Clinical trial NCT04304144
Conditions: AL Amyloidosis
Keywords: cyclophosphamide, bortezomib and dexamethasone (CyBorD) AL Amyloidosis Amyloid, Light chain Amyloidosis Mayo Stage IIIa daratumumab Mayo Stage II Mayo Stage I
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2020-03-18; Completion date: 2023-11-14
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
AL amyloidosis begins in the bone marrow where abnormal proteins misfold and create free light chains that cannot be broken down. These free light chains bind together to form amyloid fibrils that build up in the extracellular space of organs, affecting the kidneys, heart, liver, spleen, nervous system and digestive tract.

The primary purpose of this study is to determine the recommended dose of CAEL-101 to facilitate progression of further clinical trials and evaluate safety and tolerability of CAEL-101 in combination with the standard of care (SoC) cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy and daratumumab .

Detailed description:
This is a multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage I, Stage II and Stage IIIa AL amyloidosis patients. CAEL-101 will be administered in combination with the standard of care (SoC) cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy and daratumumab.

The study is divided into two parts with the following objectives:

* Part A defines the safety and tolerability of CAEL-101 in combination with SoC CyBorD and determines the recommended Phase 3 dose (RP3D) of CAEL-101
* Part B evaluates the safety and tolerability of CAEL-101 in combination with SoC CyBorD and daratumumab

The study will also evaluate the pharmacokinetic profile of CAEL-101 and explore the PK profile of CAEL-101 when given bi-weekly (q2wk) versus once-monthly (q4wk) after the first 50 weeks.

Part A of the study will employ a 3+3 dose escalation design. At least 3 patients will be enrolled in each dose cohort unless adverse events (AE) preventing further dosing are observed. CAEL-101 will be administered in combination with the SoC CyBorD chemotherapy.

In Part B, a minimum of 6 new patients will receive CAEL-101 administered in combination with SoC CyBorD and daratumumab.

Patients from both Parts A and B will receive CAEL-101 therapy weekly and SoC throughout the safety observation period. CAEL-101 study drug infusions will continue, with dosing approximately every two weeks (q2wk) thereafter. SoC will continue per the Investigator's discretion. After completing approximately 50 weeks of treatment, participants may switch to an alternative maintenance dosing regimen of every four weeks (q4wk), if agreed upon by the Investigator and the Sponsor Medical Monitor.

Approximately 25 patients will be enrolled in the study at approximately 3 investigator sites.

Patients will be treated with CAEL-101 until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.

Arms: arm 1: CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. The initial cohort dose assignments of CAEL-101 will be: Cohort 1 - 500 mg/m\^2 Cohort 2 - 750 mg/m\^2 Cohort 3 - 1000 mg/m\^2. CAEL-101 will be administered weekly for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study. Patients from Part A who are in the Continued Treatment Period and who, in the Investigator's judgment, should have their SoC treatment complemented with daratumumab may do so (Part B). arm 2: CAEL-101 is administered as an intravenous (IV) infusion at the RP3D dose level. CAEL-101 will be administered weekly for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy and daratumumab. After completing approximately 50 weeks of treatment, participants may switch to an alternative maintenance dosing regimen of every four weeks (q4wk), if agreed upon by the Investigator and the Sponsor Medical Monitor. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.
Interventions: intervention 1: CAEL-101 intervention 2: SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) intervention 3: Daratumumab
Intervention descriptions: intervention 1: The investigational product, CAEL-101, is formulated as a sterile liquid solution of protein plus excipients for dilution in a single-use, stoppered, glass vial. Each 10 mL vial contains 300 mg of CAEL-101 at a concentration of 30 mg/mL. CAEL-101 will be diluted with commercially available 0.9% Normal Saline. intervention 2: According to institutional standard of care. intervention 3: Treatment for AL amyloidosis

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 3.0 CAEL101-203 Phase 2 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
18 July 2022 
Page 1 of 73 
CLINICAL STUDY PROTOCOL
A PHASE 2, OPEN-LABEL, MULTICENTER DOSE SELECTION 
STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF 
CAEL-101 IN PATIENTS WITH AL AMYLOIDOSIS 
PROTOCOL NUMBER: CAEL101-203 
INVESTIGATIONAL PRODUCT: CAEL-101 
SPONSOR: 
Alexion Pharmaceuticals, Inc. 
121 Seaport Boulevard 
Boston MA 02210 
USA 
IND #: 117,316 
Protocol Amendment 3: 18 July 2022 
Supersedes: Protocol Amendment 2 dated December 14, 2021 
Original Protocol dated November 4, 2019 
NCT #: NCT04304144


Protocol Amendment 3.0 CAEL101-203 Phase 2
 
 
 
 
CAEL-101
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 2 of 73 
SPONSOR PROTOCOL APPROVAL PAGE
Protocol Title:  
A Phase 2, Open-Label, Multicenter Dose Selection Study to 
Evaluate the Safety and Tolerability of CAEL-101 in Patients with 
AL Amyloidosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Alexion Pharmaceuticals, Inc.
Medical Monitor Name and Contact Information can be found in the Study Contact List.


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 3 of 73 
INVESTIGATOR’S AGREEMENT 
 
By signing below, I agree that:  
I have read the CAEL101-203 study protocol and agree to conduct the study in accordance with 
this protocol, all applicable government regulations, the principles of the International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
Guideline for Good Clinical Practice, and the principles of the World Medical Association 
Declaration of Helsinki. I also agree to maintain the confidentiality of all information received or 
developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 4 of 73 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Amendment 3.0 (18 July 2022) 
This amendment is considered to be substantial according to the US Food and Drug 
Administration’s (FDA) regulation at 21 CFR part 312.30(b) and any applicable local 
regulations. 
Overall Rationale for the Amendment 
The main purpose of this document is to update the trial sponsorship, extend the End of 
Treatment period, and change contraception inclusion criteria. Other administrative changes 
made to the protocol have been incorporated in this amendment. Changes to Clinical Study 
Protocol CAEL101-203 from the Protocol Amendment 2.0 dated 14 December 2021 are 
outlined. This amendment is to: 
Change 
Rationale 
Title page, Section 9.5 SAE Reporting and 
Follow-up, Section 9.5.2 Pregnancy, headers, and 
footers  
Sponsorship updated 
To reflect the change of sponsorship of the study 
from Caelum Biosciences, Inc to Alexion 
Pharmaceuticals, Inc 
Figures 2 and 3, and throughout document 
End of Treatment period changed from 14 days to 
140 days 
 
To extend the End of Treatment period to 140 
days 
Figures 2 and 3 
Updated 
Updated for clarity and readability  
Section 1.2 Schedule of Assessments (Table 1) 
Adverse Event (AE) added to Visit 1 
Text added (“Protein”) to ‘24-hour urine 
collection’ row.  
Text added (‘Serum Free Light Chains and’) to 
Serum and Urine Immunofixation row  
Updated text describing cTnT/cTnI 
End of Treatment extended to 140 days from last 
dose 
Footnotes ‘a’, ‘b’, ‘c’, ‘f’, ‘i’, ‘j’: text updated 
Footnote ‘k’ added  
End of Treatment extended to 140 days from last 
dose (eg, Section 6.3 and throughout document) 
 
For clarity, added: 
• Added AE to Visit 1,  
• Added “protein” to ‘24-hour urine protein 
collection’ row 
• Added “and serum and urine’ to ‘Serum 
Free Light Chains and serum and urine 
immunofixation electrophoresis’ row 
•  Updated text updated from ‘cTnT/cTnI 
(cardiac patients only)’ to ‘cTnT/cTnI/hs-
cTnT/hs-cTnI (cardiac patients only)’ 
 
Text updated in: 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 5 of 73 
Change 
Rationale 
• Footnote ‘a’ for consistency with Section 4.1 
and Section 6.2 
• Footnote ‘b’ for consistency with Section 
9.1.3 
• Footnote ‘c’ for consistency with Section 
6.10  
• Footnote ‘f’ to clarify timing of PK and 
immunogenicity testing   
• Footnote ‘i’ to clarify assessments will be 
completed approximately every 90 days 
• Footnote ‘j’ for consistency with End of 
Treatment extended to 140 days from last 
dose 
Added Footnote ‘k’ to clarify that past 50 weeks, 
assessments are to be completed every 12 months 
Cardiovascular magnetic resonance imaging 
(MRI) removed to be consistent with Section 8.1 
Section 3.2 Secondary Objectives 
Added additional text to secondary objective 
To describe that the PK profile of CAEL-101 will 
be explored when CAEL-101 is given bi-weekly 
(q2wk) versus once-monthly (q4wk) after the first 
50 weeks 
Section 4.1 Summary of Study Design 
Text added 
Figure 4 added 
To provide an alternative maintenance dosing 
regimen of every four weeks (q4wk). 
 
To provide a composite hematologic and organ 
response model proposed by Sidana et al. (2020). 
The option of treatment switching from bi-weekly 
(q2wk) to once every 4 weeks (q4wk) should be 
agreed between the Investigator and the Sponsor 
Medical Monitor and based on the assessment of 
the combined hematological and organ responses 
as per the scoring system proposed. Switching 
could be considered if the score is within the 
range of 0 to 3. 
Section 5.1 Patient Inclusion Criteria 
Updated verbiage of inclusion criteria #5, #9, #10 
#5 Clarify the Kappa/ Lambda ratio for readability  
#9 Clarify contraception methods for women 
#10 Clarify contraception methods for men 
Section 5.2 Patient Exclusion Criteria  
Updated verbiage of exclusion criteria #16 
#16 Corrected units for prostate-specific antigen 
from mg to ng 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
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18 July 2022 
Page 6 of 73 
Change 
Rationale 
Section 6.1 Screening Period  
Updated Table 2 
Revised Table 2 to include the high sensitivity 
(generation 5) cardiac troponin T (hs-cTnT) 
threshold value for Mayo Staging of AL 
amyloidosis 
Section 6.2 Treatment Period 
Text added 
To describe the alternative maintenance dosing 
regimen: After completing approximately 50 
weeks of treatment, participants may switch to an 
alternative maintenance dosing regimen of every 
four weeks (q4wk), and then start following the 
assessment pattern of V29-V25-V27-V29-V25 
and so on. The option of treatment switching 
should be agreed between the Investigator and the 
Sponsor Medical Monitor and based on the 
assessment of the combined hematological and 
organ responses as per the scoring system 
proposed by Sidana et al (2020).  
 
Section 6.2.5 Dose Delay 
Updated text to clarify that Medical Monitor will 
be notified when there is a study dose delay or 
modification 
Added text about delayed dosing events and 
safety assessments 
Clarify that dose delay or modification for safety 
concerns are permitted at the Investigator’s 
discretion. When not related to safety, decisions 
regarding dose delay and dose 
reductions/modifications will be made by the 
Investigator in consultation with the Medical 
Monitor  
To provide guidance to Investigators about 
delayed dosing events and safety assessments 
Section 6.3 End of Treatment 
Number of days after the last dose of CAEL-101 
updated 
To extend the End of Treatment period to 140 
days 
Section 6.4 End of Study 
Text updated 
To update the definition of ‘end of study’ 
Section 6.7 Prohibited Medications 
Added information about Medical Monitor 
To provide guidance to Investigators about 
consultation with Medical Monitor 
Section 6.8 Pharmacokinetic Measurements 
(previously Section 8.4)  
Transposed the section to provide information in a 
more appropriate section of the protocol since the 
pharmacokinetic (PK) measurements are not an 
assessment of efficacy  
To clarify that CAEL-101 metabolites will not be 
collected 
Section 6.9 Immunogenicity Measurements 
(previously Section 8.5) 
Transposed the section to provide information in 
more appropriate section as the immunogenicity 
measurements are not an assessment of efficacy 


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Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 7 of 73 
Change 
Rationale 
Section 6.9.1 ADA Variables 
Section added 
Added ADA variables to provide better clarity on the 
expected data and analysis 
Section 6.10 
Added Contraception Requirements 
To clarify contraception requirements 
Section 7.3 Study Drug Storage 
Updated text 
For clarification of storage practices 
Section 8.1 Echocardiography 
Cardiovascular MRI removed from section header 
Revised text describing echocardiography. 
 
To reflect that Cardiovascular MRI is not being 
performed and is no longer described in this text 
To provide additional details about 
echocardiograms 
Section 9.1.3 Physical Examination 
Removed details describing a full physical 
examination 
To be consistent with data captured on the Case 
Report Form 
Section 9.1.5 Clinical Laboratory Tests 
Table 5 updated 
To include complete list of clinical laboratory 
tests to be performed at local laboratory 
Section 9.2.1.1 Adverse Event Reporting and 
Follow-up 
Revised text 
To clarify timing of AE reporting and to clarify 
‘pre-treatment AE’  
 
Section 9.5 SAE Reporting and Follow-up 
Incorporated other administrative text to clarify 
timing of reporting of SAEs and SAE reporting 
information of Sponsor 
To align with current safety reporting procedures. 
Update Sponsor contact information for SAE 
reporting and timing of SAE reporting relative to 
ICF signing. Clarify that additional records should 
not be provided unless specifically requested. 
Section 9.5.2 Pregnancy  
Incorporated other administrative text to clarify 
pregnancy reporting information of Sponsor  
To align with current pregnancy reporting 
procedures.   
Update Sponsor contact information for 
pregnancy reporting. 
Section 10.1 General Considerations 
Text added 
To describe that the PK profile of CAEL-101 will 
be explored when CAEL-101 is given q2wk 
versus q4wk after the first 50 weeks 
10.4 Analysis Sets 
Added ADA Population  
To describe the population used in the ADA 
analysis set 
10.5.6 Pharmacokinetics 
Updated text 
To describe that the PK profile of CAEL-101 will 
be explored when CAEL-101 is given bi-weekly 
versus once-monthly after the first 50 weeks and 
these details will be provided in a separate PK 
SAP. 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 8 of 73 
Change 
Rationale 
Section 10.7 Missing Data 
Modified text 
To clarify that details about handling of missing 
data will be presented in the Statistical Analysis 
Plan 
Appendix B Organ Involvement and Response 
Criteria 
Table updated 
To update the title, headers, and response criteria 
for heart, kidney, and liver 
Appendix C Hematologic Response and 
Progression Criteria 
Table updated 
To update title and description of Complete 
Response  
Appendix E COVID-19 Risk Assessment 
Added this appendix 
To align with regional COVID-19 risk assessment 
requirements 
Appendix F COVID Vaccine Risk Assessment 
Added this appendix 
To align with regional COVID-19 vaccine specific risk 
assessments  
 
Section 18 References 
(Previously Section 17) 
Relocated reference section to end of document 
Minor administrative changes 
For improved consistency and clarity 
Abbreviations:  ADA – antidrug antibody; AE  – adverse event; MRI – magnetic resonance imaging; PK – 
pharmacokinetic; q4wk – every four weeks; SAE  – serious adverse event; SAP – Statistical Analysis Plan; V – 
visit 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
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Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL PAGE ................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................14 
ABBREVIATIONS .......................................................................................................................15 
1. 
SYNOPSIS .................................................................................................................17 
1.1. 
Study Schematics ........................................................................................................21 
1.2. 
Schedule of Assessments ............................................................................................23 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Background .................................................................................................................26 
2.2. 
CAEL-101 ...................................................................................................................26 
3. 
STUDY OBJECTIVES ..............................................................................................28 
3.1. 
Primary Objective .......................................................................................................28 
3.2. 
Secondary Objectives .................................................................................................28 
3.3. 
Exploratory Objective .................................................................................................28 
4. 
STUDY DESIGN .......................................................................................................29 
4.1. 
Summary of Study Design ..........................................................................................29 
4.2. 
Number of Patients .....................................................................................................30 
5. 
SELECTION OF STUDY POPULATION ................................................................32 
5.1. 
Patient Inclusion Criteria ............................................................................................32 
5.2. 
Patient Exclusion Criteria ...........................................................................................33 
5.3. 
Continuation and Withdrawal Criteria ........................................................................34 
6. 
TREATMENT PLAN .................................................................................................36 
6.1. 
Screening Period .........................................................................................................36 
6.2. 
Treatment Period ........................................................................................................37 
6.2.1. 
Administration of Study Drug ....................................................................................38 
6.2.2. 
Concurrent Chemotherapy ..........................................................................................38 
6.2.3. 
Recommended Phase 3 Dose Selection ......................................................................39 
6.2.4. 
Dose Limiting Toxicity ...............................................................................................40 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
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6.2.5. 
Dose Delay ..................................................................................................................40 
6.3. 
End of Treatment ........................................................................................................41 
6.4. 
End of Study ...............................................................................................................41 
6.5. 
Prior and Concomitant Medications ...........................................................................41 
6.6. 
Permitted Medications ................................................................................................41 
6.7. 
Prohibited Medications ...............................................................................................42 
6.8. 
Pharmacokinetic Measurements .................................................................................42 
6.9. 
Immunogenicity Measurements ..................................................................................42 
6.9.1. 
ADA Variables ...........................................................................................................42 
6.10. 
Contraception Requirements ......................................................................................43 
6.11. 
Assigning Patient Numbers ........................................................................................44 
7. 
INVESTIGATIONAL PRODUCT ............................................................................45 
7.1. 
Study Drug ..................................................................................................................45 
7.2. 
Study Drug Packaging and Labeling ..........................................................................45 
7.3. 
Study Drug Storage .....................................................................................................45 
7.4. 
Study Drug Preparation ..............................................................................................45 
7.5. 
Accountability and Reconciliation .............................................................................45 
7.6. 
Study Drug Handling and Disposal ............................................................................45 
8. 
ASSESSMENT OF EFFICACY ................................................................................46 
8.1. 
Echocardiography .......................................................................................................46 
8.2. 
NT-proBNP, cTnT/cTnI, dFLC ..................................................................................46 
8.3. 
24-hour Urine Protein .................................................................................................46 
9. 
ASSESSMENT OF SAFETY AND ADVERSE AND SERIOUS 
ADVERSE EVENTS..................................................................................................47 
9.1. 
Safety Parameters .......................................................................................................47 
9.1.1. 
Medical History ..........................................................................................................47 
9.1.2. 
Vital Signs ..................................................................................................................47 
9.1.3. 
Physical Examination .................................................................................................47 
9.1.4. 
Twelve-Lead Electrocardiogram ................................................................................47 
9.1.5. 
Clinical Laboratory Tests ...........................................................................................47 
9.1.6. 
Pregnancy Screen ........................................................................................................48 
9.2. 
Adverse and Serious Adverse Events .........................................................................48 
9.2.1. 
Adverse Events Definition ..........................................................................................48 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
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18 July 2022 
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9.2.1.1. 
Adverse Event Reporting and Follow-up ...................................................................49 
9.2.1.2. 
Grading of Adverse Event ..........................................................................................49 
9.2.1.3. 
Causality Relationship of Adverse Event ...................................................................50 
9.3. 
Serious Adverse Event Definition ..............................................................................50 
9.4. 
Disease Progression – Not Reportable as an AE ........................................................51 
9.5. 
SAE Reporting and Follow-up ...................................................................................51 
9.5.1. 
Expedited Reporting of Serious Adverse Events ........................................................52 
9.5.2. 
Pregnancy ...................................................................................................................52 
10. 
STATISTICS ..............................................................................................................53 
10.1. 
General Considerations ...............................................................................................53 
10.2. 
Determination of Sample Size ....................................................................................53 
10.3. 
Replacement of Patients .............................................................................................53 
10.4. 
Analysis Sets ...............................................................................................................54 
10.5. 
Planned Analyses ........................................................................................................54 
10.5.1. 
Demographics and Baseline Characteristics ...............................................................54 
10.5.2. 
Subject Disposition .....................................................................................................54 
10.5.3. 
Safety ..........................................................................................................................54 
10.5.4. 
Efficacy .......................................................................................................................55 
10.5.5. 
Immunogenicity ..........................................................................................................55 
10.5.6. 
Pharmacokinetics ........................................................................................................55 
10.6. 
Concomitant Medications ...........................................................................................56 
10.7. 
Missing Data ...............................................................................................................56 
11. 
STUDY TERMINATION ..........................................................................................57 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58 
12.1. 
Changes to the Protocol ..............................................................................................58 
12.2. 
Monitoring ..................................................................................................................58 
12.3. 
Data Protection ...........................................................................................................58 
12.4. 
Audits and Inspections ................................................................................................58 
13. 
ETHICS ......................................................................................................................59 
13.1. 
IRB/IEC Approval ......................................................................................................59 
13.2. 
Written Informed Consent ..........................................................................................59 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................60 
14.1. 
Study Records .............................................................................................................60 


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14.2. 
Data Collection Instruments .......................................................................................60 
14.3. 
Retention of Records ..................................................................................................60 
15. 
FINANCIAL DISCLOSURE .....................................................................................61 
16. 
PUBLICATION POLICY ..........................................................................................62 
17. 
APPENDICES ............................................................................................................63 
APPENDIX A INTERNATIONAL MYELOMA WORKING GROUP (IMWG) 
CRITERIA FOR THE DIAGNOSIS OF MULTIPLE MYELOMA .........................63 
APPENDIX B ORGAN INVOLVEMENT AND RESPONSE CRITERIA ..............................66 
APPENDIX C HEMATOLOGIC RESPONSE AND RESPONSE CRITERIA ........................67 
APPENDIX D NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION ....................................................................................................68 
APPENDIX E  COVID-19 RISK ASSESSMENT ........................................................................69 
APPENDIX F  COVID VACCINE RISK ASSESSMENT ..........................................................71 
18. 
REFERENCES ...........................................................................................................72 
 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 13 of 73 
LIST OF TABLES 
Table 1: 
CAEL101-203 Schedule of Assessments (Parts A and B) .........................................23 
Table 2: 
Staging of AL Amyloidosis with Advanced Cardiac Involvement for 
CARES Studies based on the European Modification of the 2004 Mayo 
Staging (Palladini, 2016), adapted with (Muchtar, 2019)* ........................................37 
Table 3: 
CAEL101-203 Cohort Dose Assignment (Part A) .....................................................39 
Table 4: 
CAEL101-203 Cohort Dose Increase Guide ..............................................................39 
Table 5: 
CAEL101-203 Clinical Laboratory Tests ...................................................................48 
Table 6:  
IMWG Plasma Cell Disorders ....................................................................................63 
Table 7: 
Potential Operational Risks and Mitigation Measures due to COVID-19 .................69 
Table 8: 
Potential Operational Risks and Mitigation Measures due to COVID-19 
Vaccine .......................................................................................................................71 
 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
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18 July 2022 
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LIST OF FIGURES 
Figure 1: 
CAEL101-203 Part A Dose Selection Schema ..........................................................21 
Figure 2: 
CAEL101-203 Part A Cohort Schema Dose Selection ..............................................22 
Figure 3: 
CAEL101-203 Part B Schema ....................................................................................22 
Figure 4: 
Composite Hematologic and Organ Response Model (Sidana, 2020) .......................30 
 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 15 of 73 
ABBREVIATIONS 
Abbreviation or Term 
Definition 
AAS 
ADA Analysis Set 
ADA 
anti-drug antibodies 
AE 
adverse event 
AL 
light chain associated, primary amyloidosis 
ALECT2 
leukocyte chemotactic factor 2 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CRF 
case report form 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
Ctrough 
lowest concentration of drug before the next dose 
CyBorD 
cyclophosphamide-bortezomib-dexamethasone 
dFLC 
involved/uninvolved free light chain difference  
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FLC 
free light chain 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
ICD 
implantable cardioverter-defibrillator 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IMWG 
International Myeloma Working Group 
IRB 
institutional review board 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
mmHg 
millimeters mercury 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
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18 July 2022 
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Abbreviation or Term 
Definition 
MUGA 
multigated acquisition scan 
NT-proBNP 
b-type natriuretic peptide and N-terminal pro b-type natriuretic 
peptide 
PCD 
plasma cell dyscrasia 
PK 
pharmacokinetics  
q1wk 
every week 
q2wk 
every two weeks 
q4wk 
every four weeks 
RP3D 
recommended phase 3 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SoC 
standard of care 
SPEP 
serum protein electrophoresis 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WOCBP 
women of child-bearing potential 


Protocol Amendment 3.0 CAEL101-203 Phase 2 
 
 
 
 
 
 
 
 
CAEL-101 
Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 July 2022 
Page 17 of 73 
1. 
SYNOPSIS 
Name of Sponsor/Company: Alexion Pharmaceuticals, Inc. 
Name of Investigational Product: CAEL-101  
Name of Active Ingredient: CAEL-101 is chimeric fibril-reactive monoclonal antibody 11-1F4 
Title of Study: A Phase 2, Open-Label, Multicenter Dose Selection Study to Evaluate the Safety and 
Tolerability of CAEL-101 in Patients with AL Amyloidosis 
Study center(s): Approximately 3 US investigational centers will participate 
Number of patients: Approximately 25 
Phase of development: 2 
Objectives:  
The primary objective is:  
• 
To define the safety and tolerability of CAEL-101 and determine the recommended Phase 3 
dose (RP3D) for patients with amyloid light-chain (AL) amyloidosis 
Secondary objectives in this study are: 
• 
To define the safety and tolerability of CAEL-101 when administered in combination with 
standard of care (SoC) cyclophosphamide, bortezomib, dexamethasone (CyBorD)  
• 
To define the safety tolerability of CAEL-101 when administered in combination with SoC 
CyBorD and daratumumab 
• 
To describe the pharmacokinetic (PK) profile of CAEL-101 and to explore the PK profile of 
CAEL-101 when given bi-weekly (q2wk) versus once-monthly (q4wk) after the first 50 weeks. 
The exploratory objective is: 
• 
To assess the efficacy of CAEL-101 in terms of cardiac, liver, and renal response in patients 
with AL amyloidosis. 
Study Design and Duration 
This is a multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage 
I, Stage II and Stage IIIa AL amyloidosis patients. CAEL-101 will be administered in combination 
with the SoC CyBorD chemotherapy and daratumumab.  
The study is divided into two parts:  
- 
Part A defines the safety and tolerability of CAEL-101 in combination with SoC CyBorD and 
determines the RP3D 
- 
Part B evaluates the safety and tolerability of CAEL-101 in combination with SoC CyBorD and 
daratumumab 
Part A 
Part A consists of a Screening period, a safety and tolerability Treatment period and an End of 
Treatment period. The Treatment period of Part A, the part where the RP3D is determined, is divided 
into a Dose Limiting Toxicity (DLT) Observation period and a Continued Treatment period. During 
the DLT Observation period, patients will be seen in the clinic every week (q1wk) for 4 weeks to 
receive study drug infusions and be assessed for DLTs.  
The first CAEL-101 dose to be studied in Part A, 500 mg/m2, was determined based on the completed 
study CAEL101-101. 


