Clinical trial NCT02545907
Conditions: Amyloidosis
Keywords: Amyloidosis AL Amyloidosis
Sponsor: University College, London
Start date: 2017-09-14; Completion date: 2019-10-21
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates the safety and efficacy of carfilzomib used in combination with thalidomide and dexamethasone in patients with relapsed AL amyloidosis. The trial begins with a dose escalation phase, in which the maximum tolerated and recommended dose will be determined. The trial will then open into an expansion phase in which the combination efficacy is assessed.

Detailed description:
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that progressively disrupt tissue structure and impair function. The treatment of systemic AL amyloidosis has evolved to a risk adapted approach based on the end organ damage, particularly cardiac involvement, and the functional status of the patient. Intensive therapies like high dose melphalan followed by an autologous stem cell transplant are considered for patients with limited organ involvement, younger age and excellent functional status.

The majority of patients with AL amyloidosis, however, will not be candidates for ASCT and are generally treated with combination chemotherapy. This therapy may include bortezomib, a proteasome inhibitor which is particularly effective in AL amyloidosis but which may have a severe side-effect profile.

Carfilzomib is specific for the chymotrypsin-like active site of the 20S proteasome, is structurally and mechanistically distinct from bortezomib, and has demonstrated less reactivity against non-proteasomal proteases when compared to bortezomib. It also appears to be better tolerated. However, information regarding the use of carfilzomib in the treatment of AL amyloidosis is limited.

In the dose escalation phase of this study, a minimum of 6 (3 at dose level 0 and 3 at dose level -1)and a maximum of 18 (6 at dose level 0, 1, and 2) patients will recruited in a 3+3 design with cohorts of between 3 and 6 patients, in order to determine maximum tolerated dose and recommended dose.

At the recommended dose level identified, a further 20 (minimum) patients will be recruited to further assess safety and toxicities at the RD.

Arms: arm 1: Participants in the escalation phase will receive carfilzomib (K), thalidomide (T), and dexamethasone (D) in combination. The dose of thalidomide will be 50mg/day. The dose of dexamethasone will be 20mg on Day 1, 8, and 15. Carfilzomib will be administered on Day 1, 8, and 15, but the level of carfilzomib delivered with depend on the cohort allocation. The dose of carfilzomib may be:

* Level -1 - 27mg/m2
* Level 0 - 36mg/m2
* Level 1 - 45mg/m2
* Level 2 - 56mg/m2

Participants will receive up to six cycles of treatment. Following determination of the maximum tolerated dose and recommended dose, the trial will be opened to an expansion phase where participants will receive the RD of carfilzomib, along with thalidomide and dexamethasone, using the schedule outlined above.
Interventions: intervention 1: Carfilzomib intervention 2: Thalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL. intervention 2: 50mg capsule. intervention 3: 2mg tablet.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A single arm open labeled multicentre phase 1b dose escalation study of 
Carfilzomib 
taken 
in 
combination 
with 
Thalidomide 
and 
Dexamethasone in relapsed AL amyloidosis (CATALYST Trial) 
 
 
 
 
 
 
 
 
Protocol Version and Date 
Version 3.0 24th January 2018 
EUDRACT no: 
2015-000954-40 
Trial Sponsor: 
University College London 
Trial Sponsor reference: 
14/0786 
Trial funders: 
Amgen 
Funders reference: 
Amgen 20159879 
ISRCTN no: 
ISRCTN16308011 
ClinicalTrials.Gov no 
NCT02545907 
REC Number 
16/LO/0087 
 
Active IMP’s:   
 
Carfilzomib, Thalidomide and 
Dexamethasone (KTD) 
 
 
 
 
This document contains confidential information. It contains proprietary information, any viewing or 
disclosure of such information that is not authorised in writing by the Sponsor is strictly prohibited. It is 
provided for the sole use of the Chief Investigator, Principal Investigators, Authorised Staff, Research 
Ethics Committee and Regulatory Authorities. By accepting this document, you agree to maintain the 
information as confidential and to use it only for the purpose of conducting the study. The Sponsor and 
CTRU accept no responsibility for the accuracy of additional documentation or instructions developed by 
collaborating or third party organisations, from the content of this protocol. 
 
 
 
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Protocol version 3.0 , 24th January 2018 Authorisation signatures 
 
 
The Chief Investigator and the JRO have discussed this protocol. The investigators agrees to perform the 
investigations and to abide by this protocol.  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP and UK 
Regulations for CTIMPs (SI 2004/1031; as amended), the UK Data Protection Act (1998), the Trust 
Information Governance Policy (or other local equivalent), the current Research Governance Framework, 
the GMO (Contained Use) Regulations 2000 (and subsequent amendments), the Sponsor’s SOPs, and 
other regulatory requirements as amended. 
 
 
 
 
 


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Coordinating Centre: 
For general queries, supply of trial documentation and central data management please contact: 
 
CATALYST Trial Coordinators: 
 
Geraldine Murden                                                         Erin Peat 
Clinical Trials Research Unit                                        Clinical Trials Research Unit 
       Leeds Institute of Clinical Trials Research                    Leeds Institute of Clinical Trials Research 
University of Leeds                                                      University of Leeds 
       Leeds                                                                           Leeds 
LS2 9JT                                                                       LS2 9JT 
 
Tel: 0113 343 9369                                                     Tel: 0113 343 1658 
 
Fax: 0113 343 4345                                                     Fax: 0113 343 4345 
       Email: medcatal@leeds.ac.uk                                      Email: medcatal@leeds.ac.uk 
 
 
 
Other trial contacts: 
 
Chief Investigator: 
Dr Ashutosh Wechalekar 
Address: 
National Amyloidosis Centre 
 
University College Medical School (Royal Free Campus) 
 
Royal Free Hospital, Rowland Hill Street, London, NW3 2PF 
Tel: 
020 7433 2758 
Fax: 
020 7433 2817 
Email: 
a.wechalekar@ucl.ac.uk 
 
 
Co-Investigator: 
Dr Julian Gillmore 
Address: 
University College Medical School (Royal Free Campus) 
 
Royal Free Hospital, Rowland Hill Street, London, NW3 2PF 
Tel: 
020 7433 2726 
Fax: 
020 7433 2817 
Email: 
j.gillmore@ucl.ac.uk 
 
 
 
 
 
 
Trial Statistician: 
Nick Ward,  
Address: 
Clinical Trials Research Unit 
Leeds Institure of Clinical Trials Research 
 
University of Leeds 
Leeds 
 
LS2 9JT 
Tel: 
0113 343 4887 
Fax: 
0113 343 1471 
Email: 
N.Ward@leeds.ac.uk 
 
 


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National Amyloidosis Centre (NAC/UK NAC), Royal Free Hospital 
 
Laboratory Contact – Serum Samples 
 
To be collected, as per standard practice, on Day 1 of each chemotherapy cycle 
 
Name & Address: 
Wendy Taylor (Specimen Reception) 
National Amyloidosis Centre 
Royal Free & University College Medical School 
 
Royal Free Hospital, Rowland Hill Street, London, NW3 2PF 
Tel: 
020 7433 2890 
Fax: 
020 7433 2817 
 
 
 
Trial Management Group (TMG): 
Dr A Wechalekar 
Chief Investigator 
Royal Free Hospital 
Dr J Gillmore 
Co-Investigator 
Royal Free Hospital 
Dr Helen Lachmann 
Reader in Medicine 
UCL 
Dr Sadie Reed 
Head of Trial Management 
Leeds CTRU 
Dr Sarah Brown 
 Division Director & Scientific 
Lead 
Leeds CTRU 
 
 
 
 
 


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Trial Registration 
Only authorised members of staff from the UK NAC have permission to register participants into the trial.  
Tel: CTRU 0113 343 1658  (Monday – Friday 9am – 5pm except Public and University holidays). Details of 
University Holidays can be found in the Investigator Site File. 
 
Reporting Serious Adverse Events (SAEs)  
Complete the SAE CRF for all SAEs occurring in the trial and fax to the CTRU within 24 hours of becoming aware 
of the event: 
Fax: CTRU: 0113 343 4345 
A receipt will be sent for all received SAEs. If a receipt is not received within two working days contact the 
CTRU.  
 
Reporting Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Complete the SUSAR CRF for all SUSARs occurring in the trial and fax to the CTRU within 24 hours of becoming 
aware of the event:  
Fax: CTRU: 0113 343 4345 
A receipt will be sent for all received SUSARs. If a receipt is not received within two working days contact 
the CTRU. 
 
Reporting Dose Limiting Toxicities (DLTs) 
Complete the DLT CRF for all DLTs occurring in cycle 1 of treatment and fax to the CTRU immediately and no 
later than 24 hours of becoming aware of the event:  
Fax: CTRU: 0113 343 4345 
A receipt will be sent for all received DLTs. If a receipt is not received within two working days contact the 
CTRU. 
 
Reporting Pregnancies 
Report all pregnancies to the CTRU using the Notification of Pregnancy CRF within 24 hours Fax: CTRU: 0113 
343 4345 
A receipt will be sent for all received pregnancy reports. If a receipt is not received within two working days 
contact the CTRU. 
Pregnancies resulting in a congenital anomaly must also be reported as an SAE 
 
 


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Contents 
Contents .................................................................................................................................................................... 6 
1.0 
Protocol Summary ...................................................................................................................................... 10 
1.1  
Summary of Trial Design ................................................................................................................................... 10 
1.2 
Eligibility & Registration Schema ..................................................................................................................... 14 
1.3 
Trial Treatment Schema ..................................................................................................................................... 14 
2.0 
Introduction ................................................................................................................................................. 15 
2.1  
Background........................................................................................................................................................... 16 
2.1.1 
Assessing the risk and response to therapy ................................................................................................................ 16 
2.1.2 
Treatment of AL amyloidosis ....................................................................................................................................... 16 
2.1.3 
Carfilzomib background ................................................................................................................................................ 17 
2.2 
Carfilzomib Dosing ............................................................................................................................................. 21 
2.3 
Proposed Trial ...................................................................................................................................................... 22 
2.3.1 
Summary and Rational for Therapeutic Study ........................................................................................................... 22 
3.0 
Trial Design .................................................................................................................................................. 23 
3.1 
Aims ....................................................................................................................................................................... 24 
3.2 
Trial Activation .................................................................................................................................................... 24 
4.0 
Selection of Sites/Site Investigators ......................................................................................................... 25 
4.1 
Site (Regional Haematology Centre) selection ................................................................................................ 25 
4.1.1 
Selection of Principal Investigators and other  investigators at sites ..................................................................... 25 
4.1.2 
Training requirements for site staff ............................................................................................................................. 25 
4.2 
Site initiation and Activation ............................................................................................................................. 25 
4.2.1 
Site Initiation .................................................................................................................................................................... 25 
4.2.2 
Required documentation ................................................................................................................................................ 25 
4.2.3 
Site activation ................................................................................................................................................................... 26 
5.0 
Informed consent ........................................................................................................................................ 27 
5.1 
Referral of patients to Regional Haematology Centres ................................................................................. 28 
6.0 
Selection of Patients ................................................................................................................................... 29 
6.1 
Pre-treatment Evaluation ................................................................................................................................... 29 
6.2 
Screening Log ....................................................................................................................................................... 29 
6.3 
Patient Eligibility .................................................................................................................................................. 29 
6.3.1 
Inclusion Criteria ............................................................................................................................................................. 29 
6.3.2 
Exclusion Criteria ............................................................................................................................................................ 30 
6.3.3 
Pregnancy and Birth Control ........................................................................................................................................ 30 
7.0 
Registration Procedures ............................................................................................................................. 32 
7.1 
Patient Registration ............................................................................................................................................. 32 
8. 
Trial Treatment ............................................................................................................................................ 34 
8.1 
Treatment Schedule Summary........................................................................................................................... 34 
8.1.1 
KTD Regimen ................................................................................................................................................................. 34 
8.1.2 
Changes in Body Surface Area (BSA) ......................................................................................................................... 35 
8.1.3  
Dose Escalation ............................................................................................................................................................... 35 
8.1.4 
Dose Limiting Toxicities ................................................................................................................................................ 36 
8.1.5 
Definition of Maximum Tolerated Dose (MTD) ...................................................................................................... 36 
8.1.6 
Definition of Recommended Dose (RD) ................................................................................................................... 36 
9.0  Trial Medicinal Product Management ...................................................................................................... 37 
9.1 
Investigational Medicinal Products (IMPs). .................................................................................................... 37 
 
CARFILZOMIB (IMP).......................................................................................................................................................... 37 


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 
DEXAMETHASONE (IMP) ............................................................................................................................................... 37 
 
THALIDOMIDE (IMP) ....................................................................................................................................................... 37 
9.2 
Supportive Measures ........................................................................................................................................... 37 
9.3    Pharmacy responsibilities ....................................................................................................................................... 38 
9.3.1  
Labelling and IMP handling .......................................................................................................................................... 38 
9.3.2  
IMP Preparation .............................................................................................................................................................. 38 
9.3.3 
IMP Administration and Risk Management ............................................................................................................... 38 
9.3.4  
Drug accountability ......................................................................................................................................................... 40 
9.3.5 
Temperature Excursions ................................................................................................................................................ 40 
9.4    Clinical Management after Treatment Discontinuation .................................................................................... 40 
9.5     Out-of-hours medical care .................................................................................................................................... 41 
10.0 
Dose delays and modifications ............................................................................................................... 42 
10.1 
Cycle 1 - dose escalation phase only ................................................................................................................. 42 
10.2  
Subsequent cycles (all patients) ......................................................................................................................... 42 
10.3 
Haematological Parameters ................................................................................................................................ 43 
10.4  
Dose Reduction For Haematologic Toxicities ............................................................................................... 43 
10.5 
Dose Reductions for Non-Haematologic Toxicities ..................................................................................... 44 
10.6 
Dexamethasone Toxicity .................................................................................................................................... 45 
10.7  
Thalidomide Toxicity .......................................................................................................................................... 45 
10.8  
Increased Creatinine or Decreased CrCl ......................................................................................................... 46 
10.9 
Infections .............................................................................................................................................................. 46 
10.10 
Congestive Heart Failure ................................................................................................................................. 46 
10.11 
Conditions Not Requiring Dose Reduction ................................................................................................. 46 
10.12 
Carfilzomib Safety Considerations ................................................................................................................ 47 
11.0 
Assessments .............................................................................................................................................. 48 
11.1 
Eligibility assessments ......................................................................................................................................... 50 
11.1.1 Assessments at National Amyloidosis Centre (UK NAC) ............................................................................................ 50 
11.1.2 
Assessments at RHC to reconfirm eligibility ............................................................................................................. 50 
11.2 
Assessments during treatment ........................................................................................................................... 50 
11.3 
Assessments during follow up ........................................................................................................................... 51 
12.0  
Data Management and Data Handling Guidelines ............................................................................. 52 
12.1 
Completing Case Report Forms ....................................................................................................................... 52 
12.2 
Missing Data ......................................................................................................................................................... 52 
12.3 
Timelines for data return .................................................................................................................................... 52 
12.4 
Data Queries ........................................................................................................................................................ 52 
13.0 
 Pharmacovigilance .................................................................................................................................. 53 
13.1 
Definitions of Adverse Events .......................................................................................................................... 53 
13.2 
Reporting Procedures ......................................................................................................................................... 53 
13.2.1 
All Adverse Events (AEs) ............................................................................................................................................. 53 
13.2.2 
Serious Adverse Events (SAEs) ................................................................................................................................... 54 
13.3 
 SUSARs ................................................................................................................................................................ 57 
13.4 
Safety Monitoring ................................................................................................................................................ 58 
13.5 
Pregnancy .............................................................................................................................................................. 58 
13.5.2 
SAEs During Pregnancy ................................................................................................................................................ 58 
13.5.3 
Pregnancy Report Processing at LEEDS CTRU ...................................................................................................... 58 
13.6 
Development Safety Update Reports (DSURs) ............................................................................................. 59 
14.0 
Withdrawal of patients ............................................................................................................................ 60 
14.1 
Discontinuation of Trial Treatment ................................................................................................................. 60 


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14.1.1  
Withdrawal due to clinical reasons ............................................................................................................................... 60 
14.1.2 
Patient withdrawal from trial treatment ...................................................................................................................... 60 
14.2 
Future Data Collection ....................................................................................................................................... 60 
14.3 
Losses to follow-up ............................................................................................................................................. 60 
15.0 
Trial Closure .............................................................................................................................................. 61 
15.1 
End of Trial .......................................................................................................................................................... 61 
15.2 
Early discontinuation of trial ............................................................................................................................. 61 
15.3 
Withdrawal from trial participation by sites .................................................................................................... 61 
15.4 
Archiving of Trial Documentation ................................................................................................................... 61 
16.0  
Trial Monitoring and Oversight ............................................................................................................. 62 
16.1 
Central monitoring .............................................................................................................................................. 62 
16.2 
’For Cause’ On-Site Monitoring........................................................................................................................ 62 
16.3 
Oversight Committees ........................................................................................................................................ 63 
16.3.1 
Trial Management Group (TMG) ................................................................................................................................ 63 
16.3.2 
Safety Review Committee .............................................................................................................................................. 63 
16.3.3 
Role of LEEDS CTRU .................................................................................................................................................. 63 
17.0 
Incident Reporting and Serious Breaches ............................................................................................. 64 
17.1 
Incident Reporting .............................................................................................................................................. 64 
17.2 
Serious Breaches .................................................................................................................................................. 64 
18.0 
Endpoints .................................................................................................................................................. 65 
18.1 
Primary endpoints ............................................................................................................................................... 65 
18.2 
Secondary endpoints ........................................................................................................................................... 65 
18.3 
Endpoint definitions ........................................................................................................................................... 65 
19.0 
Statistical considerations ......................................................................................................................... 66 
19.1 
Sample size ........................................................................................................................................................... 66 
19.2 
General Considerations ...................................................................................................................................... 66 
19.3 
Primary Endpoint Analysis ................................................................................................................................ 66 
19.4 
Secondary Endpoint Analysis ............................................................................................................................ 67 
19.5 
Frequency of Analyses ........................................................................................................................................ 67 
20.0 
Data Monitoring ....................................................................................................................................... 68 
20.1 
Safety Review Committee .................................................................................................................................. 68 
20.2 
Trial Steering Committee (during the dose expansion phase only): ............................................................ 68 
20.3 
Data Monitoring .................................................................................................................................................. 68 
20.4 
Clinical Governance Issues ................................................................................................................................ 68 
21.0 
Ethical and Regulatory Approvals ......................................................................................................... 69 
21.1 
Ethical Approval .................................................................................................................................................. 69 
21.2 
Regulatory Approval ........................................................................................................................................... 69 
21.3 
Site Approvals ...................................................................................................................................................... 69 
21.4 
Protocol Amendments........................................................................................................................................ 69 
22.0 
 Sponsorship and Indemnity .................................................................................................................. 70 
22.1 
Sponsor Details: ................................................................................................................................................... 70 
22.2 
Indemnity .............................................................................................................................................................. 70 
23.0 
 Funding ..................................................................................................................................................... 71 
24.0 
 Publication Policy.................................................................................................................................... 71 
25.0 
 References ................................................................................................................................................ 72 
APPENDIX 1: 
ABBREVIATIONS ........................................................................................................................................ 75 


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APPENDIX 2: 
DEFINITION OF AMYLOIDOSIS, MYELOMA AND RELATED DISEASES ........................ 78 
APPENDIX 3: 
ECOG GRADES OF PERFORMANCE STATUS AND NYHA CLASS ....................................... 79 
APPENDIX 4: 
DEFINITIONS OF RESPONSE ............................................................................................................... 80 
APPENDIX 5: 
TOXICITY CRITERIA ................................................................................................................................. 82 
APPENDIX 6: 
DETAILS OF INVESTIGATIONS AND THEIR TIMINGS ........................................................... 83 
APPENDIX 7: 
AMYLOID STAGE ....................................................................................................................................... 85 
APPENDIX 8: 
POSSIBLE RISKS AND DISCOMFORTS WITH CARFILZOMIB ................................................ 86 
 
 
 


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1.0 
Protocol Summary 
1.1  
Summary of Trial Design  
Title: A single arm open labeled multicentre phase 1b dose escalation study of 
Carfilzomib taken in combination with Thalidomide and Dexamethasone in 
relapsed AL amyloidosis (CATALYST Trial) 
EudraCT no: 2015-000954-40 
Sponsor name & no: University College London 14/0786 
Funder name & no.: Amgen 20159879 
ISRCTN no: 16308011 
Design: Open label, multi-centre, Phase Ib clinical trial 
Aims: To determine the maximum tolerated dose of Carfilzomib withina combination 
chemotherapy regimen (KTD) and to access the the safety and tolerability of 
this regimen in patients with relapsed or refractory AL amyloidosis  
 
Primary endpoint: Define the MTD and RD of Carfilzomib in combination with TD 
Safety and toxicity of KTD 
Secondary endpoints: Clonal responses  
Improvement in amyloidotic organ function 
Overall Survival at 1 year  
Relapse free survival at 1 year 
Subjects: Any UK patient with a diagnosis of systemic AL amyloidosis with relapsed or 
refractory disease after first line treatment.   
During the dose escalation phase a minium of 6 or a maximum of 18 
participants will be recruited.   
Once the MTD and/or RD has been established a maximum of 20 
participants will be recruited.   
Inclusion & Exclusion 
criteria 
Inclusion Criteria 
Patients with the following characteristics are eligible for this study:  
1. Aged 18 years or greater 
2. Diagnosis of systemic AL amyloidosis with  
3. exclusion of genetic mutations associated with hereditary amyloidosis and   
immunohistochemical exclusion of AA and TTR amyloidosis as 
appropraite 
4. Amyloid-related organ dysfunction or organ syndrome 
5. Measurable clonal disease  
6. Clonal relapse after previous chemotherapy or autograft stem cell 
transplant OR refractory clonal disease to previous chemotherapy or stem 
cell transplant  
7. Capable of providing written, informed consent and willing to follow 
study protocol  
8. Life expectancy ≥ 6 months 
9. ECOG performance status of 0-2 
10. Platelet count ≥ 50x109/l) 
11. Neutrophil count ≥ 1x109/l) 
12. Haemoglobin ≥ 8g/dL 
13. Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of 
normal 
14. Female participants of child-bearing potential must have a negative 
pregnancy test prior to treatment and agree to use dual methods of 
contraception for the duration of the study and for 30 days following 
completion of study. Male participants must also agree to use a barrier 
method of contraception for the duration of the study and for 90 days 
following completion of study if sexually active with a female of child-
bearing potential.  Women who could become pregnant must have taken 
precautions not to become pregnant for 1 month before the start of the 
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15. Participants must comply with the Celgene pregnancy prevention 
programme for Thalidomide 
 
Exclusion Criteria 
Patients with the following characteristics are ineligible for this study (see 
Appendices for definitions): 
 
16. Overt symptomatic multiple myeloma 
17. Amyloidosis of unknown or non-AL type 
18. Localised AL amyloidosis (in which amyloid deposits are limited to a 
typical single organ, for example the bladder or larynx, in association with 
a clonal proliferative disorder within that organ) 
19. Trivial or incidental AL amyloid deposits in the absence of a significant 
amyloid-related organ syndrome (e.g., isolated carpal tunnel syndrome) 
20. Refractory to or progressive disease with an IMid and proteasome 
inhibitor combination  
21. Allogeneic stem cell transplantation 
22. Solid organ transplantation 
23. Severe peripheral or autonomic neuropathy causing significant functional 
impairment that, in the investigator’s opinion, may interfere with protocol 
adherence 
24. eGFR <20ml/min 
25. Ejection fraction < 40% or NYHA class III or IV heart failure or 
uncontrolled hypertension that concerns the investigator 
26. Severe pulmonary Hypertension that, in the investigator’s opinion, may 
interfere with protocol adherence 
27. Advanced Mayo stage III disease as defined by hs-Troponin T>0.07 and  
NT-proBNP >700 pMol/L OR NT-proBNP >1000 pMol/L OR supine  
SBP <100 mm of Hg 
28. Myocardial infarction in the proceeding 6 months or unstable angina or 
conduction abnormalities uncontrolled by medication or devices 
29. Concurrent active malignancies, except surgically removed basal cell 
carcinoma of the skin or other in situ carcinomas 
30. Pregnant, lactating or unwilling to use adequate contraception 
31. Systemic infection unless specific anti-infective therapy is employed. 
32. Known or suspected HIV infection 
33. Contraindication to any of the required concomitant drugs or supportive 
treatments 
34. Any other clinically significant medical disease or condition or psychiatric 
illness that, in the Investigator’s opinion, may interfere with protocol 
adherence or a participant’s ability to give informed consent 
35. Previous experimental agents within 3 months before the date of 
registration 
36. Known allergies to Carfilzomib, Thalidomide or Dexamethasone 
37. Positive hepatitis B viruses (HBV) test 
 
 
 
Planned number of sites: 15 
Treatment Summary: KTD (maximum of 6 x 28 day cycles) 
KTD protocol 
 
 Days 1, 8,15            30 minute IV infusions of Carfilzomib at  current dose 
level. 
                                                        
All patients will receive Carfilzomib at 20mg/m2 on day 1 of cycle 1 and then 
registered dose level on day 8 of cycle 1 onwards.  The dose levels are;   
 
level -1-  27mg/m2  
 
level 0 – 36mg/m2 
 
level 1 – 45mg/m2 


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 
level 2 - 56mg/m2s 
 
Days 1-28                   50mg Thalidomide, oral preparation for cycle 1 
                                         Up to 100mg can be considered for cycle 2 onwards  
Days 1, 8,15                20mg Dexamethasone, oral preparation 
 
A maximum of 6 cycles will be administered. 
 
Anticipated duration of 
recruitment: 24 months 
Duration of patient follow 
up: 
Minimum 6   months after registration or 1 month after last cycle for each 
patient. 
 
Definition of end of trial: The end of trial is defined as the date of the last participant’s last data item.  At 
this point, the end of trial notification will be submitted to the relevant 
regulatory authorities (e.g. UK MHRA) and ethics committees. 
 
Statistical summary: Sample Size 
In the dose escalation phase of this study, a minimum of 6 (3 at dose level 0 and 
3 at dose level -1)and a maximum of 18 (6 at dose level 0, 1, and 2) patients will 
recruited in a 3+3 design with cohorts of between 3 and 6 patients, in order to 
determine maximum tolerated dose (MTD) and recommended dose (RD).  
At the recommended dose level identified, a further 20 patients will be recruited 
to further assess safety and toxicities at the RD. 
 
Analysis sets and dose cohorts 
All patients that receive at least one dose of Carfilzomib will be included in the 
safety analysis set. 
The per protocol analysis set will include all patients with at least one post 
baseline efficacy assessment who receive at least one dose of Carfilzomib and 
have no protocol deviations with relevant impact on efficacy. 
    
Determination of the MTD in the dose escalation phase of the trial will be based 
on those patients who have received at least one cycle KTD and will be 
evaluated between the time of receiving the first dose of Carfilzomib in cycle 1 
and the first dose of treatment in cycle 2. The safety review committee will 
review each DLT and attribute the DLT to the loading dose or the registered 
dose; any DLT attributed to the loading dose will be excluded when determining 
the MTD. KTD Patients who do not receive one complete cycle due to 
experiencing a DLT will be included in the analysis; patients who do not receive 
at least one complete cycle for reasons other than toxicity, without experiencing 
a DLT, and who miss a dose of Carfilzomib, more than 14 doses of Thalidomide 
or 2 doses of Dexamethasone in the first cycle, will be replaced. Evaluability will 
be considered by the safety review committee on an individual basis to account 
for attributing DLTs and missed doses to the loading or the registered dose.   
The RD cohort will include all patients who are registered to receive and receive 
at least one dose of Carfilzomib at the RD. This cohort will include patients 
from the dose escalation and dose expansion phases of the study. All patients 
who do not fulfill this criteria will be included in the non-RD cohort.    
 
All safety analyses will be based upon the safety analysis set; safety data from 
patients not included in this analysis set will be listed separately. All Efficacy 
analyses will be based upon the per protocol set. 
 
Primary endpoints and analysis 
The number of patients experiencing DLTs within the first cycle of KTD will 
be presented, with descriptive summaries of the specific DLTs observed. 
Summaries will be presented for each dose level. This data will be presented for 
patients registered to the dose escalation phase of the study only.   
 


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Further summaries of longer-term tolerability will also be presented for patients 
registered to the dose escalation phase to include the maximum toxicity grade 
experienced within the first three cycles of treatment, overall and by cycle. 
Individual listings of the toxicities, grade and cycle of all toxicities experienced 
within the first three cycles will be presented.   
 
The number of patients experiencing any grade 3 or 4 CTCAE toxicity within 
all cycles of treatment will be summarised. This will be presented overall and by 
dose cohort, across all cycles as well as by each cycle. 
 
Secondary endpoints and analysis 
 
Clonal response rate within 3m, at 3m, within 6m and at 6m  
 
Amyloidotic organ response rate within 3m and 6m 
 
Time to amyloidotic organ response 
 
Number of deaths at 6 months 
 
Number of patients progression free at 6 months 
 
Maximum response  
 
Time to maximum response 
 
Number of patients withdrawing from treatment 
 
Number of patients experiencing dose delays, and compliance profile of 
KTD. 
 
Relative Dose intensity 
 
The secondary objective of assessing activity will be primarily assessed by the 
clonal response rate. Secondary endpoints will be descriptive with no formal 
hypothesis testing.  
 
 


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1.2 
Eligibility & Registration Schema 
 
 
 
 
Patient with AL amyloidosis with 
relapsed/refractory disease 
Patient attends UK NAC appointment 
Referral of patient to the RHC 
Patient attends RHC 
VISIT MUST BE WITHIN 28 DAYS OF 
REGISTRATION 
Eligibility re-confirmed at RHC 
CATALYST Patient Information 
Sheet and Informed Consent 
Document provided to all 
patients interested in 
participating in the trial. 
Standard UK NAC Clinical Trials 
Patient Information Sheet sent 
to all patients with their referral 
letter. 
Consent obtained, eligibility confirmed and registered  
If the patient is 
eligible, they start 
protocol treatment at 
RHC * 
If the patient is 
ineligible they are 
withdrawn and 
treated off trial at 
RHC as per local 
practice 
NO 
Please go to 
1.3 TRIAL 
TREATMENT SCHEMA 
YES 
Is patient eligible for CATALYST at 
re-confirmation of eligibility? 
UK NAC: UK National Amyloidosis Centre 
RHC: Regional Haematology Centre 
* If there is a ≥ 21 day 
delay in starting trial 
treatment after 
completion of the 
eligibility confirmation 
form at the RHC, a 
second eligibility re-
confirmation form must 
be completed. 
Patients must start 
treatment within 6 
weeks of completion of 
the initial eligibility 
confirmation form at 
the RHC.  


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1.3 
Trial Treatment Schema 
 
 
 
ELIGIBLE registered PATIENTS 
See 1.2 ELIGIBILITY AND REGISTRATION 
SCHEMA 
Treat patient at RHC as per 
protocol. 
KTD x 3 cycles 
(28 day cycles) 
(local response 
assessment each cycle) 
5ml serum samples 
sent to UK NAC prior 
to starting each cycle 
RHC: One more cycle and 
if no incremental 
response, treat off trial.  
If incremental response, 
continue to best response 
 
UK NAC: Follow up 
visit 
at 6 months after 
registration (or 1 month 
after the end of treatment 
for patients who receive 6 
cycles of chemo) 
Off trial treatment. 
UK NAC: Follow up 
visit at 6 months from 
registration  
Complete a further 3 
cycles if earlier cycles 
well tolerated*  
Stop Treatment 
UK NAC: Follow up visit at 6 
months from registration (or 1 
month after the end of 
treatment for patients who 
receive 6 cycles of chemo) 
UK NAC visit to assess response at the end of 3 cycles of chemotherapy 
Partial response with or 
without plateau 
Complete Response 
or very good partial 
response with plateau 
No Response 
UK NAC: UK National Amyloidosis Centre 
RHC: Regional Haematology Centre 
 
* If tolerance is poor, stop after one cycle after best response 


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2.0 
Introduction 
2.1  
Background 
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble 
fibrils that progressively disrupt tissue structure and impair function.  Systemic AL amyloidosis, which is the 
commonest amyloid type, is a malignant disorder occurring in a small proportion of individuals with monoclonal 
B cell dyscrasias and AL amyloidosis is a myeloma defining criteria according to the international working group 
definition of myeloma 2003  (1). AL amyloidosis occurs at an incidence of 3-5 cases per million population and is 
the cause of death of between 0.5-1 per thousand individuals in the UK. AL fibrils are derived from monoclonal 
immunoglobulin light chains which are unique in each patient underlying the remarkably heterogeneous clinical 
picture in this particular form of amyloidosis; virtually any organ or combination of organs other than the brain 
may be affected.    Treatment in AL amyloidosis is aimed at suppression of the underlying B cell dyscrasia using 
chemotherapy regimens based on those used for multiple myeloma.  Without therapy it is inexorably progressive 
and until recently the median survival was just 6-15 months.  Survival for patients who achieve a less than VGPR 
or refractory patients is even poorer  (2). 
2.1.1 Assessing the risk and response to therapy  
Many studies have demonstrated a link between hematologic responses and improved organ function and survival. 
Stopping the production of the toxic light chain species can translate into significant benefit for most patients 
except those with most advanced organ involvement, while stable hematologic disease despite therapy means it is 
likely that the effects of the toxic light chain species will continue. Consensus criteria for hematologic and cardiac 
response have been recently developed and validated (2). Advanced cardiac and extensive organ involvement limit 
benefits that can be derived from treatment including eligibility for autologous stem cell transplantation (ASCT) 
and can shorten survival despite treatment (3, 4). Another treatment limitation is related to the type of organ 
involvement predisposing patients to the adverse effects of specific drugs. In AL amyloidosis clinical trials, it has 
been a challenge to distinguish drug-specific side effects from disease-mediated organ dysfunction  (5) 
2.1.2 Treatment of AL amyloidosis 
 
The treatment of systemic AL amyloidosis has evolved to a risk adapted approach based on the end organ damage, 
particularly cardiac involvement, and the functional status of the patient.  Intensive therapies like high dose 
melphalan followed by an autologous stem cell transplant are considered for patients with limited organ 
involvement, younger age and excellent functional status.  Majority of patients with AL amyloidosis will not be 
candidates for ASCT and are generally treated with combination chemotherapy.   
High dose therapy in AL amyloidosis 
Although a systematic review and meta-analysis to evaluate the efficacy of ASCT for AL did not establish that high-
dose therapy is superior to conventional chemotherapy in improving survival, many investigators believe that stem 
cell transplantation is a preferred option if it can be performed safely. Much of the transplant-related research over 
the past five years has focused on improving patient selection to ensure a safe outcome. ASCT outcomes have 
improved significantly when comparing patients transplanted before and after 2006.  Much of this reduction in 
mortality relates to refinement in patient selection. Patients who have a troponin T >0.07 µg/L  (6) or an NT-
proBNP level >5000 pg/mL at diagnosis should not be considered for high-dose therapy  (7). The reported ten-
year survival after autologous stem cell transplantation is 43% (4), and in patients with hematologic CR, is 60%   
(8).  Patients with cardiac involvement can be safely transplanted if their biomarkers are below the thresholds listed 
above, and their systolic blood pressure is > 100 mmHg, with a median overall survival of 52 months (9). 
Incorporating refined selection criteria, treatment-related mortality can be reduced from 17 to 4%  (10). High-dose 
therapy does not preclude the use of highly active novel agents following transplant for patients who do not achieve 
an adequate response. Bortezomib-Dexamethasone following stem cell transplantation improves responses, 
resulting in high complete response rates and organ improvement  (11).   
Standard and Novel Agent-Based Chemotherapy 
Melphalan and Dexamethasone is considered the standard oral alkylator-based regimen. In a trial using melphalan 
and Dexamethasone orally in patients ineligible for stem cell transplantation, the hematologic response rate was 
67%, complete response rate was 33%, and treatment-related mortality was 4%, with a median survival of 5.1 years 
(12, 13). The outcome seen in patients treated with melphalan and Dexamethasone is highly dependent on the 
fraction of patients with advanced cardiac amyloidosis  (14). All new regimens should be compared with oral 
melphalan and Dexamethasone.   


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Thalidomide and lenalidomide have been used in the treatment of light chain amyloidosis.  Treatment-related 
toxicity was frequent when high dose Thalidomide was used.  However, lower doses of Thalidomide appear safer 
particularly when used in combination with other agents.  Thalidomide has been combined with cyclophosphamide 
and Dexamethasone  (15).  The hematologic response rate was 74%, and the median overall survival was 41 months 
and the toxicity of the dose adapted regime is manageable.  CTD was the standard treatment for all patients with 
AL amyloidosis in the UK until the last 3 years since when bortezomib has been increasingly used.  
 
Lenalidomide has been combined with Dexamethasone to treat AL. The nonhematologic toxicity is greater than 
reported in myeloma trials. Cytopenias, rash, fatigue, and cramps are commonly seen  (16). A hematologic response 
rate of 41% has been reported (17). Lenalidomide has been combined with melphalan and prednisone or 
Dexamethasone. The maximum tolerated dose of lenalidomide in this combination is 15 mg (18). The hematologic 
response rate is 58%, complete in 42%. Lenalidomide responses have been reported to be durable  (19). 
Lenalidomide, melphalan and Dexamethasone was recently reported in 16 patients. Hematologic responses were 
achieved by 43%, with a progression-free survival of 24 months. Grade 3 to 4 toxicities were experienced by 88%, 
and dose reductions occurred in 85%  (20).  Lenalidomide has been combined with cyclophosphamide and 
Dexamethasone and produced an overall hematologic response rate of 60%, including 40% very good partial 
responses or better and organ responses in 29%. The progression-free survival was 28.3 months. Nonhematologic 
toxicity > grade 3, however, was seen in 71% with 20% of patients dying on study  (21). Lenalidomide and 
Dexamethasone alone has a reported response rate of 41% in patients who have failed both bortezomib and 
Thalidomide  (22).  The toxicity of immunomodulatory drugs in amyloidosis patients is significant. Lenalidomide-
treated patients also have a higher risk for NT-proBNP rises and early drug discontinuation compared to controls. 
It is unclear whether immunomodulatory-based therapy leads to increased fluid retention and cardiac toxicity, or 
whether cardiac response can be accurately assessed patients on immunomodulatory drug therapy (23). 
 
Pomalidomide, with its higher potency, may be better tolerated in patients with light chain amyloidosis. 
Pomalidomide in patients with previously treated light chain amyloidosis confirmed a hematologic response rate of 
48% with a rapid median time to response of 1.9 months. Pomalidomide caused rises in the NT-proBNP. The 
most common adverse effects, however, were neutropenia and fatigue. This drug warrants further exploration in 
the treatment of amyloid  (24).   
 
Bortezomib is a first in class proteasome inhibitor which appears particularly effective in AL amyloidosis.  The first 
phase-1 dose-escalation study of bortezomib specifically excluded corticosteroids, to ensure that the response was 
attributable to the proteasome inhibitor, and hematologic responses were seen in 50% (20% complete) of 
relapsing/refractory patients (25). In this safety study, patients with New York Heart Association class 3-4 heart 
failure were excluded. Therefore, the safety of bortezomib in patients with advanced cardiac amyloidosis is difficult 
to gauge. Hypotension has been reported in 12 to 15% of myeloma patients treated with bortezomib, and 
congestive heart failure has been reported in up to 15% of patients; the impact on patients with cardiac amyloidosis 
is unknown, and caution needs to be exercised  (26).  Good clonal responses to Bortezomib have been reported to 
successfully improve cardiac function in AL amyloidosis (27); and as alluded to earlier, posttransplant consolidation 
with bortezomib and Dexamethasone is safe and effective.  A significant advantage of bortezomib is its ability to 
rapidly decrease the burden of light chain with a median time to response of less than two months. Both weekly 
and twice-weekly schedules of bortezomib have been investigated with no significant differences in response rates 
or progression-free survival, but with significantly less side effects, particularly neuropathy, in patients treated 
weekly  (28). Cyclophosphamide, bortezomib, and Dexamethasone produce rapid and complete hematologic 
responses in patients with light chain amyloidosis with 71% achieving complete hematologic response, and 3 
patients of 17 originally not eligible for stem cell transplantation becoming eligible  (29).  Data on long-term 
outcomes with bortezomib are currently lacking; therefore, it cannot be directly compared to melphalan 
Dexamethasone or high-dose therapy. 
2.1.3 Carfilzomib background 
 
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the chymotrypsin-like active site of 
the 20S proteasome.  Carfilzomib is structurally and mechanistically distinct from the dipeptide boronic acid 
proteasome inhibitor bortezomib (Velcade®).  In addition, when measured against a broad panel of proteases 
including metallo, aspartyl, and serine proteases, Carfilzomib demonstrated less reactivity against non-proteasomal 
proteases when compared to bortezomib.  
There is limited data on the use of Carfilzomib in AL amyloidosis, we therefore propose a gradual dose escalation 
study. There is an ongoing study of Carfilzomib in AL amyloidosis.  
 


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2.1.3.1  Phase 1 Experience with Carfilzomib as a Monotherapy in Myeloma 
 
A Phase 1 clinical trial, PX-171-002, testing Carfilzomib in subjects with relapsed/refractory hematologic 
malignancies, has been completed (30).  During the dose escalation portion of the trial, 36 subjects received 
Carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Subjects with Multiple Myeloma (MM), Non-Hodgkin’s 
Lymphoma (NHL), Waldenström’s Macroglobulinemia, and Hodgkin’s Lymphoma (HL) were enrolled on the 
study.   
 
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts (doses ranged from 1.2 to 15 mg/m2) 
of three subjects each.  At the 20 mg/m2 dose level, one of eight patients had a Grade 3 renal failure at Cycle 1, 
Day 2 which was considered possibly related to study drug and lasted for six days.  The patient continued on study 
for the remainder of Cycle 1 before having disease progression.   At the 27 mg/m2 dose level, one of six subjects 
experienced a DLT during Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following Day 2 of 
dosing.  In subjects where the 27 mg/m2 dose was efficacious, a “first dose effect” was seen that included a 
constellation of findings that appeared to be the clinical sequelae of rapid tumor lysis syndrome (TLS) and/or 
cytokine release.  This effect was notable for fever, chills, and/or rigors occurring during the evening following the 
first day of infusion.  On the second day, three of five subjects with multiple myeloma experienced an increase in 
creatinine to Grade 2 (including the subject with the DLT).  This elevation was rapidly reversible and all three 
subjects were rechallenged with Carfilzomib without recurrence of the events.  Interestingly, all three subjects had 
a rapid decline in serum and/or urine M-protein levels; two subjects achieved a PR and the third subject achieved 
a minimal response (MR).  There were no consistent changes in potassium, calcium, phosphorous, or uric acid 
levels although some increases in LDH and other markers of tumor lysis were noted.  Because of the possible TLS 
and reversible creatinine elevations, hydration and very-low dose Dexamethasone prophylaxis were instituted in 
subsequent studies and have essentially eliminated clinically significant TLS/creatinine elevations and the other 
“first-dose” effects.   
 
Hematologic toxicities were primarily mild or moderate.  The thrombocytopenia reported with Carfilzomib is 
cyclical and similar to that reported with bortezomib.  The cause and kinetics of the thrombocytopenia following 
treatment are different from those of standard cytotoxic agents.  To maximize the likely benefit of Carfilzomib, 
subjects with thrombocytopenia should be supported as clinically indicated rather than having treatment reduced 
due to thrombocytopenia. 
 
Of the 36 evaluable patients enrolled in PX-171-002, 20 had MM (30).  Four MM patients achieved a partial 
response (PR), one of two at the 15 mg/m2 dose, one of six at the 20 mg/m2 dose, and two of five at the 27 mg/m2 
dose.  The responses have been rapid in onset, beginning in some subjects after 1-2 doses.  The duration of response 
(DOR) ranged from 134 to 392 days. The minimal effective dose was 15 mg/m2 wherein >80% proteasome 
inhibition in peripheral blood and mononuclear cells was observed one hour after dosing.  The median number of 
prior therapies for subjects on this trial was five, and responses were seen in subjects who had relapsed from 
(including some refractory to) bortezomib and/or immunomodulatory agents.  Stable disease also occurred in four 
NHL and five MM subjects, with subjects on therapy for up to 409 days.  Such prolonged therapy, at “full” twice-
weekly doses, is not possible with bortezomib.   
 
 
2.1.3.2  Phase 2 Experience with Carfilzomib as a monotherapy in Myeloma 
 
Two Phase 2 clinical studies are now complete with Carfilzomib in MM patients, PX-171-003-A0 (N=46) in 
relapsed and refractory MM and PX-171-004 (N=39) in relapsed MM.  In both studies, patients were dosed with 
20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 on a 28 day schedule.  In these studies there were four cases of suspected 
or documented TLS prior to institution of the prophylaxis guidelines.  Since these guidelines were implemented, 
no further cases of TLS have been reported including in >350 additional patients with relapsed or refractory MM 
treated in ongoing Phase II studies.  In both studies, the most common adverse events were fatigue, anemia, 
thrombocytopenia (primarily cyclical), gastrointestinal, and dyspnea.  Almost all were Grades 1 or 2.  There were 
reported cases of increased in serum creatinine that were primarily < Grade 2 and were transient, rapidly reversible, 
and non-cumulative.  A very low rate of treatment-emergent peripheral neuropathy, 2.2% Grade 3/4, was observed 
in PX-171-003-A0 despite the fact that 78% of patients had Grade 1/2 neuropathy upon study entry  (31).   
The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD in these patients that entered the study 
with progressive disease and were refractory to their most recent therapy, often including bortezomib and/or an 
immunomodulatory drug (usually lenalidomide).  The median time to progression on the PX-171-003-A0 study 
was 5.1 months with a DOR of 7.4 months (mean follow up of 7.6 months) (31).   
 


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A “stepped up” dosing schedule, referred to as 20/27 mg/m2, has subsequently been incorporated into the PX-
171-003 study (referred to as PX-171-003-A1) in order to maximize the clinical benefit of Carfilzomib.  Patients 
receive 20 mg/m2 for the first cycle and 27 mg/m2 thereafter.  The study completed enrollment of 266 patietns by 
the end of 2009 and formed the basis for an accelerated approval NDA filing.  To date, this dosing schedule has 
been well tolerated (30).  An independent Safety Oversight Group (SOG) evaluated the safety data from the 40 of 
250 patients to be enrolled on the 20/27 schedule and agreed that the trial should proceed without modification.  
No cases of TLS were observed and rates of BUN and creatinine elevation dropped sharply, with Grade 3/4 renal 
impairment dropping to 2.2% in A1( from 15% in A0), most likely due to hydration and very low dose 
Dexamethasone.  The other most common adverse events were similar to the A0 portion of the study.  Treatment-
emergent peripheral neuropathy remains low on this portion of the study with 15% Grade 1/2 and one (0.7%) 
Grade 3/4 event reported to date on PX-171-003-A18.  In addition, anemia rates in the PX-171-003-A1 (higher 
dose) were lower than those reported in the PX-171-003–A0 portion of the study, possibly indicating that the 
higher dose of Carfilzomib is achieving better clearing of neoplastic cells in the bone marrow allowing superior 
normal marrow reconstitution.  Rates of thrombocytopenia and neutropenia were similar in the two cohorts, with 
Grade 3 neutropenia in ~5% without any Grade 4 neutropenia to date (31).  
 
In PX-171-004, a first cohort of patients received 20 mg/m2.  The subset of patients (N=54) that had not seen 
bortezomib had an ORR of 46% (2% CR, 9% VGPR and 35% PR), while the bortezomib treated patients (N=33) 
had an ORR of 18% (3% CR, 3% VGPR and 12% PR)(32, 33).  The median TTP was 7.6 and 5.3 months in these 
two groups, respectively.  Thus, Carfilzomib can induce very high levels of response in patients who have not 
previously been treated with bortezomib and, even in bortezomib-treated patients, substantial anti-tumor activity 
is observed.  Of note, disease control (PR + MR + SD) was achieved in ~65% of patients with progressive MM 
entering the study.  Patients on these studies have been treated for >12 cycles with good tolerability and no 
cumulative toxicity (e.g., bone marrow, severe fatigue, or neuropathy) have not been observed.  
The protocol was amended to allow patients to increase to 27 mg/m2 in Cycle 2 or later based on tolerability, similar 
to that used in PX-171-003 – A1.   
 
In a phase 2 study, Carfilzomib was administered 20 mg/m2 on days 1 to 2 of cycle 1, 56 mg/m2 thereafter (30-
minute infusion), in relapsed refractory myeloma  (R/RMM) with the option of adding Dexamethasone (20 mg) 
for suboptimal response/progression (34). Forty-four patients were enrolled, all having prior bortezomib and 
immunomodulatory drugs and a median of 5 prior regimens. Of 42 response-evaluable patients, 23 (55%) achieved 
at least partial response (PR). Median (95% confidence interval) duration of response, progression-free, and overall 
survival were 11.7 (6.7-14.7), 4.1 (2.5-11.8), and 20.3 months (6.4-not estimable), respectively. High-risk 
cytogenetics did not impact outcomes. Treatment was active in bortezomib-refractory subgroups, but these patients 
tended to have poorer outcomes. Four/10 patients with prior allogeneic transplant achieved at least PR. Of 6 
patients who responded, progressed and had Dexamethasone added, 4 achieved at least stable disease. The most 
frequent grade 3/4 adverse events (AEs) possibly related to Carfilzomib included lymphopenia (43%), 
thrombocytopenia (32%), hypertension (25%), pneumonia (18%), and heart failure (11%). Seven patients (16%) 
discontinued treatment due to AEs. Carfilzomib 56 mg/m2 +/- Dexamethasone was tolerable and provided durable 
responses. 
 
 
2.1.3.3   Carfilzomib combination therapy in myeloma 
 
PX-171-006 was a Phase 1b study in patients with relapsed multiple myeloma in which Carfilzomib is administered 
in combination with lenalidomide (Revlimid®) and Dexamethasone.  “Low-dose” Dexamethasone 40 mg/day is 
given on Days 1, 8, 15, and 22 in all cases.  Carfilzomib is administered IV on Days 1, 2, 7, 8, 15, and 16; lenalidomide 
is administered PO on Days 1 through 21.  Enrollment has closed in this study, and no MTD was reached.  The 
maximum per protocol doses of Carfilzomib (27mg/m2) with lenalidomide 25mg and low dose Dexamethasone 
are being used (35).   
 
 In a phase 1/2 study in patients with newly diagnosed multiple myeloma (N = 53) assessed CRd--Carfilzomib (20, 
27, or 36 mg/m2, days 1, 2, 8, 9, 15, 16 and 1, 2, 15, 16 after cycle 8), lenalidomide (25 mg/d, days 1-21), and weekly 
Dexamethasone (40/20 mg cycles 1-4/5+)--in 28-day cycles (36). After cycle 4, transplantation-eligible candidates 
underwent stem cell collection (SCC) then continued CRd with the option of transplantation. The maximum 
planned dose level (Carfilzomib 36 mg/m2) was expanded in phase 2 (n = 36). Thirty-five patients underwent SCC, 
7 proceeded to transplantation, and the remainder resumed CRd. Grade 3/4 toxicities included hypophosphatemia 
(25%), hyperglycemia (23%), anemia (21%), thrombocytopenia (17%), and neutropenia (17%); peripheral 
neuropathy was limited to grade 1/2 (23%). Most patients did not require dose modifications. After a median of 
12 cycles (range, 1-25), 62% (N = 53) achieved at least near-complete response (CR) and 42% stringent CR. 


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Responses were rapid and improved during treatment. In 36 patients completing 8 or more cycles, 78% reached at 
least near CR and 61% stringent CR. With median follow-up of 13 months (range, 4-25 months), 24-month 
progression-free survival estimate was 92%. CRd was well tolerated with exceptional response rates. 
 
 
Updated efficacy data are presented in the following table: 
Together, these results suggest 
that 
Carfilzomib, 
lenalidomide, and low-dose 
Dexamethasone 
(CRd) 
in 
combination are active and 
well tolerated and that there 
are no significant overlapping 
toxicities (in the dose ranges 
tested). 
Importantly, 
lenalidomide-associated neutropenia and thrombocytopenia do not appear to be exacerbated by concurrent 
treatment with Carfilzomib, even up to 27mg/m2, suggesting that Carfilzomib will combine well with other anti-
cancer agents.   
 
The combination of Carfilzomib with cyclophosphamide and Dexamethasone was studied in elderly (≥ 65 years) 
newly diagnosed patients with myeloma  in a multicenter, open-label phase 2 trial (37). Patients (N = 58) received 
CCyd for up to 9 28-day cycles, followed by maintenance with Carfilzomib until progression or intolerance. After 
a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved 
at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent 
complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival 
rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia 
(11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). 
Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required 
Carfilzomib dose reductions. In summary, 
results showed high complete response rates 
and a good safety profile.  
 
Carfilzomib- Thalidomide- Dexamethasone 
regime was studied by the HOVON Group 
(38).  This multicenter phase 2 study of the 
European Myeloma Network investigated the 
combination of Carfilzomib, Thalidomide, 
and 
Dexamethasone 
(KTd) 
as 
induction/consolidation 
therapy 
for 
transplant-eligible patients with previously 
untreated multiple myeloma (N = 91). During 
KTd induction therapy, patients received 4 
cycles of Carfilzomib 20/27 mg/m2 (n = 50), 20/36 mg/m2 (n = 20), 20/45 mg/m2 (n = 21), or 20/56 mg/m2 (n 
= 20) on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle; Thalidomide 200 mg on days 1 to 28; and Dexamethasone 20 
mg on days 1, 2, 8, 9, 15, and 16. After autologous stem cell transplantation, patients proceeded to KTd 
consolidation therapy, where the target doses of Carfilzomib were 27 mg/m2, 36 mg/m2, 45 mg/m2 or 56 mg/m2), 
respectively, and Thalidomide 50 mg. Common grade 3/4 adverse events included respiratory (15%), 
gastrointestinal (12%), and skin disorders (10%); polyneuropathy was infrequent (1%). Complete response rates 
after induction and consolidation treatment were 25% and 63%, respectively; rates of very good partial response 
or better after induction and consolidation were 68% and 89%, respectively. At a median follow-up of 23 months, 
the 36-month progression-free survival rate was 72%. The KTd induction and consolidation regimens were active, 
safe, and well tolerated.  
 
Safety data for single-agent Carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who 
took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005) (39). 
Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse 
events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia 
(46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any 
cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal 
impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events 
 
CRd: Cohorts 1–5 
(CFZ: 15 to 20  mg/m2 ; LEN: 10 to 25 mg)  
Response 
Relapsed (n=16) 
Refractory 
(n=13) 
Overall  
(n=29) 
   ≥ CR/nCR 
5 (31) 
1 (8) 
6 (21) 
   ≥ VGPR 
7 (44) 
4 (31) 
11 (38) 
   ≥ PR 
9 (56) 
8 (62) 
17 (59) 
   ≥ MR 
11 (67) 
10 (77) 
21 (72) 


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were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly 
reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or 
thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral 
neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, 
the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate 
that single-agent Carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory 
multiple myeloma. The tolerable safety profile allows for administration of full-dose Carfilzomib, both for extended 
periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing 
comorbidities. 
 
Recently a phase III trial of Carfilzomib-Lenalidomide-Dexamethasone compared with Lenalidomide-
Dexamethasone was reported.  792 patients with relapsed multiple myeloma were randomised to Carfilzomib with 
Lenalidomide and Dexamethasone (Carfilzomib group) or Lenalidomide and Dexamethasone alone (control 
group). The primary end point was progression-free survival. Progression-free survival was significantly improved 
with Carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 
0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either 
group at the interim analysis. The Kaplan–Meier 24-month overall survival rates were 73.3% and 65.0% in the 
Carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates 
of overall response (partial response or better) were 87.1% and 66.7% in the Carfilzomib and control groups, 
respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 
14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% 
and 80.7% of patients in the Carfilzomib and control groups, respectively; 15.3% and 17.7% of patients 
discontinued treatment owing to adverse events. The authors concluded that In patients with relapsed multiple 
myeloma, the addition of Carfilzomib to lenalidomide and Dexamethasone resulted in significantly improved 
progression-free survival at the interim analysis and had a favorable risk–benefit profile. (40) 
 
 
2.1.3.4 Carfilzomib in AL amyloidosis  
 
There is limited data on Carfilzomib in AL amyloidosis.  The first results of a multi-center, Phase I, dose-finding 
study of Carfilzomib in AL amyloidosis were presented in ASH 2014.  Patients had relapsed AL after ≥1 prior 
therapy.  Patients with advanced cardiac involvement (Mayo stage III, LVEF<40%, or NYHA Class III/IV) were 
excluded.  A standard 3+3 dose escalation schedule was used, with planned cohorts of 27, 36, 45, and 56 mg/m2.  
Carfilzomib was given as a 30-minute infusion on days 1, 2, 8, 9, 15, 16 of a 28-day cycle, starting at 20 mg/m2 on 
cycle 1, days 1,2, then escalating starting day 8.  Three patients each were treated at 20/27 and 20/36 mg/m2, with 
no DLTs. In the 20/45 mg/m2 cohort, there were 2 DLT's of grade 3 fatigue ≥7 days in 4 patients, establishing 
20/36 mg/m2 in a twice weekly schedule as the MTD.  Two additional patients were enrolled at MTD in the PI-
exposed expansion cohort. Median number of cycles is 5 (range 1+-13+), with 7 patients still on study, and 5 
discontinuing (3 AE, 2 patient withdrawal).  Drug-related AEs occurring in >20% of patients (n=11 evaluable) 
included fatigue (45%), nausea (36%), anemia, dyspnea, and diarrhea (27% each).  Seven patients had at least one 
Grade ≥3 AE (any cause), including cardiac (n=4 patients), fatigue (n=3), diarrhea (n=2), and nausea, 
hypoalbuminemia, and pneumonia (n=1 each).  There have been 3 AE’s possibly related to drug: 1 grade 4 cardiac 
arrest due to ventricular tachycardia during cycle 5; 1 grade 4 restrictive cardiomyopathy and CHF after cycle 3 
(with negative endomyocardial biopsy for amyloid); 1 grade 3 drop in ejection fraction after cycle 7. Rising 
NTproBNP levels correlated with clinical and/or echocardiographic manifestations of CHF in these latter 2 
patients. A 4th patient had exacerbation of atrial fibrillation during pneumonia, deemed unrelated. No deaths were 
reported. Of 9 evaluable patients, 7 responded hematologically, including 6 VGPR (≥PR rate=78%;). Responses 
were seen at all dose levels. Two patients had Dexamethasone added after cycle 4, both improving response to 
VGPR. With median follow-up of 5.1 months (range 0.2 to 12.3), no organ responses were observed (41).  
2.2 
Carfilzomib Dosing 
 
Preliminary data suggest that Carfilzomib as a single agent can produce substantial response rates in myeloma 
subjects across a variety of dosing cohorts.  Responses were seen over a wide therapeutic window, from 15 to 27 
mg/m2.  Maximum proteasome inhibition was seen at doses 11 mg/m2 and higher in whole blood samples taken 1 
hour after the first dose.  Carfilzomib is rapidly cleared from plasma with an elimination half life of < 60 minutes 
at the 20 mg/m2 dose.  Large, single arm studies of the 27 mg/m2 dose are ongoing and suggest that this dose is 
very well tolerated with patients being treated for >10 cycles without cumulative toxicities. 
 


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A total of 266 patients with relapsed and refractory multiple myeloma were enrolled in the PX-171-003-A1 study, 
with a “stepped up” dosing schedule of 20/27 mg/m2 (39). The goal of dose escalating to 27 mg/m2 beginning 
with Cycle 2 is to improve ORR, DOR, and TTP. 
 
In multiple preclinical studies, the tolerability of Carfilzomib in rats has been shown to be significantly higher when 
administered as a 30 min infusion as compared to a rapid IV bolus.  Toxicities observed with IV bolus injection of 
Carfilzomib above the MTD at a dose of 48 mg/m2 include evidence of prerenal azotemia (transient increases in 
BUN > creatinine) as well as lethargy, piloerection, dyspnea, and gastrointestinal bleeding. Notably, death occurred 
in ~50% of animals at 48 mg/m2 when Carfilzomib was given as a bolus. Administration of the same dose (48 
mg/m2) as a 30 min continuous infusion was well tolerated, with no changes in BUN and creatinine and 
substantially reduced signs of lethargy, piloerection, or dyspnea.  Moreover, all animals in the infusion treatment 
groups survived.  The only toxicity observed following infusion of Carfilzomib for 30 min was gastrointestinal 
bleeding.  The reduced toxicity seen with dosing by infusion may reflect the reduced Cmax of Carfilzomib vs that 
with bolus dosing.  Inhibition of the pharmacological target of Carfilzomib (the chymotrypsin-like activity of the 
proteasome) was equivalent in the bolus and infusion treatment groups.   
 
In the clinic, the MTD of Carfilzomib has not been reached in the multiple myeloma (MM) setting, particularly 
when administered as a 30’ infusion.  27mg/m2 of Carfilzomib (bolus administration over 2-10’) is well tolerated in 
MM patients overall and can be tolerated for >12 cycles in late stage MM patients with substantial comorbidities.  
 
Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent Carfilzomib on 
days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (42). Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter 
by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, Carfilzomib was combined with low-dose 
Dexamethasone (40 mg/wk). Thirty-three patients were treated with single-agent Carfilzomib. Dose-limiting 
toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 
mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were 
the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56- mg/m2 cohort). 
Increasing Carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time 
curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 
0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated 
with 45 or 56 mg/m2 of Carfilzomib plus low-dose Dexamethasone, the ORR was 55% with a safety profile 
comparable to that of single-agent Carfilzomib. Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 
(as single agent or with low-dose Dexamethasone) was generally well tolerated and highly active in patients with 
relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial 
ENDEAVOR 
 
A phase II study suggests that Carfilzomib is safe in patients with renal impairment (43).  Carfilzomib was 
administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: mg/m2 (Cycle 1), mg/m2 (Cycle 2) and 27 mg/m2 (Cycles 
3+). There were no differences in Carfilzomib clearance or exposure among patients with normal renal function 
and any group with renal impairment. were similar among groups. At 15  mg/m2, proteasome inhibition up to 85% 
was observed and did not differ among groups. Although nearly 50% of patients were refractory to both 
bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 
months median duration of response. The authors concluded that the pharmacokinetics and safety of Carfilzomib 
were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and Carfilzomib 
was well tolerated in patients with renal impairment. 
 
2.3 
Proposed Trial  
2.3.1 Summary and Rational for Therapeutic Study 
 
Proteasome inhibitors are associated with highest response rates in AL amyloidosis.  Bortezomib has toxicity and 
limitations in AL amyloidosis.  In particular, the high specificity of Carfilzomib for proteosome inhibition and it’s 
favorable toxicity profile makes it very appealing in AL amyloidosis.   For instance, toxicities which commonly 
complicate Bortezomib use, such as autonomic and peripheral neuropathy, appear uncommon with Carfilzomib. 
Combination of proteosome inhibitors with Immunomodulatory Drug (IMiDs) appears to be synergistic in 
myeloma and the phase II data using Carfilzomib with lenalidomide or Thalidomide appears promising.  In the 
UK, we have extensive experience using Thalidomide in the treatment of patients with AL amyloidosis.  Combining 
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due to their non-overlapping toxicity profile.  Low dose Thalidomide is generally well tolerated by patients with AL 
amyloidosis but as single agent has limited efficacy.  However, in combination with other agents, response rates are 
high as we have documented by using risk adapted CTD regime.  This study is designed to improve the response 
rates seen with CTD protocol by using Carfilzomib in combination with Thalidomide and Dexamethasone.  
 
Since there is limited data on use of Carfilzomib in AL amyloidosis, we propose a gradual dose escalation study. In 
the ongoing phase I study of Carfilzomib in AL amyloidosis, a  dose of 36mg/m2 twice weekly (total weekly 
Carfilzomib of 72 mg/m2) was considered as MTD when used as single agent or with Dexamethasone.    Based on 
this, we propose to use half of this dose at 36mg/m2 once weekly as  our dose level 0 increasing to a maximum of 
56 mg/m2 once weekly.  The synergy Thalidomide and Carfilzomib should allow for lower doses of both drugs to 
be used.   
 
Within the design of the trial, several procedures may be carried out at a higher frequency than would be expected 
with standard treatment. Information about these risks and associated advice for patients are discussed at length in 
the Patient Information Sheet. In accordance with the MRC/DH/MHRA Joint Project Risk-adapted Approaches 
to the Management of Clinical Trials of Investigational Medicinal Products, this trial is categorised as Type B, 
somewhat higher than standard medical care. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          
 
 
 
 
 
 


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3.0 
Trial Design 
 
This will be a single arm open label multicentre phase Ib study with dose escalation and expansion phases.  Patients 
will receive treatment with Carfilzomib in escalating dose cohorts along with a fixed dose of Dexamethasone and 
Thalidomide (KTD).  The dose escalation phase of the study will use a 3+3 dose escalation design. Cohorts of 3-6 
participants will be treated with KTD as outlined in the Section 8. Carfilzomib doses will be increased between 
cohorts until the occurrence of dose limiting toxicities (DLTs) define the MTD.  The Safety Reviev Committee will 
review the safety and ethics of the trial by reviewing interim data after each cohort of treatment during recruitment 
to the Dose Escalation Cohort.  Once the MTD and/or RD has been established a maximum of 20 participants 
will be recruited for entry into the expansion phase of the study at the RD. The study will run in 15 UK centres. 
The study duration is expected to be approximately 42 months – including 6 months of set up, 24 months of 
recruitment, 6 months of follow-up and 6 months of analysis/write-up.  
 
3.1 
Aims 
The Catalyst (Carfil-thal-Dex in AL Amyloidosis treatment) Trial aims to assess the safety and tolerability of KTD 
(Carfilzomib-Thalidomide-Dexamethasone) using the phase 1 dose escalating component to define the maximum 
tolerated dose (MTD) and recommended dose (RD) and the expansion cohort to further assess the safety and 
tolerability and to gain an understating of efficacy to allow design for further trials.  
 
Primary:  
Dose escalation 
To define the MTD and RD of Carfilzomib used in combination with Thalidomide and Dexamethasone 
in patients with relapsed or refractory AL amyloidosis 
Dose expansion 
To further assess the safety and tolerability of KTD at the RD of Carfilzomib identified in the dose 
escalation phase  
 
Secondary: 
 
To make a preliminary assessment of the activity of KTD in patients with relapsed refractory AL 
amyloidosis  
 
3.2 
Trial Activation 
Leeds Clinical Trials Research Unit (CTRU) will ensure that all trial documentation has been reviewed and approved 
by all relevant bodies and that the following have been obtained prior to activating the trial: 
 
• 
Research Ethics Committee approval. 
 
Clinical Trial Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA)  
 
Adequate funding for central co-ordination 
 
Adoption into NIHR portfolio 
 
NHS permission 
 
Confirmation of sponsorship 
 
Adequate insurance provision 
 


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4.0 
Selection of  Sites/Site Investigators 
4.1 
Site (Regional Haematology Centre) selection 
In this protocol trial  “site” refers to the hospital where trial-related activities are conducted. 
 
Sites must be able to comply with: 
 
Trial treatments, clinical care, follow up schedules and all requirements of the trial protocol 
 
Requirements of the Research Governance Framework and the Medicines for Human Use (clinical 
trials) Act (SI 2004/1031 and all amendments) 
 
Monitoring requirements, as outlined in the protocol (section 16.0 and Trial Monitoring Plan)  
 
Data collection requirements including adherence to CRF submission timelines as per section 12.0 
 
Sample collection and processing requirements 
 
4.1.1 Selection of Principal Investigators and other  investigators at sites 
Sites must have an appropriate Principal Investigator (PI) i.e. a health care professional authorised by the site, ethics 
committee and regulatory Authority to lead and coordinate the work of the trial on behalf of the site.  Other 
investigators at site wishing to participate in the trial must be trained and approved by the PI.  All investigators 
must be medical doctors and have experience of treating amyloidosis. 
 
4.1.2 Training requirements for site staff 
All site staff must be appropriately qualified by education, training and experience to perform the trial related duties 
allocated to them, which must be recorded on the site delegation log. 
CVs for all staff must be kept up-to-date, signed and dated and copies held in the Investigator Site File (ISF).  An 
up-to-date, signed copy of the CV for the PI must be forwarded to CTRU upon request. 
GCP training is required for all staff responsible for trial activities.  The frequency of repeat training may be dictated 
by the requirements of their employing institution, or 2 yearly where the institution has no policy, and more 
frequently when there have been updates to the legal or regulatory requirements for the conduct of clinical trials. 
4.2 
Site initiation and Activation 
4.2.1 Site Initiation 
 
Before a site is activated, the CTRU trial team will arrange a site initiation with the site which the PI, the pharmacy 
lead and site research team must attend. The site will be trained in the day-to-day management of the trial and 
essential documentation required for the trial will be checked. 
 
The site initiation will be performed by site visit or teleconference. 
 
4.2.2 Required documentation 
The following documentation must be submitted by the site to CTRU prior to a site being activated by the CTRU 
trial team: 
 
Trial specific Feasibility/Site Registration Form (identifying relevant local staff and contact details) 
 
All relevant institutional approvals (e.g. local NHS permission) 
 
A completed authorised personnel log and pharmacy personnel logthat is signed and dated by the PI 
 
A copy of the PI’s current CV that is signed and dated 
 
A copy of the PI’s GCP certificate 
 
PI declaration that is signed and dated 
 
Lead pharmacist declaration that is signed and dated 
 
Local lab ranges and lab accreditations 
 
Trial specific prescriptions & labels 
 
In addition, the following agreement must be in place: 


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 a fully signed model non-commercial agreement (mNCA) between the Sponsor and the relevant institution 
(usually a NHS Trust) 
 
4.2.3 Site activation  
Once the CTRU trial team at Leeds has received all required documentation and the site has been initiated, a site 
activation email will be issued to the PI and other key site contacts, at which point: 
 
If the site in question is the UK National Amyloidosis Centre (UK NAC), they may start to approach 
patients 
 
If the site is a Regional Haematology Centre (RHC), the UK NAC can begin to refer patients to them. 
 
Once the site has been activated by CTRU, the PI is responsible for ensuring:  
 
adherence to the most recent approved version of the protocol 
 
all relevant site staff are trained in the protocol requirements 
 
appropriate recruitment and medical care of patients in the trial 
 
timely completion and return of CRFs (including assessment of all adverse events) 
 
prompt notification and assessment of all serious adverse events 
 
that the site has facilities to provide 24 hour medical advice for trial patients 
 
Please note, for the CATALYST trial, all patients will be approached by the UK National Amyloidosis 
Centre (UK NAC) and referred by UK NAC to a suitable Regional Haematology Centre (RHC)/Site.  No 
patients may be referred to an RHC/Site that is not activated by Leeds CTRU.  Leeds CTRU will provide 
UK NAC with an up to date list of activated RHCs. 


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5.0 
Informed consent 
 
The UK NAC must ensure that all patients have been given the current approved version of the patient information 
sheet(s), are fully informed about the trial and have confirmed their willingness to take part in the trial by signing 
the current approved consent form.   
 
The UK NAC must assess a patient’s ability to understand verbal and written information in English and whether 
or not an interpreter would be required to ensure fully informed consent. If a patient requires an interpreter and 
none is available,  the patient should not be considered for the trial. 
 
The UK NAC PI, or, where delegated by the PI, other appropriately trained site staff (trained on the study protocol, 
Patient Information Sheet and are GCP trained), are required to provide a full explanation of the trial and all 
relevant treatment options to each patient prior to trial entry.  During these discussions the current approved  
patient information sheet for the trial should be discussed with the patient (including the aims, methods, possible 
benefits and possible disadvantages of taking part).  The patient will be allowed as much time as needed  to consider 
and discuss their participation in the trial.  Patients will be given the option to take the patient information sheet 
and consent form away and return it by post (this is standard practice at UK NAC).  Upon receipt at UK NAC, the 
consent form must be checked for completeness and then signed by the appropriate investigator.  Dated entries 
for this consent process must be recorded in the patient’s medical notes.  No clinical trial procedures will be 
conducted prior to obtaining consent.  Consent will not denote enrolment to the trial. If new safety information 
results changes in the significant risk/benefit the consent will be reviewed and updated and patients will be given 
an opportunity to re-consent to participating in the study.  
 
Healthcare professionals have specific obligations that must be followed when prescribing or dispending 
thalidomide. As such, patients must be fully educated on the risks of thalidomide in accordance with the Celgene 
Pregnancy Prevention Programme. This should be done by an authorised member of staff at the research centre at 
the time the patient is given a full verbal explanation of the trial. 
 
 
Written informed consent on the current approved version of the consent form for the trial must be obtained 
before any trial-specific procedures are conducted. 
 
UK NAC staff are responsible for: 
 
Checking that the correct (current approved) version of the patient information sheet and consent form 
are used 
 
Checking that information on consent forms is complete and legible 
 
Checking that the patient has completed/initialled all relevant sections and signed and dated the consent 
form 
 
Checking that an appropriate member of staff has countersigned and dated the consent form to confirm 
that they provided information to the patient 
 
Checking that an appropriate member of staff has made dated entries in the patient’s medical notes 
relating to the informed consent process (i.e. information given, consent signed etc.) 
 
Giving the patient a copy of their signed consent form, patient card and Red Flag card 
 
Adding details of all consented patients to the informed consent form log 
 
Following registration and confirmation of eligibility: adding the patient trial number to all copies of the 
consent form, which should be filed in the patient’s medical notes and investigator site file 
 
Sending a copy of the completed consent form to the CTRU and the appropriate RHC following 
registration (see 4.1 & 6.1) 
 
The original signed consent form must be stored at the UK NAC, one copy forwarded to the CTRU, one copy 
forwarded to the Regional Haematology Centre (RHC), and a copy given to the patient. 
 
The right of the patient to refuse to participate in the trial without giving reasons must be respected.  All patients 
are free to withdraw at any time.  Also refer to section 14.0 (Withdrawal of patients). 


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5.1 
Referral of patients to Regional Haematology Centres 
Following consent and registration (see section 7.1), patients will be referred to the appropriate Regional 
Haematology Centre (RHC).  The choice of RHC will be discussed and agreed with the patient during their UK 
NAC visit.  
 
UK NAC are responsible for forwarding a copy of the signed informed consent form (fax or email is acceptable) 
to the RHC in order that trial specific activities may be undertaken, with an additional copy being sent to the CTRU.  
 
Following referral the RHC will contact the patient to arrange their first visit (to include confirmation of eligibility 
to the trial).  This visit must be within 28 days of the patient’s registration.  
 
Authorised members of the study team at the RHC should give the participant an opportunity to ask any further 
questions about the trial and to check they are still willing to take part in the trial.(as part of the re-confirmation 
of eligibility visit)  
 


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6.0 
Selection of  Patients 
6.1 
Pre-treatment Evaluation 
Patients referred to the UK NAC with AL amyloidosis are routinely sent a ‘General Clinical Research Information 
Sheet’ with their UK NAC appointment letter.  Nationally, patients are followed up at the UK NAC as part of 
standard practice, where a full ‘Amyloid Evaluation’ is undertaken, usually over a period of two days; follow up 
visits are approximately 6 monthly.  The Amyloid Evaluation includes Serum Amyloid Protein component (SAP) 
scintigraphy, echocardiography, full haematological, biochemical and urine examinations for evidence of organ 
dysfunction, clonal disease, a bone marrow (if indicated) and cardiac biomarkers.  This standard amyloid assessment 
will form the baseline pre-treatment evaluation. The patient will also have a blood test to check hepatitis B 
status.  Patients who may receive thalidomide treatment or other chemotherapy outside of the trial have this test as 
standard of care.  Any UK patient with a diagnosis of systemic AL amyloidosis who has relapsed disease is 
potentially eligible for entry into the trial (see 6.3 for patient eligibility). 
 
Please see protocol section 11 for assessment summary and Appendix 6 for diagnostic sample requirements and 
investigations. 
 
UK NAC will confirm eligibility for the trial and consent patients, following this, registration will take place at 
Leeds CTRU.  All registered patients will have a brief pre-treatment evaluation to reconfirm eligibility at their 
allocated RHC (Regional Haematology Centre). 
6.2 
Screening Log 
A screening log must be maintained by the UK NAC and kept in the UK NAC CATALYST Site File. This must 
record each patient screened for the trial/all patients identified with  proven systemic AL amyloidosis and the 
reasons why they were not registered in the trial if this is the case.   
 
The log must be sent to Leeds CTRU from UK NAC when requested, with patient identifiers removed prior to 
sending. 
 
Individual RHC sites will not be asked to maintain a screening log. 
 
6.3 
Patient Eligibility 
There will be no exception to the eligibility requirements at the time of registration. Ensuring patient eligibility is 
the responsibility of the UK NAC PI or other delegated Investigator(s).  Queries in relation to the eligibility criteria 
must be addressed prior to calling/faxing registration. Patients are eligible for the trial if all the inclusion criteria are 
met and none of the exclusion criteria applies.  
6.3.1 Inclusion Criteria 
Patients with the following characteristics are eligible for this study:  
1. Aged 18 years or greater 
2. Diagnosis of systemic AL amyloidosis with  
i. exclusion of genetic mutations associated with hereditary amyloidosis and   
immunohistochemical exclusion of AA and TTR amyloidosis as appropraite 
ii. Amyloid-related organ dysfunction or organ syndrome (see Appendix 2) 
3. Measurable clonal disease  
4. Clonal relapse after previous chemotherapy or autograft stem cell transplant OR refractory clonal disease 
to previous chemotherapy or stem cell transplant  
5. Capable of providing written, informed consent and willing to follow study protocol 
6. Life expectancy ≥ 6 months 
7. ECOG performance status of 0-2 
8. Platelet count ≥ 50x109/l 
9. Neutrophil count ≥ 1x109/l 
10. Haemoglobin ≥ 8g/dL 
11. Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of normal. 
12. Female participants of child-bearing potential must have a negative pregnancy test prior to treatment and 
agree to use dual methods of contraception for the duration of the study and for 30 days following 
completion of study. Male participants must also agree to use a barrier method of contraception for the 


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duration of the study and for 90 days following completion of study if sexually active with a female of 
child-bearing potential.  Women who could become pregnant must have taken precautions not to 
become pregnant for 1 month before the start of the study.  Because of the increased risk of venous 
thromboembolism in patients, combined oral contraceptive pills are not recommended. 
 
13. Participants must be willing to comply with the Celgene pregnancy prevention programme for Thalidomide 
 
6.3.2 Exclusion Criteria 
Patients with the following characteristics are ineligible for this study (see Appendices for definitions): 
 
1. Overt symptomatic multiple myeloma 
2. Amyloidosis of unknown or non-AL type 
3. Localised AL amyloidosis (in which amyloid deposits are limited to a typical single organ, for example the 
bladder or larynx, in association with a clonal proliferative disorder within that organ) 
4. Trivial or incidental AL amyloid deposits in the absence of a significant amyloid-related organ syndrome 
(e.g., isolated carpal tunnel syndrome) 
5. Refractory to or progressive disease with an IMid and proteasome inhibitor combination  
6. Allogeneic stem cell transplantation 
7. Solid organ transplantation 
8. Severe peripheral or autonomic neuropathy causing significant functional impairment that, in the 
investigator’s opinion, may interfere with protocol adherence 
9. eGFR <20ml/min 
10. Ejection fraction < 40% or NYHA class III or IV heart failure or uncontrolled hypertension that 
concerns the investigator 
11. Severe pulmonary Hypertension that, in the investigator’s opinion, may interfere with protocol adherence 
12. Advanced Mayo stage III disease as defined by hs-Troponin T>0.07 and  NT-proBNP >700 pMol/L 
OR NT-proBNP >1000 pMol/L OR supine  SBP <100 mm of Hg 
13. Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities 
uncontrolled by medication or devices 
14. Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in 
situ carcinomas 
15. Pregnant, lactating or unwilling to use adequate contraception 
16. Systemic infection unless specific anti-infective therapy is employed 
17. Known or suspected HIV infection 
18. Contraindication to any of the required concomitant drugs or supportive treatments 
19. Any other clinically significant medical disease or condition or psychiatric illness that, in the Investigator’s 
opinion, may interfere with protocol adherence or a participant’s ability to give informed consent 
20. Previous experimental agents within 3 months before the date of registration 
21. Known allergies to Carfilzomib, Thalidomide or Dexamethasone  
22. Positive hepatitis B viruses (HBV) test 
 
6.3.3 Pregnancy and Birth Control  
 
The risks to the human embryo or foetus from exposure to Carfilzomib are currently unknown.  Thalidomide is 
teratogenic.  The ability of corticosteroids to cross the placenta varies between individual drugs, however, 
Dexamethasone readily crosses the placenta. Administration of corticosteroids to pregnant animals can cause 
abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain 
growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital 
abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly 
during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, 
in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously 
following birth and is rarely clinically important. Corticosteroids may pass into breast milk, although no data are 
available for Dexamethasone. Infants of mothers taking high doses of systemic corticosteroids for prolonged 
periods may have a degree of adrenal suppression.  
 
All patients will have to comply with the Thalidomide pregnancy prevention programme.   
 


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Pregnancy Testing 
All women of child bearing potential who are at risk of becoming pregnant must undergo a pregnancy test  prior 
to commencing the trial drugs and prior to start of each cycle.  
Sterilisation of either partner is not usually regarded as completely reliable enough to ensure that pregnancy can 
never occur.  
A woman of childbearing potential is a sexually mature woman (i.e. any female who has experienced menstrual 
bleeding) who has not: 
• undergone a hysterectomy or bilateral oophorectomy/salpingectomy 
• been postmenopausal for 24 consecutive months (i.e. who has not had menses at any time in the preceding 
24 consecutive months without an alternative medical cause) 
 
Contraceptive advice 
Due to the effects of the trial treatment during pregnancy and lactation, patients must consent to use one of the 
following acceptable methods of contraception during the study and for 30 days (in the case of female participants) 
or 90 days (in the case of male participants)  after the end of the study treatment. Women who could become 
pregnant must have taken precautions not to become pregnant for 1 month before the start of the study 
Acceptable methods of effective contraception for this trial are:  
• Established use of oral methods of contraception. Because of the increased risk of venous 
thromboembolism in patients, combined oral contraceptive pills are not recommended. 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository. The use of barrier contraceptives should always be 
supplemented with the use of a spermicide. The following should be noted:  
o Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective 
forms of contraception. Therefore the use of additional spermicides does confer additional 
theoretical contraceptive protection.  
o However, spermicides alone are inefficient at preventing pregnancy when the whole ejaculate is 
spilled. Therefore, spermicides are not a barrier method of contraception and must not be used 
alone. 
• Male sterilisation (with appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate). For female patients, the vasectomised male partners must be the sole partner for that patient. 
Please note that sterilisation is not usually regarded as completely reliable enough on its own to ensure that 
pregnancy can never occur.  
• Absolute and continuous abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. Please note that periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  
 
Because of the potential for serious undesirable effects in breast-fed infants, lactation should be discontinued 
during trial treatment. Women should not breastfeed for 3 months following their last dose of study treatment.  
The method(s) of contraception used must be stated in the patient medical notes. 
 
Should a pregnancy occur, either to a female patient or to a female partner of a male patient while on the trial Leeds 
CTRU must be informed immediately (Please refer to section 13.5 Pregnancy for details on the reporting 
procedure).  
 
 
 


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7.0 
Registration Procedures 
7.1 
Patient Registration 
Patient registration will be administered by telephone at Leeds CTRU.  Patients should be assessed for eligibility 
prior to consent and registration as part of the amyloid evaluation at the UK NAC. Patients must be consented and 
registered prior to trial-specific assessments. 
 
Following pre-treatment evaluations (as detailed in section 6.1), confirmation of eligibility and consent of a patient 
at the UK NAC, the registration form must be fully completed.  The following information will be required at 
registration: 
 
Hospital name and NIHR site code (RHC details) 
 
Name of person registering the participant 
 
Name of treating clinician 
 
Patient details, including initials, date of birth, and gender 
 
Confirmation of eligibility 
 
Confirmation of written informed consent 
A trial number will be assigned for the patient and details added to the form. 
 
Direct line for participant registration 
0113 343 1658 
Monday – Friday 9am-5pm except Public and University holidays 
Please ensure you have completed the Registration CRF before phoning  
Authorisation codes and PINs will be provided to the UK NAC for registration 
 
Immediately after registration, please fax the Consent Form, Registration CRF and Eligibility Checklist 
to CTRU 
 
Fax: 0113 343 4345 
 
UK NAC/Leeds CTRU registration process: 
1. A standard amyloid evaluation will be carried out at the UK NAC.  Eligibility will be assessed and written 
informed consent obtained 
2. Upon receipt of a completed consent form (see section 5.0) for an eligible patient, UK NAC will register 
the patient using the CTRU direct registration line.  A trial number will be assigned to the patient during 
registration  and these details will need to be added to the form 
3. A fully completed registration form will be sent to Leeds CTRU.  A copy of the consent form and 
eligibility checklist will also need to be sent to Leeds CTRU to confirm patient eligibility 
4. If there are any queries about eligibility, trial staff at Leeds CTRU will contact UK NAC immediately 
Registration confirmation to UK NAC and RHC 
5. Following registration,  the UK NAC will refer the patient to their allocated RHC (sections 5.1 & 11.1.2) 
and forward consent form and patient trial information to the RHC 
6. Leeds CTRU will also fax registration confirmation to the UK NAC and to the key contacts at the RHC   
Re-confirmation of eligibility at the RHC 
7. The RHC will contact the patient to arrange the first RHC visit (sections 5.1 & 11.1.2), which must be 
within 28 days of registration, and at which eligibility for the trial must be reconfirmed 


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8. For patients still eligible for the trial, the RHC will fax a fully completed eligibility confirmation form to 
Leeds CTRU (see point 12 below). If there are any queries about eligibility, trial staff at Leeds CTRU will 
contact staff at the RHC immediately 
9. Leeds CTRU will confirm the patient’s inclusion in the trial and also confirm their registered dose level 
by fax to the main contact at site and the site pharmacy 
10. During the dose escalation phase, the treatment start date must be confirmed and agreed with Leeds 
CTRU.  A minimum of 15 days must have elapsed between the start of treatment of the first patient in 
each cohort and subsequent patients    
11. For patients found to be ineligible for the trial, the RHC will fax a fully completed withdrawal form to 
Leeds CTRU 
12. If there is a ≥ 21 day delay in starting trial treatment after completion of eligibility confirmation form at 
the RHC, a second eligibility confirmation form must be completed.  Patients must start treatment within 
6 weeks of completion of the initial eligibility confirmation form at the RHC 
13. If after registration a patient decides to withdraw consent to the trial, or is found not to satisfy the 
eligibility criteria, the site must inform CTRU.  Sites must complete a withdrawal form to confirm 
withdrawal details  
  
Please see protocol section 11 for assessment summary and Appendices 6 and 7 for diagnostic 
sample requirements and investigations.  
 
Once a patient has been registered onto the trial they must be provided with the following: 
• 
A copy of their signed consent form and patient information sheet 
• 
A patient contact card.  Site on-call contact details for 24 hour medical care must be added to this card and 
patients advised to carry this with them at all times while participating in the trial 
• 
A patient Red Flag card.  A list of symptoms which need urgent medical attention 
 
 
 


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8. 
Trial Treatment 
For the purpose of this protocol, the IMPs are Carfilzomib, Thalidomide and Dexamethasone.  
 
All trial patients must be treated according to the following schedule in order to isolate the effects of the 
Carfilzomib. 
Please refer to the current Carfilzomib IB  and SPCs for Thalidomide and Dexamethasone, provided in the 
Investigator Site File and Pharmacy Site File,   for drug/drug or drug/food interactions. 
 
8.1 
Treatment Schedule Summary 
8.1.1 KTD Regimen 
 
All treatment will take place at the patient’s RHC/Site. 
 
If there is a ≥ 21 day delay in starting trial treatment after completion of eligibility confirmation form at the RHC, 
a second eligibility confirmation form must be completed.  Patients must start treatment within 6 weeks of 
completion of the initial eligibility confirmation form.  
 
 
Treatment will be as below with three regimes based on gradually increased dose and addition of Dexamethasone 
based on clonal response at end of each cycle.  
 
 
KTD protocol – dose escalation phase 
 
 Carfilzomib 
 
 
30 minute IV infusions of Carfilzomib at a dose according to table 1 below. 
 Days 1, 8,15                           A maximum of  6 cycles will be administered.  All patients will be  
recommended oral hydration with 250 ml of fluids 2 hours before and one hour 
after the infusion at day 1.Oral hydration with 250 ml of fluids 2 hours before the 
infusion is recommended from day 8 onwards. Post infusion hydration is optional 
and at the discretion of the treating physician for patients at risk of tumour lysis 
syndrome and/or dehydration. Patients should be monitored closely for fluid 
overload.  
 
All patients will receive Carfilzomib at 20mg/m2  on day 1 of cycle 1 and then at the allocated dose level on day 8 
and day 15 of cycle one, and during all subsequent cycles.  
 
Thalidomide 
 
 
50mg Thalidomide, oral preparation (potentially increasing to 100mg if well Days 
1-28 
 
 
tolerated - to  be discussed with the Chief Investigator before increasing dose)  
  
Dexamethasone 
20mg Dexamethasone, oral preparation.  This should be taken prior to all  
Days 1, 8,15 
 
 
Carfilzomib doses.  
 
 
Table 1: Dose Levels 
 
Dose level 
Carfilzomib IV (mg/m2 ) 
(Days 1, 8 & 15) 
Thalidomide (mg) 
 (Days 1-28) 
Dexamethasone (mg)  
(Days 1, 8 & 15) 
-1 
27 
50 
20 
0 
36 
50 
20 
1 
45 
50 
20 
2 
56 
50 
20 
 
 
A minimum of 15 days must have elapsed between the start of treatment of the first patient in each cohort 
and subsequent patients.   


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KTD protocol – dose expansion phase 
The dose escalation phase will then be extended once maximum tolerated dose (MTD) and the Recommended 
Dose (RD) has been established.  All patients will then receive Carfilzomib-Thalidomide -Dexamethasone as 
follows (repeated every 28 days) 
 
Carfilzomib  
 
 
Carfilzomib intravenous infusion at Recommended Dose (RD) .   
Days 1, 8,15                     
A maximum of 6 cycles will be administered.   
 
All patients will receive Carfilzomib at 20mg/m2  on day 1 of cycle 1 and then RD from day 8 onwards  
 
Thalidomide  
50 mg, p.o Thalidomide (consider increase to 100 mg from cycle 2 if well  
Days 1-28                        
 tolerated.  To  be discussed with the Chief Investigator before increasing dose 
 
  
 
Dexamethasone  
  
20mg Dexamethasone, oral preparation.  This should be taken prior to all   
Days 1, 8,15 
  
Carfilzomib doses. 
 
 
 
  
 
8.1.2 Changes in Body Surface Area (BSA) 
Participants must be weighed prior to the start of each cycle of treatment but the BSA should only be recalculated 
if weight changes by greater than 10% (loss or gain).  BSA to be calculated as per standard practice. 
 
8.1.3  Dose Escalation 
Dose escalation will begin at DL0 and will proceed until MTD or the highest planned dose level has been reached.  
Toxicity data for each cohort will be reviewed by the Safety Review Commitee prior to dose escalation, according 
to the following schema (Table 2).   
 
Table 2. Scheme for dose escalation decision 
Identifying MTD 
Number of patients with a DLT following 1 
cycle at a given dose level 
Escalation decision rule 
0 out of 3 
Enter 3 patients at the next highest dose level.  
If current dose level is the highest dose level, this is 
the MTD; proceed to identifying RD 
≥2 out of 3 
Dose escalation stopped and next lowest dose 
identified as MTD. Proceed to identifying RD.  
If current dose level is lowest dose, no MTD 
identified.   
1 out of 3 
Enter 3 more patients at the current dose level. 
 If 0 out of these additional 3 experience DLT (i.e. 
total DLTs 1/6), proceed to the next highest dose 
level. If current dose level is the highest dose level, 
this is the MTD & current dose level is identified 
as RD 
 If 1 or more of these additional 3 experience DLT 
(i.e. total DLTs >1/6), dose escalation stopped 


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and next lowest dose identified as MTD. Proceed 
to identifying RD 
Identifying RD 
Once the MTD is identified, at least 6 patients must have completed cycle 1 at the RD before enrolment 
to the dose expansion phase can commence.  
The RD is defined as the highest dose level at which at most 1/6 patients experience a DLT.  If only 3 
patients have been treated at the next lowest dose an additional 3 patients are recruited to this dose level. 
If >1/6 DLTs are then experienced at this dose level, dose level de-escalation continues until the RD is 
identified. 
If the MTD is identified as the highest dose level with 0/3 DLTS then an additional 3 patients are recruited 
to this highest dose level. If >1/6 DLTs are then experienced at this dose level, dose level de-escalation 
continues until the RD is identified.  If ≤1/6 DLTs are experienced then the highest dose level is identified 
as the RD. 
If no MTD is identified, no RD is identified and the study will not continue to the dose expansion phase.  
 
 
8.1.4 Dose Limiting Toxicities 
Dose limiting toxicities (DLTs) will be collected from the time of receiving the first dose of Carfilzomib in cycle 1 
up to the first dose of treatment administered in cycle 2. Only DLTs that are attributed to the registered dose of 
Carfilzomib will be included when determining the MTD (i.e those attributed to the loading dose will be excluded) 
(see section 19.2). A DLT will be defined as any of the following events that are determined to be related to trial 
drug administration: 
1. Any non-haematological toxicity ≥ Grade 3 according to NCI CTCAE Version 4.03 which fails to return to 
≤Grade 1 or baseline after 7 days. Nausea, vomiting, diarrhoea and electrolyte imbalances will be considered 
DLTs only if they reach ≥ Grade 3 severity despite adequate supportive care measures. Similarly, fluid retention 
or worsening symptoms of heart failure will be considered as DLTs if they are persistent ≥Grade 3 despite 
increase in oral diuretics or there is an increase in dyspnoea by ≥ 2 NYHA grades within 12 hours of 
administration of Carfilzomib which persists for > 6 hours or needs hospital admission 
2. Grade 4 neutropenia lasting > 7 days or Grade 4 neutropenia with sepsis despite adequate supportive measures. 
3. Any grade 4 thrombocytopenia which fails to return to Grade 2 within 7 days without platelet support 
4. Delay of >8 days within cycle 1 or delay of commencement of 2nd cycle by more than 14 days, due to significant 
toxicity or tolerability issue* 
5. Any other event which, in the opinion of the Safety Review Committee, is considered to be clinically significant 
and related to treatment 
 
*This will not be defined as a DLT if the delay is due to one of the other specified DLT criteria. 
8.1.5 Definition of Maximum Tolerated Dose (MTD) 
The highest dose level at which no more than 1 patient experiences a DLT, from the time of receiving the first 
registered dose of Carfilzomib in cycle 1 up to the first dose of treatment administered in cycle 2, i.e. the dose level 
below that at which 2 or more patients experiences a DLT.  If no more than one patient experiences a DLT at the 
highest dose level then this will be considered as the MTD. 
8.1.6 Definition of Recommended Dose (RD) 
Once the MTD has been established, a minimum of 6 patients will be treated at this dose level in order to establish 
the RD. The RD is the dose which will be used in the dose expansion phase of the study to evaluate activity. 
 
 
 


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9.0  Trial Medicinal Product Management  
9.1 
Investigational Medicinal Products (IMPs). 
The following are classified as Investigational Medicinal Products (IMPs). 
 CARFILZOMIB (IMP) 
Lyophilized Carfilzomib for Injection 
Composition: Lyophilized parenteral drug product in 60 mg single use vials. Upon reconstitution, 
Carfilzomib for injection consists of 2 mg/mL solution. 
Carfilzomib will be supplied solely for use in this trial by Amgen  free of charge. Please refer to the trial 
supplied Investigator Brochure  
 DEXAMETHASONE (IMP) 
Dexamethasone Tablet  
Composition: 2.0 mg Dexamethasone.   
Generic supply of Dexamethasone as determined by individual hospital sites.  Please refer to the trial 
supplied summary of product characteristics. 
 THALIDOMIDE (IMP) 
 
Thalidomide Capsule 
 
Composition 50 mg Thalidomide 
Generic supply of Thalidomide as determined by individual hospital sites.  Thalidomide will be ordered 
through the Celgene-approved process for Thalidomide risk management and pregnancy prevention, as 
for standard hospital supplies. Please refer to the trial supplied summary of product characteristics.. 
 
9.2 
Supportive Measures 
The following supportive measures should be considered for all patients in the trial: 
a.  
Antiviral such as oral acyclovir 400 mg twice  daily (or as per local standard practice) with dose 
modified according to renal function or appropriate alternative. Acyclovir should be continued for 
three months after the last dose of Carfilzomib if medically appropriate. 
b.   Medication to prevent gastric irritation such as oral Lansoprazole 15 mg once daily or Omeprazole 
20mg once daily or appropriate alternative  
c.  Antibiotics such as oral Co-trimoxazole 480 mg twice daily given three times weekly (unless 
contraindicated).  Prophylaxis to be continued for the duration of chemotherapy 
d.   Allopurinol is recommended to be prescribed, unless contraindicated (e.g. allergy). to all participants 
at 300 mg po daily (or dose adjusted for renal impairment), from Cycle 1 Day -1 or earlier until day 
+17 of cycle 1.  For participants at high risk of TLS (see above), the dose may be escalated to 300 mg 
po bd for days -1 to +4 of cycle 1, then reduced to 300mg od until day +17. Allopurinol dose should 
be adjusted according to the package insert.  Participants who do not tolerate allopurinol should be 
discussed with the Lead Principal Investigator.  In some circumstances (e.g. participants are 
exceptionally high risk of TLS); rasburicase may be used at the investigator’s discretion. 
e.  
Oral hydration. Participants must be well hydrated (i.e., volume replete).All patients will be 
recommended oral hydration with 250 ml of fluids 2 hours before and one hour after the infusion at 
day 1.Oral hydration with 250 ml of fluids 2 hours before the infusion is recommended from day 8 
onwards. Compliance will  be reviewed with the participant and documented by the site personnel 
prior to initiating treatment with Carfilzomib; treatment may be delayed or withhthromobeld.  In 
patients with poorly controlled heart failure, this can be reduced at the clinicans discretion. 
f:  
Routine Anticoagulation All patients will need routine thromboprophylaxis during the study.  
Patients not considered at high risk of thrombosis can receive aspirin 150 mg daily as 
thromboproplylaxis.  Patients considered at high risk of thrombosis will need formal anticoagulation 
with LMW heparin, warfarin or a thrombin inhibitor.  
 
All side-effects will be managed as per standard care by the treating clinician. Discontinuation of supportive 
measures may be considered if deemed appropriate in light of the toxicities seen by the treating clinician. 
 


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Antiemetics should be administered as per local protocols.  Oral domperidone or ondansteron  should be given on 
as required basis.  
 
9.3    Pharmacy responsibilities 
All pharmacy aspects of the trial at participating sites are the responsibility of the PI, who may delegate this 
responsibility to the local pharmacist or other appropriately qualified personnel, who will be the Pharmacy Lead.  
The delegation of duties must be recorded on the site staff delegation log. 
Carfilzomib supplied for the CATALYST trial is for CATALYST patients only and must not be used outside the 
context of this protocol. 
9.3.1  Labelling and IMP handling 
Carfilzomib supplies will contain a trial specific label, in line with Directive 2001/20/EC and the Medicines for 
Human Use (Clinical Trials) Regulations 2004 (amended 2006). It must be ring fenced for this trial in a separate 
area to non-trial products and records retained in the Pharmacy Site File noting the location of the storage. 
 
 
Dexamethasone tablets and Thalidomide capsules will be sourced from hospital stock as the marketed product  and 
a labelling exemption has been has been granted as part of the Clinical Trial Authorisation. Please refer to the 
Pharmacy and IMP Management Trial Site Operating Procedure for full details of the trial IMP management 
requirements. 
 
9.3.2  IMP Preparation 
All IMPs will be prepared and handled in line with manufacturers’ recommendations and the SPCs. IMPs requiring 
reconstitution will be reconstituted under conditions approved by the hospital pharmacy. 
9.3.3 IMP Administration and Risk Management 
Carfilzomib  
Carfilzomib for Injection is supplied as a lyophilized parenteral product in single-use vials. The lyophilized product 
is reconstituted with Water for Injection to a final Carfilzomib concentration of 2 mg/mL prior to administration.  
The dose will be calculated, as per standard practice,  using the participant’s actual BSA at baseline .  Participants 
with a BSA > 2.2 m2 will receive a dose capped at 2.2 m2 BSA.   
• 
At least 48 hours before Cycle 1 Day 1, oral hydration may  be given as follows:  500 mls of extra fluid per 
day  and 250 mls 2 hours before  the time of treatment.  Participant compliance will  be assessed before 
initiating treatment, which may  be delayed if oral hydration is not adequate.  In participants considered at 
risk for TLS, oral hydration may  be continued in Cycle 2 and beyond as required by the participant’s 
medical condition and at the Investigator’s discretion. 
 
• 
Oral hydration is at the discretion of the treating physician for patients at risk of tumour lysis syndrome 
and/or dehydration. Patients should be monitored closely for fluid overload.   
 
• 
If the participant has a dedicated line for Carfilzomib administration, the line must be flushed with a 
minimum of 20 mL of normal saline prior to and after drug administration. 
 
• 
Carfilzomib will be given as an IV infusion over approximately 30 minutes. The dose will be administered 
at a facility capable of managing hypersensitivity reactions.  Participants will remain at the clinic under 
observation for at least 1 hour following each dose of Carfilzomib in Cycle 1 and following the dose on 
Cycle 2 Day 1.   
 
• 
Dexamethasone will be administered prior to all Carfilzomib doses to prevent infusion reactions. 
 
• 
Known risks of Carfilzomib therapy include adverse drug reactions. Please refer to the latest IB for full 
tables of known adverse drug reactions associated with Carfilzomib. 
 


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The most common adverse reactions observed (frequency of greater than 15%) include anaemia, 
thrombocytopenia, neutropenia, diarrhoea, nausea, constipation, vomiting, fatigue, pyrexia, peripheral oedema, 
respiratory tract infections, increased blood creatinine, hypokalemia, anorexia, back pain, muscle spasms, 
headaches, insomnia, dyspnoea, and cough.  
 
Important identified risks include pulmonary hypertension, new or worsening cardiac failure, acute renal failure, 
tumour lysis syndrome, infusion reactions, hepatic toxicity, TTP/HUS, and PRES. 
 
Please refer to 10.12, “Carfilzomib safety considerations”, for details of how the risks of tumour lysis syndrome, 
decreased creatinine clearance, infection, anaemia, thrombocytopenia, and gastro-intestinal toxicities will be 
managed. The incidence of other toxicities should be managed as outlined in 10.4 and 10.5. 
 
Specific management is in place for cardiac toxicities are outlined in 10.10.   
 
Thalidomide 
Thalidomide is available as a capsule and a supply will be provided to patients for use in this trial. Thalidomide 
should be taken as per the provided instructions (50mg p/o per day, potentially increasing to 100mg per day, if well 
tolerated) at bed time to reduce the impact of somnolence. This medication may be taken by the patient with or 
without food. If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 
hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next 
dose at the normal time on the following day. 
 
Known risks of Thalidomide therapy include adverse drug reactions. Please refer to the SPC for Thalidomide for 
an exhaustive list of known risks.  
 
Very common side effects (≥10%) include neutropenia, leukopenia, anaemia, lymphopenia, thrombocytopenia, 
peripheral neutopathy, tremor, dizziness, paraestheia, dysaesthesia, somnolence, constipation, and peripheral 
oedema. 
 
Foetal teratogenicity, should women of child-bearing potential become pregnant during treatment, is well described, 
and there is also a risk of PRES, venous and arterial thrombo-embolitic events, and the development of MDS and 
AML. 
 
Viral reactivation of the varicella-zoster virus or hepatitis B virus (HBV) has been documented. Some of these cases 
have resulted in disseminated herpes zoster and acute hepatic failure, respectively.  Patients who test positive for 
HBV will not be eligibile for the CATALYST trial. 
 
Patients will be closely monitored throughout the trial as per the protocol to detect haematological toxicities, which 
may then be treated as per local practice.  
 
To prevent pregnancy and the risk of foetal malformation, The Celgene Pregnancy Prevention Programme should 
be adhered to by patients at all times. 
 
The risk of embolism will be managed by the administration of routine thromboprophylaxis during the study, as 
outlined in section 9.2. 
 
 
Dexamethasone 
Dexamethasone is available as a tablet and should be administered 30 minutes to 4 hours prior to all Carfilzomib 
doses during all cycles of treatment.  If a patient misses a dose of Dexamethasone, this can be taken only if the 
patient becomes aware of the missed dose within 24 hours of the time the dose was due. 
Known risks of Dexamethasone therapy include adverse drug reactions. Please refer to the SPC for Dexamethasone 
for an exhaustive list of known risks.  
 
Known side effects of Dexamethasone include immunosuppressive effects and associated recurrence of dormant 
infection, osteoporosis, hyper-tension, psychiatric reactions, ocular reactions, dyspepsia, dermatological problems, 
allergic reactions, and water retention. 
 


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Refer to 10.6, Dexamethasone toxicity, for details on how risks will be managed when patients are administered 
Dexamethasone. The occurrence of fluid retention and other toxicities should be subject to close monitoring. Fluid 
retention may be treated with diuretics. Dexamethasone discontinuation and replacement with other corticosteroids 
may be implemented.  
 
9.3.4  Drug accountability 
The Pharmacy Lead must ensure that appropriate records are maintained. 
These records must include accountability for each drug including receipt, dispensing, returned medication and 
destruction of returned/unused medication.  Template accountability forms will be supplied, however, sites may 
be permitted to use their own drug accountability records providing the same information is captured, as a 
minimum.  Such in-house records must be submitted to LEEDS CTRU for review and authorisation for use prior 
to patient enrolment.  
Copies of completed drug accountability logs must be submitted to LEEDS CTRU for all trial patients at the end 
of treatment or upon request.  Also refer to section 16.1 (Central Monitoring). 
 
Used vials can be immediately destroyed by aseptic pharmacy. Unused Carfilzomib (packets or vials) will be 
destroyed/disposed of as per local policy upon authorisation by Leeds CTRU. Authorisation for displosal will be 
granted after accountability has been verified by CTRU. 
 
For accountability of Thalidomide and Dexamethasone, sites are permitted to use their standard procedure for 
recording drug allocation and dispensing. Patients will also be instructed to keep a drug diary to detail all taken and 
missed doses.  The information collected must adhere to local policy and be made available to the Sponsor upon 
request.  Information regarding dosing and any reductions/delays of non IMPs will be collected in the CRFs. 
 
Patients must be instructed to return any dispensed unused Thalidomide and Dexamethasone to hospital pharmacy 
for appropriate destruction/disposal according to local policy. 
 
9.3.5 Temperature Excursions  
All temperature excursions outside the storage conditions for Carfilzomib specified in the IB must be reported to 
LEEDS CTRU. 
Upon identifying an excursion: 
 
all affected trial stock must be quarantined IMMEDIATELY  
 
the ‘Notification of Temperature Excursion’ form must be completed and e-mailed to 
medcatal@leeds.ac.uk  or faxed to 0113 343 4345. 
Please note that LEEDS CTRU must be informed immediately if a patient has been administered drug 
affected by a temperature excursion. 
 
9.4    Clinical Management after Treatment Discontinuation 
Patients whose underlying plasma cell dyscrasia does not respond by the end of three cycles or who have a clonal 
progression on treatment will be treated and followed up off trial at the discretion of the treating clinician but will 
have a final follow-up visit 6 months after registration. 
 
Patients that receive 6 cycles of chemotherapy will be followed up 1 month after end of trial treatment. 
 
Also refer to section 14 (Withdrawal of Patients) for further details regarding treatment discontinuation, patient 
withdrawal from trial treatment and withdrawal of consent to data collection. 


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9.5     Out-of-hours medical care 
Medical care, including out-of-hours medical care is the responsibility of the site.  Sites must ensure that all patients 
registered onto the have received a CATALYST patient card and Red Flag card (which lists symptoms needing 
immediate medical attention) with out-of-hours contact details. 


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10.0 Dose delays and modifications 
 
The dose of Carfilzomib should be delayed and / or reduced according to the guidelines given below (CTCAE 
v4.03).  Dose re-escalation may occur if the toxicities were considered to be disease related, however dose re-
escalation should only be undertaken following discussion with the CI.  
 
Please see appendix 8 for known risk and discomforts from Carfilzomib. 
 
10.1 
Cycle 1 - dose escalation phase only 
 
If toxicity occurs between day 1 of cycle 1 and first dose of treatment administered in cycle 2 treatment of the dose 
escalation phase, please refer to Section 8.1.4 for DLT definitions. 
 
Any patient experiencing a DLT during cycle 1 of the dose escalation phase will have his or her treatment withheld 
until toxicity resolves to baseline or Grade ≤1.  Upon resolution, the patient may have therapy re-instituted at the 
next lowest dose level, unless this occurs dose level -1, where patients will stop therapy. 
 
If a patient experiences an SAE or grade 3/4 toxicity after the day 1 dose of cycle 1 (loading carfilzomib dose) 
treatment should be delayed until toxicity has resolved to baseline or Grade ≤1 and then discussed with the CI to 
see whether it is safe to proceed as planned.   
 
If there is a greater than 8 day delay in dosing due to toxicity attributable to the loading dose of Carfilzomib, the 
safety review committee will be notified.   
 
10.2  Subsequent cycles (all patients) 
 
In summary treatment should be delayed for any patient experiencing: 
 
 
Grade 4 thrombocytopnia with active bleeding 
Grade 4 anaemia and Grade 4 thrombocytopenia (without active bleeding) do not require the Carfilzomib 
dose to be withheld.  Participants should receive supportive measures in accordance with institutional 
guidelines.   
 
 
Grade 4 neutropenia or neutropenic fever 
 
 
Grade 3/4 non-haematological toxicity 
 
Treatment should continue to be withheld until the neutrophil count and platelet count return to ≥0.75 x 109/L 
and ≥25 x 109/L, respectively (during a cycle). Drug-induced non-haematological toxicities have to have reached 
baseline, or become Grade ≤1 prior to re-treatment. Treatment may be delayed up to 8 days to allow sufficient 
time for recovery from toxicities.  Please check table 3 and table 5 for dose reduction guidelines.   
 
If the haematological or non-haematological AE has not resolved within 14 days the patient must discontinue from 
therapy, if the haematological or non-haematological toxicities have resolved within 14 days, the patient may have 
their therapy re-instituted at the next lowest dose level. Please check table 3 and table 5 for dose reduction 
guidelines.   
 
A dose delay of up to 14 days (up to 3 weeks for infection treatment) is permitted at the beginning of a cycle to 
allow resolution of toxicity.  If there is no resolution of toxicity as stated above after 2 weeks of withholding 
treatment (3 weeks for infection treatment), the participant will be discontinued from treatment.  Withholding 
treatment for more than 2 weeks for other reasons, eg elective surgery such as vertebroplasty, may be permitted 
after discussion with the CI. 
 


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No more than three dose reductions or delays in two consecutive cycles will be permitted in an individual participant 
on study.  If toxicity continues or recurs after three dose reductions or delays, the participant should be discontinued 
from treatment. 
 
 
If a patient vomits after taking a dose of an oral agent, no repeat dose should be taken and patient will continue as 
per schedule but the clinical team should consider prophylactic antiemetics.  
 
All previously established or new toxicities observed at any time, with the exception of neuropathic pain and 
peripheral sensory neuropathy, are to be managed as detailed in table 3 recommended action for haematologic 
toxicities and table 5 dose adjustment guidelines for non-haematological toxicities. 
  
 
10.3 Haematological Parameters 
The following parameters must be met on the first day of a new cycle (other than cycle one, when the inclusion 
for initial registration parameters must be met): 
 
Platelet count ≥50x109/L, Haemoglobin ≥8g/dl, (prior red blood cell transfusion or recombinant Human 
Erythropoietin usage is allowed), ANC ≥1x109/L. 
 
On any day of Carfilzomib administration during a cycle (other than day one of each cycle), the haematological 
results must be: 
 
Platelet count ≥25x109/L, Haemoglobin ≥8g/dl (prior red blood cell transfusion or recombinant Human 
Erythropoietin usage is allowed), ANC ≥0.75x109/L. 
 
10.4  Dose Reduction For Haematologic Toxicities  
Patients will have a FBC prior to each dose of Carfilzomib during treatment. 
 
Carfilzomib will be withheld from participants with: 
 
Grade 4 thrombocytopenia with active bleeding 
 
Grade 4 neutropenia 
 
 
The following table outlines the dose reduction guidelines for Carfilzomib for thrombocytopenia and neutropenia: 
 
 
Table 3: Recommended Action for Haematologic Toxicities 
 
Haematologic Toxicity 
Recommended Action 
Thrombocytopenia 
 
 
When platelets fall to ≤ 25 x 109 / L 
 
If platelets 10 – 25 x 109 / L without 
evidence of bleeding 
Continue at same dose 
If evidence of bleeding or platelets < 
10 x 109 / L 
Withhold dose until platelets return 
to ≥ 10 x 109 / L and/or bleeding is 
controlled, then resume at same dose. 
 
For each subsequent drop to ≤ 25 x 
109 / L 
 
If platelets 10 – 25 x 109 / L without 
evidence of bleeding 
Continue at same dose 
If evidence of bleeding or platelets < 
10 x 109 / L 
Withhold dose until platelets return 
to ≥ 10 x 109 / L and/or bleeding is 
controlled, then resume at 1 dose 
decrement 
Neutropenia 
When ANC falls to ≤ 0.75 x 109 / L 
If ANC 0.5-0.75 x 109 / L 
Continue at same dose 


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If ANC <0.5 x 109 / L 
Withhold dose until ANC returns to 
≥ 0.5 x 109 / L, then resume at same 
dose. 
For each subsequent drop to ≤ 0.75 
x 109 / L 
If ANC 0.5-0.75 x 109 / L 
Continue at same dose 
If ANC <0.5 x 109 / L 
Withhold dose until ANC returns to 
≥ 0.5 x 109 / L, then resume at 1 dose 
decrement. 
Neutropenic fever 
If 
< 
1000/mm3 
and 
single 
temperature 
> 
38.3⁰C 
OR 
temperature > 38.0⁰C for more than 
one hour. 
Withhold dose until ANC returns to 
baseline grade, then resume at same 
dose. 
 
Please note; if doses of carfilzomib need to be delayed then the dexamethasone dose must also be delayed so that 
it can be taken prior to the carfilzomib dose.  Thalidomide can be taken continuously unless there is toxicity directly 
attributable to Thalidomide. 
 
10.5 Dose Reductions for Non-Haematologic Toxicities 
Carfilzomib should be withheld for events ≥ Grade 3 until resolved to ≤ Grade 1 or return to baseline.  
After resolution of the event to ≤ Grade 1 or return to baseline, if the adverse event was not treatment-related, 
subsequent treatment with Carfilzomib may resume at full dose.  If the event was treatment-related, subsequent 
treatment with Carfilzomib will resume at one level dose reduction except for nausea, vomiting or diarrhoea which 
can be attributed to Carfilzomib  (see table 5 below).  If toxicity continues or recurs, a 2nd Carfilzomib dose 
reduction may be permitted at the discretion of the investigator.  No more than three dose reductions will be 
permitted in an individual participant on study.  If toxicity continues or recurs after three dose reductions, the 
participant should be discontinued from treatment. 
Dose reduction guide for Carfilzomib: 
Table 4: Dose Reduction Guide for Carfilzomib Dosing 
 
Current dose 
Reduce to 
27mg/m2 
20mg/m2  
36 mg/m2 
27 mg/m2 
45 mg/m2 
36 mg/m2 
56 mg/m2 
45 mg/m2 
 
If the participant tolerates the reduced dose for two cycles, participant may be dose escalated to the dose prior to 
reduction following discussion with the CI and CTRU. 
 
Dose adjustment guidelines for non-haematologic toxicities are summarised as follows: 
 
Table 5: Dose Adjustment Guidelines for Non-Haematological Toxicities. 
Symptom 
Recommended Action 
 
Carfilzomib 
Allergic reaction/hypersensitivity 
Withhold until ≤ Grade 1, reinstitute at full dose. 
Grade 2 – 3 
 
Grade 4 
Discontinue (refer to section 14) 
Tumour 
lysis 
syndrome  
(≥ 3 of following: ≥ 50% increase in 
creatinine, uric acid, or phosphate; ≥ 30% 
increase in potassium; ≥ 20% decrease in 
calcium; or ≥ 2-fold increase in LDH 
Withhold Carfilzomib until all abnormalities in serum chemistries 
have resolved.  Reinstitute at full doses. 


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Infection Grade 3 or 4 
Withhold Carfilzomib until systemic treatment for infection complete 
and infection resolves.  If no neutropenia, restart at same dose.  If 
neutropenic, follow neutropenia instructions. 
Herpes zoster of any grade 
Withhold Carfilzomib until lesions are dry. Reinstitute at full dose 
Grade 3 Nausea or vomiting despite 
maximal anti-emetic therapy or diarrhoea 
Withhold Carfilzomib until this resolves and re-start at full dose.  If 
recurrent, re-start at one dose level lower 
Grade 2 treatment emergent neuropathy 
with pain or Grade 3 neuropathy 
Continue to dose.  If neuropathy persists for more than two weeks 
hold Carfilzomib until resolved to ≤ Gr 2 without pain. Then restart 
at 1 dose decrement 
≥ Grade 3 elevation in LFTs (AST, ALT, or 
total bilirubin) 
Withhold dose. Resume at 1 dose decrement when toxicity has 
resolved to baseline. 
Grade 4 neuropathy 
Discontinue (refer to section 14) 
 
 
Renal Dysfunction  
Serum creatinine equal to or greater than 2 x 
baseline, or CrCl < 15mL/min (or CrCl 
decreases to ≤50% of baseline) or need for 
dialysis. 
 Withhold dose and continue monitoring renal function (serum 
creatinine or serum creatinine clearance). 
If attributable to Carfilzomib, resume when renal function has 
recovered to within 25% of baseline. Start at 1 dose level reduction. 
If not attributable to Carfilzomib, dosing may be resumed at the 
discretion of the physician. 
If tolerated, the reduced dose may be escalated to the previous dose 
at the discretion of the physician. For patients on dialysis during 
Carfilzomib, the dose is to be administered after the dialysis 
procedure. 
Congestive heart failure and other cardio-
pulmonary disorders. 
See section 10.10. 
Any participant with marked worsening of symptoms of congestive 
heart failure, whether or not drug related, must have the dose withheld 
until resolution or return to baseline, after which treatment may 
continue at a reduced dose, or the subject may be permanently 
discontinued 
Other non-haematologic toxicity assessed as 
Carfilzomib-related > Grade 3 
Withhold dose until toxicity resolves to ≤ Grade 2 or baseline.  Restart 
at 1 dose decrement. If tolerated, the reduced dose may be escalated 
to the previous dose at the discretion of the physician.  
PRES (posterior reversible encephalopathy 
syndrome 
with 
symptoms 
including 
headaches, altered mental status, seizures, 
visual loss, and hypertension). 
If PRES suspected, withhold Carfilzomib.  
Consider evaluation with neuroradiological imaging for onset of visual 
or neutrological symptoms suggestive of PRES. 
If PRES diagnosis is excluded, Carfilzomib administration may 
resume if clinically appropriate. 
 
 
 
10.6 Dexamethasone Toxicity  
Fluid retention is common with Dexamethasone in patients with amyloidosis.  Optimisation and close monitoring 
of fluid balance including alteration of diuretic therapy according to daily weights should be considered as the first 
step.  For fluid retention, switching to an alternative corticosteroid, e.g. methylprednisolone, is unlikely to be of 
major benefit as the mineralocorticoid action is greater for most other corticosteroids than for Dexamethasone at 
comparable doses. 
If a patient experiences grade 3 or 4 toxicity directly attributable to Dexamethasone a dose reduction should be 
considered. Dose adjustments should be at the discretion of the treating physicians in view of appreciable variability 
in the manifestation of such side effects.  Dexamethasone should be reduced in 4mg steps. 
Please see the SPC for expected toxicities.  
 
10.7  Thalidomide Toxicity 
 
Cases of viral reactivation, some serious, have been reported following treatment with thalidomide, particularly in 
patients previous infected with the varicella zoster virus or hepatitis B virus (HBV). Some of the cases of 
reactivation resulted in disseminated herpes zoster, requiring antiviral treatment and thalidomide treatment 


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interruption. Some cases of HBV reactivation progressed to acute hepatic failure and resulted in thalidomide 
treatment discontinuation.  
Hepatitis B virus status should be established before initiating treatment with thalidomide. For patients who test 
positive for HBV, consultation with a physician with expertise in the treatment of hepatitis B is recommended. 
Previously infected patients should be closely monitored for signs and symptoms of viral reactivation, including 
active HBV infection, throughout therapy.  Patients who test positive for HBV will not be eligibile for the 
CATALYST trial.   
 
 
Cases of pulmonary hypertension, some fatal, have been reported following treatment with thalidomide.  
 
If a patient experiences grade 3 or 4 toxicity directly attributable to Thalidomide a dose reduction should be 
considered.  Dose adjustments should be at the discretion of the treating physicians in view of appreciable variability 
in the manifestation of such side effects.  Patients receiving 100mg should be reduced to 50mg.  Patients receiving 
50mg should have their dose discontinued.   
Please see the SPC for expected toxicities.  
 
10.8  Increased Creatinine or Decreased CrCl 
Carfilzomib should be withheld for CrCl < 15 mL/min, and re-commenced as detailed in Table 5. Patients whose 
renal function fails to recover may re-commence therapy after discussion with the CI.  
10.9 Infections  
Participants with active or suspected infections of grade III or greater should have treatment withheld until infection 
has resolved and anti-infective treatment has been completed.  After the infection has resolved and anti-infective 
treatment has been completed, treatment may continue at the original dose.  If there is no resolution of toxicity to 
≤ Grade 1 or baseline after 3 weeks, the participant will be discontinued from treatment (see section 14). 
10.10 Congestive Heart Failure 
New or worsening cardiac failure, myocardial ischaemia, and myocardial infarction have occurred following 
Carfilzomib administration, with the risk of cardiac failure increased in elderly subjects (≥ 75 years). Worsening of 
congestive cardiac failure and other cardiopulmonary disorders including pulmonary oedema, and decreased 
ejection fraction will need careful assessment in relation to baseline cardiac status for the patient since many amyloid 
patients will have stable heart failure prior to trial entry. 
If left ventricular ejection fraction (LVEF) decreases occur (for resting LVEF < 40% or reduction of LVEF to 
<55% if the drop is greater than 20% from baseline), withhold Carfilzomib until LVEF returns to > 40% or, if 
held due to a drop, < 55% within 15% of baseline. Resume at a 1-dose decrement.  
Any participant with marked worsening of symptoms of congestive heart failure, whether or not drug related, must 
have the dose withheld until resolution or return to baseline, after which treatment may continue at a reduced dose, 
or the subject may be permanently discontinued. If no resolution after 2 weeks, participant will be permanently 
discontinued. 
Any participant with significant worsening symptoms of CHF which has not resolved with an increase in diuretics 
prior to the next dose, or any other acute cardiac event, whether or not drug related, must have treatment withheld 
until resolution.  After the event has resolved, treatment may continue at the previous dose, or one dose level lower 
than the previous dose.  If there is no resolution of worsening of CHF after 2 weeks or further worsening after the 
next dose, the participant will be discontinued from treatment. 
 
10.11 Conditions Not Requiring Dose Reduction 
The following conditions are exceptions to the above guidelines.  Carfilzomib dosing does not need to be withheld 
in the following cases: 
 
Grade 3 nausea, vomiting or diarrhoea (unless persisting >5 days with adequate use of anti-emetics or anti-
diarrhoeal medication)  
 
Grade 3 fatigue (unless persisting for >14 days) 


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 
Alopecia 
 
≥ Grade 3 hyperglycaemia attributed to Dexamethasone 
 
10.12 Carfilzomib Safety Considerations 
Based upon the experience in the Phase 1 and 2 clinical studies with Carfilzomib, the following observations are 
noted:  
 
A “first dose effect” has been seen, which is notable for fever, chills, rigors, and/or dyspnoea occurring 
during the evening following the first day of infusion and an increase in creatinine on Day 2, which may 
be the clinical sequelae of rapid tumour lysis and/or cytokine release.    
 
Should a “first dose” effect occur at any point during Cycle 1 or 2, treatment with high dose glucocorticoids 
(e.g. methylprednisolone 50–100 mg) is recommended.  In addition, intravenous fluids, vasopressors, 
oxygen, bronchodilators, and acetaminophen should be available for immediate use and instituted, as 
medically indicated.  
 
Dexamethasone will be administered prior to all Carfilzomib doses to prevent infusion reactions.  See 
section 9.3.3 for more details.  
 
Acyclovir or similar should be given to all participants with a history of herpes simplex or zoster, per 
institutional prophylaxis guidelines, unless contraindicated. 
 
CrCl changes are mostly transient, reversible, and non-cumulative. All participants should be well hydrated.  
Clinically significant electrolyte abnormalities should be corrected prior to dosing with Carfilzomib. Renal 
function must be monitored closely during treatment with Carfilzomib.  Serum chemistry values, including 
creatinine, must be obtained and reviewed prior to each dose of Carfilzomib during Cycles 1 and 2. 
Carfilzomib must be withheld for participants with a CrCl < 15 mL/min at any time during study 
participation. 
 
Participants with active or suspected infection of any kind that required systemic treatment should not be 
dosed with Carfilzomib until the infection has resolved.  
 
Cases of gastrointestinal, pulmonary, and intracranial haemorrhage have been reported in patients treated 
with Carfilzomib, and are often associated with thrombocytopenia. Thrombocytopenia has been transient, 
with platelet nadirs seen between Day 8 and Day 15 of dosing, and typically resolves to baseline by the 
start of the next cycle. Platelet counts should be monitored frequently during treatment with Carfilzomib.  
For platelet counts ≤ 10 x 109/L with evidence of bleeding, Carfilzomib dosing must be withheld.  If 
platelet counts do not recover, the dose of Carfilzomib may be reduced or held according to the Dose 
Reductions / Adjustments rules outlined in Section 10.4. 
 
Thromboembolic events, including deep vein thrombosis and pulmonary embolisms, have been reported 
in patients taking Carfilzomib, and some events have had fatal outcomes. Thromboprophylaxis, as outlined 
in section 9.2, should be administered to all participants receiving Carfilzomib.   
 
Participants should have anaemia corrected in accordance with the Institutional guidelines. 
 
Carfilzomib treatment can cause nausea, vomiting, diarrhoea, or constipation sometimes requiring the use 
of antiemetics or antidiarrhoeals.  Fluid and electrolyte replacement should be administered to prevent 
dehydration.   
 
Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible posterior 
leukoencephalopathy syndrome (RPLS), is a rare neurological disorder, which can present with seizure, 
headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological 
disturbances, along with hypertension. The diagnosis is confirmed by neuro-radiological imaging. If 
diagnosed early and treated, the symptoms of PRES may be reversed. Cases of PRES have been reported 
in subjects receiving Carfilzomib. Discontinue Carfilzomib if PRES is suspected. Refer to the study 
protocol for further instructions regarding dose modifications. The safety of reinitiating Carfilzomib 
therapy in subjects previously experiencing PRES is not known. 
 
Cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) including 
those with fatal outcome have been reported in subjects who received Carfilzomib. Monitor for signs 
and symptoms of TTP/HUS. If the diagnosis is suspected, stop Carfilzomib and manage per standard of 
care including plasma exchange as clinically appropriate. If the diagnosis of TTP/HUS is excluded, 
Carfilzomib can be restarted.  
 
Hypertensive crises have been infrequently reported in subjects treated with Carfilzomib. Hypertensive 
crises can present as hypertensive urgency or as a hypertensive emergency. Hypertensive urgency is defined 
as sustained or persistent systolic blood pressure 180mmHg or higher or diastolic blood pressure 
110mmHg or higher, with no associated organ damage. A hypertensive emergency occurs when blood 


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pressure reaches levels that result in end organ damage. All patients should be routinely evaluated for 
hypertension and treated as needed. If the hypertension cannot be controlled Carfilzomib should be 
reduced, per protocol. In cases of hypertensive crises, stop Carfilzomib until resolved or returned to 
baseline and consider whether to restart Carfilzomib based on a risk/benefit assessment. 
 
Cases of pulmonary hypertension have been commonly reported in subjects treated with Carfilzomib. 
Pulmonary hypertension is generally defined as a mean pulmonary arterial pressure ≥ 25mmHg at rest. 
Echocardiography is usually the first test to suggest pulmonary hypertension. Pulmonary hypertension 
can be a progressive, fatal disease if untreated, although the rate of progression is highly variable. 
Amyloid patients often have pulmonary hypertension at baseline.  Stop Carfilzomib until pulmonary 
hypertension has resolved or returned to baseline and consider whether to restart Carfilzomib based on a 
risk/benefit assessment.  Cases of interstitial lung disease (including pneumonitis), acute respiratory 
failure and Acute Respiratory Distress Syndrome (ARDS) have been uncommonly reported in subjects. 
Evaluate and stop Carfilzomib until resolved and consider whether to restart Carfilzomib based on a 
risk/benefit assessment. 
 
Acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary 
disease such as pneumonitis and interstitial lung disease have been reported in subjects receiving 
Carfilzomib. Suspected acute respiratory conditions should be evaluated and Carfilzomib stopped until 
resolution. Consider whether to re-start Carfilzomib based on a risk/benefit assessment. 
 
Dyspnoea is commonly reported in participants receiving Carfilzomib, and should be evaluated to 
exclude cardiopulmonary conditions (cardiac failure, pulmonary  syndromes). Carfilzomib shall be 
stopped for Grade 3 or 4 dyspnoea until resolves or returned to baseline. Consider whether to re-start 
Carfilzomib based on a risk/benefit assessment.  
 
Cases of Tumor Lysis Syndrome (TLS) including fatal outcome, have been reported in subjects who 
received Carfilzomib. Subjects with a high tumor burden should be considered to be at greater risk for 
TLS. Ensure that subjects are well hydrated before administration of Carfilzomib in Cycle 1 and in 
subsequent cycles as needed. Uric acid-lowering drugs should be considered in subjects at high risk for 
TLS. Monitor for evidence of TLS during treatment, including regular measurement of serum electrolytes, 
and manage promptly. Interrupt Carfilzomib until TLS is resolved. Refer to the study protocol for further 
instructions regarding dose modifications. 
 
Please refer to the trial supplied Investigator Brochure to see the full adverse drug reaction tables. 
 
 
 
 
11.0 Assessments  
 
The trial consists of an initial treatment period of up to 6 cycles of chemotherapy treatment (approximately 7 
months) for all patients.  Follow up will be 6 months after registration or 1 month after the end of treatment if 6 
cycles of chemotherapy was adminisitered.  
 
Trial data will be recorded by UK NAC and RHCs research staff on the CRFs and submitted to the LEEDS CTRU.  
It is the responsibility of each trial site to retain copies of all completed CRFs and to maintain their Investigator 
Site File which contains all essential documentation for the trial that is required at site.  
 
5ml serum samples will be sent to the UK NAC by the RHCs for central testing as part of routine clinical practice; 
as noted in the following sections of the protocol.  Packs, containing appropriately labelled sample tubes for the 
central testing associated with this trial, will be provided to participating RHCs by the UK NAC. 
 
The central investigations are of key importance in relation to the in-depth assessment of the disease, 
prognostic factors, and the analysis of response to treatment and outcome. 
 
See Trial Contacts at the beginning of the protocol for addresses for sending samples for central analysis and CRFs. 
 
 
 
 


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Assessment summary table: 
 
Investigation 
Baseline 
(Registration 
at UK NAC) 
Re-
confirmation 
of Eligibility 
(at RHC)e 
Treatment 
 
Carfilzomib and Dexamathasone 
days 1, 8 , 15 
 
Thalidomide days 1-28 
Prior to 
beginning 
of 4th Cycle 
(at UK 
NAC) 
 
 
 
 
End of 
treatment 
visit (at 
RHC) 
 
Follow up 
visit 
 (at UK NAC) 
Prior to each 
treatment 
cycle (at 
RHC)f 
Day 8 
Day 15 
Informed consent 
X 
 
 
 
 
 
 
 
Patient details 
(including initials, date 
of birth, sex) 
X 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
X 
 
 
X 
X 
X 
Laboratory testsb 
Xb 
X 
X 
 
Xj 
 
Xj 
X 
X 
Xb 
Pregnancy test 
X 
X 
Xh 
 
 
X 
X 
Xi 
Assessment of 
response at UK NAC  
 
 
 
 
 
X 
 
X 
Echocardiography 
incl. Tissue Doppler 
X 
 
Xg 
 
 
Xg 
 
X 
24 Hour Holter 
monitor 
X 
 
 
 
 
 
 
 
Bone marrow 
examinationc 
X 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B test 
X 
 
 
 
 
 
 
 
5ml serum sample to 
UK NACd 
Used to assess 
response to treatment 
 
 
On Day 1 of treatment cycle 1, 2, 3, 5, 6 (to be taken at RHC and sent to UK NAC) AND 
within a week of the planned start date of the 4th  cycle  
 
a Including height, weight, lying and 5 minute standing blood pressure, ECOG performance status 
b Including haematology, biochemistry, paraprotein and immunoglobulins (see Appendix 6 for details) 
c  Only if clinically indicated  
d Send to UK NAC as per standard practice. Results will be used to assess haematological response and relapse. 
e visit must be within 28 days of registration 
f Patient must receive 1st cycle of treatment within 6 weeks of reconfirmation of eligibility at the RHC (see 11.1.2). 
g Repeat echocardiogram at end of cycle 2 only (echocardiograms at baseline, prior to cycle 4 and end of treatment will be done at NAC).  Echocardiogram 
to be repeated at any cycle if clinically indicated for unexpected worsening of cardiac function. 
h To be supervised and performed on the day of prescription or in the 3 days prior to the visit to the prescriber.  
I To be supervised and performed four weeks after the end of treatment during the follow-up visit 
j FBC and creatine levels to be checked at day 8 and day 15 (see appendix 6 for details) 


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11.1 
Eligibility assessments 
 
PLEASE ALSO SEE APPENDIX 6 
11.1.1 Assessments at National Amyloidosis Centre (UK NAC) 
Once written informed consent has been obtained, patients will be registered as described in section 7.1.  The 
results of investigations and assessments carried out as part of the standard Amyloid Evaluation by the UK NAC 
(detailed in Appendix 6) will be recorded as part of the trial dataset as baseline evaluation. 
11.1.2 Assessments at RHC to reconfirm eligibility 
Following consent and registration, patients will be referred by UK NAC to a Regional Haematology Centre (RHC), 
see section 5.1.  Upon attendance at the relevant RHC, patient eligibility for the trial will be reconfirmed by the 
treating Haematologist.  This visit must be within 28 days of registration.  The following investigations and 
assessments will be carried out by the RHC to confirm eligibility of the patient for the trial: 
 
 
Physical examination 
 
FBC (including Hb, White Cell Count, Platelets), clotting screen (PT, APTT, Factor X (if indicated)), 
biochemistry (including creatinine, eGFRcalcium, phosphate, CRP, ALP, GGT, AST, ALT, bilirubin, 
albumin, sodium, potassium) 
 
Pregnancy test 
 
For all patients who still fulfil the eligibility criteria for the trial, the RHC must complete the eligibility confirmation 
form and fax to LEEDS CTRU.  LEEDS CTRU will confirm patient’s entry into trial and upon receipt of this at 
RHC, the patient will receive the protocol treatment regimen.   
 
If there is a ≥ 21 day delay of reconfirmation of eligibility, the RHC will have to carry out the above 
investigations and assessments again and complete another eligibility confirmation form, to allow the 
patient to continue on the trial.  If the patient is unable to start treatment within 6 week of completion of 
the first eligibility confirmation form completed by the RHC, he/she will be withdrawn from the trial. 
 
Patients who are no longer eligible for the trial will be withdrawn from the trial and treated according to standard 
local practice (the RHC site staff will complete the Withdrawal Form and fax to LEEDS CTRU). 
 
LEEDS CTRU will inform UK NAC of all patients entering/withdrawing from the trial at this point. 
11.2 
Assessments during treatment 
 
Prior to each chemotherapy cycle 
During treatment the patient should be seen prior (within 3 days) to each chemotherapy cycle and the following 
assessments performed: 
 
Physical examination, including lying and 5 minute standing blood pressure. 
 
FBC (Hb, White Cell Count, Platelets), clotting screen (PT, APTT, Factor X (if indicated)), biochemistry 
(urea, creatinine, eGFR, calcium, phosphate, CRP, ALP, GGT, AST, ALT, bilirubin, albumin, sodium, 
potassium). 
 
Assess and record any adverse events  
 
Record concomitant medications 
 
Repeat echocardiogram at end of cycle 2 only (echocardiograms at baseline, prior to cycle 4 and end of 
treatment will be done at UK NAC).  Echocardiogram to be repeated at any cycle if clinically indicated for 
unexpected worsening of cardiac function.  
 
Pregnancy test 
 
A 5ml serum sample must be sent to the UK NAC as per standard practice prior to the start of 
each chemotherapy cycle * 
 
*The 5 ml serum sample is used by the UK NAC to assess haematological response and relapse (through 
biochemical tests including serum free light chain assessments), the results of which will be used as part of the trial 
dataset.  The sample will be frozen and stored at the UK NAC indefinitely as per standard practice (separate written 


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consent is obtained for this as per standard clinical practice for all patients attending UK NAC). In addition, the 
following data will be collected for each treatment cycle: 
 
Treatment cycle number and cycle details, including dose given, dose alterations, and reasons 
 
Toxicities relating to treatment 
 
Day 8 and day 15 of cycle 
Patients will also be seen on day 8 and day 15 of each cycle and the following assessement performed: 
 
FBC (Hb, White Cell Count, Platelets) and creatinine 
 
Assess and record any adverse events  
 
Record concomitant medications 
 
 
 
All patients with stage III disease will be assessed once weekly for the first three cycles for signs or 
symptoms of worsening heart failure or “red flag” symptoms ** .  
All patients will be given a card for “red flag” symptoms** with advice to seek urgent medical attention  
 
** Red Flag symptoms: Significant worsening dyspnoea, hypotension, unexplained persistent dizziness, syncopal 
episodes.  
 
The continuation of chemotherapy in this trial beyond the third cycle depends on assessment and classification of 
response at the end of the third cycle of treatment.  An Investigator at the UK NAC will send a confirmatory letter 
from the UK NAC about the classification of response and further treatment though treatment for the next cycle 
may commence immediately if indicated. 
 
 
Patients will be seen at the UK NAC after three cycles and either 6 months after registration or in patients receiving 
a full 6 cycles of chemotherapy, 1 month after the final cycle of treatment. 
 
Thereafter, patients will be monitored off protocol as per their clinical need. 
11.3 
Assessments during follow up  
 
Follow up investigations will be carried out at 6 months after registration or one month after the last cycle of 
chemotherapy, if all 6 cycles were received, as detailed in the Assessment Summary table in section 11.0. 
 
   
 
 
 


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12.0  Data Management and Data Handling Guidelines 
 
Data will be collected from sites on version controlled case report forms (CRFs) designed for the trial and supplied 
by LEEDS CTRU.  Data entered onto CRFs must be verifiable from source data at site. 
Source data are contained in source documents and must be accurately transcribed on to the CRF. Examples of 
source documents are hospital records which include laboratory and other clinical reports etc. 
Where copies of supporting source documentation (e.g. autopsy reports, pathology reports, etc) are being submitted 
to LEEDS CTRU, the patient’s trial number must be clearly indicated on all material and any patient identifiers 
removed/blacked out prior to sending to maintain confidentiality.  The exception to this is the participant consent 
form, where the participant name and signature must not be obliterated.  If signed consent forms are posted to 
CTRU, they must be sent in a separate envelope and not accompanied by any CRFs containing clinical data. 
12.1 
Completing Case Report Forms 
All CRFs must be completed and signed by staff who are listed on the site staff delegation log and authorised by 
the PI to perform this duty.  The PI is responsible for the accuracy of all data reported in the CRF. 
All entries must be clear, legible and written in ball point pen. Any corrections made to a CRF at site must be made 
by drawing a single line through the incorrect item ensuring that the previous entry is not obscured.  Each correction 
must be dated and initialled.  Correction fluid must not be used.   
The use of abbreviations and acronyms must be avoided.  
Once completed the original CRFs must be sent to LEEDS CTRU and a copy kept at site. 
12.2 Missing Data 
To avoid the need for unnecessary data queries CRFs must be checked at site to ensure there are no blank fields 
before sending to the LEEDS CTRU.  When data is unavailable because a measure has not been taken or test not 
performed, enter “ND” for not done.  If an item was not required at the particular time the form relates to, enter 
“NA” for not applicable.  When data are unknown enter the value “NK” (only use if every effort has been made 
to obtain the data). 
12.3 Timelines for data return 
CRFs must be completed at site and returned to LEEDS CTRU as soon as possible after patient visit and within 2 
weeks of the patient being seen.  
Sites who persistently do not return data within the required timelines may be suspended from recruiting further 
patients into the trial by LEEDS CTRU and subjected to a ‘for cause’ monitoring visit. See section 16.2 (’For cause’ 
on-site monitoring) for details. 
Completed SAE Reports must be faxed within 24 hours of becoming aware of the event to LEEDS 
CTRU 
Fax: 0113 343 4345 
 
12.4 Data Queries 
Data arriving at LEEDS CTRU will be checked for legibility, completeness, accuracy and consistency, including 
checks for missing or unusual values. Query Reports will be sent to the data contact at site.  Further guidance on 
how data contacts should respond to Data Queries can be found on the Query Reports. 
 
 
 
 
 
 


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13.0  Pharmacovigilance 
13.1 
Definitions of Adverse Events 
 
The following definitions have been adapted from Directive 2001/20/EC, ICH E2A “Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting” and ICH GCP E6: 
Adverse Event (AE) 
Any untoward medical occurrence or effect in a patient treated on a trial protocol, which does not necessarily have 
a causal relationship with a trial treatment.  An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the use of a trial 
treatment, whether or not related to that trial treatment. 
 
Adverse Reaction (AR) 
All untoward and unintended responses to a trial treatment related to any dose administered.  A causal relationship 
between a trial treatment and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be 
ruled out. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
An adverse event or adverse reaction that at any dose: 
• 
Results in death 
• 
Is life threatening (The term “life-threatening” refers to an event in which the subject was at risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death if it were 
more severe.) 
• 
Requires in-patient hospitalisation or prolongs existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is otherwise medically significant (e.g. important medical events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention 
to prevent one of the other outcomes listed above.) 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a Serious Adverse Reaction which also 
demonstrates the characteristics of being unexpected, the nature, seriousness, severity or outcome of which is not 
consistent with the information about the medicinal product in question set out in the Summary of Product 
Characteristics or Investigator Brochure.  
13.2 Reporting Procedures 
13.2.1 All Adverse Events (AEs) 
 
All adverse events that occur between informed consent and 30 days post last trial treatment administration must 
be recorded in the patient notes and the trial CRFs. Those meeting the definition of a Serious Adverse Event (SAE) 
must also be reported to LEEDS CTRU within 24 hours of becoming aware of the event using the trial specific 
SAE Report.  Also refer to section 13.2.2 (Serious Adverse Events (SAEs)). 
 
Pre-existing conditions do not qualify as adverse events unless they worsen. 
Overdoses  
All accidental or intentional overdoses, whether or not they result in adverse events, must be recorded in the patient 
notes and CRFs.  Overdoses resulting in an adverse event are classified as SAEs and must be reported to LEEDS 
CTRU according to SAE reporting procedures.  The fact that an overdose has occurred must be clearly stated on 
the SAE Report.  Also refer to section 13.2.2 (Serious Adverse Events (SAEs)). 
Sites must inform LEEDS CTRU immediately when an overdose has been identified.  Also refer to section 17 
(Incident Reporting and Serious Breaches).  


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Adverse Event Term 
An adverse event term needs to be provided for each adverse event, preferably using the term listed in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03, available online at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
Severity 
Severity for each adverse event will be determined by using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 as a guideline, wherever possible.  The criteria are available online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.  Appendix 5 also 
details some toxicity criteria.   
 
In those cases where the CTCAE criteria do not apply, severity should be coded according to the following criteria: 
 
1 = Mild (awareness of sign or symptom, but easily tolerated) 
2 = Moderate (discomfort enough to cause interference with normal daily activities) 
3 = Severe (inability to perform normal daily activities) 
4 = Life threatening (immediate risk of death from the reaction as it occurred) 
5 = Fatal (the event resulted in death) 
Causality 
The PI, or other delegated site investigator, must perform an evaluation of causality for each adverse event.  Causal 
relationship to each trial treatment must be determined as follows: 
• 
None 
There is no evidence of any causal relationship. 
• 
Unlikely 
There is little evidence to suggest a causal relationship (e.g. because the event did not occur within a 
reasonable time after administration of a trial treatment).  There is another reasonable explanation for the 
event (e.g. the patient’s clinical condition, other concomitant treatments). 
• 
Possibly 
There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable 
time after administration of a trial treatment).  However, the influence of other factors may have 
contributed to the event (e.g. the patient’s clinical condition, other concomitant treatments). 
• 
Probably 
There is evidence to suggest a causal relationship and the influence of other factors is unlikely. 
• 
Definitely 
There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled 
out. 
13.2.2 Serious Adverse Events (SAEs) 
All SAEs that occur between informed consent and 30 days after the last trial treatment administration (or after 
this date if the site investigator feels the event is related to the trial treatment) must be submitted to LEEDS CTRU 
by fax within 24 hours of observing or learning of the event, using the trial specific SAE Report.  All sections on 
the SAE Report must be completed. If the event is not being reported within 24 hours to LEEDS CTRU, the 
circumstances that led to this must be detailed in the SAE Report to avoid unnecessary queries. 
Events not classed as SAEs  
 
The following events will not be recorded as SAEs within this trial:  
Hospitalisation for:  
 
Routine treatment or monitoring of the studied indication not associated with any deterioration in condit 
ion.  
 
Treatment which was elective or pre-planned, for a pre-existing condition not associated with any 
deterioration in condition.  
 
Admission to hospital or other institution for general care, not associated with any deterioration in 
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 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions for serious 
as given above and not resulting in hospital admission.  
 
Disease progression  
 
Deaths attributable to amyloidosis beyond 30 days of the last administration of the study agent 
 
Expected SAEs related to Amyloidosis:  
 
Hypercalcaemia  
 
Pain control necessitating admission to hospital  
 
Infections requiring intravenous antibiotics  
 
Blood product support necessitating admission to hospital  
 
Spinal cord compression  
 
Renal failure  
 
Fractures and / or corrective surgery  
 
 
Expected SAEs common to all treatments:  
 
Anaemia  
 
Neutropenia  
 
Thrombocytopenia  
 
Infections requiring intravenous antibiotics  
 
Nausea/Vomiting  
 
Bowel disturbance  
 
Extravasation  
 
Expected SAEs for specific drugs/treatments:  
When determining whether an SAE is expected or not, please refer to the version of the SPC / IB supplied in the 
Investigator Site File or the latest updated version as instructed by the CTRU. 
 
 
Completed SAE Reports must be faxed within 24 hours of becoming aware of the event 
to LEEDS CTRU 
Fax: 0113 343 4345 
 
 
 
 
 


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Adverse Event Reporting Flowchart 
 
 
Adverse event
Assign severity grade 
Investigator to assess causality
Is the event causally related to  
the trial treatment?
Was the event serious?
Criteria:
• Results in death
• Is life threatening
• Results in persistent or significant disability/incapacity
• Requires in-patient hospitalisation or prolongs existing hospitalisation
• Results in a congenital anomaly or birth defect
• