations only and can be tailored to an individual patient’s 
needs based on the judgment of the investigator or treating physician. Management that differs 
from these recommendations will not be considered a protocol deviation. 
3.3.6.1 
Febrile Reaction 
Between Days 7 and 21 (or 14 days after first Descartes-11 infusion if cell infusion is delayed) of 
Cycle 1, fevers greater than 37.9°C will be assessed by the clinician and should be admitted for 
observation.  To treat ordinary fever, a dose of > 500 mg acetaminophen is recommended.  Cooling 
blankets may be given if fever is greater than 40°C.  In the unlikely event that the subject develops 


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sepsis or systemic bacteremia following Descartes-11 cell infusion, appropriate cultures and 
medical management should be initiated. If a contaminated CAR T-cell product is suspected, the 
product can be retested for sterility using archived samples that are stored in the central 
manufacturing facility. 
3.3.6.2 
Infusion Reaction 
Infusion-related reactions that occur during or within 24 hours following infusion were reported 
in less than 10% of patients participating in T-cell therapy trials, and most of the episodes were 
recorded as Grade 1 with a few reported as Grade 2.79 The most recorded adverse event is nausea 
and taste disturbance (most likely due to the cryoprotectant, DMSO) and usually do not require 
any medical intervention. Oral ondansetron or prochlorperazine can be given for mild to moderate 
nausea. Additional doses of diphenhydramine and acetaminophen (if patient does not have > Grade 
2 transaminitis) can be administered for mild to moderate infusion-related chills, itching, rash. 
3.3.6.3 
Allergic Reactions 
Infusion-related allergic reactions should not occur frequently since Descartes-11 is an autologous 
cell product and its murine-derived sequences have been extensively humanized. Although highly 
unlikely, anaphylaxis has been reported in one patient who received mRNA-transfected anti-
mesothelin CAR T-cell80 and therefore an emergency cart should be present in the area where the 
patient receives the infusion. The clinical site’s standard protocol for management of anaphylaxis 
should be followed. In addition, serum should be collected in the first 2 hours of the reaction to 
measure tryptase levels (See Section 4.3.1.3 and Descartes-11 Laboratory Manual for collection 
details) to confirm diagnosis.  A minimum of two, 3 ml aliquots of this serum should be frozen for 
future analysis. 
3.3.6.4 
Cytokine Release Syndrome 
This protocol has adopted the CRS grading system and management guidelines published by Lee 
et al.22  See Table 1 for the grading system and Appendix 1 for a treatment algorithm. See Section 
4.3.1.2 for CRS-related blood collection procedures. 
3.3.6.5 
Neurotoxicity (ICANS) 
Management guidelines are summarized in Appendix 1.  One of the earliest signs of developing 
neurotoxicity is aphasia, and should be monitored closely as these patients may require high-dose 
steroids for treatment of their neurotoxicity. 
3.3.7 
Concomitant Medications 
3.3.7.1 
Antibiotic Prophylaxis 
It is recommended that patients with a CD4 T-cell count less than 200 will be maintained on 
pneumocystis prophylaxis as per institution guidelines. Other antimicrobial (antibacterial, antiviral 
or antifungal) prophylaxis is left to the discretion of the investigator. Antibiotics are typically 
indicated in neutropenic patients.  


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3.3.7.2 
Blood Product Support 
Using CBCs as a guide, the patient will receive platelets and packed red blood cells (PRBC's) as 
needed. Attempts will be made to keep Hb >7.0 gm/dL and platelets >10,000/mm3. Except for 
CAR T-cells, all blood products will be prepared and infused as per investigator’s discretion. 
3.3.7.3 
Granulocyte Colony-Stimulating Factor 
If the absolute neutrophil count becomes less than 1000/microliter and there is suspicion of or 
documented bacterial infection, then based on the investigator’s discretion, growth factor support 
can be given. Growth factors should be discontinued once the ANC is above 1000/microliter. 
3.3.7.4 
Corticosteroids 
Patients should not take systemic corticosteroids (including prednisone, dexamethasone or any 
other corticosteroid) that exceeds a dose equivalent to 40 mg/day or more of prednisone for any 
purpose from Cycle 1 Day 1 until cell infusions are completed unless approved by without 
approval of the Principle Investigator. In addition, corticosteroids should be withheld for 12 hours 
before and after the Descartes-11 infusion.  
3.3.7.5 
IMiDs 
For patients who are in Dose Levels 4D and 4E, the management of IMiD treatment will be left to 
PI’s discretion. IMiDs should be interrupted when neutrophil and platelet counts are below the 
levels recommended in the package insert of each drug. Once IMiDs are resumed after cell counts 
recover, they should be typically resumed at the same dose and further dose titration should be 
done based on recommendations outlined in the package insert of each drug. Venous 
thromboembolism prophylaxis is left to the PI’s discretion.  


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4 Protocol Evaluation and Biospecimen Collection 
4.1 Study Procedures 
4.1.1 
Baseline Evaluation (Day -60 to Day -8) 
1. 
Obtain informed consent  
2. 
Review of records for documentation of at least 2 prior lines of therapy and failure of last 
line of treatment and confirm all other eligibility 
3. 
Complete medical history and physical examination, including, height, weight and vital 
signs (should always include pulse oximetry unless stated otherwise), and ECOG 
performance score. 
4. 
Concomitant medications 
5. 
Complete blood count, differential 
6. 
Chemistry panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Uric Acid, Cr, ALT, AST, lactate dehydrogenase).  
7. 
PT/INR, PTT 
8. 
D-Dimer, fibrinogen 
9. 
Urinalysis 
10. CRP, ferritin 
11. b2-microglobulin 
12. Anti-HIV 1 and 2 antibody 
13. Hepatitis B antigen (HBV DNA if Hepatitis B antigen positive) 
14. Anti-HCV (HCV RNA if anti-HCV positive) and anti-HIV antibody 
15. Lymphocyte sub-set counts (CD19, CD3, CD4, CD8) 
16. Quantitative immunoglobulins (IgG, IgM, IgA, IgE) 
17. Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE)  
18. 24-h urine for urine protein electrophoresis (UPEP) and urine immunofixation 
electrophoresis (UIFE)  
19. Serum free light chain (FLC) assay  
20. Unilateral bone marrow aspirate + biopsy, including bone marrow immunohistochemistry 
and bone marrow flow cytometry 
21. If the prospective subject has known or suspected extramedullary plasmacytomas, previous 
imaging results will be reviewed to confirm the status of the lesions and a repeat imaging 
(i.e., CT scan) can be done if the principal investigator deems it necessary to document the 
size/scope of the lesion.  
22. ECG 
23. ABO typing 
24. Echocardiogram to assess left ventricular function if not performed within the last 6 months  


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25. b- HCG for all women of child-bearing potential.  Female subjects of reproductive 
potential (women who have reached menarche and who have not been post-menopausal for 
at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, 
or have not undergone a sterilization procedure (hysterectomy or bilateral oophorectomy) 
must have a negative serum pregnancy test performed at the time of screening and must 
agree not to participate in a conception process (e.g., active attempt to become pregnant or 
to impregnate sperm donation or in vitro fertilization) until 4 months after receiving 
preconditioning chemotherapy. Additionally, if participating in sexual activity that could 
lead to pregnancy, the subject must agree to use a reliable method of contraception during 
their participation in the study (e.g., condoms (male or female) with or without a 
spermicidal agent, diaphragm or cervical cap with spermicide, or intrauterine device 
(IUD)). 
26. Research blood (See Laboratory Manual for collection details) 
 
4.1.2 
Leukapheresis (Day -59 to Day -7) 
A central or peripheral line will be placed prior to the procedure. Prior to leukapheresis, following 
assessments should be completed: 
1. 
Medical history for adverse events 
2. 
Vital signs (should always include pulse oximetry unless stated otherwise) and physical 
exam including brief neurological exam 
3. 
Concomitant medications 
4. 
ECOG performance status 
Leukapheresis and plasma collection will take place as per institutional standards. A sample will 
be collected from the apheresis product bag to perform CBC analysis that will be reported to the 
Sponsor prior to shipment of the product. See “Apheresis collection and shipping instructions” for 
more details. 
4.1.3 
First day of Pre-conditioning chemotherapy (Day 1 (± 1 d) of Cycle 1)  
In patients enrolled into Dose Level 4C, 4E and 4F do not administer lymphodepletive 
chemotherapy. These patients receive Descartes-11 on Day 1, which is described in Section 
4.1.5. 
Prior to chemotherapy infusion, the following assessments must be completed (Laboratory tests 
can be obtained within 48 hours of infusion): 
1. 
Medical history for adverse events 
2. 
Vital signs (should always include pulse oximetry unless stated otherwise), and physical 
exam including brief neurological exam 
3. 
Concomitant medications 
4. 
ECOG performance status 
5. 
Complete blood count, differential 


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6. 
Chemistry panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Uric Acid, Cr, ALT, AST, lactate dehydrogenase) 
7. 
Urine pregnancy test for all women of child-bearing potential 
8. 
Urinalysis (if abnormal then urine culture) 
9. 
Research Blood (See Laboratory Manual for collection details) 
 
4.1.4 
Second and Third day of Preconditioning chemotherapy (Day 2 to Day 3 of Cycle 
1) 
Prior to chemotherapy infusion, the following assessments must be completed: 
1. 
Medical history for adverse events 
2. 
Vital signs (should always include pulse oximetry unless stated otherwise) and physical 
exam including brief neurological exam 
3. 
Concomitant medications 
4. 
ECOG performance status 
Dose Level 4C does not administer lymphodepletive chemotherapy. 
 
4.1.5 
Descartes-11 infusion 
Please refer to Table 2 for Descartes-11 infusion schedule per Cycle. 
Disease reassessment: Within one day of the first Descartes-11 infusion of each cycle, at least 
one of the following should be performed if abnormal at screening:  
• Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE);  
• 24-h urine for urine protein electrophoresis (UPEP) and urine immunofixation 
electrophoresis (UIFE);  
• Serum free light chain (FLC) assay;  
 
Prior to infusion of cells, the following assessments must be completed: 
1. 
Medical history for adverse events 
2. 
Vital signs including pulse oximetry and physical exam including brief neurological exam 
3. 
Concomitant medications 
4. 
ECOG performance status 
5. 
Complete blood count, differential 
6. 
Chemistry panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Uric Acid, Cr, ALT, AST, lactate dehydrogenase) 
7. 
CRP, ferritin 


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8. 
Lymphocyte sub-set counts (CD19, CD3, CD4, CD8) 
9. 
Urinalysis 
10. Urine pregnancy test for all women of child-bearing potential 
11. ECG 
12. Research Blood (See Laboratory Manual for collection details) 
 
Within 30±5 min of each infusion: 
1. 
Vital signs – Please see Section 3.3.5 for details.  
2. 
Complete blood count, differential 
3. 
Research blood (See Laboratory Manual for collection details) 
 
4.1.6 
Safety Review and Response Assessment Visit (Day 21+3 days) 
During the visit, the following assessment must be completed: 
1. 
Medical history for adverse events 
2. 
Vital signs including pulse oximetry, weight and physical exam including brief 
neurological exam 
3. 
ECOG performance status 
4. 
Concomitant medications 
5. 
Complete blood count, differential 
6. 
Chemistry panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Uric Acid, Cr, ALT, AST, lactate dehydrogenase) 
7. 
Urinalysis 
8. 
Urine pregnancy test for all women of child-bearing potential 
9. 
CRP, ferritin 
10. Lymphocyte sub-set counts (CD19, CD3, CD4, CD8) 
11. Research blood (See Laboratory Manual for collection details) 
12. If present at baseline, serum protein electrophoresis (SPEP), serum immunofixation  
electrophoresis (SIFE)  
13. If present at baseline, 24-h urine for total protein, urine protein electrophoresis (UPEP),  
urine immunofixation electrophoresis (UIFE)  
14. If present at baseline, serum free light chain (FLC) assay  
15. b2- microglobulin 


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16. If required for depth-of-response evaluation based on peripheral markers, then unilateral 
bone marrow aspirate + biopsy, including bone marrow immunohistochemistry and bone 
marrow flow cytometry. MRD assessment (with NGS) is performed if patient is in sCR. 
17. Imaging of a previously known plasmacytoma if already imaged at baseline visit 
18. Quantitative immunoglobulins (IgG, IgM, IgA, IgE) 
4.1.7 
Follow-up Months 3, 6, 9, 12 (+ 2 weeks) 
1. 
Medical history for adverse events 
2. 
Current medical conditions and physical examination (including weight, vital signs, pulse 
oximetry) 
3. ECOG performance status  
4. 
Concomitant medications  
5. 
Complete blood count, differential 
6. 
Chemistry panel (Glucose, Ca, Mg, Phos, Alk Phos, Albumin, Total Protein, Total 
Bilirubin, K, Na, Cl, HCO3, BUN, Uric Acid, Cr, ALT, AST, lactate dehydrogenase) 
7. 
Lymphocyte sub-set counts (CD19, CD3, CD4, CD8) 
8. 
Quantitative immunoglobulins (IgG, IgM, IgA, IgE) 
9. 
Urinalysis 
10. Urine pregnancy test for all women of child-bearing potential 
11. If present at baseline, serum protein electrophoresis (SPEP), serum immunofixation 
electrophoresis (SIFE)  
12. If present at baseline, 24-h urine for total protein, urine protein electrophoresis (UPEP), 
urine immunofixation electrophoresis (UIFE)  
13. If present at baseline, serum free light chain (FLC) assay  
14. b2- microglobulin 
Additional notes: 
• 
If required for depth-of-response evaluation based on peripheral markers, then unilateral 
bone marrow aspirate + biopsy, including bone marrow immunohistochemistry and bone 
marrow flow cytometry. MRD assessment (with NGS) is performed if patient is in sCR. 
• 
Imaging of a previously known plasmacytoma if already imaged at baseline visit 
• 
Research Blood (See Laboratory Manual for collection details)  


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4.2 Study Calendar 
Procedures 
Screening 
LePha 
 
Each Cycle of Treatment 
Follow-Up 
 
Day -60 
to Day -8 
Day -59 
to Day -7 
Day 1 
+1d 
Day 2 
Day 3 
Day 4 
+ 1dd 
Day 7 
+1d 
 Day 10 
+1de 
Day 14 
+1d 
Day 17 
+1de 
Day 21 
+1d 
Months 
3, 6, 9, 12 
±2 weeks 
Informed consent 
Eligibility 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs, O2 saturation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fludarabineb 
 
 
Xb 
Xb 
Xb 
 
 
 
 
 
 
 
Cyclophosphamideb 
 
 
Xb 
Xb 
Xb 
 
 
 
 
 
 
 
Descartes-11 
 
 
Xc, 
 
 
X 
X 
X 
X 
X 
Xf 
 
CBC w/ differential 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistriesg 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Magnesium, phosphate 
X 
 
X 
 
 
 
X 
 
 
 
 
 
PT/INR, PTT 
X 
 
X 
 
 
 
 
 
 
 
 
 
ABO typing 
X 
 
 
 
 
 
 
 
 
 
 
 
D-Dimer, fibrinogen 
X 
 
 
 
 
 
 
 
 
 
 
 
CRP, ferritin 
 
 
Xc 
 
 
 
X 
X 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
b-HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
X 
 
 
 
X 
X 
X 
 
X 
X 


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Procedures 
Screening 
LePha 
 
Each Cycle of Treatment 
Follow-Up 
 
Day -60 
to Day -8 
Day -59 
to Day -7 
Day 1 
+1d 
Day 2 
Day 3 
Day 4 
+ 1dd 
Day 7 
+1d 
 Day 10 
+1de 
Day 14 
+1d 
Day 17 
+1de 
Day 21 
+1d 
Months 
3, 6, 9, 12 
±2 weeks 
Lymphocyte counts 
X 
 
Xc 
 
 
 
X 
X 
X 
 
X 
X 
Quantitative 
Immunoglobulins 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Serum FLC ratio 
X 
 
Xc 
 
 
 
X 
 
 
 
Xl 
Xl 
Serum electrophoresis and 
immunofixation 
X 
 
Xc 
 
 
 
X 
 
 
 
Xl 
Xl 
b2-microglobulin 
X 
 
 
 
 
 
 
 
 
 
X 
X 
24-hour urine for 
electrophoresis and 
immunofixation 
X 
 
Xc 
 
 
 
X 
 
 
 
Xl 
Xl 
Bone marrow biopsy and 
aspiration  
X 
 
 
 
 
 
 
 
 
 
Xk 
Xm 
Research Blood 
X 
 
Xh 
 
 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
Echocardiogrami 
X 
 
 
 
 
 
 
 
 
 
 
 
Central or peripheral 
venous catheter placement 
 
X 
 
 
 
 
 
 
 
 
 
 
Imaging 
Xj 
 
 
 
 
 
 
 
 
 
Xk,l 
Xl 
Viral serologies  
X 
 
 
 
 
 
 
 
 
 
 
 
a LePh: Leukapheresis 
b Preconditioning chemotherapy administered in Cycle 1 only.   
c Only in Dose Level 4C, 4E and 4F. NOTE:  DL4C, 4E and 4F does not administer preconditioning chemotherapy in any Cycle. 
d Only in Dose Level 4C and 4E. 
e Only in Dose Level 4B and 4D. 
f  Only in Dose Level 4A. 
g Includes Glucose, Ca, Alk Phos, Albumin, Total Protein, Total Bilirubin, K, Na, Cl, HCO3, BUN, Uric Acid, Cr, ALT, AST, lactate dehydrogenase. 
h On days of Descartes-11 infusion, there is 1x pre- and 1x post-infusion collection. See Laboratory Manual for details. 
i If not done in the previous 6 months. 
j ONLY if there is known plasmacytoma in medical history. 
k Procedure should be done only after completing all intended Decartes-11 infusions. 
l If present at baseline. 
m Bone marrow aspiration and biopsy tests will be performed ONLY if needed for depth-of-response or relapse evaluation.


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4.3 Biospecimen Collection for Exploratory Studies 
4.3.1 
Explanation of Research Blood Assays 
4.3.1.1 
Direct measurement of circulating Descartes-11 cells 
Pharmacokinetics of circulating Descartes-11 cells will be performed by quantitative PCR or flow 
cytometry. Blood concentration of Descartes-11 cells will be determined by multiplying the 
percentage of CAR+CD8+ within the CD3+ population with the absolute number of CD3+ cells 
obtained from lymphocyte subsets. Ex vivo immunological assays will be used to measure the 
BCMA-specific functional activity of the CAR+ T-cells and will consist of assays such as 
intracellular cytokine staining, anti-CD107a degranulation assays and killing of BCMA-
expressing myeloma cells. Serum BCMA levels will be measured with a validated assay. 
4.3.1.2 
Serum Biomarkers related to CRS 
Monitoring serum biomarkers of inflammation following infusion of CAR-T cells may facilitate 
identification of factors that are associated with severe CRS and thereby may be used in the future 
to predict the reaction of a patient to Descartes-11 infusion. Thus, serum at baseline, prior to cell 
infusion and at Safety Review and Response Assessment visits will be used to monitor the 
inflammatory markers in the absence of > Grade 2 CRS. Following Descartes-11 infusion, if a 
> Grade 2 CRS occurs then serum for research should be collected daily until CRS regresses to 
Grade 1 or less. Collected serum will be tested for the following cytokines that are associated with 
severe CRS following CAR-T infusion: C-reactive protein, ferritin, IFNγ, IL-6, soluble gp130, 
soluble IL-6R, TNFα, IL-2, IL-10, IL-8, IL-5 and fractalkine.33 Additional cytokines and 
inflammatory markers including, but not limited to sIL-1Rα, sIL-2Rα, IL-8, IL-12, IL-13, IL-15, 
MCP1, GM-CSF and MIP1α, will be tested as needed to address changes in standards and/or 
literature findings. 
4.3.1.3 
Additional Assays 
Patients may be asked to undergo biopsies or additional blood draws for research purposes. 
Additional blood draws might be necessary to investigate T-cell responses and serum cytokine 
levels in cases of clinical events such as rapid regressions of malignancy or toxicity. These research 
biopsies or blood draws are optional and will not impact patient participation in this study.  These 
biopsies will only be performed if minimal morbidity is expected based on the procedure 
performed and the granulocyte and platelet count.   
Immunogenicity will be assessed by a commercially available human anti-mouse antibody ELISA 
kit. 
4.3.2 
Future Studies 
With patient informed consent, blood and tissue specimens collected during this research project 
may be banked and used in the future to investigate new scientific questions related to this study. 
However, this research may only be done if the risks of the new questions were covered in the 
consent document. If new risks are associated with the research, a protocol amendment will be 
required, and informed consent will be obtained from all research subjects to whom these new 
studies and risks pertain. 


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4.3.3 
Research Blood Sample and Remaining Study Drug Destruction Upon Protocol 
Completion 
Any remaining frozen study drug after completing treatment should be returned to Sponsor. 
Research blood samples, and associated data, can only be permanently archived if the subject has 
provided informed consent for future use. If researchers have samples remaining once they have 
completed all studies associated with the protocol, they must be returned to Sponsor. 
The principal investigators will contact Sponsor if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities 
or misplaced by a researcher. 
4.4 Treatment Response Assessment 
IMWG response criteria published in 2016 will be used for response assessment. Below is a table 
summarizing the parameter to stratify a response. 
Table 4. 
IMWG response criteria82 
Response 
Category 
Parameters 
Stringent 
complete 
response 
Complete response as defined below plus normal FLC ratio and absence of clonal 
cells in bone marrow biopsy by immunohistochemistry (Kappa/Lambda < 4:1 or 
>1:2) or kappa and lambda patients, respectively, after counting > 100 plasma cells 
Complete 
response 
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrow aspirates 
Very good 
partial response 
Serum and M-protein detectable by immunofixation but not on electrophoresis or 
> 90% reduction in M-protein plus urine M-protein level <100 mg/24 hours 
Partial response 
> 50% reduction of serum M-protein plus reduction in 24 hours urinary M-protein 
by > 90% or to <200 mg/24 hours. 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 the serum and urine 
M-protein as well as serum-free light chains are unmeasurable, > 50% reduction in 
plasma cells is required, provided baseline bone marrow plasma-cell percentage was 
> 30%. In addition to these criteria, if present at baseline, > 50% reduction in size 
(sum of the products of the maximum perpendicular diameters (SPD) of measured 
lesions) of soft tissue plasmacytomas is also required.  
Minimal 
response 
> 25% but < 49% reduction of serum M-protein and reduction in urine M-protein by 
50-89%. In addition to these criteria, if present at baseline, > 50% reduction in size 
(sum of the products of the maximum perpendicular diameters of measured lesions) 
of soft tissue plasmacytomas is also required.  


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Response 
Category 
Parameters 
Progressive 
disease 
Any one or more of the following 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 patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 
mg/dL) 
• In patients without measurable serum and urine M-protein levels and without 
measurable involved FLC levels, 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 SPD 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 per µL) if this is 
the only measure of disease  
To investigate disease-free survival, the following relapse criteria will be used. 
 
Table 5. 
Relapse from sCR or MRD-negative Criteria 
Relapse from complete 
response 
Any of the following criteria: 
• 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• 
Development of ≥5% plasma cells in the bone marrow 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, 
lytic bone lesion, or hypercalcemia) 
Relapse from MRD-
negative complete 
response 
Any one or more of the following criteria: 
• 
Loss of MRD negative state (evidence of clonal plasma cells on NGF or 
NGS, or positive imaging study for recurrence of myeloma) 
• 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• 
Development of ≥5% clonal plasma cells in the bone marrow; 
Appearance of any other sign of progression (i.e., new plasmacytoma, 
lytic bone lesion, or hypercalcemia)  
 


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4.5 Criteria for Removal from Protocol Therapy and Off-Study 
Criteria 
4.5.1 
Criteria for Removal from Descartes-11 Therapy 
Off-treatment criteria mainly apply to eligibility for potential repeat Descartes-11 treatments.  
Completion of each cycle includes a response assessment visit. Patients will be taken off treatment 
for the following: 
• 
DLT as defined in Section 5.1.5 directly attributable to Descartes-11 cells. 
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment on this study in the judgment of the investigator. 
4.5.2 
Criteria for Off-Study 
Patients will be taken off study for the following: 
• 
The patient voluntarily withdraws  
• 
There is significant patient noncompliance  
• 
Death  
• 
Development of progressive or relapsed MM after completing all intended anti-BCMA CAR 
T-cell infusions. 
Patients must be followed until all adverse events have resolved to grade 2 or less other than 
lymphopenia or alopecia. If an adverse event is not expected to resolve to Grade 2 or less, this will 
be noted in the patient medical record and the patient will be taken off-study. 


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5 Safety, Adverse Events, Protocol Deviation and Stopping 
Rules 
5.1 Definitions 
5.1.1 
Adverse Events (AE) 
An adverse event (AE) is defined as any reaction, side effect, or untoward event that occurs during 
the clinical trial associated with the use of a test article in humans, whether or not the event is 
considered related to the treatment or clinically significant. For this study, AEs will include events 
reported by the patient, as well as clinically significant abnormal findings on physical examination 
or laboratory evaluation. A new illness, symptom, sign or worsening of a pre-existing condition or 
abnormality is considered an AE. An abnormal laboratory value will be considered an AE if the 
laboratory abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study  
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention  
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution.  
5.1.2 
Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the test article caused the adverse event. For the purposes of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the test article and 
the adverse event. A suspected adverse reaction implies less certainty about causality than adverse 
reaction, which means any adverse event caused by a test article. 
5.1.3 
Serious Unexpected Adverse Reaction (SUSAR) 
An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected" 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of the test article or as anticipated from the pharmacological 
properties of the drug but are not specifically mentioned as occurring with the test article under 
investigation. 


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5.1.4 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death within 30 days of Descartes-11 infusion 
• 
Grade 4 or 5 CRS, infusion reaction, neurotoxicity  
• 
Inpatient hospitalization or prolongation of existing hospitalization (except for protocol-
mandated ~24-hour admission for observation due to new-onset fever) 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
5.1.5 
Dose Limiting Toxicity (DLT) 
DLTs are defined as any Descartes-11-related Grade 3 to 5 toxicity occurring within the 14 days 
immediately after infusion of the drug product, with the following exceptions: 
• ≤Grade 3 to 4 Tumor Lysis Syndrome (TLS) lasting <7 days 
• Grade 3 CRS associated with fever, hypotension or hypoxia lasting less than 72 hours 
(i.e., improves to ≤Grade 2 CRS in less than 72 hours) 
• Hematologic toxicities: 
o ≤Grade 3 neutropenia of any duration or Grade 4 neutropenia lasting <28 days 
o ≤Grade 3 anemia of any duration or Grade 4 anemia lasting <28 days 
o ≤Grade 3 thrombocytopenia of any duration or Grade 4 thrombocytopenia lasting 
<28 days 
o All cytopenias except neutropenia, anemia, and thrombocytopenia as described above 
• Non-hematologic toxicities: 
o Fever of any grade, including febrile neutropenia 
o ≤Grade 3 diarrhea lasting <72 hours 
o ≤Grade 3 nausea and/or vomiting lasting <72 hours 
o ≤Grade 3 fatigue lasting <7 days 
o ≤Grade 4 transaminase, bilirubin, blood urea nitrogen (BUN), or creatinine elevation 
lasting <7 days 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 5 will be used to grade toxicities during the trial unless specified above. 


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5.1.6 
Protocol Deviation 
A one-time, unintentional action or process that departs from the IRB-approved study protocol, 
involving one incident and identified retrospectively, after the event occurred.  Any leukapheresis-
related failure or deviation will be recorded, even if it does not constitute a per-protocol AE. 
5.2 Recording of Adverse Events 
5.2.1 
Adverse Event Recording Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the protocol therapy completion. For this study, 
collection of adverse events will begin with enrollment until the subject is off-study. Serious 
Adverse Event reporting period starts with leukapheresis and ends at 30 days after last Descartes-
11 infusion.    
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled 
visit, the investigator should instruct each subject to report any suspected adverse event(s) that 
might reasonably be related to participation in this study. The investigator should notify the 
Sponsor of any death or adverse event occurring at any time after a subject has discontinued or 
terminated study participation if the event may reasonably be related to this study. The Sponsor 
should also be notified if the investigator should become aware of the development of cancer or of 
a congenital anomaly in a subsequently conceived offspring of a subject that has participated in 
this study. 
5.2.2 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise as 
below. Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event. Neither the condition, hospitalization, prolonged 
hospitalization, nor surgery are reported as an adverse event in the following circumstances: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition. Surgery should not be reported as an outcome of an adverse event if 
the purpose of the surgery was elective or diagnostic and the outcome was uneventful.  
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless there is clinical worsening or an increase in frequency of hospital admissions as judged 
by the clinical investigator. 
• 
Hospitalization for protocol-mandated 24-hour observation following new onset of fever 
following infusion of Descartes-11. 
5.2.3 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to the 
Sponsor within 24 hours of learning of its occurrence. The pregnancy must be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 


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complications. Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported 
by the investigator to the Sponsor. Pregnancy follow-up should be recorded on the same form and 
must include an assessment of the possible relationship to the study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
5.2.4 
Recording of Adverse Events 
At each contact with the subject during the adverse event recording period (defined in 
Section 5.2.1), the investigator must seek information on adverse events by specific questioning 
and, as appropriate, by examination. Information on all adverse events should be recorded 
immediately in the source document, and in the appropriate adverse event module of the case 
report form (CRF). All clearly related signs, symptoms, and abnormal diagnostic procedures 
results should be recorded in the source document, though should be grouped under one diagnosis. 
To the extent possible, adverse events should be recorded as a diagnosis and symptoms used to 
make the diagnosis recorded within the diagnosis event. Do not list symptoms if a diagnosis can 
be assigned. 
Conditions that were already present at the time of informed consent should be recorded in the 
Medical History CRF. Any condition listed in a subject’s medical history for which the severity 
increases at the time of, or post-Descartes-11 infusion, should be captured as an adverse event. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event. The clinical course of each event should be followed until resolution, stabilization, or until 
it has been determined that the study treatment or participation is not the cause. As detailed as 
possible, each adverse event should be evaluated to determine: 
• 
The severity grade (CTCAE Version 5.0 Grade 1-5)  
• 
Its duration (start and end dates)  
• 
Its relationship to the study treatment (Descartes-11 vs lymphodepletion): Is there a reasonable 
possibility that the AE is related to Descartes-11 or lymphodepletion treatment- No (unrelated) 
or Yes. If yes- is the event definitely, probably, possibly or unlikely related to the 
investigational 
treatment 
(Descartes-11) 
or 
the 
non-investigational 
treatment 
(i.e., cyclophosphamide or fludarabine).  
• 
Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)  
• 
Whether medication or therapy taken (i.e., no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)  
• 
Whether it is serious, as defined in Section 5.1.  
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. Adverse events should 


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be entered into the eCRF system within 10 working days from the knowledge of the event took 
place. Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), documented appropriately in the medical 
records, should not be reported as a serious adverse event. Adverse events that occur concurrently 
with the progression of malignancy but that are not related to disease progression (i.e., deep vein 
thrombosis) will be reported as an adverse event as described above. 
5.2.5 
SAE and SUSAR Reporting 
To ensure patient safety, every SAE and SUSAR, regardless of suspected causality, occurring 
during the adverse event reporting period defined in Section 5.2.1 must be reported to the Sponsor 
within 24 hours of learning of its occurrence. Recurrent episodes, complications, or progression of 
the initial SAE must be reported as follow-up information is received. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event. 
5.2.5.1 
Study Sponsor notification by the investigator 
Any SUSAR and SAE as defined in Section 5.1 must be reported to the Sponsor by email or fax 
within 24 hours of knowledge of the event. To the extent possible, adverse events should be 
recorded as a diagnosis. Do not list symptoms if a diagnosis can be assigned. At the time of the 
initial notification, a serious adverse event (SAE) report form should be filled. Following 
parameters will be asked in the form: 
• 
Subject information 
• 
A description of the event (if there is a diagnosis, it should be included) 
• 
Date of onset  
• 
Current status  
• 
Whether study treatment was discontinued  
• 
The reason why the event is classified as serious  
• 
Investigator assessment of the association between the event and study treatment  
• 
Concomitant medications when the event happened 
• 
Narrative summary of the event 
 
Follow-up information on this event should be reported when received. The follow-up information 
should describe 1) whether the event has resolved or continues, 2) if and how it was treated, and 
3) whether the patient continued or withdrew from study participation. 


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5.2.5.2 
IRB notification by the investigator 
Following events should be reported to IRB: 
• 
Information that indicates a change to the risks or potential benefits of the research, in terms 
of severity or frequency. For example:  
• 
Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected.  
• 
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol.  
• 
Breach of confidentiality. 
• 
Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard 
to a research participant.  
• 
Complaint of a participant when the complaint indicates unexpected risks, or the complaint 
cannot be resolved by the research team.  
• 
Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased 
risk or affects the rights or welfare of subjects. 
 
Deaths that occur during the study should be reported within the IRB-specified time frame. 
For reportable deaths, the initial submission to the IRB may be made by contacting the IRB 
Director or Associate Director. The AE/Unanticipated Problem Form is required as a follow up to 
the initial submission. 
5.2.5.3 
FDA notification by the study sponsor 
The Sponsor is required to report certain study events in an expedited fashion to the FDA. These 
written notifications of adverse events are referred to as IND safety reports. The sponsor must 
report an IND safety report as described in:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf 
The following describes the safety reporting requirements by timeline for reporting and associated 
type of event: 
• 
Within 7 Calendar Days any study event that is unexpected, fatal or life-threatening suspected 
adverse reaction.  
• 
Within 15 Calendar Days any study event that is unexpected, suspected adverse reaction that 
is serious, but not fatal or life-threatening -or- a previous adverse event that was not initially 
deemed reportable but is later found to fit the criteria for reporting, any finding from tests in 
laboratory animals that suggest a significant risk for human subjects including reports of 
mutagenicity, teratogenicity, or carcinogenicity or reports of significant organ toxicity at or 
near the expected human exposure. 


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5.3 Medical Monitor 
The medical monitor will be a Sponsor physician or Sponsor-appointed physician with appropriate 
experience and Board Certification to oversee study conduct on the Sponsor’s behalf, consult with 
site investigators, review and synthesize safety information from the various clinical sites, and to 
apply study-stopping criteria.  All decisions by the medical monitor affecting study conduct, 
including the application of study-stopping or dose-escalation rules, will be documented in the 
study record. 
5.4 Recording of Protocol Deviations 
If the impact on the protocol disrupts the study design, may affect the outcome (objectives), or 
compromises the safety and welfare of the subjects, the deviation must be reported to the medical 
monitor within three business days. Include the following information on the Sponsor-supplied 
exception/deviation form: protocol number, subject study number, description of the 
exception/deviation from protocol and rationale. Ensure all completed exception/deviation forms 
are signed by the Site Investigator and submitted to the Study Sponsor and medical monitor for 
review. Once approval of the exception request or acknowledgement of the deviation has been 
granted by the Sponsor and medical monitor, the exception or deviation will be submitted to IRB 
and all other applicable committees. 
Other deviations should be explained in a memo to file (example: a subject missing a visit is not 
an issue unless a critical/important treatment or procedure was missed and must have been 
performed at that specific time). 
5.5 Stopping Rules and Study Termination 
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB or medical monitor. Additionally, recruitment may be stopped for 
reasons of particularly low recruitment, protocol violations, or inadequate data recording. 
Specifically, study will be stopped if: 
• 
Study Sponsor or a Regulatory Body decides for any reason that subject safety may be 
compromised by continuing the study.  
• 
The Sponsor decides to discontinue the development of the intervention to be used in this 
study.  
 
The study will be paused if: 
• 
There is death that is reasonably attributed to study drug within the first 30 days after first 
infusion 
• 
Two subjects with Grade 4 adverse events to vital organs that are assessed as possibly, probably 
or definitely related to study drug within the first 30 days after first infusion 
 
If the study is paused for the reasons above, the PI and members of the study team will meet in 
person or by teleconference within 24 hours of the event to have a thorough discussion of the 
event. Meeting minutes capturing the review of any ongoing investigations, including next steps 


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in the management of the subject and any proposed changes to the protocol will be forwarded to 
the medical monitor. If all parties agree as to the event resolution, then the pause will be lifted. If 
the study is paused for manufacturing reasons, the Sponsor will make recommendations for 
process improvements to be implemented. Pending successful completion of a process validation 
run, the manufacturing pause will be lifted. 


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6 Statistical Considerations 
6.1 Primary Endpoints 
6.1.1 
Safety and Tolerance 
Study results will be descriptive.  Safety and tolerability endpoints will include descriptive 
statistics of AEs and SAEs. Patients must be followed until all AEs have resolved to Grade 2 or 
less except for lymphopenia and alopecia. 
6.1.2 
Feasibility 
The number of manufactured products that do not meet release criteria for potency, T cell purity, 
viability and sterility will be determined (defined as “manufacturing failures”). 
6.2 Secondary Endpoints 
6.2.1 
Efficacy 
Efficacy will be assessed by descriptive statistics of treatment response per IMWG criteria.82 
6.3 Exploratory Endpoints 
6.3.1 
Descartes-11 Biology 
1. Characterize Descartes-11 persistence, homing, phenotype, and function in patients with MM. 
2. Determine impact of Descartes-11 on systemic soluble immune factors by cytokine assays. 
3. Determine the correlation between serum BCMA levels and response. 
6.3.2 
Immunogenicity Assessment 
Immunogenicity will be assessed by a commercially available human anti-mouse antibody ELISA 
kit and results will be reported as descriptive. 


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7 Ethical Considerations 
7.1 General Issues 
This study is to be conducted according to US and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures.  
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB) for formal approval of the study conduct. The decision of the 
IRB concerning the conduct of the study will be made in writing to the investigator and a copy of 
this decision will be provided to the sponsor before commencement of this study. The investigator 
should provide a list of IRB members and their affiliations to the Sponsor.  
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure. This consent form must be signed 
by the subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent. 
7.2 Rationale for Subject Selection 
The patients to be entered in this protocol have MM which is an almost always incurable disease 
and therefore these patients have limited life expectancies. Subjects from both genders and all 
racial/ethnic groups are eligible for this study if they meet the eligibility criteria. To date, there is 
no information that suggests that differences in disease response would be expected in one group 
compared to another. It is not considered reasonable to administer a previously uncharacterized 
cell therapy to pregnant or lactating women.  Children do not develop MM.  Efforts will be made 
to extend accrual to a representative population, but in this preliminary study, a balance must be 
struck between patient safety considerations and limitations on the number of individuals exposed 
to potentially toxic and/or ineffective treatments on the one hand and the need to explore gender 
and ethnic aspects of clinical research on the other hand. If differences in outcome that correlate 
to gender or to ethnic identity are noted, accrual may be expanded, or a follow-up study may be 
written to investigate those differences more fully. 
7.3 Evaluation of Benefits and Risks 
Clinical trial summarized above demonstrated that targeting BCMA in MM by the CAR construct 
that will be used in the current protocol demonstrated mainly activity-associated toxicity and no 
off-target or on-target off-tumor effects. Furthermore, as noted above, Descartes-11 is expected to 
have even a better safety profile than the one used in that trial. Taken together, the potential 
benefits of the trial outweigh its risks. 


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7.4 Recordkeeping 
7.4.1 
Source Data 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents.  Examples of these original documents and data records include 
hospital records, clinical and office charts, laboratory notes, memoranda, subject diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
7.4.2 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All entries will be entered into an electronic data capture 
system (eCRF). The Principal Investigator is responsible for assuring that the data entered into 
eCRF is complete, accurate, and that entry and updates are performed in a timely manner. 
7.4.3 
Confidentiality 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to the sponsor. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. Information about 
study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed 
subject authorization informing the subject of the following: 
• 
What protected health information (PHI) will be collected from subjects in this study  
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
If a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects 
that have revoked authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e., that the subject is alive) at the end of their scheduled study 
period. 
7.4.4 
Records Retention 
It is the sponsor’s responsibility to retain study essential documents for at least 2 years after the 
last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by a Regulatory Body. 


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8 Pharmaceutical Information 
Study drug will be provided by the Study Sponsor. For manufacturing and packaging details of the 
drug 
please 
see 
Section 
1.3. 
 
FDA-approved 
Acetaminophen, 
Diphenhydramine, 
Cyclophosphamide, Fludarabine and Tocilizumab, IMiDs (Lenalidomide, Pomalidomide) will be 
sourced from commercial suppliers of the clinical site.  Investigators will be referred to the 
approved labeling for those products. 


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9 References 
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30. 
2. Cancer Stat Facts: Myeloma. (Accessed July 14, 2017, at 
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10 Appendix 1 Management Guidelines for CAR T-cell-
related Toxicities 
The clinical signs and symptoms of CAR T-related toxicities guide the grading and management 
of CRS and neurotoxicity. This protocol adapts management recommendations described by Lee 
et al.22 A copy of this reference will be provided to the investigator and staff are encouraged to 
review it prior to enrolling the first patient.  The following is recommended: 
1. All patients with suspicion of CRS or fever above 37.90C should be admitted for at least a 
24-hour observation. 
2. Infectious disease work-up with blood cultures should be initiated each time CRS is 
suspected. Empiric broad-spectrum intravenous antibiotics are recommended. 
3. Vital signs should be checked at least every 4 hours with strict urine input and output 
monitoring.  
4. Patients with poor oral intake should be started on intravenous fluids. Patients with 80% of 
their baseline systolic blood pressure (or if systolic BP<90mmHg) should be given a 0.5-
1L fluid bolus. Fluid boluses can be repeated as needed; however, they should be kept to a 
minimum with a low threshold of starting low dose vasopressor as the capillary leak during 
CRS can lead to fluid overload. 
5. Patients should be transferred to the Intensive Care Unit (ICU) if: 
a. the patient’s systolic pressure does not respond to the first fluid bolus; 
b. the patient requires 2 or more fluid boluses within 24 hours; 
c. the patient’s heart rate remains above 125/min for at least 4 hours; 
d. the patient’s supplemental oxygen requirement is more than 40% FiO2; or 
e. the patient has >Grade 2 neurotoxicity. 
6. Patients admitted to the ICU should have the following: 
a. vital signs checked every 2 hours; 
b. cardiac enzymes, ECG and echocardiogram evaluation; 
c. if systolic blood pressure is below 75% of baseline or below 85 mmHg, 
norepinephrine should be started; 
d. CBC should be checked twice a day and cytopenias should be treated as follows: 
i. blood transfusion to keep Hgb above 8.0 g/dL; 
ii. platelet transfusion to keep platelet above 20k; 
iii. growth factors for neutropenia can be started if ANC is below 1000/µL. 
Filgrastim is recommended due to a shorter half-life compared with 
pegfilgrastim. 
7. Tocilizumab at the FDA-approved dose for CRS should be administered in the following 
circumstances: 
a. grade 3 CRS; 
b. grade 2 CRS that is not resolving within 72 hours; or 
c. grade 2 CRS in the context of other co-morbidities or old age. 
 


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8. TOCILIZUMAB SHOULD NOT BE GIVEN FOR ISOLATED NEUROTOXOCITY. 
9. If the patient does not respond to tocilizumab within 12 hours, a repeat dose of tocilizumab 
can be given. If the patient does not respond to the second dose, corticosteroids 
(i.e. methylprednisolone 1mg/kg every 12 hours) should be prescribed. 
10. Patients who are recovering from CRS should not be discharged until they are afebrile for 
at least 24 hours. 
11. If neurotoxicity is suspected, the patient should be evaluated with the Immune Effector 
Cell Encephalopathy (ICE) scale22.  Patients with Grade 2 neurotoxicity should get a 
neurology consult and thorough evaluation, e.g., with lumbar puncture and MRI, for other 
etiologies.  
12. Patients who have Descartes-11 related neurotoxicity (except for headache) should receive 
dexamethasone in the following situations at 0.5-1.0 mg/kg every 4-6 hours until symptoms 
regress to Grade 1: 
a. grade 3 neurotoxicity lasting for 24 hours; 
b. grade 4 neurotoxicity; or 
c. any generalized seizure (in conjunction with other anti-seizure therapies).