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The initial cohort dose assignments in Part A will be: Cohort 1 500 mg/m2, Cohort 2 750 mg/m2 and 
Cohort 3 1000 mg/m2. 
DLT Observation period to determine the RP3D 
Part A of the study will employ a 3+3 dose escalation design. At least 3 patients will be enrolled in 
each dose cohort unless adverse events (AEs) preventing further dosing are observed. Enrollment into 
a new cohort with a higher dose of CAEL-101 cannot begin until the DLT observation period has 
completed for the last patient enrolled in the previous cohort. 
If 0 out of 3 patients experience a DLT during the DLT observation period, the next dose cohort will 
be opened. If 1 out of 3 patients experience a DLT during the DLT observation period, the cohort may 
be expanded to 6 patients. If no further patients in the expanded cohort experience a DLT during the 
DLT observation period (i.e., 1 out of 6 patients experiences a DLT), increase to the next dose may 
take place. If 2 or more patients in a cohort experience a DLT during the DLT observation period, 
further dose increase will cease. New patients will be enrolled at the lower (tolerated) dose level if only 
3 patients were previously enrolled in that cohort. The recommended dose will require at least 6 
patients treated with CAEL-101 at that dose and ≤ 1 patient having experienced a DLT during the DLT 
observation period. Based on clinical safety and laboratory data, the safety review team (Sponsor and 1 
or more Investigators) may direct that an intermediate dose between the dose demonstrating the DLT 
and the previously documented safe dose may be explored, or a different dosing regimen starting at a 
lower dose be explored. Dose increases may be discontinued based on safety or PK findings that may 
influence the decision about a recommended dose. 
The Sponsor and at least one Investigator will jointly decide the following: 
• 
Dose increases in the next cohort and/or dose schedule 
• 
Recommended Phase 3 dose  
• 
Dose reductions based on severity, duration and frequency of toxicities observed at the 
previous dose level 
The Sponsor may choose to evaluate CAEL-101 in additional patients and at other/higher doses and 
dosing schedules to further assess the PK profile, the benefit/risk profile and/or based on the safety 
findings from ongoing CAEL-101 clinical trials. 
All patients will remain on the dose level assigned to the cohort in which they were originally enrolled 
until a RP3D is identified. When the RP3D is identified, all patients will be changed to the RP3D. Part 
B will commence after the RP3D has been identified and enrolled patients have been changed to the 
RP3D. 
Part B 
Part B consists of a Screening period, a safety and tolerability Treatment period and an End of 
Treatment period. The Treatment period of Part B is divided into a Safety Observation period and a 
Continued Treatment period. During the Part B Safety Observation period, new patients will be seen in 
the clinic q1wk for 4 weeks to receive study drug infusions and have various safety assessments. A 
minimum of 6 new patients will receive CAEL-101 administered in combination with SoC CyBorD 
and daratumumab. Once the newly enrolled patients have completed the Safety Observation period, 
patients from Part A who are in the Continued Treatment Period and who, in the Investigator’s 
judgment, should have their SoC treatment complemented with daratumumab may do so. 
Continued Treatment Period 
Patients from both Parts A and B will continue receiving CAEL-101 therapy and SoC. CAEL-101 
study drug infusions will continue, with dosing approximately every two weeks (q2wk). After 
completing approximately 50 weeks of treatment, participants may switch to an alternative 
maintenance dosing regimen of every four weeks (q4wk), and then start following the assessment 


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pattern of V29-V25-V27-V29-V25 and so on. The option of treatment switching from bi-weekly 
(q2wk) to once every 4 weeks (q4wk) should be agreed between the Investigator and the Sponsor 
Medical Monitor and based on the assessment of the combined hematological and organ responses as 
per the scoring system proposed by Sidana et al. (Sidana, 2020). Switching could be considered if the 
score is within the range of 0 to 3. Approximately every month or every visit as noted in the Schedule 
of Assessments, patients will be assessed for changes in free light chains (FLC), 24-hour urine protein, 
PK and immunogenicity tests. Approximately every 90 days from the first dose of study drug, all 
patients will be assessed for safety and changes in B-type natriuretic peptide and N-terminal pro b-type 
natriuretic peptide (NT-proBNP). Patients with cardiac AL amyloidosis will be assessed for changes in 
cardiac troponin T (cTnT)/cardiac troponin I (cTnI). 
Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator 
decision, patient decision or Sponsor decision to terminate the study. 
End of Treatment Period 
Patients from both Part A and Part B who discontinue from the study should have the End of 
Treatment assessments completed as indicated in the Schedule of Assessments. 
Investigational product, dosage and mode of administration: 
CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. 
Study Population: 
Eligible patients for both Part A and Part B will meet the same inclusion and exclusion criteria, except 
as noted. 
Key Inclusion Criteria: 
1. AL amyloidosis Mayo stage I, II or IIIa 
2. For Part A only, measurable hematologic disease defined by at least one of the following: 
a. 
involved/uninvolved free light chain difference (dFLC) > 5mg/dL or 
b. free light chain (FLC) > 5mg/dL with abnormal Kappa/Lambda ratio or  
c. 
serum protein electrophoresis (SPEP) m- spike > 0.5 g/dL  
Patients with confirmed AL amyloid diagnosis without measurable disease may be enrolled with 
consultation and approval by the Sponsor Medical Monitor or their designee. 
3. a. For Part A, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD 
administered weekly as SoC. 
b. For Part B, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD 
and daratumumab administered as SoC. 
Key Exclusion Criteria: 
1. Any form of secondary, hereditary, senile, localized, dialysis related or ALECT2 amyloidosis 
2. Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma. Patients 
with signs and/or symptoms attributable ONLY to amyloidosis and who do NOT meet IMWG definition 
of smoldering myeloma may be enrolled upon approval of the medical monitor. 
3. Supine systolic blood pressure < 90 millimeter of mercury (mmHg), or symptomatic orthostatic 
hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mmHg despite 
medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion 
4. Receiving dialysis 


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5. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
percutaneous cardiac intervention with recent stent, coronary artery bypass grafting or major 
cerebrovascular accident within 6 months prior to screening  
6. Left ventricular ejection fraction (LVEF) < 45% by echocardiogram or multigated acquisition scan 
(MUGA) 
Statistical methods: 
Safety 
Safety assessments will include AEs, clinical laboratory tests, vital signs, physical examinations and 
electrocardiograms (ECGs). The incidence of DLTs will be evaluated for each dose escalation cohort. 
All treatment-emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred term for each dose cohort. All TEAEs will be summarized by incidence, severity and 
potential causality to study drug. 
Clinical laboratory tests and vital signs will be summarized descriptively for each dose cohort. All 
abnormal findings in clinical laboratory test results, vital signs, physical examinations and ECGs will 
be listed. 
Pharmacokinetics 
PK parameters will be tabulated and summarized with descriptive statistics by cohort and/or study part. 
Patients in Part A who discontinue for non-safety reasons may be replaced. 
Efficacy 
Efficacy endpoints, including NT-proBNP, cTnT/cTnI, proteinuria, will be assessed for absolute 
changes (and percent changes) over time. Patients with organ involvement (eg, cardiac, renal) will be 
identified at baseline through minimum thresholds for each relevant biomarker and defined as being 
Cardiac Evaluable, Renal Evaluable, etc, accordingly. These specific analysis populations will then be 
assessed for changes over time in the organ-specific biomarkers. Patients may be classified as 
responders (by organ) according to varying definitions of response, eg, for NT-proBNP, a decrease of 
30% may be defined as one type of cardiac responder. As this analysis is exploratory, various 
definitions may be used to allow for a thorough understanding of the treatment benefit over time. 
Organ-specific outcomes for renal, hepatic, and cardiac biomarker response from pre-CAEL-101 
treatment will be collected retrospectively and prospectively. The retrospective collection may include 
a review of the patient record at the site. Further, prospective collection of these data has been added to 
collect future organ response outcomes. The combination of retrospective and prospective data 
collection will allow for a more robust determination of the effects of CAEL-101 on efficacy in these 
patients. 
 
 


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1.1. 
Study Schematics 
Figure 1: 
CAEL101-203 Part A Dose Selection Schema 
 
 
 


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Figure 2: 
CAEL101-203 Part A Cohort Schema Dose Selection 
 
 
Note:  There are 3 cohorts in Part A: 500, 750 and 1000 mg/m2   
Abbreviations: DLT – dose limiting toxicity; q1wk – every week; q2wk – every two weeks 
 
 
Figure 3: 
CAEL101-203 Part B Schema 
 
 
Abbreviations: q1wk – every week; q2wk – every two weeks 


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1.2. 
Schedule of Assessments 
Table 1: 
CAEL101-203 Schedule of Assessments (Parts A and B) 
 
Screening DLT/Safety Observation 
Period 
Continued Treatment Period 
EOT 
Visit 
V1 
V2 V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26 V27 V28 V29a 140 d from 
last dose 
Week -3 to 0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50a 
 
Day ≤ 21 days 
prior to V2 1 
8 
15 
22 
29 
36 
50 
64 
78 
92 
106 
120 
134 
148 
162 
176 
190 
204 
218 
232 
246 
260 
274 
288 
302 
316 
330 
344 
14, 28, 56, 
84, 112, & 
140 days 
from last 
dose  
Procedure Window 
 
 
+/- 1 day 
+/- 2 days 
+/- 1 day 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion & exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AL amyloidosis confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Vital signs & weight 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NYHA classificationh 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
X 
Twelve-lead electrocardiogram 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Safety laboratory testsd 
X 
X 
X 
X 
X 
X 
Xe 
Xe 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
24-hour urine protein 
collectionh,j 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Serum Free Light Chains and 
serum and urine 
immunofixation electrophoresish 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Echocardiogramh,j 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xk 
 


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NT-proBNPh 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xi 
X 
cTnT/cTnI/hs-cTnT/hs-cTnI 
(cardiac patients only) 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Immunogenicity testsf 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Study drug infusion 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK samples f, g 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X  
DLT (Part A only) 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
Concomitant medications 
X 
X 
X 


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Table 1: 
CAEL101-203 Schedule of Assessments (Parts A and B) 
a. Once a patient completes V29/Week 50, continue to follow the schedule of assessments repeating the procedures at V24-V29/Weeks 40-50 for as long as the patient remains on study treatment. After completing approximately 50 weeks 
of treatment, participants may switch to an alternative maintenance dosing regimen of every four weeks (q4wk) and then start following the assessment pattern of V29-V25-V27-V29-V25 and so on. The option of treatment switching 
from bi-weekly (q2wk) to once every 4 weeks (q4wk) should be agreed between the Investigator and the Sponsor Medical Monitor and based on the assessment of the combined hematological and organ responses as per the scoring 
system proposed by Sidana et al. (Sidana, 2020), switching could be considered if the score is within the range of 0 to 3 (Figure 4). 
b. The Investigator or a licensed team member, per local regulations, will perform physical examinations. 
c. For women of childbearing potential only, serum human chorionic gonadotropin (hCG) required at screening. Subsequent pregnancy tests may be performed using urine dipstick. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient 
d. Chemistry – ALT, albumin, ALP, AST, BUN, eGFR, calcium, chloride, creatinine, GGT, globulin, glucose, phosphorus, potassium, sodium, total bilirubin, total protein, uric acid. Hematology – CBC with differential, RDW, reticulocyte 
count. Urinalysis -- bilirubin, blood, glucose, ketones, leukocytes, pH, protein and specific gravity. Patients in Part B beginning treatment with daratumumab after the Safety Observation period will have weekly CBC with differential 
tests for at least 8 weeks. 
e. For Patients in Part B, only CBC with differential test required on V7 and V8. Patients should also have a CBC with differential test performed on Week 7/Day 43. 
f. Collect PK and immunogenicity tests (pre-dose within 1 hour of the start of the infusion) every other visit (i.e., every 28 days +/- 2d) from V15 through V29. After V29/Week 50, samples collected approximately every 182 days and at 
end of treatment. 
g. PK sample times – pre-dose within 1 hour of the start of the infusion and post-dose between 30 minutes and 1 hour from the end of the infusion. PK samples must be drawn from the opposite arm from the CAEL-101 infusion, unless 
approved by the Sponsor. 
h. Ensure that all available assessments have been recorded in the CRF for each visit (detailed above) during the study. Any additional measurements, if already collected at time points other than the pre-defined visits, shall be recorded in 
the CRF. 
i. Past 50 weeks, assessments will be completed approximately every 90 days. 
j. Evaluations obtained after Screening may be within a +/-30 day window from the study day. Evaluations should not be skipped. If the patient cannot undergo an evaluation within the assessment window (e.g., the patient is hospitalized), 
it should be completed as soon as possible. EOT evaluation is required ONLY at 140 days following the last dose of study drug. 
k. Past 50 weeks, assessment will be completed every 12 months 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Amyloidosis is a rare and serious heterogeneous group of diseases characterized by fibrillar 
protein deposits and amyloids localized in a single organ or systematically in many organs 
(Hemminki, 2012). Amyloid light-chain (AL) amyloidosis is the most common form of systemic 
amyloid disease, accounting for approximately 70% of all subjects suffering from the disease 
(Milani, 2018). All organs, except for the brain, can be affected in AL amyloidosis leading to 
irreversible organ dysfunction and death if unrecognized or treated ineffectively (Milani, 2018). 
The disease is inevitably progressive and accumulating amyloid protein deposits interfere with 
the tissue or organ’s healthy function causing clinical symptoms, organ failure and death. Thirty 
to 40% of patients die within 12 months of diagnosis (Dispenzieri, 2015a). The prognosis is very 
poor, with less than 5% of all subjects with AL amyloidosis surviving more than 10 years after 
diagnosis (Kyle, 1986; Palladini, 2017; Palladini, 2015). The prognosis of patients with AL 
amyloidosis depends on the burden of the amyloid in the tissues, especially the heart, and the 
size of the plasma cell clone and its biology, which predict the ability to achieve a hematologic 
response. 
Treatment of AL amyloidosis is largely based on chemotherapy and/or autologous stem cell 
transplants and are targeted to eradicate the pathologic plasma cells and stop the production of 
new amyloid and the resulting fibrils. There are no approved treatments for organ-deposits of AL 
amyloidosis, and the only available options for patients is to be treated with experimental 
treatments, most often in clinical trials (Dispenzieri, 2015a; Palladini, 2018). Subjects suffering 
from AL amyloidosis are at high risk of death and are extremely susceptible to treatment toxicity 
in the first few months after diagnosis. Whereas, if they survive this initial treatment, they enjoy 
a better long-term outcome (Dispenzieri, 2013). There is a high unmet need for a therapeutic 
treatment that removes existing amyloid deposits to limit and reverse organ dysfunction. 
2.2. 
CAEL-101 
CAEL-101 (Ch11-1F4, NSC-711516), is a chimeric immunoglobulin G1 kappa isotype version 
of m11-1F4, the parent murine monoclonal antibody of CAEL-101, which binds to a cryptic 
epitope at the N-terminal of both κ and λ light chain proteins that adopt a non-native structure. 
CAEL-101 was found to react with specificity in a conformation-dependent manner with light 
chain components in amyloid fibrils, but not with free non-amyloid light chains. 
The first in human experience with CAEL-101 was study protocol CAEL101-101, in which 
doses from 0.5 mg/m2 up to 500 mg/m2 were tested for safety and tolerability in both single-dose 
and multi-dose regimens. No dose-limiting toxicities (DLTs) were observed in that dose range, 
including up to the maximum dose of 500 mg/m2. 
The primary objective of this study was to describe the safety and tolerability of CAEL-101 in 
combination with cyclophosphamide-bortezomib-dexamethasone (CyBorD) and to determine the 
recommended Phase 3 dose during an initial 14-day (Cohort 1) or 27-day (Cohorts 2 and 3) 
treatment and follow-up period (referred to as the Dose-Limiting Toxicity, ie, DLT, Observation 
period). 


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This assessment has been completed, with all three tested dose levels of CAEL-101 
(500, 750, and 1000 mg/m2), when administered with concurrent CyBorD, found to be safe and 
well-tolerated by the patients enrolled. No dose-limiting toxicities were observed in any patients 
at any of these dose levels during the DLT Observation period. Based on these safety and 
tolerability data, and protocol guidance, the final cohort review by the study site Principal 
Investigator and the Sponsor Medical Monitor concluded that the 1000 mg/m2 dose is 
recommended for the Phase 3 studies. 
The pharmacokinetic (PK) review of the three CAEL-101 dose levels showed that PK exposure 
increases in a generally linear manner with increasing dose over the studied dose range. In 
addition to overall exposure levels, dose selection included assessment of target receptor site 
occupancy for the patient with the lowest exposure levels (Ctrough) (with a minimum of 90% 
receptor site occupancy desired). To support the broadest range of patients and to account for 
patient exposure variability, the 1000 mg/m2 dose fulfills these requirements and achieves the 
desired Ctrough levels after the second dose.  
Therefore, based on safety, tolerability outcomes and pharmacokinetics, the 1000 mg/m2 dose 
was selected for use in the Phase 3 studies, CAEL101-301 and CAEL101-302, as well as in 
Part B of this study.  
Refer to the CAEL-101 Investigator’s Brochure for detailed preclinical and clinical study data. 


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3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
The primary objective in this study is to define the safety and tolerability of CAEL-101 and 
determine the recommended Phase 3 dose (RP3D) for patients with AL amyloidosis. 
3.2. 
Secondary Objectives 
The secondary objectives in this study are to: 
• define the safety and tolerability of CAEL-101 when administered in combination with 
standard of care (SoC) CyBorD  
• define the safety and tolerability of CAEL-101 when administered in combination with 
SoC CyBorD and daratumumab 
• describe the PK profile of CAEL-101 and to explore the PK profile of CAEL-101 when 
given bi-weekly (q2wk) versus once-monthly (q4wk) after the first 50 weeks. 
3.3. 
Exploratory Objective 
The exploratory objective in this study is to assess the efficacy of CAEL-101 in terms of cardiac, 
liver, and renal response in patients with AL amyloidosis. 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo 
Stage I, Stage II and Stage IIIa AL amyloidosis patients. CAEL-101 will be administered in 
combination with SoC CyBorD chemotherapy and daratumumab. 
The study is divided into two parts: 
− Part A defines the safety and tolerability of CAEL-101 in combination with SoC 
CyBorD and determines the RP3D 
− Part B evaluates the safety and tolerability of CAEL-101 in combination with SoC 
CyBorD and daratumumab 
Part A 
Part A consists of a Screening period, a safety and tolerability Treatment period and an End of 
Treatment period. The Treatment period of Part A, the part where the RP3D is determined, is 
divided into a DLT Observation period and a Continued Treatment period. During the DLT 
Observation period, patients will be seen in the clinic every week (q1wk) for 4 weeks to receive 
study drug infusions and be assessed for DLTs. 
Part A of the study will employ a 3+3 dose escalation design. At least 3 patients will be enrolled 
in each dose cohort unless adverse events (AEs) preventing further dosing are observed. 
Enrollment into a new cohort with a higher dose of CAEL-101 cannot begin until the DLT 
observation period has completed for the last patient enrolled in the previous cohort. 
The recommended dose will require at least 6 patients treated with CAEL-101 at that dose and 
≤ 1 patient having experienced a DLT during the DLT observation period. Dose increases may 
be discontinued based on safety or PK findings that may influence the decision about a 
recommended dose. 
All patients will remain on the dose level assigned to the cohort in which they were originally 
enrolled until an RP3D is identified. When the RP3D is identified, all patients will be changed to 
the RP3D. Part B will commence after the RP3D has been identified and enrolled patients have 
been changed to the RP3D. 
Part B 
Part B consists of a Screening period, a safety and tolerability Treatment period and an End of 
Treatment period. The Treatment period of Part B is divided into a Safety Observation period 
and a Continued Treatment period. During the Part B Safety Observation period, new patients 
will be seen in the clinic q1wk for 4 weeks to receive study drug infusions and have various 
safety assessments. A minimum of 6 new patients will receive CAEL-101 administered in 
combination with SoC CyBorD and daratumumab. 


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Continued Treatment Period 
Patients from both Parts A and B will continue receiving CAEL-101 therapy and SoC. 
CAEL-101 study drug infusions will continue, with dosing approximately every two weeks 
(q2wk). 
After completing approximately 50 weeks of treatment, participants may switch to an alternative 
maintenance dosing regimen of every four weeks (q4wk), and then start following the 
assessment pattern of V29-V25-V27-V29-V25 and so on. The option of treatment switching 
from bi-weekly (q2wk) to once every 4 weeks (q4wk) should be agreed between the Investigator 
and the Sponsor Medical Monitor and based on the assessment of the combined hematological 
and organ responses as per the scoring system proposed by Sidana et al. (Sidana, 2020). 
Switching could be considered if the score is within the range of 0 to 3 (Figure 4). 
 
Figure 4: 
Composite Hematologic and Organ Response Model (Sidana, 2020) 
 
 
End of Treatment Period 
Patients from both Part A and Part B who discontinue from the study should have the End of 
Treatment assessments completed as indicated in the Schedule of Assessments. 
Schematics of the study design are presented in Figure 1, Figure 2, and Figure 3 while the 
Schedule of Assessments is presented in Table 1. 
4.2. 
Number of Patients 
Approximately 25 patients will be enrolled in the study. Part A enrolled approximately 13 
patients. 


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For Part B, a minimum of 6 newly enrolled patients are expected to receive CAEL-101 
administered in combination with SoC CyBorD and daratumumab. Once the newly enrolled 
patients have completed the Safety Observation period, patients from Part A who are in the 
Continued Treatment Period and who, in the Investigator’s judgment, should have their SoC 
treatment complemented with daratumumab may do so. 


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5. 
SELECTION OF STUDY POPULATION 
5.1. 
Patient Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1. Provide written informed consent and be willing and able to comply with all study 
procedures 
2. Adult, 18 years and older 
3. Minimum life expectancy of 6 months 
4. AL amyloidosis Mayo stage I, II, or IIIa at the time of Screening 
5. For Part A only, measurable hematologic disease defined by at least one of the following: 
a. dFLC > 5mg/dL or 
b. FLC > 5mg/dL with abnormal Kappa/Lambda ratio or 
c. SPEP m- spike > 0.5 g/dL  
Patients with confirmed AL amyloid diagnosis without measurable disease may be 
enrolled with consultation and approval by the Sponsor Medical Monitor or their 
designee. 
6. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry 
and polarizing light microscopy of green bi-refringent material in Congo red stained 
tissue specimens (in an organ other than bone marrow) or characteristic electron 
microscopy appearance 
7. a. For Part A, currently on and continuing OR planned to start concurrent chemotherapy 
with CyBorD administered weekly as SoC. Mayo stage IIIa patients will not have 
received CyBorD for more than 3 months at the time of first dose of CAEL-101. 
b. For Part B, currently on and continuing OR planned to start concurrent chemotherapy 
with CyBorD and daratumumab administered as SoC. Mayo stage IIIa patients will not 
have received CyBorD for more than 3 months at the time of first dose of CAEL-101. 
8. Adequate bone marrow reserve and hepatic function as demonstrated by: 
a. Absolute neutrophil count ≥ 1.5 x10^9/L 
b. Platelet count ≥ 75 x 10^9/L 
c. Hemoglobin ≥ 9 g/dL 
d. Total bilirubin ≤ 2 times the upper limit of normal (x ULN) 
e. Aspartate aminotransferase (AST) ≤ 3 x ULN 
f. Alanine aminotransferase (ALT) ≤ 3 x ULN 
g. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly and 
isozymes specific to liver, rather than bone) 
9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
during Screening and must agree to use highly effective contraception (Section 6.10) 
from Screening to at least 5 months following the last study drug administration or 12 
months following the last dose of her plasma cell dyscrasia (PCD) therapy, whichever is 
longer 


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10. Men must be surgically sterile or must agree to use highly effective contraception 
(Section 6.10) and refrain from donating sperm from Screening to at least 5 months 
following the last study drug administration or 12 months following the last dose of their 
PCD therapy, whichever is longer 
5.2. 
Patient Exclusion Criteria 
Patients who meet any of the following criteria will not be permitted entry to the study. 
1. Any form of secondary, hereditary, senile, localized, dialysis-related or leukocyte 
chemotactic factor 2-related (ALECT2) amyloidosis 
2. Meets the International Myeloma Working Group (IMWG) definition of multiple 
myeloma (Appendix A). Patients with signs and/or symptoms attributable ONLY to 
amyloidosis and who do NOT meet IMWG definition of smoldering myeloma may be 
enrolled upon approval of the medical monitor. 
3. Supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, 
defined as a decrease in systolic blood pressure upon standing of > 20 mmHg despite 
medical management (e.g., midodrine, fludrocortisones) in the absence of volume 
depletion 
4. Taking prednisone or its equivalent > 10 mg/day 
5. Receiving dialysis 
6. Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell 
collection during the protocol therapy is permitted 
7. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
or percutaneous cardiac intervention with recent stent, coronary artery bypass grafting or 
major cerebrovascular accident within 6 months prior to screening  
8. Left ventricular ejection fraction (LVEF) < 45% by echocardiogram or multigated 
acquisition scan (MUGA) within the last 6 months 
9. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or 
severe congenital heart disease 
10. History of sustained ventricular tachycardia or aborted ventricular fibrillation or with a 
history of atrioventricular nodal or sinoatrial nodal dysfunction for which a 
pacemaker/implantable cardioverter-defibrillators (ICD) is indicated but not placed 
(participants who do have a pacemaker/ICD are allowed on study) 
11. QTcF > 500 msec. Participants who have a pacemaker may be included regardless of 
calculated QTc interval. 
12. Evidence of acute ischemia or active conduction system abnormalities with the exception 
of any of the following: 
a. First degree AV-block 
b. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) 
c. Right or left bundle branch block 


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d. Atrial fibrillation with a controlled ventricular rate (uncontrolled [i.e., >110 bpm] 
ventricular rate is not allowed [determined by an average of three beats in Lead II or 
representative beats if Lead II is not representative of the overall electrocardiogram 
{ECG}]) 
13. Major surgery within 4 weeks of first dose or planned major surgery during the study. 
Patients with surgical procedures conducted under local anesthesia may participate. 
14. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein [M-protein] and skin changes) (Appendix A) 
15. Active malignancy (including lymphoma) with the exception of any of the following: 
a. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical 
cancer 
b. Adequately treated Stage I cancer from which the patient is currently in remission and 
has been in remission for > 2 years 
c. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen 
< 10 ng/mL 
16. Patients receiving an investigational drug/device in another clinical investigational study 
within 60 days before Screening. 
17. Nursing mothers will not be permitted entry into the study. 
5.3. 
Continuation and Withdrawal Criteria 
Any patient receiving clinical benefit from the administration of CAEL-101 (as determined by 
the Investigator) in the absence of unacceptable toxicity will be allowed to remain on the study 
and should continue to receive CAEL-101 per protocol. 
Patient participation in this clinical study may be discontinued for any of the following reasons: 
• The patient withdraws consent or requests discontinuation from the study for any reason 
• Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol 
• Any serious adverse event (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition which indicates to the 
Investigator that continued participation in the study is not in the best interest of the 
patient 
• Pregnancy 
• Requirement of a prohibited concomitant medication 
• Patient failure to comply with protocol requirements or study-related procedures 
• Termination of the study by the Sponsor or the regulatory authority 
If the patient withdraws prematurely from the study, the Investigator will promptly notify the 
Sponsor and ensure every effort is made to complete the full panel of End of Treatment (EOT) 
assessments specified in the Schedule of Assessments (see Table 1).  


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In the event a patient is lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical record.  


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6. 
TREATMENT PLAN 
The study is divided into two parts:  
− Part A evaluates the safety and tolerability of CAEL-101 in combination with SoC 
CyBorD and determines the RP3D 
− Part B evaluates the safety and tolerability of CAEL-101 in combination with SoC 
CyBorD and daratumumab 
Part A consists of a Screening period, a Treatment period and an End of Treatment period. The 
Treatment period of Part A, the part where the RP3D is determined, is divided into a DLT 
Observation period and a Continued Treatment period. During the DLT Observation period, 
patients will be seen in the clinic q1wk for 4 weeks to receive study drug infusions and be 
assessed for DLTs. 
Part B consists of a Screening period, a Treatment period and an End of Treatment period. The 
Treatment period of Part B is divided into a Safety Observation period and a Continued 
Treatment period. During the Safety Observation period, new patients will be seen in the clinic 
q1wk for 4 weeks to receive study drug infusions and have various safety assessments. A 
minimum of 6 new patients will receive CAEL-101 administered in combination with SoC 
CyBorD and daratumumab. Once the newly enrolled patients have completed the Safety 
Observation period, patients from Part A who are in the Continued Treatment Period and who, in 
the Investigator’s judgment, should have their SoC treatment complemented with daratumumab 
may do so. 
During the Continued Treatment period for Part A and Part B, patients will receive study drug 
infusions approximately q2wk. Approximately every month or every visit as noted in the 
Schedule of Assessments, patients will be assessed for changes in FLC, 24-hour urine protein, 
PK and immunogenicity tests. Approximately every 90 days from the first dose of study drug, all 
patients will be assessed for safety and changes in B-type natriuretic peptide and N-terminal pro 
b-type natriuretic peptide (NT-proBNP). Patients with cardiac AL amyloidosis will be assessed 
for changes in cardiac troponin T (cTnT)/cardiac troponin I (cTnI). 
Every effort should be made to schedule visits within the protocol-specified windows. Refer to 
the Schedule of Assessments in Table 1 for the list and timing of assessments. 
6.1. 
Screening Period 
The Screening Period is the same for Part A and for new patients enrolling in Part B. Patients 
will provide written informed consent to participate in this study before completing any 
protocol-specified procedures or evaluations not considered to be part of the patient’s SoC. 
Patients will be eligible to enter the Screening period if they have a clinical diagnosis of Stage I, 
II or IIIa AL amyloidosis consistent with the 2013 modifications to the 2004 Mayo staging 
criteria (Table 2) at the time of Screening. One Stage I patient will be permitted to enroll per 
cohort in Part A and a maximum of two Stage I patients will be permitted to enroll in Part B. 


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Table 2: 
Staging of AL Amyloidosis with Advanced Cardiac Involvement for CARES 
Studies based on the European Modification of the 2004 Mayo Staging 
(Palladini, 2016), adapted with (Muchtar, 2019)* 
Stage I 
Stage II 
Stage IIIa 
Stage IIIb 
Zero markers above 
threshold: 
• NT-proBNP < 332 
ng/L 
AND one of the 
following:  
• hs-cTnT < 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≤ 0.035 ng/mL 
• cTnI ≤ 0.1 ng/mL 
One marker above 
threshold: 
• NT-proBNP ≥ 332 ng/L 
OR one of the following 
• hs-cTnT ≥ 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≥ 0.035 ng/mL 
• cTnI ≥ 0.1 ng/mL 
Two markers above 
threshold: 
• 332 ng/L ≤ NT-proBNP 
≤ 8,500 ng/L 
AND one of the following: 
• hs-cTnT ≥ 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≥ 0.035 ng/mL 
• cTnI ≥ 0.1 ng/mL 
Two markers 
above threshold: 
• NT-proBNP > 
8,500 ng/L 
AND one of the 
following: 
• hs-cTnT ≥ 50 
pg/mL 
(0.05 ng/mL) 
• cTnT ≥ 0.035 
ng/mL 
• cTnI ≥ 0.1 
ng/mL 
* The 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac 
involvement is based on the conventional (generation 4) cTnT assay. However, high sensitivity cardiac troponin 
(hs-cTnT), or generation 5 assay, is becoming more widely available and is used more commonly in clinical 
practice. It is established that a cTnT value of > 0.035 ng/mL can be extrapolated to a hs-cTnT value of 
≥ 50 pg/mL (0.05 ng/mL) for the determination of Mayo stage (Muchtar, 2019).  
Abbreviations: cTnI – cardiac troponin I, cTnT – cardiac troponin T, hs-cTnT – high sensitivity cardiac troponin T, 
NT-proBNP – N-terminal pro b-type natriuretic peptide 
After signing the informed consent form (ICF), patients will be evaluated for entry criteria 
during the Screening period (within 21 days before administration of the study drug). Screening 
assessments with abnormal results may be repeated at the discretion of the Investigator. 
6.2. 
Treatment Period 
Patients in both Part A and Part B of the study, who meet all of the inclusion criteria and none of 
the exclusion criteria will be treated with CAEL-101 plus CyBorD chemotherapy (and 
daratumumab in Part B) until death, unacceptable toxicity, symptomatic deterioration, 
Investigator decision (see Section 6.2.2 for allowed changes to CyBorD regimen), patient 
decision or Sponsor decision to terminate the study. All patients in Parts A and B will receive 
CAEL-101 q1wk (+/-1d) for the first 4 infusions. During the Continued Treatment period, 
patients will receive CAEL-101 q2wk (+/-2d). After completing approximately 50 weeks of 
treatment, participants may switch to an alternative maintenance dosing regimen of every four 
weeks (q4wk), and then start following the assessment pattern of V29-V25-V27-V29-V25 and so 
on. The option of treatment switching should be agreed between the Investigator and the Sponsor 
Medical Monitor and based on the assessment of the combined hematological and organ 
responses as per the scoring system proposed by Sidana et al. (Sidana, 2020) Switching could be 
considered if the score is within the range of 0 to 3 (Figure 4). 


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6.2.1. 
Administration of Study Drug 
In Part A, each patient’s CAEL-101 dose will be determined by the CAEL101-203 Dose 
Assignment scheme (see Table 3) and the patient’s body surface area in meters squared. 
In Part B, patients will receive the RP3D. When administered on the same day, CAEL-101 will 
be administered first before CyBorD chemotherapy or daratumumab. Patients will receive 
CAEL-101 by an IV infusion over approximately 2 hours q1wk (+/-1d) for 4 infusions then 
q2wk (+/-2d) thereafter. Patients will be observed in the clinic for 90 minutes, or as long as the 
Investigator deems appropriate, following the completion of the study drug infusion for the first 
4 infusions for infusion reactions, injection site reactions and overall well-being of the patient 
(may include vital signs at the Investigator’s discretion). 
Every effort should be made to assure the patient receives CAEL-101 according to the Schedule 
of Assessments (see Table 1). All doses of study drug should be administered on schedule based 
on the first dose received. For example, if dose 2 (V3) is administered on study day 8, dose 3 
(V4) should still be administered on study day 14 (+/-1d). If the patient misses a dose entirely, 
the Investigator must contact the Medical Monitor before resuming dosing. All patients will 
remain on the dose level assigned to the cohort in which they were originally enrolled (Table 3) 
until the RP3D is identified. When the RP3D is identified, all patients will be changed to the 
RP3D. 
Additional details for study drug administration are included in the Pharmacy Manual. 
6.2.2. 
Concurrent Chemotherapy 
In addition to CAEL-101, all patients in Part A will receive concurrent chemotherapy with 
CyBorD according to institutional SoC. Patients may initiate their chemotherapy regimen within 
7 days of the receiving the first dose of CAEL-101 or may be on CyBorD at the time they enroll 
in the study. Patients with Mayo Stage IIIa AL amyloidosis will not have received CyBorD for 
more than 3 months at the time of their first dose of CAEL-101. Patients will receive concurrent 
CyBorD chemotherapy in combination with CAEL-101 throughout the DLT Observation period. 
Once the DLT Observation period is complete and if the patient is not benefiting from or 
tolerating CyBorD in the Investigator’s judgement, the Investigator may change the CyBorD 
regimen or stop it. 
New patients enrolled in Part B will receive concurrent chemotherapy with CyBorD plus 
daratumumab according to institutional SoC along with CAEL-101. Patients may initiate their 
concurrent regimen within 7 days of the receiving the first dose of CAEL-101 or may be on 
CyBorD plus daratumumab at the time they enroll in the study. Patients with Mayo Stage IIIa 
AL amyloidosis will not have received CyBorD for more than 3 months at the time of their first 
dose of CAEL-101. Patients will receive concurrent CyBorD chemotherapy and daratumumab in 
combination with CAEL-101 throughout the Safety Observation period. It is the intent of this 
protocol that patients will receive CyBorD plus daratumumab per institution SoC in the study, as 
long as they are tolerating it. However, after two cycles of CyBorD, if the patient is not 
benefiting from or tolerating CyBorD or daratumumab in the Investigator’s judgment, the 
Investigator may change the regimen or stop it.  
Once the newly enrolled patients in Part B complete the Safety Observation period, 
daratumumab may be added to the SoC treatment regimen for patients in Part A at the 


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Investigator’s discretion. At the start of daratumumab treatment, patients will have additional 
complete blood count (CBC) with differential tests performed for at least 8 weeks to assess any 
changes in blood cell counts.  
Patients in Part A and Part B may be considered for other plasma cell dyscrasia (PCD)-directed 
therapies after consultation with the sponsor Medical Monitor or designee. 
6.2.3. 
Recommended Phase 3 Dose Selection 
Part A of the study will employ a 3+3 dose escalation design. Initial cohort dose assignments are 
described in Table 3 and movement between cohorts will be carried out as listed in Table 4. 
The first CAEL-101 dose to be studied 500 mg/m2 was determined based on the completed study 
CAEL101-101.  
The Sponsor and at least one Investigator will jointly decide the following: 
• Dose increases in the next cohort and/or dose schedule 
• Recommended Phase 3 dose  
• Dose reductions based on severity, duration and frequency of toxicities observed at the 
previous dose level 
Table 3: 
CAEL101-203 Cohort Dose Assignment (Part A) 
Cohort 
CAEL-101 
1 
500 mg/m2 
2 
750 mg/m2 
3 
1000 mg/m2 
Table 4: 
CAEL101-203 Cohort Dose Increase Guide  
Number of Patients with DLT at a 
Given Dose Level 
Cohort Dose Increase Decision Guide 
0 out of 3 
Enter 3 patients at the next higher dose level. 
1 out of 3 
Enter at least 3 more patients at the current dose level. If 0 of 
the additional patients experience a DLT, proceed to the next 
dose level. If 1 or more of the additional patients experience a 
DLT, stop the dose escalation. Enter 3 additional patients at 
the lower dose level if only 3 patients were treated previously 
at that dose. 
≥ 2 
Stop dose increases. Enter 3 additional patients at the lower 
dose level if only 3 patients were treated previously at that 
dose. 
≤ 1 out of 6 at highest dose level given 
This is the RP3D. 
Abbreviations: DLT = dose limiting toxicity; RP3D = recommended Phase 3 dose 
The 500 mg/m2 dose was studied in the CAEL101-101 study. CAEL-101 was well tolerated and 
there were no DLTs observed in that study. Further, the preclinical data does not point to safety 
concerns which would require an extended DLT observation period for this dose level. 


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Therefore, the DLT observation period for the first cohort will be 14 days. For subsequent 
cohorts, the DLT observation period will be 27 days following the first dose of CAEL-101. 
At least 3 patients will be enrolled in each dose cohort unless AEs preventing further dosing are 
observed. Enrollment into a new cohort with a higher dose of CAEL-101 cannot begin until the 
DLT observation period has completed for the last patient enrolled in the previous cohort. 
Definition and instructions for assessment of DLT is presented in Section 6.2.4. If 0 out of 
3 patients experience a DLT during the DLT observation period, the next dose cohort will be 
opened. If 1 out of 3 patients experience a DLT during the DLT observation period, the cohort 
may be expanded to 6 patients. If no further patients in the expanded cohort experience a DLT 
during the DLT observation period (i.e., 1 out of 6 patients experiences a DLT), increase to the 
next dose may take place. If 2 or more patients in a cohort experience a DLT during the DLT 
observation period, further dose increase will cease. New patients will be enrolled at the lower 
(tolerated) dose level if only 3 patients were previously enrolled in that cohort. The 
recommended dose will require at least 6 patients treated with CAEL-101 at that dose and ≤ 1 
patient having experienced a DLT during the DLT observation period. Based on clinical safety 
and laboratory data, the safety review team (Sponsor and 1 or more Investigators may direct that 
an intermediate dose between the dose demonstrating the DLT and the previously documented 
safe dose may be explored, or a different dosing regimen starting at a lower dose be explored. 
Dose increases may be discontinued based on safety or PK findings that may influence the 
decision about a recommended dose.  
The Sponsor may choose to evaluate CAEL-101 in additional patients and at other/higher doses 
and dosing schedules to further assess the PK profile, the benefit/risk profile and/or based on the 
safety findings from ongoing CAEL-101 clinical trials. 
6.2.4. 
Dose Limiting Toxicity 
For Part A of this study, a DLT is defined as any Grade 3 or greater study drug-related AE that is 
clinically significant.  
DLTs will be assessed during the DLT observation period for each cohort in Part A (See 
Section 6.2.3). DLTs that occur after the DLT observation period will not be used to determine 
dose increases or the RP3D dose but will be collected and evaluated by the Investigators and the 
Medical Monitor on an ongoing basis. 
6.2.5. 
Dose Delay 
Dose delay or modification for safety concerns are permitted based on the Investigator’s 
discretion. When not related to safety, decisions regarding dose delay and dose 
reductions/modifications will be made by the Investigator in consultation with the Medical 
Monitor based on the clinical evaluation of the patient. Patients will receive study drug every 7 
(+/-1) days for 4 infusions then every 14 (+/-2) days. Doses may be delayed due to patient care 
requirements (e.g., hospitalization, side effects). 
The study drug infusion may be delayed, or the dose reduced for infusion reactions. If the study 
drug infusion is delayed and in the absence of chemotherapy-related toxicities that would 
warrant PCD treatment delay, the patient may continue to receive their concurrent PCD 
treatment.  


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Guidelines for study drug dose reduction or delay: 
• Grade 1 or 2 reactions: No requirement for dose delay or dose reduction. If the reaction 
persists at Grade 2 following completion of 4 doses of CAEL-101, a dose delay or dose 
reduction may be implemented at the discretion of the Investigator.  
• Grade 3 reactions: Study drug may be withheld if an infusion reaction cannot be managed 
by adequate medical intervention. Study drug dosing may resume at the same dose and 
infusion rate or at the lower dose level (750 mg/m2) when an infusion reaction resolves to 
Grade 1 or symptoms return to baseline, except for instances where the potential 
recurrence of the even poses an undue risk for the patient (e.g., Grade 3 reaction that is 
deemed to be related to the study drug in the Investigator’s judgement). 
• Grade 4 reactions: Study drug should be stopped, and the study treatment withheld. Study 
drug should be permanently discontinued after the occurrence of a Grade 4 infusion 
reaction. 
If a dosing event is delayed by > 14 days, the patient can be resumed with the investigational 
product after a safety assessment. The local lab testing is acceptable to confirm the patient’s 
eligibility to continue receiving the study drug. The safety assessments are determined by the 
primary investigator, however, the following are recommended: vital signs, medical history, 
physical exam, ECG, safety laboratory tests (detailed in Table 1, footnote d), pregnancy 
screen (if applicable), and SAE- and AE-specific follow up (if applicable and there are any 
safety concerns due to residual disease). 
6.3. 
End of Treatment 
Patients may choose to discontinue the trial at any time, for any reason, and without prejudice to 
further treatment. (See Section 5.3) Patients who permanently discontinue CAEL-101 treatment 
should complete the EOT visits according to the Schedule of Assessments (Table 1) within 
140 days after the last dose of CAEL-101. 
6.4. 
End of Study 
End of study is defined as when the Sponsor decides to terminate the study. 
6.5. 
Prior and Concomitant Medications 
All prior medications for AL amyloidosis that the patient has ever taken will be recorded. All 
medications (prescription and over the counter), vitamin and/or mineral supplements, and/or 
herbs the patient is taking at screening will also be recorded. Start and stop date, dose and route 
of administration, dosing frequency and indication will be documented. 
6.6. 
Permitted Medications 
Patients may take topical, ocular, intra-articular, intranasal, and inhalational corticosteroids with 
minimal systemic absorption. A brief course of less than 3 weeks of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-immune conditions is permitted 
with consultations with the medical monitor. Patients may take up to 10 mg of corticosteroids for 
other conditions. 


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Concomitant palliative and supportive care, including diuretics, for disease related symptoms is 
allowed. 
6.7. 
Prohibited Medications 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as noted in Section 6.6) 
• Any chemotherapy other than CyBorD during the DLT observation period (Part A) 
Please consult the Medical Monitor for any questions regarding immunosuppressive agents or 
live vaccine. 
6.8. 
Pharmacokinetic Measurements 
Blood samples for PK analyses of CAEL-101 will be collected according to the Schedule of 
Assessments (Table 1). Post-dose samples should only be obtained from an extremity opposite 
the administration site, unless approved by the Sponsor.  
6.9. 
Immunogenicity Measurements 
Samples for immunogenicity tests for CAEL-101 will be collected according to the Schedule of 
Assessments (Table 1). Samples will be analyzed by screening assays to determine the presence 
of anti-drug antibodies (ADAs) for all patients at all time points. Based on the presence of 
antibodies, additional characterization will be done (confirming positivity, dissecting specificity, 
neutralizing assays, and assays for assessing cell mediated immune responses) and assessment of 
correlation to clinical responses.  
6.9.1. 
ADA Variables 
ADA variables include ADA response category incidence and titer over the duration of the study 
as follows.  ADA response category definitions and titer thresholds will be provided in the 
Statistical Analysis Plan (SAP). 
ADA response categories 
• ADA Negative 
• ADA Positive 
Patients who are ADA positive will be categorized as follows: 
• Pre-existing Immunoreactivity 
• Treatment-emergent ADA Responses 
Patients with a treatment-emergent ADA response will be further categorized as 
follows: 
o Persistent Treatment-emergent Responses 
o Indeterminate Treatment-emergent Responses 
o Transient Treatment-emergent Reponses 


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• Treatment-boosted ADA Responses 
• NAb Positive or Negative 
ADA Maximum Titer Value Categories: 
• Lower Titer 
• Moderate Titer 
• High Titer 
6.10. 
Contraception Requirements 
A woman is considered a WOCBP following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Female patients of childbearing potential are eligible to participate in this trial (Section 5.1) if 
they agree to use a highly effective method of contraception consistently and correctly from 
Screening until at least 5 months following the last study drug administration or 12 months 
following the last dose of her PCD therapy, whichever is longer. 
Birth control methods which may be considered as highly effective can achieve a failure rate of 
less than 1% a year when used consistently and correctly and include: 
• Combined (estrogen and progestogen containing): oral, intravaginal or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Progestogen-only oral, injectable or implantable hormonal contraception associated 
with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner: a vasectomized partner is a highly effective birth control 
method provided that the partner is the sole sexual partner of the WOCBP patient and 
that the vasectomized partner has received medical assessment of the surgical 
success. 
• Sexual abstinence: sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient. 


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Fertile male patients are eligible to participate in this trial (Section 5.1) if they agree to use 
condoms during heterosexual intercourse with WOCBP from Screening until at least 5 months 
following the last study drug administration or 12 months following the last dose of his PCD 
therapy, whichever is longer.  
Non-pregnant WOCBP partners of fertile male patients should also use highly effective methods 
of contraception during the male patient’s treatment and until at least 5 months following the last 
study drug administration or 12 months following the last dose of the male patient’s PCD 
therapy, whichever is longer.  
Patients should be permitted to seek advice about donation and cryopreservation of germ cells 
prior to starting treatment with study drug or PCD therapy, if possible and as their need to start 
treatment allows. 
Refer to the package insert or Summary of Product Characteristics (SmPC) for PCD medications 
for additional guidance on contraceptive use requirements. 
6.11. 
Assigning Patient Numbers 
Each patient will be assigned a unique patient number after signing the ICF. The patient number 
will be used on all of the patient’s study information. Patient numbers will not be reassigned. The 
first 4 digits will be the site number (XXXX) followed by a 4-digit patient ID (YYYY) that 
together will be the patient number (XXXX-YYYY). The second set of 4 digits (YYYY) will be 
sequential within sites, starting with 0001. 


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7. 
INVESTIGATIONAL PRODUCT 
CAEL-101 will be supplied to the Investigator by the Sponsor or its designee. Commercially 
available CyBorD chemotherapy drugs and daratumumab may be locally procured.  
7.1. 
Study Drug 
The investigational product, CAEL-101, is formulated as a sterile, liquid solution of protein plus 
excipients for dilution in a single-use, stoppered, glass vial. Each 10 mL vial contains 300 mg of 
chimeric fibril-reactive monoclonal antibody 11-1F4 at a concentration of 30 mg/mL. CAEL-101 
will be diluted with commercially available 0.9% Normal Saline. 
7.2. 
Study Drug Packaging and Labeling 
CAEL-101 will be packaged and labeled as per country regulations. CAEL-101 solution for 
infusion is packaged in cartons containing 10 mL vials.  
7.3. 
Study Drug Storage 
CAEL-101 investigational product should be refrigerated at 2°C to 8°C (36°F to 46°F). 
CAEL-101 should not be frozen. The vials should be stored in the original package until time of 
use. Vials do not contain preservative and are intended for single use only. Vials should be 
discarded after use and product reconciliation. 
7.4. 
Study Drug Preparation 
The instructions for dilution and administration of CAEL-101 are described in the Pharmacy 
Manual. 
7.5. 
Accountability and Reconciliation 
CAEL-101 will be supplied to the Investigator by the Sponsor or its designee.  
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drugs received and that any discrepancies are reported and 
resolved before dosing a patient. 
Only participants enrolled in the study may receive study drugs and only authorized site staff 
may prepare, supply or administer the drug. All study drug must be stored in a secure, 
environmentally controlled and monitored area in accordance with the labeled storage 
conditions. Access to study drug will be limited to the Investigator and authorized site staff. 
The Investigator is responsible for study drug accountability, reconciliation and record 
maintenance. 
7.6. 
Study Drug Handling and Disposal 
Sponsor may authorize sites to destroy unused and partially used study drug per site specific 
procedures. If site does not have adequate procedures in place, study drug may be returned to the 
Sponsor for destruction. 


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8. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed through the evaluation of cardiac, renal, hepatic, and hematologic 
response (see Appendix B and Appendix C). 
Organ-specific outcomes for renal, hepatic, and cardiac biomarker response will be assessed 
using both retrospective and prospective data. The retrospective collection may include a review 
of the patient record at the site. Further, prospective collection has been added to collect future 
organ response outcomes. The combination of retrospective and prospective data collection will 
allow for a more robust determination of the effects of CAEL-101 on efficacy in patients with 
AL amyloidosis. 
8.1. 
Echocardiography 
Cardiac structure and function will be assessed through echocardiograms according to the 
Schedule of Assessments (Table 1). Echocardiograms obtained after screening may be within a 
+/- 30 day window from the study day. Echocardiograms should not be skipped. If the patient 
cannot undergo an echocardiogram within the assessment window (e.g., the patient is 
hospitalized), it should be completed as soon as possible. 
8.2. 
NT-proBNP, cTnT/cTnI, dFLC 
Blood samples for NT-proBNP, cTnT/cTnI, and FLC will be collected according to the Schedule 
of assessments (Table 1). Investigators may continue to collect samples for NT-proBNP, 
cTnT/cTnI, and FLC for local analysis and patient care per the local SoC. Such analyses will not 
be considered part of the study and will not be recorded in the electronic case report form 
(eCRF). 
8.3. 
24-hour Urine Protein 
Urine for protein will be collected from all patients over 24 hours according to the Schedule of 
Assessments (Table 1).  


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9. 
ASSESSMENT OF SAFETY AND ADVERSE AND SERIOUS 
ADVERSE EVENTS 
9.1. 
Safety Parameters 
9.1.1. 
Medical History 
Relevant and significant medical history and concurrent illnesses will be collected for all patients 
and noted as to whether the condition is active at the first visit of the Screening period. 
9.1.2. 
Vital Signs 
Vital signs measurements will be recorded at every visit. Vital signs include pulse rate, 
respiratory rate, systolic and diastolic blood pressure and oral temperature. It is preferred that the 
same arm be used for all blood pressure readings. Pulse and blood pressure measurements will be 
taken after the subject has been resting quietly for at least 5 minutes. 
9.1.3. 
Physical Examination 
The Investigator or a licensed team member, per local regulations, will perform physical 
examinations according to the Schedule of Assessments (Table 1).  
9.1.4. 
Twelve-Lead Electrocardiogram  
Electrocardiograms will be performed on a calibrated Twelve-lead machine according to the 
Schedule of Assessments (Table 1). Patients must be resting quietly in a supine position for at 
least 5 minutes before the Twelve-lead ECG. 
9.1.5. 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed according to the Schedule of Assessments in Table 1. 
Clinical laboratory tests will be performed by the site’s local laboratory. Results of laboratory 
tests will be recorded in the eCRF.  
The Investigator or qualified sub-Investigator should review and evaluate out of range laboratory 
results. Any clinically significant abnormal laboratory value should be immediately re-checked 
whenever possible and documented as an AE as applicable.  
Clinical laboratory tests that will be performed for this study are listed in Table 5. 


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Table 5: 
CAEL101-203 Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cells 
• 
White blood cells 
• 
Platelet count 
• 
Neutrophils (absolute) 
• 
Lymphocytes (absolute) 
• 
Monocytes (absolute) 
• 
Eosinophils (absolute)  
• 
Basophils (absolute) 
• 
MCH 
• 
MCHC 
• 
MCV 
• 
MPV 
• 
RDW 
• 
Reticulocyte count 
• 
AST 
• 
ALT 
• 
ALP (ALP isozyme, if 
applicable) 
• 
GGT 
• 
Albumin 
• 
Globulin 
• 
Creatinine 
• 
Glucose 
• 
Total protein 
• 
Total bilirubin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
CO2 or Bicarbonate 
• 
Calcium 
• 
Phosphorus 
• 
Blood urea nitrogen 
• 
eGFR 
• 
Uric acid 
• 
Specific gravity  
• 
pH 
• 
Glucose 
• 
Protein 
• 
Bilirubin 
• 
Ketones 
• 
Leukocytes 
• 
Blood 
Pregnancy 
• 
Serum hCG 
• 
Urine pregnancy test 
Special 
• 
Serum Free Light 
Chains and serum and 
urine immunofixation 
electrophoresis 
• 
dFLC or SPEP m-spike 
• 
Troponin 
• 
NT-proBNP 
9.1.6. 
Pregnancy Screen 
Serum pregnancy tests will be performed on WOCBP at the screening visit. WOCBP must have 
a negative pregnancy screening in order to continue in the study. Additional urine pregnancy 
tests will be provided by the Sponsor and will be performed at the site according to the Schedule 
of Assessments (Table 1). A negative pregnancy test result must be obtained before the 
administration of the study drug. 
A pregnancy test does not need to be performed on women who are postmenopausal for at least 
1 year or surgically sterile prior to signing the ICF. 
9.2. 
Adverse and Serious Adverse Events 
9.2.1. 
Adverse Events Definition 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product, at any dose, that is not necessarily related to the treatment. 
An AE can therefore be any unfavorable and/or unintended sign, symptom or disease temporally 
associated with the use of a medicinal product, regardless of whether it is considered related to 
the medicinal product. An AE can also arise from any use of the drug and from any route of 
administration, formulation or dose. This definition includes intercurrent illnesses or injuries and 
exacerbation of preexisting conditions as well as events attributed to protocol-mandated 


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procedures. A clinical laboratory abnormality will only be reported as an AE if it is deemed 
clinically significant by the Investigator and/or is associated with signs and symptoms, requires 
treatment or requires follow-up. 
An AE does not include the following: 
• A medical or surgical procedure (e.g. surgery, endoscopy, tooth extraction or 
transfusion); an AE is the underlying condition that leads to the procedure 
• Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen or increase in severity or frequency after the 
administration of study drug 
• Situations where an untoward medical occurrence has not occurred (e.g. hospitalization 
for elective surgery for a condition that has not worsened on study, social and/or 
convenience admissions to grant families respite in caring for a patient). 
9.2.1.1. 
Adverse Event Reporting and Follow-up 
All AEs will be assessed by the Investigator and recorded in the case report form (CRF). Data to 
be entered includes but is not limited to the following: the event term, the date of onset and 
resolution, seriousness, severity, relationship to study drug, outcome, treatment of the event and 
action taken with the study drug. AEs will be reported starting from the date of signing of the 
ICF until day 140 (5 months) after the last dose of study drug. 
An AE occurring after the patient has provided written informed consent and before the first 
dose of study treatment will be collected as a pre-treatment AE. 
Example 1: 
Thrombophlebitis associated with a blood draw for assessments required prior to dosing per 
protocol is an event that is related to protocol-mandated procedures. In this scenario, the 
event of “thrombophlebitis” will be captured as an AE and it will be documented as being 
“unrelated” to the study drug. 
Example 2: 
An ankle sprain following an unexpected fall from a flight of stairs while at home, after the 
patient has provided informed consent, but before the first dose of study drug, is clearly 
unrelated to any protocol-mandated procedures and would also be captured as an AE. 
All ongoing AEs will be followed to resolution or for 140 days after the patient’s last dose of 
study drug, whichever is earlier. In case the AE has not completely resolved by the end of 
treatment visit, the final outcome of the ongoing AE will be captured as “Not Recovered/Not 
Resolved” or “Recovering/Resolving”, whichever is applicable. Any new AEs occurring after 
the end of treatment visit will not be captured unless related to the study drug. 
9.2.1.2. 
Grading of Adverse Event 
The severity of an event and the seriousness are not to be considered synonymous. The severity 
is grading the intensity of an event. The seriousness of an event is based on the patient/event 
outcome or action. All AEs will be assessed for severity using NCI-CTCAE version 5 by the 


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Investigator. If a particular AE is not listed in the NCI-CTCAE, the following criteria will be 
used: 
• Grade 1 (Mild): the event results in mild or transient discomfort, not requiring or needing 
only minimal intervention or treatment; does not limit or interfere with daily activities 
(e.g., insomnia, mild headache). 
• Grade 2 (Moderate): the event is sufficiently discomforting so as to limit or interfere with 
daily activities; may require interventional treatment (e.g., fever requiring antipyretic 
medication). 
• Grade 3 (Severe): the event results in significant symptoms that prevent normal daily 
activities; may require hospitalization or invasive intervention. 
• Grade 4: Life threatening or disabling. 
• Grade 5: Death 
9.2.1.3. 
Causality Relationship of Adverse Event 
The relationship of each AE to the study drug as applicable will be evaluated by the Investigator 
using the following definitions: 
• Not related: The AE is clearly not related to the study drug. The AE can be explained to 
be likely related to other factors such as concomitant medications or the patient’s clinical 
state. 
• Possibly related: The AE may be related to the study drug. A plausible temporal sequence 
exists between the time of administration of the study drug and the development of the 
AE, and it follows a known response pattern to the study drug. The reaction may have 
been produced by the patient’s clinical state or other concomitant therapies or 
interventions. 
• Related: The AE is clearly related to the study drug. A plausible temporal sequence exists 
between the time of administration of the study drug and the development of the AE, and 
it follows a known response pattern to the study drug. The occurrence of the AE can be 
confirmed with a positive re-challenge test or supporting laboratory data. 
The causality criteria of related and possibly related will be considered “related” to the study 
drug for regulatory reporting requirements. 
9.3. 
Serious Adverse Event Definition 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
• Results in death 
o Death is an outcome of an AE and not an AE in itself. 
o All events leading to death (except natural disease progress), regardless of 
causality, must be reported. 


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• Is life threatening, i.e., in the opinion of the Investigator, the AE places the patient at 
immediate risk of death from the event as it occurred; it does not include a reaction that, 
had it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization for medical reasons for any length of time, or 
prolongation of an existing hospitalization that occurs during the course of a patient’s 
participation in a clinical study, except for those due to the following: 
o A surgery or procedure that was planned before the patient entered the study and 
which is part of the planned study procedure is not an SAE 
o Nonmedical reasons, in the absence of an AE, are not considered SAEs 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent one of 
the other outcomes listed above. 
9.4. 
Disease Progression – Not Reportable as an AE 
It is anticipated that during this study a proportion of patients will experience progression of their 
AL amyloidosis resulting in hospitalization or death prior to study discontinuation. Such events 
leading to hospitalization or death of a study patient are typically considered “serious”, requiring 
submission of an SAE report. However, reporting the term “disease progression” as either an AE 
or SAE in this study is not necessary. 
9.5. 
SAE Reporting and Follow-up 
All SAEs regardless of causality attribution will be reported from the date of signing of the ICF 
through 140 days following the patient’s last dose of study drug. Any SAEs occurring after ICF 
signature but before the first dose of treatment are captured as pre-treatment SAEs. All SAEs 
will be reported to Alexion Global Drug Safety (GDS) within 24 hours of the Investigator or site 
staff awareness using the paper Safety Report Form via email: ClinicalSAE@alexion.com or 
facsimile: +1-203-439-9347. All paper forms MUST be accompanied by the Alexion GDS 
Email/Fax Cover Sheet signed by the Investigator or Sub-Investigator. The timelines for 
reporting SAE information to Alexion GDS need to be followed for the initial SAE report and 
for all follow-up SAE information. SAEs deemed possibly related to protocol-specified 
procedures occurring after the patient signed the ICF will also be reported to the Sponsor drug 
safety representative within 24 hours of when the site becomes aware of the event. In addition, if, 
in the opinion of the Investigator, an SAE occurring outside the specified time window occurs 
and is deemed to be related to study drug, the event will be reported to the Sponsor drug safety 
representative within 24 hours of when the site becomes aware of it. 
Any additional records (such as hospital records, consultant reports and autopsy findings) are to 
be provided upon Sponsor request. 


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The Investigator must complete the SAE form, assess the causality relationship to the study drug 
as applicable, record any medication or therapeutic measures taken to treat the event and send the 
completed form to the Sponsor drug safety representative.  
Reporting of SAEs to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
will be done in accordance with the procedures and policies of the IRB/IEC. Documentation 
must be provided to the sponsor, showing that the IRB/IEC was properly notified. SAEs will be 
reported by the Sponsor or designee to the regulatory authorities per local regulations. 
All SAEs will be followed until resolution, stabilization of condition, return to baseline, 30 days 
from the end of the study or until follow-up is no longer possible. 
9.5.1. 
Expedited Reporting of Serious Adverse Events 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions (SUSARs) in accordance with International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP), Food and Drug Administration (FDA) and all applicable regulatory 
guidelines. The Sponsor will also inform all Investigators as required. When required due to 
local regulations, the Investigator will provide expedited reports to the IRB/IEC. 
9.5.2. 
Pregnancy 
The Sponsor will be notified within 24 hours of the initial report and any follow-up reports of a 
female patient or a male patient’s female partner becoming pregnant during the course of the 
study and for 5 months after the last dose of the study drug or 12 months after the last dose of 
PCD treatment, whichever is longest.  
If a female patient becomes pregnant, administration of the study drug must be discontinued 
immediately. 
A pregnancy notification form is provided by the Sponsor drug safety representative.  
Cases of pregnancy that occur during maternal or paternal exposure to study drug will be 
reported to Alexion GDS within 24 hours of Investigator or site staff awareness using the 
Pregnancy Report Form via email: ClinicalSAE@alexion.com or facsimile: +1-203-439-9347. 
All paper forms MUST be accompanied by the Global Drug Safety Email/Fax Cover Sheet 
signed by the Investigator or Sub-Investigator. 
Pregnancy, although reportable, is not considered an AE/SAE unless a female patient or a male 
patient’s female partner experiences signs or symptoms of pregnancy complications. Female 
patients who become pregnant and female partners of male patients will be followed until the 
outcome of the pregnancy is known. Pregnancy follow-up should describe the outcome of the 
pregnancy, including any voluntary or spontaneous termination, details of the birth and the 
presence or absence of any congenital abnormalities or birth defects of the offspring. 


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10. 
STATISTICS 
10.1. 
General Considerations 
The primary objective in this study is to define the safety and tolerability of CAEL-101 and 
determine the recommended Phase 3 dose. Secondary objectives include describing the 
pharmacokinetic profile of CAEL-101 and exploring the PK profile of CAEL-101 when given 
q2wk versus q4wk after the first 50 weeks, and assessing the safety and tolerability of CAEL-
101 when administered with CyBorD, and with the combination of CyBorD and daratumumab. 
The statistical methods are consistent with these objectives. Specifically, the use of descriptive 
statistics is the primary method for presentation of data outcomes; descriptive statistics 
(and by-patient listings of data) will form the basis from which conclusions regarding study 
objectives will be made. There are no plans to generate inferential (e.g., p-values) statistics, 
as the sample size is generally insufficient to allow for use of such methods. 
In general, data will be tabulated by cohort to allow for comparison of key outcomes by dose 
level, recognizing that if a given cohort has only N=2 or 3 patients, that the interpretation of 
descriptive statistics is limited. All data will be listed by cohort and patient, with the primary 
determination of safety/tolerability outcomes based on review of these data listings. 
Figures/graphics of by-patient data will be presented where these will enable optimal review of 
outcomes across dose levels and over time. 
Consistent with the study objectives for Part A vs Part B (as well as due to the number of cohorts 
in this study), Part A data may be tabulated separately from Part B data. This will allow for 
review of data in the context of the objectives for each study part. Further, analysis populations 
and other analysis considerations may be performed separately for Part A from Part B, where 
appropriate. 
10.2. 
Determination of Sample Size 
The Part A sample size was based on similar studies in which a safe dose is to be selected for use 
in future larger efficacy/safety clinical trials (and thus the sample size was not selected based on 
a specific testable study hypothesis). A sample size of N=3 patients for a given dose level 
without a DLT is judged to be clinically sufficient to allow for escalation to the next higher dose 
level. For both Part A and Part B, a sample size of N=6 patients for a given CAEL-101/SoC 
treatment regimen is judged to be sufficient to allow for determination of tolerability in 
expectation that the CAEL-101/SoC regimen may be used in the subsequent Phase 3 programs. 
The total study sample size will be data-driven and dependent upon how many doses are tested 
and safety and tolerability outcomes from that testing. 
10.3. 
Replacement of Patients 
For Part A, patients who discontinue for non-safety reasons prior to the DLT period having 
elapsed may be replaced. 


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10.4. 
Analysis Sets 
Several populations will be identified for purposes of analysis. 
• Safety Population: All subjects treated with at least one dose of CAEL-101 (the study 
treatment) will be included in the Safety Population. 
• PK Population: The PK Population will include all subjects who have sufficient PK 
concentrations to be included in the PK analysis. The study pharmacokineticist will 
determine which patients have sufficient data to be included in the PK population and 
will document instances where a patient is excluded. 
• ADA Population: The ADA Analysis Set (AAS) includes all study participants who 
received any study drug and who after the first dose have at least one reportable result 
in the ADA assay. ADA analysis in study participants will be conducted based on the 
actual treatment they receive. 
For Part A, this study will include cohort safety reviews after the DLT observation periods. 
Analyses for these reviews may include data listings, tabulations and graphs. 
For Part A, an analysis will be performed for the completed cohorts (dosing levels) and an 
abbreviated CSR will be generated to document the findings and conclusions for the selected 
dose to be carried forward into the subsequent study. This report will be limited to the data 
collected to inform the dose selection decision.  
After study completion, a final ICH-compliant clinical study report will be written that will 
include both study parts. 
10.5. 
Planned Analyses 
10.5.1. 
Demographics and Baseline Characteristics 
Baseline characteristics (including age, gender, race, disease Stage, and other disease-specific 
characteristics) will be tabulated descriptively (e.g., number and percent of subjects for each 
category for categorical parameters, and the number, mean, standard deviation, and range for 
continuous parameters). 
Additionally, NYHA status (see Appendix D) and organ involvement will be summarized. 
10.5.2. 
Subject Disposition 
Subject completion status and reasons for early termination will be tabulated descriptively. 
Exposure characteristics will be tabulated (i.e., number of patients treated with each dose level, 
and number of doses of CAEL-101 received). Total dose given will be tabulated by cohort. 
10.5.3. 
Safety 
Safety assessments will include AEs, clinical laboratory tests, vital signs, physical examinations 
and ECGs. In Part A, the incidence of DLTs will be evaluated for each dose escalation cohort.  
All treatment-emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred term for each dose cohort. All TEAEs will be summarized by incidence, severity and 
potential causality to study drug. 


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Clinical laboratory tests and vital signs will be summarized descriptively for each dose cohort 
and/or study part. All abnormal findings in clinical laboratory test results, vital signs, physical 
examinations and ECGs will be listed. 
Adverse events will be coded using the MedDRA coding dictionary; subject incidence of each 
system organ class and unique term will be tabulated. AE incidence will also be tabulated 
according to relationship to study medication and severity. Serious AEs and AEs resulting in 
premature discontinuation will be tabulated. 
Adverse events starting after the first dose of treatment will be considered treatment-emergent 
AEs and will be reported as occurring during the treatment phase and will be associated with the 
most recent treatment (dose level) given. 
10.5.4. 
Efficacy 
Summary statistics (mean, standard deviation, standard error of mean < minimum, maximum, 
95% confidence interval) will be presented for the following efficacy endpoint. No hypothesis 
testing will be performed. 
• Cardiac: 
− NT-proBNP 
− cTnT/cTnI 
− Global Longitudinal Strain 
• Renal: 
− 24-hour urine protein 
• Hepatic: 
− Alkaline phosphatase 
The organ-specific outcomes for renal, hepatic, and cardiac biomarker response will be assessed 
using both retrospective and prospective data. The retrospective collection may include a review 
of the patient record at the site. Further, prospective data collection has been added to collect 
future organ response outcomes. The combination of retrospective and prospective data 
collection will allow for a more robust determination of the effects of CAEL-101 on efficacy in 
patients with AL amyloidosis. 
10.5.5. 
Immunogenicity 
Immunogenicity assessments will be listed and tabulated as provided in the SAP. 
10.5.6. 
Pharmacokinetics 
While PK parameters will be tabulated and summarized with descriptive statistics by cohort 
and/or study part, the primary assessment of PK concentrations will be via by-patient data 
assessment (including listings and figures of PK data over time). In addition, the PK profile of 
CAEL-101 when given bi-weekly (q2wk) versus once-monthly (q4wk) after the first 50 weeks 
will be assessed via population PK modeling. Details will be provided in a separate population 
PK SAP.  


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10.6. 
Concomitant Medications 
Prior and concomitant medications will be reviewed and coded using the WHO Drug Dictionary 
and tabulated by treatment. Concomitant medications will be reported in a fashion similar to that 
of AEs. 
10.7. 
Missing Data 
For the primary, secondary, and exploratory endpoints, handling of missing data will be 
described in the SAP. 


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11. 
STUDY TERMINATION 
The Sponsor may discontinue the study at any time. Reasons for discontinuation may include, 
but are not limited to, any of the following: 
• Safety concerns that preclude continuation of the study 
• A request from a regulatory authority to discontinue the study 
• Insufficient enrollment 
• Issues with the manufacture and/or supply of CAEL-101 
• Business or financial factors that preclude continuation of the study 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor will implement and maintain quality control and quality assurance procedures with 
written SOPs to ensure the study is conducted and data are generated, documented and reported 
in compliance with the protocol, GCP and applicable regulatory requirements. 
12.1. 
Changes to the Protocol 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/IEC except when necessary to eliminate 
immediate hazards to the patient. Protocol deviations may result in the requirement to withdraw 
the patient from the study and may render their data not evaluable. 
12.2. 
Monitoring 
In accordance with the Code of Federal Regulations 21CFR 312 Subpart D, ICH GCP and local 
regulations, the study monitor will assess the adequacy of Investigator site research facilities and 
evaluate the progress of the study. The monitor will verify the accuracy and completeness of the 
CRF; ensure that all protocol requirements are being met, that Investigator responsibilities are 
being fulfilled and provide aid and support to ensure any inconsistencies in study records are 
satisfactorily resolved. 
12.3. 
Data Protection 
Each patient will be assigned a unique identifier after signing the ICF. Patient numbers will not 
be reassigned. Any patient records or datasets transferred to the Sponsor must contain only the 
unique identifier and must not include patient names or any information which would make the 
patient identifiable. Patients will be informed that their personal study-related data will be used 
by the Sponsor in accordance with local data protection laws and that their medical records may 
be examined by representatives of the Sponsor, IRB/IEC members and by inspectors from 
regulatory authorities. Study monitors will inspect all documents and records that are required to 
be maintained by the Investigator for this study. 
12.4. 
Audits and Inspections 
The Sponsor or designee may conduct monitoring and auditing activities at the Investigator site 
at any time during study conduct or after completion of the study. The Investigator will be 
informed if an audit is to take place and advised as to its scope. Inspections and audits will 
typically be carried out during the clinical and reporting phases of the study to ensure that the 
study is conducted, and data are generated, documented and reported in compliance with the 
protocol, ICH GCP, written SOPs and applicable regulations and laws. 
Representatives of the FDA or other regulatory agencies and IRB/IEC representatives may also 
conduct an audit of the study. If informed of such an inspection, the Investigator should notify 
the Sponsor immediately. The Investigator will ensure that the auditors have access to the 
clinical supplies and study site facilities and that all data, including original source records and 
study files are available upon request. 


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13. 
ETHICS 
This study will be conducted in accordance with the protocol and with:  
• the consensus international ethical principles that have their origin in the Declaration of 
Helsinki and the Council for International Organizations of Medical Sciences (CIOMS) 
international ethical guidelines, and 
• applicable ICH GCP guidelines, and 
• applicable laws and regulations. 
13.1. 
IRB/IEC Approval 
Before enrollment of patients into the study as required by applicable regulations and ICH GCP, 
the current protocol, ICF, advertisements and any written information for patients will be 
reviewed and approved by an appropriate IRB or IEC. A letter documenting the IRB/IEC 
approval must be received by the Sponsor or designee before the initiation of the study at the 
Investigator’s site. Amendments to the protocol will be subject to the same requirements as the 
original protocol. 
The Investigator will submit a progress report at least once yearly to the IRB/IEC or more 
frequently as required. As soon as possible after completion or termination of the study, the 
Investigator will submit a final report to the IRB/IEC per their requirements and in compliance 
with applicable regulations and ICH GCP. 
The Investigator, the Sponsor or designee shall promptly notify the IRB/IEC of any SAEs, or any 
other information that may affect the safe use of the study drug during the course of the study.  
No study drug will be released to the Investigator’s site until IRB/IEC authorization has been 
received by the Sponsor, or Sponsor’s designee. 
13.2. 
Written Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
the Sponsor or designee and the IRB/IEC prior to its use. The ICF must be in compliance with all 
ICH GCP and applicable regulatory and legal requirements. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The Investigator must 
ensure that each patient has been informed of his/her rights to privacy. The patients must be 
notified that they are free to discontinue from the study at any time and should be given the 
opportunity to ask questions and allowed time to consider the information provided. The 
Investigator will obtain written informed consent from each patient before any study-specific 
activity is performed and will document in the source records that consent was obtained prior to 
the patient’s enrollment in the study. The original signed copy of the ICF must be maintained by 
the Investigator and is subject to inspection by the Sponsor, their representatives, auditors, the 
IRB/IEC and regulatory authorities. A copy of the signed and dated ICF will be given to each 
patient. 


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14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Study Records 
During the study, the Investigator will provide evidence of the existence of the patient and 
substantiate the integrity of the data collected. Source documents filed at the investigator site 
include records of potential study patients screened, medical records, and records detailing the 
progress of the study for each enrolled patient, laboratory reports, CRF, signed ICF, drug 
accountability records, correspondence with the IRB/IEC and regulatory agencies, AE reports 
and information regarding patient discontinuation. The Investigator will ensure the accuracy, 
completeness, legibility and timeliness of data reported to the Sponsor in the CRF and in all 
required reports. Changes to source data should be traceable, should not obscure the original 
entry and should be explained when necessary (e.g. via an audit trail).  
14.2. 
Data Collection Instruments 
Various data collection instruments (DCIs) such as the electronic CRF and/or paper forms will 
be used in this study. These instruments transmit the information collected during the conduct of 
the study to the Sponsor, the Sponsor’s designee and regulatory authorities. The Investigator 
retains full responsibility for the appropriateness and accuracy of all data collected. S/he will 
review all DCIs and will approve all data, including any changes made. 
14.3. 
Retention of Records 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for at least 2 years after FDA approval or the approval of a 
marketing application in an ICH region, or for a at least 2 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without the written approval of the Sponsor. The 
Investigator/institution will permit the Sponsor or the regulatory authority access to study records 
and documents for inspection. 


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15. 
FINANCIAL DISCLOSURE 
Investigators and sub-investigators will provide the Sponsor with financial information as 
requested to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 


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16. 
PUBLICATION POLICY 
All data are the property of the Sponsor. Each Investigator is obliged to keep data pertaining to 
the study confidential. However, it is intended that the results of the study will be published 
and/or presented at scientific meetings. Formal presentation of data from this study will be 
considered for joint publication by the Investigator(s) and appropriate Sponsor personnel. 
Authorship will be determined by mutual agreement. 
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries. 


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17. 
APPENDICES 
APPENDIX A INTERNATIONAL MYELOMA WORKING GROUP 
(IMWG) CRITERIA FOR THE DIAGNOSIS OF MULTIPLE 
MYELOMA 
The new definition of active multiple myeloma is: 
Clonal bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma 
and any one or more of the following CRAB features and myeloma-defining events: 
• Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically: 
o Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the upper 
limit of normal or > 2.75 mmol/L (> 11mg/dL) 
o Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine 
> 177mol/L (> 2mg/dL) 
o Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a 
hemoglobin value < 100g/L 
o Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or 
PET/CT. If bone marrow has < 10% clonal plasma cells, more than one bone 
lesion is required to distinguish from solitary plasmacytoma with minimal marrow 
involvement 
• Any one or more of the following biomarkers of malignancy (MDEs): 
o 60% or greater clonal plasma cells on bone marrow examination 
o Serum involved / uninvolved free light chain ratio of 100 or greater, provided the 
absolute level of the involved light chain is at least 100mg/L (a patient's involved 
free light chain either kappa or lambda is the one that is above the normal 
reference range; the uninvolved free light chain is the one that is typically in, or 
below, the normal range) 
o More than one focal lesion on MRI that is at least 5mm or greater in size. 
Table 6:  
IMWG Plasma Cell Disorders 
Plasma Cell Disorder 
Definition 
Smoldering Multiple Myeloma 
Both criteria must be met: 
Serum monoclonal protein (IgG or IgA) >30g/L or urinary 
monoclonal protein >500mg per 24h and/or clonal bone marrow 
plasma cells 10-60% 
Absence of myeloma-defining events or amyloidosis 


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Table 6:  
IMWG Plasma Cell Disorders 
Plasma Cell Disorder 
Definition 
Non-IgM monoclonal gammopathy 
of undetermined significance 
(MGUS) 
Serum monoclonal protein < 30g/L 
Clonal bone marrow plasma cells < 10% 
Absence of end-organ damage such as hypercalcemia, renal 
insufficiency, anemia, and bone lesions (CRAB) or amyloidosis 
that can be attributed to the plasma cell proliferative disorder 
IgM MGUS 
Serum IgM monoclonal protein < 30g/L 
No evidence of anemia, constitutional symptoms, hyperviscosity, 
lymphadenopathy, hepatosplenomegaly, or other end-organ 
damage that can be attributed to the plasma cell proliferative 
disorder 
Light chain MGUS 
Abnormal FLC ratio (< 0.26 or > 1.65) 
Increased level of the appropriate free light chain (increased FLC 
in patients with ratio > 1.65 and increased FLC in patients with 
ratio < 0.26) 
No immunoglobulin heavy chain expression on immunofixation 
Absence of end-organ damage such as hypercalcemia, renal 
insufficiency, anemia, and bone lesions (CRAB) or amyloidosis 
that can be attributed to the plasma cell proliferative disorder 
Clonal bone marrow plasma cells < 0% 
Urinary monoclonal protein < 500mg/24h 
Solitary plasmacytoma 
Biopsy-proven solitary lesion of bone or soft tissue with evidence 
of clonal plasma cells 
Normal bone marrow with no evidence of clonal plasma cells 
Normal skeletal survey and MRI (or CT) of spine and pelvis 
(except for the primary solitary lesion) 
Absence of end-organ damage such as hypercalcemia, renal 
insufficiency, anemia, and bone lesions (CRAB) or amyloidosis 
that can be attributed to the plasma cell proliferative disorder 
Solitary plasmacytoma with minimal 
marrow involvement 
Biopsy-proven solitary lesion of bone or soft tissue with evidence 
of clonal plasma cells 
Clonal bone marrow plasma cells < 10% 
Normal skeletal survey and MRI (or CT) of spine and pelvis 
(except for the primary solitary lesion) 
Absence of end-organ damage such as hypercalcemia, renal 
insufficiency, anemia, and bone lesions (CRAB) or amyloidosis 
that can be attributed to the plasma cell proliferative disorder 


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Table 6:  
IMWG Plasma Cell Disorders 
Plasma Cell Disorder 
Definition 
POEMS syndrome 
Polyneuropathy 
Monoclonal plasma cell proliferative disorder 
Any one of the 3 other major criteria: sclerotic bone lesions, 
Castleman's disease, elevated levels of VEGFA 
Any one of the following 6 minor criteria: 
Organomegaly (splenomegaly, hepatomegaly, or 
lymphadenopathy) 
Extravascular volume overload (edema, pleural effusion, or 
ascites) 
Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, 
pancreatic) 
Skin changes (hyperpigmentation, hypertrichosis, glomeruloid 
hemangiomata, plethora, acrocyanosis, flushing, white nails) 
Papilledema 
Thrombocytosis/polycythemia 
Systemic AL amyloidosis 
Presence of an amyloid-related systemic syndrome (e.g., renal, 
liver, heart, gastrointestinal tract, or peripheral nerve involvement) 
Positive amyloid staining by Congo red in any tissue (e.g., fat 
aspirate, bone marrow, or organ biopsy) 
Evidence that amyloid is light-chain-related established by direct 
examination of the amyloid using mass spectrometry-based 
proteomic analysis or immunoelectron microscopy 
Evidence of a monoclonal plasma cell proliferative disorder 
(serum monoclonal protein, abnormal free light chain ratio, or 
clonal plasma cells in the bone marrow) 
Source: International Myeloma Working Group 
 
 


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APPENDIX B ORGAN INVOLVEMENT AND RESPONSE CRITERIA 
Organ 
Organ Involvement 
Response 
Progression 
No 
Response/Stability 
Cardiac 
NT-proBNP 
> ng/L 
(0.33 mg/mL or 
39.2 pmol/L) 
Decrease of > 30% in NT-
proBNP levels AND a decrease 
of NT-proBNP > 300 ng/L in 
patients with a baseline NT-
proBNP of ≥ 650 ng/La 
Increase of 
> 30% in 
NT-proBNP 
levels (in the 
absence of 
eGFR decline 
of ≥ 25%) and 
≥ 300 ng/L 
increase in 
NT-proBNP (in 
the absence of 
eGFR decline 
of ≥ 25%) 
Neither response 
nor progression 
Renal 
24-hr urine protein 
> 0.5 g/day 
predominantly 
albumin 
Decrease of ≥ 30% in 
proteinuria or drop of proteinuria 
below 0.5 g/24 h in the absence 
of ≥ 25% decrease in eGFR 
Worsening of 
≥ 25% in eGFR 
Neither response 
nor progression 
Liver 
ALP > 1.5 times 
institutional upper 
limit of normal 
Decrease of ≥ 50% and/or 
normalization of serum ALP 
level 
Increase of 
≥ 50% in the 
serum ALP 
level 
Neither response 
nor progression 
Abbreviations: ALP – alkaline phosphatase, eGFR – estimated glomerular filtration rate; hr – hour; NT-proBNP – 
N-terminus pro-brain natriuretic peptide. 
aPatients with baseline NT-proBNP < 650 ng/L are not considered to have cardiac involvement. 
Source: (Dispenzieri, 2015b; Palladini, 2014) 
 
 


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APPENDIX C HEMATOLOGIC RESPONSE AND RESPONSE CRITERIA 
Response  
Criteria 
Complete response (CR) 
Complete response (CR) (both criteria must be met): 
• Absence of amyloidogenic light chains (either free and/or 
as part of a complete immunoglobulin) defined by negative 
immunofixation electrophoresis of both serum and urine 
• Either a FLC ratio within the reference range or the 
uninvolved FLC concentration is greater than involved 
FLC concentration with or without an abnormal FLC ratio 
Very good partial response (VGPR) 
dFLC < 4 mg/dL 
Partial response (PR) 
dFLC decrease ≥ 50% from baseline 
No response (NR) 
Less than a partial response 
Abbreviations: dFLC – involved/uninvolved free light chain difference; FLC – free light chain. 
Sources: (Dispenzieri, 2015b); University of Rochester Medical Center 
 
 


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APPENDIX D NEW YORK HEART ASSOCIATION (NYHA) 
FUNCTIONAL CLASSIFICATION 
NYHA Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 
Abbreviation: NYHA – New York Heart Association. 
Source: Adapted from Dolgin 1994 
 
 
 


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APPENDIX E  COVID-19 RISK ASSESSMENT 
 
AL amyloidosis can cause irreversible morbidity and even mortality, if untreated. As such, the 
benefit a participant may receive from treatment with CAEL-101 is potentially significant.  
Given that treatment for AL amyloidosis does involve immunosuppression, there is a theoretical 
concern that the risk for infection may be higher than in participants not receiving 
immunosuppressants. However, there is no specific data to further inform this risk. No 
participant should be discontinued or excluded from the study due to COVID-19 infection. The 
site Investigator will therefore balance the risk/benefit considerations in the study participant 
taking these factors into account.  
The potential operational risks identified and mitigation measures put in place in light of the 
COVID-19 pandemic are provided in Table 7. 
Table 7: Potential Operational Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 pandemic may impact the workload of 
healthcare institutions globally and may reduce staff 
availability to perform non-urgent activities and 
non-COVID-19 related activities. 
 
During the time that the 
COVID-19 pandemic is active, 
Alexion will not open study 
sites or enroll new participants 
at sites unless the sites have the 
resourcing and capabilities to 
implement the study per 
protocol. 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study specific data in 
a timely manner and to maintain adequate quality 
standards. 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, storage 
conditions, and monitoring for investigational 
product and biological samples. 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
Missing data (COVID-19 pandemic may impact 
study visit schedules, and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the 
COVID-19 pandemic is active, 
Alexion will only open study 
sites that report enough 
personnel capacity to 
sufficiently conduct clinical 
study-related activities.  
During this timeframe, site 
capacity will be reviewed by the 
site Investigator and the study 
Medical Monitor prior to 
Screening. Each site is also 
evaluated for the capacity to 
perform remote monitoring 
visits and remote source data 
verification. 
During the time that the 
COVID-19 pandemic is active, 
it will be important to capture 
specific information in the 
eCRF that explains the reason 


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Table 7: Potential Operational Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
the data is missing (eg, missed 
study visits or participant study 
discontinuations due to 
COVID-19). 
Abbreviations: COVID-19 – coronavirus disease 2019; eCRF – electronic case report form. 
 
 


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APPENDIX F  COVID VACCINE RISK ASSESSMENT 
There is currently no information available evaluating the safety and efficacy of COVID-19 
vaccines in participants treated with CAEL-101. It is unlikely that the immune response to a 
COVID-19 vaccine (and therefore the efficacy of the vaccination) would be diminished by 
CAEL-101 administration, based on CAEL-101 mechanism of action. It is also unlikely that 
COVID-19 vaccination would impact CAEL-101 mechanism of action. 
Local and national guidelines should be consulted for recommendations related to COVID-19 
vaccination. 
The potential operational risks identified and mitigation measures put in place in light of the 
COVID-19 vaccination rollout are provided in Table 8. 
Table 8: 
Potential Operational Risks and Mitigation Measures due to COVID-19 
Vaccine 
Risks Category 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risks 
Data quality and 
integrity 
Missing data due to appointments for COVID-19 
vaccination or side effects of COVID-19 vaccine 
may impact study visit schedules, and increase 
missed visits and/or participant study 
discontinuations, inadvertently resulting in 
missing data (eg, for protocol-specified 
procedures). 
Capture specific information in the 
eCRF that explains the reason for 
missing data (eg, missed study 
visits due to appointments for 
COVID-19 vaccination or side 
effects of COVID-19 vaccine). 
Abbreviations: COVID-19 – coronavirus disease 2019; eCRF – electronic case report form. 
 


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18. 
REFERENCES 
Dispenzieri A, Seenithamby K, Lacy MQ, et al. Patients with immunoglobulin light chain 
amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared 
with patients with multiple myeloma: a retrospective review from a tertiary referral center. Bone 
Marrow Transplant. 2013;48(10):1302-1307. 
Dispenzieri A, Gertz MA, Saenger A, et al. Soluble suppression of tumorigenicity 2 (sST2), but 
not galactin-3, adds to prognostication in patients with systemic AL amyloidosis independent of 
NT-proBNP and troponin T. Am J Hematol. 2015a;90(6):524-528. 
Dispenzieri A, Buadi F, Kumar SK, et al. Treatment of Immunoglobulin Light Chain 
Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) 
Consensus Statement. Mayo Clin Proc. 2015b;90(8):1054-1081. 
Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. 
Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great 
vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994. 
 
Hemminki K, Li X, Forsti A, Sundquist J, Sundquist K. Incidence and survival in non-hereditary 
amyloidosis in Sweden. BMC Public Health. 2012;12:974. 
International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma. 
International Myeloma Foundation. https://www.myeloma.org/international-myeloma-working-
group-imwg-criteria-diagnosis-multiple-myeloma. Accessed 30 October 2019 
 
Kyle RA, Greipp PR, O'Fallon WM. Primary systemic amyloidosis: multivariate analysis for 
prognostic factors in 168 cases. Blood. 1986;68(1):220-224. 
Milani P, Merlini G, Palladini G. Light Chain Amyloidosis. Mediterr J Hematol Infect Dis. 
2018;10(1):e2018022. 
Muchtar E, Kumar SK, Gertz MA, et al. Staging systems use for risk stratification of systemic 
amyloidosis in the era of high-sensitivity troponin T assay. Blood. 2019;133(7):763-766. 
Palladini G, Merlini G. What is new in diagnosis and management of light chain amyloidosis? 
Blood. 2016;128(2):159-168. 
Palladini G, Milani P, Foli A, et al. Presentation and outcome with second-line treatment in AL 
amyloidosis previously sensitive to nontransplant therapies. Blood. 2018;131(5):525-532. 
Palladini G, Sachchithanantham S, Milani P, et al. A European collaborative study of 
cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL 
amyloidosis. Blood. 2015;126(5):612-615. 
Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers 
of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-2332. 


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Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Palladini G, Milani P, Basset M, et al. Severity and reversibility of cardiac dysfunction and 
residual concentration of amyloidogenic light chain predict overall survival of patients with AL 
amyloidosis who attain complete response. Amyloid. 2017;24(sup1):54-55. 
Sidana S, Milani P, Binder M, et al. A validated composite organ and hematologic response 
model for early assessment of treatment outcomes in light chain amyloidosis. Blood Cancer J. 
2020;10(4):41. 
 
University of Rochester Medical Center. Free Light Chains. 
https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=seru
m_free_light_chains. Accessed May 21, 2020. 

SAP_001.pdf: 
Statistical Analysis Plan 
 Version 2.0 
CAEL101-203 
25 April 2024 
Page 1 of 45 
Alexion Confidential 
STATISTICAL ANALYSIS PLAN 
Version Number: 2.0 
Protocol Title: A Phase 2, Open-label, Multicenter, Dose Selection Study to Evaluate the Safety 
and Tolerability of CAEL-101 in Patients With AL Amyloidosis 
Protocol Number: CAEL101-203 Protocol Amendment 3 
Compound: CAEL-101 
Short Title: A Phase 2 Study of CAEL-101 to Evaluate the Safety and Tolerability in Patients 
With AL Amyloidosis 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address:  
121 Seaport Boulevard 
Boston, MA 02210 
Author: 
 
Version Date:  25 April 2024 
NCT #: NCT04304144


Statistical Analysis Plan 
 
 Version 2.0 
CAEL101-203 
 
25 April 2024 
Page 2 of 45 
Alexion Confidential 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ............................................................................................ 1 
TABLE OF CONTENTS ............................................................................................................ 2 
LIST OF TABLES ...................................................................................................................... 4 
LIST OF FIGURES .................................................................................................................... 4 
VERSION HISTORY ................................................................................................................. 5 
APPROVAL SIGNATURES ...................................................................................................... 6 
1. 
INTRODUCTION .................................................................................................... 7 
1.1. 
Objectives and Endpoints ......................................................................................... 8 
1.2. 
Study Design ............................................................................................................ 8 
2. 
STATISTICAL HYPOTHESES ............................................................................. 12 
3. 
SAMPLE SIZE DETERMINATION ...................................................................... 13 
4. 
ANALYSIS SETS .................................................................................................. 14 
5. 
STATISTICAL ANALYSES .................................................................................. 15 
5.1. 
General Considerations ........................................................................................... 15 
5.2. 
Study Participants ................................................................................................... 22 
5.3. 
Primary Endpoints Analysis .................................................................................... 23 
5.3.1. 
Endpoints ............................................................................................................... 23 
5.3.2. 
Main Analytical Approach ...................................................................................... 23 
5.3.2.1. 
Adverse Events ....................................................................................................... 23 
5.3.2.2. 
Clinical Laboratory Assessments ............................................................................ 25 
5.3.2.3. 
Vital Signs .............................................................................................................. 26 
5.3.2.4. 
12-Lead ECG.......................................................................................................... 26 
5.3.2.5. 
Physical Examinations ............................................................................................ 26 
5.4. 
Secondary Endpoints Analysis ................................................................................ 26 
5.4.1. 
Key Secondary Endpoints ....................................................................................... 26 
5.4.1.1. 
Main Analytical Approach ...................................................................................... 26 
5.5. 
Exploratory Endpoints Analysis .............................................................................. 27 
5.5.1. 
Exploratory Endpoints ............................................................................................ 27 
5.5.2. 
Main Analytical Approach ...................................................................................... 27 
5.5.3. 
Biomarker Evaluation ............................................................................................. 31 
5.6. 
Other Safety Analyses ............................................................................................ 31 


Statistical Analysis Plan 
 
 Version 2.0 
CAEL101-203 
 
25 April 2024 
Page 3 of 45 
Alexion Confidential 
5.6.1. 
Extent of Exposure ................................................................................................. 31 
5.6.2. 
Pregnancy Test ....................................................................................................... 32 
5.6.3. 
Background Plasma Cell Dyscrasia Treatments ...................................................... 32 
5.7. 
Other Analyses ....................................................................................................... 32 
5.7.1. 
Immunogenicity Assessment .................................................................................. 32 
5.7.2. 
Demographics and Baseline Characteristics ............................................................ 34 
5.7.3. 
Participant Disposition ............................................................................................ 34 
5.7.4. 
Medical History ...................................................................................................... 34 
5.7.5. 
Prior and Concomitant Medications ........................................................................ 34 
5.7.6. 
Overall Survival Assessment .................................................................................. 35 
5.7.7. 
Missing Data .......................................................................................................... 35 
5.8. 
Interim Analyses ..................................................................................................... 35 
6. 
SUPPORTING DOCUMENTATION..................................................................... 36 
6.1. 
Appendix 1: Technical Specifications for Derived Variables .................................. 36 
6.1.1. 
Age ......................................................................................................................... 36 
6.1.2. 
Adverse Events ....................................................................................................... 36 
6.1.3. 
Medical History ...................................................................................................... 37 
6.1.4. 
Estimated Glomerular Filtration Rate (eGFR) ......................................................... 37 
6.2. 
Appendix 2: Study and Participant Characteristics .................................................. 37 
6.2.1. 
Protocol Deviations ................................................................................................ 37 
6.2.2. 
Demographics, Disease Characteristics, and History ............................................... 38 
6.2.2.1. 
Demographics......................................................................................................... 38 
6.2.2.2. 
Disease Characteristics ........................................................................................... 39 
6.2.2.3. 
Medical/Surgical History and Baseline Physical Examination ................................. 40 
6.2.3. 
Prior and Concomitant Medications/Therapies ........................................................ 40 
6.3. 
Appendix 3: Instrument Scoring Details ................................................................. 41 
6.4. 
Appendix 4: Additional Details on Statistical Methods ........................................... 42 
6.4.1. 
Analysis Considerations Related to COVID-19 ....................................................... 42 
6.5. 
Appendix 5: Changes to Protocol-Planned Analyses ............................................... 42 
6.6. 
Appendix 6: List of Abbreviations .......................................................................... 43 
7. 
REFERENCES ....................................................................................................... 45 
 


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LIST OF TABLES 
Table 1: 
Analysis Visit Windows for Physical Examination ................................................. 17 
Table 2: 
Analysis Visit Windows for Vital Signs and Weight ............................................... 18 
Table 3: 
Analysis Visit Windows for 12-Lead Electrocardiogram ......................................... 18 
Table 4: 
Analysis Visit Windows for Safety Laboratory Tests .............................................. 19 
Table 5: 
Analysis Visit Windows for CTnT/cTnI and 24-Hr Urine Protein ........................... 19 
Table 6: 
Analysis Visit Windows for NT-proBNP, Serum FLC, and Serum and Urine 
Immunofixation Electrophoresis ............................................................................. 20 
Table 7: 
Analysis Visit Windows for Immunogenicity Tests and PK Samples ...................... 21 
Table 8: 
Analysis Visit Windows for NYHA Class Assessment ........................................... 22 
Table 9: 
Organ Involvement and Response Criteria .............................................................. 29 
Table 10: Staging of AL Amyloidosis With Advanced Cardiac Involvement for 
CARES Studies Based on the European Modification of the 2004 Mayo 
Staging ................................................................................................................... 40 
 
LIST OF FIGURES 
Figure 1: 
CAEL101-203 Part A Dose-Selection Schema ........................................................ 10 
Figure 2: 
CAEL101-203 Part A Cohort Dose-Selection Schema ............................................ 10 
Figure 3: 
CAEL101-203 Part B Schema ................................................................................ 10 
Figure 4: 
Composite Hematologic and Organ Response Model .............................................. 11 
 
 


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VERSION HISTORY 
 
This statistical analysis plan (SAP) for Study CAEL101-203 is based on Protocol Amendment 3, 
dated 18 Jul 2022.  
SAP Version 
Version Date 
Change 
Rationale 
1.0 
20 March 2023 
Original 
Final version 
2.0 
25 April 2024 
Additional 
Analyses 
added 
• Added the following analyses: 
1. Graded renal response 
2. Graded cardiac response 
3. Deep Hematologic response 
4. Summary of subsequent lines of 
anti-PCD therapy 
5.  Cardiac, renal, and liver (hepatic) 
response by hematologic response 
6. Time to first organ response, time 
to graded first response 
7. Adverse events by SMQ 
8. Summaries of liver enzymes and 
eDISH plot 
• Added visit windowing for End of 
Treatment visits 
• Added clarity for the definition of 
concomitant medication 
• Updated the cohort being 
presented for the CSR 
• Added the equation to be used for 
eGFR calculation 
• Added spaghetti plots for all 
biomarkers 
 


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APPROVAL SIGNATURES 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
29-Apr-2024
29-Apr-2024
29-Apr-2024


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1. 
INTRODUCTION  
This is a Phase 2 study that was designed sequentially and was amended dynamically to allow 
for identification of the optimal dose to carry forward into Phase 3, as well as to assess the safety 
and tolerability of the said dose in combination with multiple plasma cell dyscrasia concomitant 
medications. The study itself has 2 parts as follows: 
• Part A: designed to determine the recommended Phase 3 dose (RP3D) and define the 
safety and tolerability of CAEL-101 in combination with standard-of-care 
cyclophosphamide, bortezomib, and dexamethasone (CyBorD). The outcomes from 
the first 4 weeks of treatment (i.e., the dose-limiting toxicity [DLT] Observation 
Period) formed the basis for the determination of the dosing regimen for the Phase 3 
study. 
• Part B: designed to determine the safety and tolerability of CAEL-101 in combination 
with standard-of-care CyBorD and daratumumab to allow for use of daratumumab in 
the Phase 3 study. Part B commenced after the RP3D was determined from Part A. 
The outcomes from the first 4 weeks of treatment (i.e., the Safety Observation Period) 
formed the basis for allowing the use of daratumumab in the Phase 3 program. 
Part A consists of a Screening period, a safety and tolerability Treatment Period, and an EOT 
Period. The Treatment Period of Part A is divided into a DLT Observation Period and a 
Continued Treatment Period. A clinical study report has been written that described the 
outcomes from Part A DLT Observation Period through 31 Jul 2020, with the primary focus on 
the determination of the RP3D. Part B consists of a Screening Period, a safety and tolerability 
Treatment Period, and an EOT Period. The Treatment Period of Part B is divided into a Safety 
Observation Period and a Continued Treatment Period. The Continued Treatment Period for both 
Parts A and B is designed to follow the long-term safety and tolerability of CAEL-101, with dose 
titration up to the Phase 3 dose. Last participant last visit was completed on 14 November 2023. 
Although this study is open label and unrandomized, select efficacy outcomes (e.g., biomarkers 
for cardiac, hepatic, and renal organ response) may be assessed. 
This statistical analysis plan (SAP), in general, describes the statistical methods for analyzing 
data for the protocol titled “A Phase 2, Open-label, Multicenter, Dose Selection Study to 
Evaluate the Safety and Tolerability of CAEL-101 in Patients with AL Amyloidosis.” The 
current SAP includes Parts A and B of the study design described in the protocol. 
Standard data presentation instructions, along with the table, figure, and listing specifications, are 
contained in the data presentation plan in a separate document. Analyses related to safety and 
tolerability objectives of the study are specified in this SAP. 


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1.1. 
Objectives and Endpoints 
The objectives and endpoints for this study are as follows:  
Objectives 
Endpoints 
Primary 
 
• 
To define the safety and tolerability of 
CAEL101 for participants with amyloid light 
chain (AL) amyloidosis in Parts A and B of 
the study 
• 
Safety parameters to be assessed: 
treatment-emergent serious adverse events 
(SAEs) and adverse events (AEs), AEs 
leading to treatment discontinuation, 
abnormal laboratory tests of clinical 
significance, abnormal physical examination, 
abnormal vital signs, and abnormal 
electrocardiogram (ECG) parameters of 
clinical relevance 
• 
To determine the RP3D for patients with AL 
amyloidosis in Part A of the study 
• 
DLTs during the DLT Observation Period in 
Part A of the study 
Secondary 
 
Part A 
• 
To define the safety and tolerability of 
CAEL-101 when administered in combination 
with standard-of-care CyBorD 
Part B 
• 
To define the safety and tolerability of 
CAEL-101 when administered in combination 
with standard-of-care CyBorD and 
daratumumab 
• 
Safety parameters to be assessed separately 
for Parts A and B: treatment-emergent SAEs 
and AEs, AEs leading to treatment 
discontinuation, abnormal physical 
examination findings, abnormal vital signs, 
abnormal ECG parameters of clinical 
relevance, and changes in clinical safety 
laboratory parameters of potential clinical 
concern  
 
For both Parts A and B:  
• 
To describe the pharmacokinetic (PK) profile 
of CAEL-101 and to explore the PK profile of 
CAEL-101 when given biweekly (q2wk) 
versus once monthly (q4wk) after the first 
50 weeks 
 
• 
PK parameters (eg, maximum concentration, 
minimum concentration, and area under the 
concentration-time curve) 
Exploratory  
 
• 
To assess the efficacy of CAEL-101 in terms 
of cardiac, hepatic, and renal response in 
participants with AL amyloidosis 
The following parameters will be assessed:  
• 
Cardiac: N-terminal pro b-type natriuretic 
peptide (NT-proBNP), cardiac Troponin T 
(cTnT), cardiac Troponin I (cTnI), global 
longitudinal strain (GLS)% 
• 
Renal: 24-hr urine protein and eGFR 
• 
Hepatic: Alkaline phosphatase  
1.2. 
Study Design  
This section summarizes the planned study design. This study is ongoing, with participants from 
both Parts A and B participating in the Continued Treatment Period. Therefore, although the core 
objectives of Part A (DLT Observation Period) and Part B (Safety Observation Period) have 
been completed, they are described below to put the study into perspective. 


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This is a multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo 
Stage I, II, and IIIa AL amyloidosis participants. The study is divided into 2 parts:  
• Part A defines the safety and tolerability of CAEL-101 in combination with 
standard-of-care CyBorD and determines the RP3D 
• Part B evaluates the safety and tolerability of CAEL-101 in combination with 
standard-of-care CyBorD and daratumumab 
Part A  
Part A consists of a Screening Period, a safety and tolerability treatment period, and an EOT 
Period. The treatment period of Part A is divided into a DLT Observation Period and a 
Continued Treatment Period. Part A employed a 3 + 3 dose escalation design. 3 participants were 
enrolled in each dose cohort unless AEs preventing further dosing were observed. Enrollment 
into a new cohort with a higher dose of CAEL-101 did not begin until the DLT Observation 
Period was complete for the last participant enrolled in the previous cohort.  
The recommended dose required at least 6 participants to be treated with CAEL-101 at that dose 
and ≤ 1 participant having experienced a DLT during the DLT Observation Period. A DLT was 
defined as any Grade 3 or greater study intervention-related AE. Dose increases were 
discontinued based on safety or PK findings that may influence the decision about a 
recommended dose.  
All participants remained on the dose level assigned to the cohort in which they were originally 
enrolled until an RP3D was identified. When the RP3D was identified, all participants changed 
to the RP3D. Part B commenced after the RP3D had been identified.  
The assessment for RP3D has been completed. No DLTs were observed in any participants at 
any of the dose levels (500, 750, and 1000 mg/m2) when administered with concurrent CyBorD 
during the DLT Observation Period. Based on the safety and tolerability data, and protocol 
guidance, the final cohort review by the study site Principal Investigator and the Caelum 
Biosciences, Inc. Medical Monitor concluded that the 1000 mg/m2 dose is recommended for the 
Phase 3 studies and Part B of this study. For detailed discussion on the determination of RP3D, 
refer to Section 8 of the Abbreviated Summary Report for CAEL101-203 Safety Summary for 
Recommended Phase 3 Dose Selection Period by Caelum Biosciences, Inc. on 07 Aug 2020.  
Part B  
Part B consists of a Screening Period, a safety and tolerability treatment period, and an EOT 
Period. The treatment period of Part B is divided into a Safety Observation Period and a 
Continued Treatment Period. Although the original design indicated a minimum of 6 participants 
to receive CAEL101, 12 participants have received CAEL-101 in combination with 
standard-of-care CyBorD and daratumumab. 
Schematics of the study design are presented in Figure 1, Figure 2, and Figure 3. 


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Figure 1: 
CAEL101-203 Part A Dose-Selection Schema 
 
Abbreviation: DLT = dose-limiting toxicity 
Figure 2: 
CAEL101-203 Part A Cohort Dose-Selection Schema 
 
Note: There are 3 cohorts in Part A: CAEL-101 500, 750, and 1000 mg/m2 
All participants in Part A will receive CyBorD 
Abbreviations: DLT = dose-limiting toxicity; q1wk = every week; q2wk – every two weeks 
Figure 3: 
CAEL101-203 Part B Schema 
 
Note: All participants enrolled in part B will receive Daratumumab in addition to CAEL-101 and CyBorD. 
Abbreviations: q1wk = every week; q2wk – every two weeks 
After completing approximately 50 weeks of treatment, participants may switch to an alternative 
maintenance dosing regimen of every four weeks (q4wk), and then start following the 
assessment pattern of V29-V25-V27-V29-V25 and so on. The option of treatment switching 


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from bi-weekly (q2wk) to once every 4 weeks (q4wk) should be agreed between the Investigator 
and the Sponsor Medical Monitor and based on the assessment of the combined hematological 
and organ responses per the scoring system proposed by Sidana et al (2020). Switching could be 
considered if the score is within the range of 0 through 3 (Figure 4). 
Figure 4: 
Composite Hematologic and Organ Response Model 
 


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2. 
STATISTICAL HYPOTHESES  
This is a Phase 2, open-label, dose-selection study in which safety and tolerability outcomes 
were used to determine the dosing regimen to carry into Phase 3. No formal statistical 
hypotheses were defined as part of the design, and no formal inferential testing will be 
performed. 


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3. 
SAMPLE SIZE DETERMINATION  
The Part A sample size was based on similar studies in which a safe dose was selected for use in 
future larger efficacy/safety clinical studies (thus, the sample size was not selected based on a 
specific testable study hypothesis). A sample size of N = 3 participants for a given dose level 
without a DLT was judged to be clinically sufficient to allow for escalation to the next higher 
dose level. For both Parts A and B, a sample size of N = 6 participants for a given 
CAEL-101/standard of care treatment regimen was judged to be sufficient to allow for 
determination of tolerability in expectation that the CAEL-101/standard of care regimen may be 
used in the subsequent Phase 3 programs.  
The total study sample size was data driven and dependent on how many doses were tested and 
on safety and tolerability outcomes from that testing. 
25 participants were enrolled in the study at 3 Investigator sites. Part A enrolled 13 participants. 
For Part B, 12 participants have received CAEL-101 administered in combination with standard 
of care CyBorD and daratumumab. Once the newly enrolled participants had completed the 
Safety Observation Period, participants from Part A who were in the Continued Treatment 
Period and who, in the Investigator’s judgment, could have their standard of care treatment 
complemented with daratumumab were allowed to do so. One participant from Part A was 
therefore enrolled into Part B. 


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4. 
ANALYSIS SETS 
Three populations have been identified for purposes of analysis.  
Analysis Set 
Description 
Safety Set (SS) 
All participants treated with at least 1 dose of CAEL-101 (the study treatment) 
will be included in the SS.  
PK Analysis Set (PKS) 
The PKS will include all participants who have at least 1 measurable plasma 
concentration.  
Antidrug Antibody Analysis Set 
(AAS) 
The AAS includes all study participants who received any study intervention 
and who, after the first dose, have at least 1 reportable result in the antidrug 
antibody (ADA) assay. An ADA analysis will be conducted based on the 
actual treatment the participants have received. 
 


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5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations  
All assessments will use descriptive statistics, and no inferential analysis will be performed. 
Descriptive statistics (and by-participant listings of data) will form the basis from which 
conclusions regarding study objectives will be made. There are no plans to generate inferential 
(e.g., p-values) statistics, as the sample size is generally insufficient to allow for use of such 
methods.  
In general, data will be tabulated by cohort to allow for comparison of key outcomes by dose 
level, recognizing that, if a given cohort has only N = 2 or N = 3 participants, the interpretation 
of descriptive statistics is limited. A within-cohort t-test on changes from Baseline may be 
performed to evaluate if the change from Baseline is significant or not, but no formal inference 
from this result will be derived. All data will be listed by cohort, participant, and visit, with the 
primary determination of safety and tolerability outcomes based on review of these data listings. 
Figures/graphics of by-participant data will be presented where these will enable optimal review 
of outcomes across dose levels and over time. For clarity, the following are the definitions of the 
4 cohorts in this study:  
• Part A Cohort 1: participants treated with CAEL-101 500 mg/m2 + CyBorD 
• Part A Cohort 2: participants treated with CAEL-101 750 mg/m2 + CyBorD 
• Part A Cohort 3: participants treated with CAEL-101 1000 mg/m2 + CyBorD 
• Part B: participants treated with CAEL-101 1000 mg/m2 + CyBorD + Dara 
For the DLT observation period, tables for Part A will be structured with cohorts presented left 
to right (by ascending dose) and referred to in the tables (as well as other statistical outputs) as 
Cohort 1, 2, or 3.  
For the Clinical study report, the 2 study parts will be presented together, tables (as well as other 
statistical outputs) will be structured with cohorts presented from left to right as follows: 
• Part A 
• Part B 
Part A will include cohorts 1, 2 and 3. 
All study data will be listed by (part A and B), participant, and visit (as applicable). No 
preliminary rounding will be performed; rounding will only occur after analysis.  
Categorical variables will be summarized by cohort and visit using frequency counts and 
percentages. Continuous variables will be summarized by cohort and visit using descriptive 
statistics (number of participants (N), number of participants with available data (n), mean, SD, 
median, minimum, and maximum values). Minimum and maximum will be presented to the 
same number of decimal places as the raw data. Mean and median will be presented to 1 more 
decimal place than the raw data, and SD will be presented to 2 more decimal places than the raw 
data. 


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In general, the baseline value is the last non-missing value prior to the first study intervention. If 
the Day 1 assessment is missing, then last Screening assessment will be used as the Baseline 
assessment. 
All data and all outcomes derived from the data will be presented in detailed data listings or 
summary tabulations. Figures/graphics of by-patient data will be presented where these will 
enable optimal review of outcomes across dose levels and over time. 
All analyses will be performed using Statistical Analysis Software® (SAS®; Version 9.4 or 
higher; SAS Institute, Inc, Cary, NC, USA) release or other validated statistical software. 
Medical history information and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA; Version 25.0 or higher). 
Medications will be mapped to a generic term using the World Health Organization Drug 
Dictionary (WHO-DD) of 15 Mar 2018 or later.  
The analysis visit windows are defined in Table 1 to 7. 
 
 


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Table 1: 
Analysis Visit Windows for Physical Examination 
Visit 
Scheduled Study 
Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
-21 to 1 
-21 
1 
Week 2 
8 
2 
12 
Week 3 
15 
13 
19 
Week 4 
22 
20 
57 
Week 14 
92 
58 
134 
Week x (x = 26, 38, 50a) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 40] 
[((x - 1) * 7) + 43] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until the End of Study, whichever comes first. 
Abbreviation: SoA = Schedule of Assessments; EOT = End of Treatment 
 
 
 


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Table 2: 
Analysis Visit Windows for Vital Signs and Weight 
Visit 
Scheduled Study Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
-21 to 1 
-21 
1 
Week 2 
8 
2 
12 
Week 3 
15 
13 
19 
Week 4 
22 
20 
29 
Week 6 
36 
30 
43 
Week x (x = 8, 10, 12, 14, 16, 
18, 20, 22, 24, 26, 28, 30, 32, 34, 
36, 38, 40, 42, 44, 46, 48, 50a) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 5] 
[((x - 1) * 7) + 8] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until the End of Study, whichever comes first. 
Abbreviation: SoA = Schedule of Assessments; EOT = End of Treatment 
 
Table 3: 
Analysis Visit Windows for 12-Lead Electrocardiogram  
Visit 
Scheduled Study 
Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
-21 to 1 
-21 
1 
Week 5 
29 
2 
61 
Week 14 
92 
62 
134 
Week x (x = 26, 38, 50a) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 40] 
[((x - 1) * 7) + 43] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment Day + 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until End of Study, whichever comes first. 
Abbreviation: SoA = Schedule of Assessments; EOT = End of Treatment 
 


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Table 4: 
Analysis Visit Windows for Safety Laboratory Tests 
Visit 
Scheduled Study 
Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
-21 to 1 
-21 
1 
Week 2 
8 
2 
12 
Week 3 
15 
13 
19 
Week 4 
22 
20 
26 
Week 5 
29 
27 
33 
Week 6 
36 
34 
43 
Week 8 
50 
44 
71 
Week 14 
92 
72 
134 
Week x (x = 26, 38, 50a) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 40] 
[((x - 1) * 7) + 43] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond 50 weeks will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until End of Study, whichever comes first. 
Abbreviation: SoA = Schedule of Assessments; EOT = End of Treatment 
 
Table 5: 
Analysis Visit Windows for CTnT/cTnI and 24-Hr Urine Protein 
Visit 
Scheduled Study Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
1 
1 
1 
Week 14 
92 
2 
134 
Week x (x = 26, 38, 50a) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 68] 
[((x - 1) * 7) + 15] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until End of Study, whichever comes first. 
Abbreviations: CTnI = cardiac Troponin I; CTnT = cardiac Troponin T; SoA = Schedule of Assessments; EOT = 
End of Treatment 
 


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Table 6: 
Analysis Visit Windows for NT-proBNP, Serum FLC, and Serum and 
Urine Immunofixation Electrophoresis 
Visit 
Scheduled Study 
Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
1 
1 
1 
Week 6 
[((x - 1) * 7) + 1] 
2 
43 
Week 10 
44 
71 
Week 14 
72 
106 
Week x (x = 18, 22, 26, 30, 
34, 38, 42, 46, 50a) 
[((x - 1) * 7) - 12] 
[((x - 1) * 7) + 15] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until End of Study, whichever comes first. 
Abbreviations: FLC = free light chain; NT-proBNP = N-terminal pro b-type natriuretic peptide; SoA = Schedule 
of Assessments; EOT = End of Treatment 
 
 
 


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Table 7: 
Analysis Visit Windows for Immunogenicity Tests and PK Samples 
Visit 
Scheduled Study 
Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 (Baseline) 
1 
1 
1 
Week 2 
8 
2 
12 
Week 3 
15 
13 
19 
Week 4 
22 
20 
29 
Week x (x = 6, 8, 10, 12, 14, 16, 
18, 20) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 5] 
[((x - 1) * 7) + 8] 
Week 22 
142 
162 
Week x (x = 26, 30, 34, 38, 42, 
46, 50a) 
[((x - 1) * 7) - 12] 
[((x - 1) * 7) + 15] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until End of Study, whichever comes first. 
Abbreviations: PK = pharmacokinetic; SoA = Schedule of Assessments; EOT = End of Treatment 
 
 
 


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Table 8: 
Analysis Visit Windows for NYHA Class Assessment 
Visit 
Scheduled Study Day 
Window Study Day 
Lower Limit 
Upper Limit 
Week 1 
1 
1 
1 
Week 6 
36 
2 
36 
Week 10 
64 
37 
78 
Week x (x = 14, 18, 22, 26, 
30, 34) 
[((x - 1) * 7) + 1] 
[((x - 1) * 7) - 12] 
[((x - 1) * 7) + 15] 
Week 38 
247 
302 
Week 50a 
[((x - 1) * 7) - 40] 
[((x - 1) * 7) + 43] 
End of Treatment + Day 14 
EOT +14 
EOT + 1 
EOT + 21 
End of Treatment + Day 28 
EOT + 28 
EOT + 22 
EOT + 42 
End of Treatment + Day 56 
EOT + 56 
EOT + 43 
EOT + 70 
End of Treatment + Day 84 
EOT + 84 
EOT + 71 
EOT + 98 
End of Treatment + Day 112 
EOT +112 
EOT + 99 
EOT + 126 
End of Treatment + Day 140 
EOT + 140 
EOT + 127 
EOT + 154 
a 
Since the End of Study is defined as no more than 3 years after the last participant received the first dose of 
CAEL-101 or the Sponsor’s decision to terminate the study, whichever comes first, some participants will 
be treated beyond 50 weeks. Data collection may be longer than what is specified in SoA. The scheduled 
study day and window study day for visits beyond Week 50 will follow the formula used for Week 50. 
Analysis will be performed using all data through the time at which the participant remains on study 
treatment or until End of Study, whichever comes first. 
Abbreviations: NYHA = New York Heart Association; SoA = Schedule of Assessments; EOT = End of 
Treatment 
 
No analysis windowing is used for echocardiograms as most of the data is being collected and 
retrospectively. Echocardiogram data is not being used for any analysis, it will just be presented 
in a listing. 
5.2. 
Study Participants  
The number and percentage of participants in the following disposition categories will be 
summarized using the SS: 
• Participants in each analysis set 
• Participants who completed study intervention 
• Participants who discontinued study intervention along with the reasons for 
discontinuation 
• Participants who completed the study 
• Participants who discontinued from the study along with the reasons for 
discontinuation 
A listing of participants will be provided for the following: 
• Participants who failed the screening 


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• Participants included or excluded in the given analysis sets along with the reasons for 
exclusion from the respective analysis sets 
• Participants who discontinued study intervention 
• Participants who discontinued study 
5.3. 
Primary Endpoints Analysis 
The primary analysis set for the primary endpoints will be the Safety Set. 
5.3.1. 
Endpoints 
Safety assessments will include the following endpoints: 
• Treatment-emergent SAEs. 
• AEs. 
• AEs leading to treatment discontinuation. 
• Abnormal laboratory tests of clinical relevance. 
• Abnormal vital signs.  
• Abnormal ECG parameters of clinical relevance. 
• Evaluation of DLTs for each dose escalation cohort for Part A only. A DLT was 
defined as any Grade 3 or greater study intervention-related AE. 
5.3.2. 
Main Analytical Approach 
For Part A only, a table on the incidence of DLTs per cohort during the DLT Observation Period 
was derived. The RP3D was determined as the dose level with at least 6 participants treated with 
CAEL-101 at that dose and ≤ 1 participant having experienced a DLT during the DLT 
Observation Period. The assessment of RP3D was completed in which no incidence of DLTs has 
been observed at any dose level, and thus, the RP3D was concluded to be the 1000 mg/m2 dose. 
Safety assessments will include AEs, clinical laboratory tests, vital signs, and ECGs.  
Clinical laboratory tests and vital signs will be summarized descriptively for part A and B and 
overall. All abnormal findings in clinical laboratory test results, vital signs, and ECGs will be 
listed. 
5.3.2.1. 
Adverse Events 
AEs will be coded using MedDRA (Version 25.0 or higher); AEs will be reported starting from 
the date of signing of the informed consent form (ICF) until Day 140 (5 months) after the last 
dose of study intervention. Participant incidence of each System Organ Class (SOC) and 
Preferred Term (PT) will be tabulated. AE incidence will also be tabulated according to 
relationship to study medication and severity. Serious AEs and AEs resulting in premature 
discontinuation will be tabulated. 


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AEs starting after the first dose of treatment and before the last dose of study drug +140 days 
will be considered treatment-emergent AEs (TEAEs), will be reported as occurring during the 
treatment phase, and will be associated with the most recent treatment (dose level) given.  
AEs occurring after the participant has provided written informed consent and before the first 
dose of study treatment will be considered as pretreatment AEs. 
All TEAEs will be summarized by SOC and PT for part A and B and overall. All TEAEs will be 
summarized by incidence, severity, and potential causality to study intervention. 
5.3.2.1.1. Across Cohorts 
A summary of AEs and SAEs across part A and B and overall will be presented. The number of 
events (E) and the number and percentage of participants with events (n, %) will be shown by the 
relationship of events to study intervention (i.e., not related or related).  
The AEs resulting in study intervention withdrawal and the severity grades of the AEs (Grade 1 
through Grade 5) will be summarized similarly.  
These statistics will be prepared separately for all AEs and SAEs. In addition, the number and 
percentage of participants who died during the study will be presented. 
5.3.2.1.2. Adverse Events and Serious Adverse Events by System Organ Class and 
Preferred Term  
The number of AEs and the number and percentage of participants with events will be presented 
by SOC and PT. Participants are counted once in each SOC and PT. Percentages will be based 
on the total number of participants in the SS. SOCs will be listed in alphabetical order, and PT 
will be listed in order of frequency of occurrence within the SOC.  
Additional summary tables stratifying AEs by age, gender, and race will also be provided. SAEs 
will be summarized similarly. 
5.3.2.1.3. Adverse Events and Serious Adverse Events by System Organ Class, Preferred 
Term, and Relationship  
The number of AEs and the number and percentage of participants with events will be presented 
by SOC and PT as described above by relationship (related versus not related). If a participant 
has > 1 occurrence of an AE, the strongest relationship to study intervention will be used in the 
summary table.  
The causality criteria of related and possibly related will be considered “related” to the study 
intervention.  
SAEs will be summarized similarly. 
5.3.2.1.4. Adverse Events and Serious Adverse Events by System Organ Class, Preferred 
Term, and Severity Grade  
The number of AEs and the number and percentage of participants with events will be presented 
by SOC and PT as described above by severity grade (Grades 1 through 5). If a participant has 
> 1 occurrence of an AE, the highest grade will be used in the summary table.  


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SAEs will be summarized similarly. 
5.3.2.1.5. Deaths, Other Serious Adverse Events, and Other Significant Adverse Events   
AEs leading to death, AEs leading to withdrawal of study intervention, and AEs resulting in the 
modification of the study intervention, including interruption and reduction, will also be 
presented by SOC and PT as described above.  
Listings for the SAEs and deaths will be produced. 
5.3.2.1.6. Adverse Events of Special Interest 
The following adverse event categories will be analyzed by part A and B and overall: 
• Narrow SMQ for ‘Hypersensitivity’ or ‘Anaphylactic reaction’ 
o Narrow SMQ for ‘Hypersensitivity’ or ‘Anaphylactic reaction’ that occurred 
within 24 hours of drug administration. 
• Narrow SMQ for ‘Hypersensitivity’ or ‘Anaphylactic reaction’ excluding High Level 
Term (HLT) of ‘Infusion site reactions and administration site reactions NEC’ 
o Narrow SMQ for ‘Hypersensitivity’ or ‘Anaphylactic reaction’ excluding High 
Level Term (HLT) of ‘Infusion site reactions and administration site reactions 
NEC’ that occurred within 24 hours of drug administration. 
• HLT of Infusion site reactions and administration site reactions NEC 
o HLT of ‘Infusion site reactions and administration site reactions NEC’ that 
occurred within 24 hours of drug administration. 
For time period calculation (within 24 hours), if AE start time is missing or infusion time is 
missing then Infusion start date < AE Start Date < (Infusion Start Date + 1) per subject, infusion 
start date. 
Overall summaries, summaries by SOC and PT, Serious adverse events, summaries by 
relationship and by severity will be provided for the above categories. 
5.3.2.2. 
Clinical Laboratory Assessments 
Descriptive statistics by time of assessment will be presented for each laboratory parameter. 
Changes from Baseline, as well as shift tables, will be presented. All laboratory values will be 
classified as normal, below normal, or above normal based on the normal ranges supplied by the 
local laboratory. Frequencies of abnormal values will be presented in tabular form, as 
appropriate. For purposes of analyses, laboratory results based on standardized units will be 
used. For consistency, the Estimated Glomerular Filtration Rate will be calculated using the 
CKD- EPI Creatinine equation (2021) (without race). A listing of each laboratory parameter will 
be presented by participant, visit, and part A and B. In addition, a listing of serum free light 
chains (FLCs; kappa and lambda), their changes from Baseline, and their ratio of kappa/lambda 
will be listed by cohort, participant, and visit. A listing that shows the Mayo staging and 
European staging will also be produced by participant, visit, and part A and B for cardiac-
evaluable participants.  
 


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Evaluation of Drug Induced Serious Hepatotoxicity 
A Hy’s law case refers to an increase in aminotransferase >3 X the reference upper limit of 
normal (ULN), with bilirubin >2 X ULN. Possibly Hy’s law cases can be visualized with use of 
evaluation of drug- induced serious hepatotoxicity (eDISH) plots, a log-log scatter plot where the 
x-axis is the peak post- baseline ALT as a multiple of ULN, and the y-axis is the peak post-
baseline Bilirubin as a multiple of ULN. An eDISH plot by quadrant will be presented for each 
part A and B. 
Summaries of liver enzymes will be provided in a separate table as well. 
5.3.2.3. 
Vital Signs 
Observed values and changes from Baseline in vital signs (systolic and diastolic blood pressure, 
pulse rate, oral temperature and respiratory rate) at each visit will be summarized descriptively. 
A listing of vital signs will be presented by participant, visit, and part A and B and overall. 
5.3.2.4. 
12-Lead ECG 
The number and percentage of participants with abnormal 12-lead ECG findings will be 
summarized by visit and part A and B and overall. A listing will also be created. 
5.3.2.5. 
Physical Examinations 
 A listing will be created to present the visits when physical examination was conducted.  
5.4. 
Secondary Endpoints Analysis 
The secondary endpoint analysis will evaluate PK parameters. The analysis set for the PK profile 
analysis is the PKS. 
5.4.1. 
Key Secondary Endpoints 
The plasma concentrations will be determined from the blood samples collected at the following 
time points: Weeks 1 to 4, Weeks 6 to 22, and then at every other 2-week study visit after Week 
22. After Week 50, samples will be collected approximately every 182 days and at the EOT. The 
PK profile of CAEL-101 when given bi-weekly (q2wk) versus once-monthly (q4wk) after the 
first 50 weeks will also be explored. 
5.4.1.1. 
Main Analytical Approach 
For PK concentration summaries, values below the limit of quantification will be set to 0. Missing 
values will not be imputed.  
PK concentration data will be summarized using the following descriptive statistics: number of 
participants (N), number of participants with available data (n), arithmetic mean, SD, median, 
minimum, and maximum. The following conventions will be applied to PK presentations and 
summaries: 
• For continuous variables, all mean and median values are formatted to 1 more 
decimal place than the raw data. SD values are formatted to 2 more decimal places 


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than the raw data. Minimum and maximum values are presented with the same 
number of decimal places as the raw data. 
• Date variables are formatted as DDMMMYYYY for presentation. Time is formatted 
in military time as HH:MM for presentation. 
Plasma concentrations versus time data will be presented in a data listing by participant. Plasma 
concentration data will be summarized separately by analyte, visit (week), nominal study day, 
and time point using descriptive statistics. In addition, plasma concentrations will be plotted to 
allow for visual comparison of concentrations between cohorts and over time. 
5.5. 
Exploratory Endpoints Analysis  
The analysis set for the exploratory endpoints will be the SS. 
5.5.1. 
Exploratory Endpoints 
The organ-specific outcomes for cardiac, renal, and hepatic biomarker response will be assessed 
using both retrospective and prospective data. The following parameters will be evaluated.  
• Cardiac:  
− NT-proBNP 
− cTnT, cTnI 
− GLS% 
• Renal:  
− 24-hr urine protein 
• Liver (Hepatic):  
− Alkaline phosphatase 
• Hematologic response: 
− Involved - uninvolved FLC difference (dFLC) 
5.5.2. 
Main Analytical Approach 
Summary statistics (mean, SD, SEM, minimum, maximum) will be computed and displayed for 
each efficacy endpoint. For GLS%, only a listing will be presented. 
Efficacy endpoints will also be assessed for absolute changes (and percent changes) over time. 
Participants with organ involvement (e.g., cardiac and renal, liver (hepatic)) will be identified at 
Baseline through minimum thresholds for each relevant biomarker and defined as being cardiac 
evaluable, renal evaluable, and hepatic evaluable, accordingly. These specific analysis 
populations will then be assessed for changes over time in the organ-specific biomarkers. 
Participants may be classified as responders, progressors, and stable (by organ) according to 
varying definitions of response.  
The criteria in Table 9 will be used for organ involvement and response status. Missing values 
will not be imputed. 


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By-visit summaries of response status by organ will be presented for evaluable participants. Most 
recent response status (by organ) will also be tabulated for the evaluable participants. 
Biomarker values and change from Baseline values for NT-proBNP (for cardiac evaluable 
participants), urine protein and estimated glomerular filtration rate (eGFR) (for renal evaluable 
participants), and alkaline phosphatase (for liver (hepatic) evaluable participants) will be plotted 
by visit by participant. The timepoint at which the participant progressed to Q4 dosing will be 
marked. 
A waterfall plot of percent change from Baseline in NT-proBNP for the last assessment will be 
plotted for each cardiac evaluable participant. Similarly, a waterfall plot for percent change from 
Baseline in 24-hr urine protein and eGFR will be plotted for renal evaluable participants and 
percent change from Baseline for alkaline phosphatase for liver (hepatic) evaluable participants. 
A spaghetti plot will be presented for percent change from Baseline in NT-proBNP by visit for 
cardiac evaluable participants. 
For renal evaluable participants, a side-by-side spaghetti plot of percent change from Baseline 
for 24-hr urine protein and eGFR by visit will be presented for renal evaluable participants. 
Similarly, for hepatic evaluable participants, a spaghetti plot for percent change from Baseline in 
Alkaline Phosphatase by visit will be presented. 
In addition, a spaghetti plot for NT-proBNP values for cardiac evaluable participants, 24-hr urine 
protein and eGFR for renal evaluable participants and Alkaline phosphatase for hepatic evaluable 
participants for will also be presented by visit. 
 
 


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Table 9: 
Organ Involvement and Response Criteria 
Organ 
Organ 
Involvement 
Response 
Progression 
No Response / 
Stability 
Cardiac 
NT-proBNP ≥ 
332ng/L (39.2 
pmol/L) 
A decrease of 
> 30% in 
NT-proBNP levels 
and a decrease of 
NT-proBNP 
> 300 ng/L in 
participants with a 
baseline 
NT-proBNP of 
≥ 650 ng/La 
An increase of 
> 30% in 
NT-proBNP levels 
(in the absence of 
eGFR decline of 
≥ 25%) and an 
increase of 
≥ 300 ng/L in 
NT-proBNP (in 
the absence of 
eGFR decline of 
≥ 25%) 
Neither response nor 
progression 
Renal 
24-hr urine protein 
> 0.5 g/day  
A decrease of 
≥ 30% in urine 
protein or decrease 
of urine protein to 
< 0.5 g/24 hr in the 
absence of an eGFR 
decrease of ≥ 25% 
Worsening of 
≥ 25% in eGFR 
Neither response nor 
progression 
Liver (Hepatic) 
ALP > 1.5 times 
institutional upper 
limit of normal 
A decrease of 
≥ 50% and/or 
normalization of the 
serum ALP level 
An increase of 
≥ 50% in the 
serum ALP level 
Neither response nor 
progression 
Dispenzieri et al (2015) and Palladini (2014) 
a Abbreviations: ALP = alkaline phosphatase; eGFR = estimated glomerular filtration rate; 
NT-proBNP = N-terminus pro-brain natriuretic peptide 
eGFR calculated using the CKD- EPI Creatinine equation (2021) (without race) will be used to 
derive the response status.  
CKD-EPI Creatinine Equation (2021) 
𝑒𝐺𝐹𝑅𝑐𝑟= 142 ∗min (𝑆𝑐𝑟
𝐾, 1)
𝛼
∗max (𝑆𝑐𝑟
𝐾, 1)
−1.200
∗0.9938𝐴𝑔𝑒∗1.012(𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
Where: 
Scr = standardized serum creatinine in mg/dL 
K = 0.7 (females) or 0.9 (males) 
α = -0.241 (female) or -0.302 (males) 
min (Scr/K,1) is the minimum of Scr/K or 1.0 
max (Scr/K,1) is the maximum of Scr/K or 1.0 
Age (years) 
In addition to the above criteria, graded cardiac response and graded renal response will also be 
presented by visit. 


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• Graded cardiac response, determined using the following definitions, will be assessed 
in participants with cardiac involvement: 
− Cardiac complete response (CarCR) defined as NT-proBNP < 350 ng/L (< 41.39 
pmol/L) 
− Cardiac very good partial response (CarVGPR) defined as a >60% reduction in 
NT-proBNP from baseline level not meeting CarCR  
− Cardiac partial response (CarPR) defined as a 31–60% reduction in NT-proBNP 
from baseline level not meeting CarCR 
− Cardiac no response (CarNR) defined as ≤ 30% reduction in NT-proBNP from 
baseline level   
• Graded renal response, determined using the following criteria, will be assessed in 
participants with renal involvement:  
− Renal complete response (RenCR, 24-hr urine protein ≤200 mg/24 h, in the 
absence of ≥ 25% decrease in eGFR) 
− Renal very good partial response (RenVGPR, > 60% reduction in baseline 24-hr 
urine protein and not meeting RenCR, in the absence of ≥ 25% decrease in eGFR) 
− Renal partial response (RenPR, 31-60% reduction in baseline 24-hr urine protein, 
in the absence of ≥ 25% decrease in eGFR) 
− Renal no response (RenNR, 30% or less reduction in baseline 24-hr urine protein) 
− Renal progression (≥ 25% decrease in eGFR) 
The following endpoints will be assessed by part A and B and overall: 
• Time to first cardiac response 
• Time to first graded cardiac response, defined as the first of any responses (CarCR, 
CarVGPR or CarPR) 
• Time to first CarCR 
• Time to first CarVGPR 
• Time to first CarPR 
• Best Cardiac Response, defined as the best cardiac response (by NT-proBNP) of a 
participant among all assessed timepoints, best being a responder and worst being a 
progressor. 
• Time to first renal response  
• Time to first graded renal response, defined as the first of any responses (RenCR, 
RenVGPR, RenPR), best being a responder and worst being a progressor.    
• Time to first RenCR 
• Time to first RenVGPR 


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• Time to first RenPR 
• Best Renal Response, defined as the best renal response (by 24-hr urinary protein) of a 
participant among all assessed timepoints. 
• Time to first liver (hepatic) response 
The organ-specific outcomes for cardiac, renal, and hepatic biomarker response will be assessed 
using both retrospective and prospective data. The retrospective collection may include a review 
of the participant record at the site. The combination of retrospective and prospective data 
collection will allow for a more robust determination of the effects of CAEL-101 on efficacy in 
participants with AL amyloidosis.  
Hematological Response: 
Hematologic response will be evaluated using the below criteria  
Proportion of participants in the following categories will be presented by treatment group at 
each visit: 
• Very good partial response or better (dFLC < 4 mg/dL) 
• Partial response or no response (dFLC ≥ 4 mg/dL)  
Proportion of participants who achieved  
• Deep hematologic response by dFLC < 1mg/dL 
• Deep hematologic response by iFLC < 2mg/dL 
Deep hematologic response by dFLC < 1mg/dL or iFLC < 2mg/dL 
Hematologic response by visit will also be presented in a listing for each participant. 
Immunoglobulin results for both serum and urine sample will be presented by visit in a listing. 
Organ (Cardiac, renal, and liver(hepatic)) responses will also be presented by hematologic 
response by visit. For example, for cardiac involvement participants having cardiac response, 
they will be further categorized by hematologic response categories: 
1. VGPR or Better  
2. Partial response or no response for each visit and cohort. 
5.5.3. 
Biomarker Evaluation 
AL amyloidosis-related biomarkers (NT-proBNP, cTnT, cTnI, hs-cTnT, hs-cTnI, and serum 
FLCs) are collected and will be assessed by part A and B and overall and visit via descriptive 
statistics, as well as observed and change from Baseline values over time. These will also be 
presented in the listings. 
5.6. 
Other Safety Analyses 
5.6.1. 
Extent of Exposure 
The SS will be used to summarize study treatment duration, study intervention exposure, and 
treatment compliance.  


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The duration (month) of exposure to study intervention will be calculated as [(date of last 
exposure to treatment – date of first dose) + 1]/30.4375, regardless of dose interruptions or dose 
reductions. Non-integer values will be rounded to 1 decimal place. Exposure will be summarized 
by descriptive statistics and by categories of < 3 months, 3 to < 6 months, 6 to < 9 months, 
9 to < 12 months, 12 to < 15 months, 15 to < 18 months, and ≥ 18 months. 
The number (%) of participants by exposure duration will be tabulated. Tabulation of the number 
of participants by individual study center will be provided.  
Participants will receive the dose based on the cohort to which they belong. The planned total 
dose will be based on the participant’s body surface area (BSA) in square meters, which is 
calculated using the height and weight obtained during the Screening Period.  
The treatment compliance of CAEL-101 is defined as the actual total doses administered (where 
doses are expected every 2 weeks) divided by the planned total doses over treatment period. 
𝑂𝑣𝑒𝑟𝑎𝑙𝑙 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 𝐴𝑐𝑡𝑢𝑎𝑙 𝑡𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒𝑠 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑡𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒𝑠
 × 100 
The planned dose for a missed visit is the planned dose based on the participant’s BSA from the 
previous non-missing visit, and the actual dose administered is 0. 
Treatment compliance will be summarized by descriptive statistics and as frequency counts and 
percentages for the following categories: < 80% versus ≥ 80%. Participants will be grouped into 
3 columns corresponding to 500/750/1000 mg/m2 CAEL-101 + CyBorD (Part A), 1000 mg/m2 
CAEL-101 + CyBorD + Dara (Part B), and Total (both Parts A and B) in the tables. Participants 
being treated with a lower dose will be identified in the listings but pooled with all participants in 
the tables. 
5.6.2. 
Pregnancy Test 
Serum or urine pregnancy test will be listed and tabulated as the data warrant. 
5.6.3. 
Background Plasma Cell Dyscrasia Treatments 
Background plasma cell dyscrasia treatments will be listed and tabulated. 
5.7. 
Other Analyses 
5.7.1. 
Immunogenicity Assessment 
ADA and neutralizing antibody (NAb) response and associated categorical variables will be 
collected according to the Schedule of Assessments.  
Samples for immunogenicity testing will be collected according to the Schedule of Assessments 
and prior to infusion of study intervention. Samples collected at designated time points will be 
analyzed using validated ADA assays in all participants included in the AAS. Samples positive 
in the ADA assay will be further characterized in the ADA titer and the NAb assays (when the 
NAb assay is available). The impact of ADA on PK analysis will be described as part of the 
population PK SAP and thus is not included in this current SAP. 
All immunogenicity assessments will be performed on the AAS using the following ADA 
variables: 


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• ADA negative: defined as a negative signal in the ADA assay at all timepoints 
collected for the AAS 
• ADA positive: defined as a positive signal in the ADA assay at any timepoint 
collected for the AAS 
ADA-positive participants will be further categorized for ADA response as follows: 
− Pre-existing immunoreactivity: defined as either an ADA-positive response at 
Baseline in the ADA assay with all post-first dose ADA results negative OR a 
positive response at Baseline with all post-first dose ADA responses < 4-fold over 
baseline titer levels 
− Treatment-boosted ADA responses: defined as a positive response in the ADA 
assay post-first dose that is ≥ 4-fold over baseline titer levels, when baseline 
results are positive  
− Treatment-emergent ADA responses: defined as a positive response in the ADA 
assay post-first dose when baseline results are negative or missing 
Participants with a treatment-emergent or treatment-boosted responses will be further 
categorized based on the duration of the response as follows: 
− Persistent response: defined as an ADA-positive response with 2 or more 
consecutive ADA-positive sampling timepoints separated by at least a 16-week 
period, with no ADA negative samples in between, irrespective of missing 
samples 
− Indeterminate response: defined as an ADA-positive sample only at the last 
collected sample 
− Transient response: defined as an ADA response that is neither a persistent nor an 
indeterminate response 
ADA-positive samples will be further characterized for neutralizing activity in the NAb assay. 
NAb status categories for a participant are defined as follows: 
• NAb negative: defined as a negative signal in the NAb assay for the participant at all 
timepoints 
• NAb positive: defined as a positive signal in the NAb assay for the participant at any 
timepoint 
The incidence of ADA response categories will be summarized as absolute occurrence (n) and 
percentage (%) of all participants by part A and B and overall. Maximum ADA titer levels will 
be listed and summarized for ADA-positive participants by part A and B and overall. 
NAb-positive and NAb-negative participants will be summarized as absolute occurrence (n) and 
percentage (%) of all participants by part A and B and overall. 
Associations between ADA response categories and systemic exposure to CAEL-101 may be 
explored for CAEL-101-treated participants. 
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• Associations between ADA response categories and SAEs and severe AEs, including 
SAEs such as systemic hypersensitivity, anaphylaxis, (injection/infusion) site 
reactions lasting > 24 hours, and other immune-related SAEs, may be explored. 
For analyses of the association of immunogenicity with impact on efficacy:  
• Associations between ADA response categories and key efficacy endpoints or 
variables may be explored for CAEL-101-treated participants. Plots of key efficacy 
endpoints may be analyzed for potential impact of immunogenicity on drug efficacy. 
5.7.2. 
Demographics and Baseline Characteristics 
Baseline characteristics (including age, gender, race, disease stage, and other disease-specific 
characteristics) will be tabulated descriptively (e.g., the number and percentage of participants 
for each category for categorical parameters and the number of participants, mean, SD, and range 
for continuous parameters).  
Additionally, New York Heart Association (NYHA) class (see Appendix D of the protocol) and 
organ involvement will be summarized.  
5.7.3. 
Participant Disposition 
Participant completion status and reasons for early termination will be tabulated descriptively. 
Exposure characteristics will be tabulated (i.e., treatment duration and the number of doses of 
CAEL-101 received). Total dose given will be tabulated by part A and B.  
5.7.4. 
Medical History 
Relevant and significant medical history and concurrent illnesses will be presented in data 
listings for all participants and noted as to whether the condition is active at the first visit of the 
Screening Period. Any AEs occurring after the participant has provided written informed consent 
and before the first dose of treatment will be included in the medical history. 
5.7.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO-DD and tabulated by cohort. 
Concomitant medications will be reported in a manner similar to that of AEs. The number and 
percentage of participants who take concomitant medications will be summarized by Anatomical 
Therapeutic Chemical (ATC Level 3) drug class and PT, across all cohorts and by cohort, and 
presented in a by-participant listing. Prior and concurrent plasma cell dyscrasia (PCD) treatments 
will be summarized separately. Proportion of participants who received subsequent lines of anti-
PCD treatments will be presented. For Part A - Any participant who proceeded to a non-CyBorD 
regimen would be defined as requiring subsequent line of therapy (and daratumumab would be 
included as subsequent line of therapy). Similarly for part B - Any participant who proceeded to 
a non-CyBorD + daratumumab would be defined as requiring a subsequent line of therapy. 
Medications will be classified as follows: 
• Prior medications: prior medications are those that have a start date/time and end 
date/time prior to the start of the first treatment administration. 


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• Concomitant medications: medications will be considered as concomitant if the 
medication either started prior to first dose of study medication and was continuing at 
the time of first dose of study medication; or started on or after the date of the first 
dose of study medication.  
• New-onset concomitant medications: medications starting on or after the start of the 
first dose of study medication. 
If a missing medication start date cannot be definitively determined as having started after the 
first dose, the medication will be considered as started prior to the first dose; similarly, if a 
missing medication stop date/time cannot be determined as having stopped prior to the first dose, 
the medication will be considered concomitant (taken after the first dose). 
However, for medications that are clearly prior medications (e.g., the stop year is 2018, while 
this study is being run in 2020), imputation of the date will be performed to properly allocate the 
medication to the correct table. When this is done, if the year and month are present but the day 
is missing, the first day of the month will be used as the imputed value. 
5.7.6. 
Overall Survival Assessment 
The overall survival will be produced for exploratory evaluation through Kaplan-Meier plots by 
part A and B. In addition, Kaplan-Meier plots stratified by baseline Mayo stage will be produced.  
5.7.7. 
Missing Data 
Missing data will not be replaced or imputed except for missing dates as stated in Section 6.1. 
5.8. 
Interim Analyses 
This is an open-label study in which analyses will be performed for safety reporting, publication, 
and internal scientific exploratory purposes. Thus, although there is no planned “formal” interim 
analysis for this study, analysis of data during the course of the study will be performed for the 
afore-mentioned purposes. 
 


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6. 
SUPPORTING DOCUMENTATION  
6.1. 
Appendix 1: Technical Specifications for Derived Variables 
The following derived data will be calculated prior to the analysis. 
6.1.1. 
Age 
Age at enrollment will be presented as the number of years between the date of birth and the date 
of signing ICF.  
In cases where only the month and year are provided for a date, the day for the date will be 
imputed as 15. A missing month will be imputed as June. In cases where the day is observed but 
the month is missing, the date will be imputed as 15 Jun.  
6.1.2. 
Adverse Events 
The analysis of AEs is described in detail in Section 5.3.2.1. 
TEAEs are events with start dates and start times on or after the date and time of the first study 
intervention dose and before the last dose +140days. If the start date of an AE is partially or 
completely missing and the end (stop) date and time of the AE do not indicate that it occurred 
prior to the first dose, then the AE is considered as treatment emergent if: 
• The start year is after the year of the first study intervention dose. 
• The start year is the same as the year of the first study intervention dose: 
− The start month is missing. 
− The start month is present and is the same or after the month of the first study 
intervention dose. 
• The start date is completely missing. 
An AE occurring after the participant has provided written informed consent and before the first 
dose of study treatment is considered a pretreatment AE.  
Percentages are based on the total number of participants in the SS. 
To be able to calculate time from the first dose to AE, the following are the imputation rules for 
AE start dates: 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for AEs 
D 
M and Y same as M and Y of the first 
dose of study intervention 
Date of the first dose of study 
intervention 
M and/or Y not same as the date of the 
first dose of study intervention 
First day of the month 
D and M 
Y same as Y of the first dose of study 
intervention 
Date of the first dose of study 
intervention 
Y is after Y of the first dose 
Set to 01 Jan 
D, M, 
and Y 
None; date is completely missing 
Date of the first dose of study 
intervention 


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AE duration (days) = date of stop of AE – date of start of AE + 1 
Duration will be set to “missing” if the stop date of AE is incomplete or if the AE is ongoing. 
6.1.3. 
Medical History 
To be able to calculate the amount of time since diagnosis of a medical condition, the imputation 
rules for missing start date of medical history are as follows:  
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Imputation 
Start date for medical history 
D 
First day of the month 
D and M 
Set to 01 Jan 
D, M, and Y 
Informed consent date 
Time (months) since diagnosis of a condition = (informed consent date – start date for medical 
history + 1)/365.25 
6.1.4. 
Estimated Glomerular Filtration Rate (eGFR) 
 eGFR will be calculated using the CKD- EPI Creatinine equation (2021) (without race) using 
the below formula.  
CKD-EPI Creatinine Equation (2021) 
𝑒𝐺𝐹𝑅𝑐𝑟= 142 ∗min (𝑆𝑐𝑟
𝐾, 1)
𝛼
∗max (𝑆𝑐𝑟
𝐾, 1)
−1.200
∗0.9938𝐴𝑔𝑒∗1.012(𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
Where: 
Scr = standardized serum creatinine in mg/dL 
K = 0.7 (females) or 0.9 (males) 
α = -0.241 (female) or -0.302 (males) 
min (Scr/K,1) is the minimum of Scr/K or 1.0 
max (Scr/K,1) is the maximum of Scr/K or 1.0 
Age (years) 
6.2. 
Appendix 2: Study and Participant Characteristics 
6.2.1. 
Protocol Deviations 
Protocol deviations will be presented in a listing, including severity, protocol deviation category, 
and the action taken, if any. The decision whether a protocol deviation is a major or minor 
deviation will be made on a case-by-case basis. The possible reasons of major protocol 
deviations include, but are not limited to, the following: 
• Failure to obtain informed consent. 
• Violation of inclusion/exclusion criteria. 


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• SAE (pregnancy) reporting requirement not followed. 
• Any known study medication administration error. 
• Any study-specific related procedure done before the signature of the informed 
consent. 
• Noncompliance with study intervention. A participant is defined as noncompliant if 
the participant took < 80% of the planned doses during the time the participant was 
enrolled in the study. Participants whose dose has been adjusted (reduced) due to 
tolerability will be considered to have been fully compliant for purposes of this 
assessment. 
• Intake of prohibited medication. 
• Source document/data missing. 
Major protocol deviations will be summarized by part A and B and overall based on the SS. All 
participants with protocol deviations including those specified above will be listed. Protocol 
deviations from monitoring reports and other relevant sources will also be reviewed, and any 
important deviations will be included in the list that is summarized and reported. Coronavirus 
disease 2019 (COVID-19)-related major protocol deviations will also be summarized by part A 
and B and overall. 
6.2.2. 
Demographics, Disease Characteristics, and History 
All demographic and baseline characteristics information will be summarized and listed using 
the SS.  
Descriptive statistics (number of participants (N), number of participants with available data (n), 
mean, SD, median, minimum, and maximum) will be provided for all continuous variables. 
Frequency counts and percentages of participants in each category will be provided for all 
categorical variables. 
6.2.2.1. 
Demographics 
The following demographic and baseline characteristic variables will be summarized: 
• Gender (male or female) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, not reported, or unknown) 
• Race (American Indian or Alaska Native, Asian, Black or African American, 
Hawaiian or other Pacific Islander, White Caucasian, or other) 
• Age (years) at Baseline (continuous) 
• Age (years) at Baseline (categorical; < 65 or ≥ 65)  
• Height at Baseline (centimeters) 
• Weight at Baseline (kilograms) 
• BSA (m2) 


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6.2.2.2. 
Disease Characteristics 
The following disease characteristics at Baseline will be summarized descriptively: 
• Mayo stage (I, II, and IIIa) as reported by the Investigator at Screening 
• AL amyloidosis in the heart (yes and no) 
• NT-proBNP 
• cTnT, cTnI, hs-cTnT, and hs-cTnI 
• FLC subtype (kappa and lambda)  
• FLC ratio 
• Time since diagnosis of AL amyloidosis (years) 
• NYHA class (I, II, or III) 
• Cardiac evaluable (yes and no) 
• Renal evaluable (yes and no) 
• Liver evaluable (yes and no) 
Time since diagnosis of the disease will be presented as the number of years between the date of 
the first dose and the date of diagnosis (i.e., time since diagnosis of the disease = [date of the first 
dose – date of diagnosis + 1]/365.25, rounded up to 1 decimal place). 
Participants Staging (Mayo Staging 2012 and European Modification of 2004 Mayo Staging) 
will be provided by presented in a listing. 
Mayo 2012 Staging:  Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT 
≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 
points, respectively. 
 
 


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Table 10: 
Staging of AL Amyloidosis With Advanced Cardiac Involvement for 
CARES Studies Based on the European Modification of the 2004 Mayo 
Staging 
Stage I 
Stage II 
Stage IIIa 
Stage IIIb 
Zero markers above 
threshold: 
• NT-proBNP < 332 ng/L 
AND 1 of the following:  
• hs-cTnT < 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≤ 0.035 ng/mL 
• cTnI ≤ 0.1 ng/mL 
One marker above 
threshold: 
• NT-proBNP ≥ 332 ng/L 
OR 1 of the following 
• hs-cTnT ≥ 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≥ 0.035 ng/mL 
• cTnI ≥ 0.1 ng/mL 
Two markers above 
threshold: 
• 332 ng/L ≤ NT-proBNP 
≤ 8500 ng/L 
AND 1 of the following: 
• hs-cTnT ≥ 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≥ 0.035 ng/mL 
• cTnI ≥ 0.1 ng/mL 
Two markers above 
threshold: 
• NT-proBNP 
> 8500 ng/L 
AND 1 of the following: 
• hs-cTnT ≥ 50 pg/mL 
(0.05 ng/mL) 
• cTnT ≥ 0.035 ng/mL 
• cTnI ≥ 0.1 ng/mL 
Palladini and Merlini (2014), adapted with Muchtar et al (2019) 
a The 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac 
involvement is based on the conventional (generation 4) cTnT assay. However, hs-cTnT, or generation 5 assay, 
is becoming more widely available and is used more commonly in clinical practice. It is established that a cTnT 
value of > 0.035 ng/mL can be extrapolated to a hs-cTnT value of ≥ 50 pg/mL (0.05 ng/mL) for the 
determination of Mayo stage (Muchtar, 2019). 
Abbreviations: AL = amyloid light chain; cTnI = cardiac Troponin I; cTnT = cardiac troponin T; hs-cTnT = high-
sensitivity cardiac Troponin T; NT-proBNP = N-terminal pro b-type natriuretic peptide 
6.2.2.3. 
Medical/Surgical History and Baseline Physical Examination 
Medical history information will be coded to primary SOC and PT using MedDRA 
(Version 25.0 or higher). Medical history will be summarized by SOC and PT. Summaries will 
be presented as prior disease and concomitant disease, with the prior and concomitant status 
determined by whether the condition was active at the time of Screening. Participant listings will 
be presented including medical history condition, start and end dates, and status as ongoing. 
6.2.3. 
Prior and Concomitant Medications/Therapies 
Medications will be mapped to a generic term using the WHO-DD of 15 Mar 2018 or later.  
The following steps will be implemented to categorize the medications: 
Algorithm for Categorization of Medications (Prior or Concomitant) 
Parameter 
Value 
Additional Conditions 
Medication Category/Action 
Ongoing flag 
Yes 
Not applicable 
Concomitant 
No 
Medication end date is partial or 
missing 
Perform the imputation on medication 
end date and then assign the medication 
category 
Medication end date is before the first 
dose of study intervention 
Prior 
Medication end date is on or after the 
first dose of study intervention 
Concomitant 
 


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Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date of 
medication 
D 
M and Y same as M and Y of the first 
dose of study intervention 
Day of the earlier of (date of the first 
dose of study intervention, end date of 
medication) 
M and/or Y not same as the date of the 
first dose of study intervention 
First day of the month 
D and M 
Y same as Y of the first dose of study 
intervention 
Day and month of the earlier of (date of 
the first dose of study intervention, end 
date of medication) 
Y is after Y of the first dose 
Day and month of the end date of 
medication 
D, M, and 
Y 
None; date is completely missing 
Earlier of (date of the first dose of study 
intervention, end date of medication) 
 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
End date of 
medication 
D 
M and Y same as M and Y of the first 
dose of study intervention 
Day of the later of (date of the first dose 
of study intervention, start date of 
medication) 
M and/or Y not same as the date of the 
first dose of study intervention 
Last day of the month 
D and M 
Y same as Y of the first dose of study 
intervention 
Day and month of the later of (date of 
the first dose of study intervention/start 
date of medication) 
Y is after Y of the first dose 
Day and month of the start date of 
medication 
D, M, and 
Y 
None - date is completely missing 
Later of (date of the first dose of study 
intervention, start date of medication) 
Summaries of prior and concomitant medications will be presented separately. Summaries of 
prior and concomitant background plasma cell dyscrasia treatment will also be presented 
separately. The number and percentage of participants who took concomitant medications will be 
summarized by ATC drug class and PT, overall and by part A and B, and presented in a by-
participant listing. The data listing will include start and end dates (or indication of ongoing), 
dose, unit, frequency, route, indication, and a flag of whether the medication usage is prior or 
concomitant. A separate listing will be created for background plasma cell dyscrasia treatments 
and prohibited medications. 
Nonpharmacologic therapies and procedures will be coded using MedDRA (Version 25.0 or 
higher). All data will be listed, including the start and end dates (or indication of ongoing) of the 
procedure, procedure (including SOC, PT, and reported term), indication, results for diagnostic 
tests, and whether the procedure was performed prior to the first dose of study intervention 
(prior/concomitant). 
6.3. 
Appendix 3: Instrument Scoring Details 
Not applicable. 


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6.4. 
Appendix 4: Additional Details on Statistical Methods 
6.4.1. 
Analysis Considerations Related to COVID-19 
On 11 Mar 2020, COVID-19 was declared a pandemic by the WHO (Cucinotta, 2020). This 
section summarizes additional analysis considerations to assess the potential impact of 
COVID-19 (Meyer, 2020). The following additional sensitivity and supplementary analyses will 
be included to assess the impact of the pandemic disruption on the study and to address 
pandemic-related missing data.  
1. The summary of participant disposition will include COVID-19-related discontinuations 
and withdrawals.  
2. A summary of known COVID-19 exposure or diagnosis will be provided using the SS.  
3. A summary of COVID-19-related important protocol deviations will be provided. 
A by-participant listing of all protocol deviations will be provided.  
6.5. 
Appendix 5: Changes to Protocol-Planned Analyses 
The following additional analyses will be done that were not planned in the protocol: 
- 
Graded cardiac response 
- 
Graded renal response 
- 
Deep hematologic response 
The following analyses that were planned in the protocol, but will not being conducted: 
- 
Analyses of GLS% - Since GLS% was added as an exploratory analysis in a protocol 
amendment, the baseline data for most subjects was not available. Only a listing will be 
provided for the same. 
- 
Physical Examination – Though physical examinations were done as per the schedule of 
assessments; the data for abnormality was not collected by body system. Only a listing will 
be provided. 
 
 


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6.6. 
Appendix 6: List of Abbreviations 
Abbreviation 
Definition 
AAS 
Antidrug Antibody Analysis Set 
ADA 
antidrug antibody 
AE 
adverse event 
AL 
 
amyloid light chain 
ATC 
Anatomical Therapeutic Chemical 
BSA 
body surface area 
COVID-19 
coronavirus disease 2019 
cTnI 
cardiac Troponin I 
cTnT 
cardiac Troponin T 
CyBorD 
cyclophosphamide, bortezomib, and dexamethasone 
DLT 
dose-limiting toxicity 
dFLC 
Involved-uninvolved free light-chain difference 
iFLC 
Involved free light-chain difference 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EOT 
End of Treatment 
FLC 
free light chain 
GLS 
global longitudinal strain 
hs-cTnT 
high-sensitivity cardiac Troponin T 
hs-cTnI 
high-sensitivity cardiac Troponin I 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
neutralizing antibody 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
PCD 
Plasma cell dyscrasia 
PK 
pharmacokinetic 
PKS 
Pharmacokinetic Analysis Set 
PT 
Preferred Term 
q2wk 
biweekly 
q4wk 
once monthly 
RP3D 
recommended Phase 3 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS® 
Statistical Analysis Software®  
SOC 
System Organ Class 


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Abbreviation 
Definition 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


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7. 
REFERENCES 
Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomedica, 2020 Mar 
19;91(1):157-60. 
Dispenzieri A, Buadi F, Kumar SK, et al. Treatment of immunoglobulin light chain amyloidosis: 
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement. 
Mayo Clin Proc. 2015;90:1054-81.  
Meyer RD, Ratitch B, Wolbers M, et al. Statistical issues and recommendations for clinical trials 
conducted during the COVID-19 pandemic. Stat Biopharm Res. 2020 Jun;20:399-411. 
Muchtar E, Kumar SK, Gertz MA, et al. Staging systems use for risk stratification of systemic 
myloidosis in the era of high-sensitivity troponin T assay. Blood. 2019;133(7):763-6. 
Palladini G, Merlini G. What is new in diagnosis and management of light chain amyloidosis? 
Blood. 2016;128(2):159-68.  
Sidana S, Milani P, Binder M, et al. A validated composite organ and hematologic response model 
for early assessment of treatment outcomes in light chain amyloidosis. Blood Cancer J. 
2020;10(4):41. 
Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers 
of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-2332. 
University of Rochester Medical Center. Free Light Chains. Available from: 
https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=seru
m_free_light_chains. Accessed May 21, 2020.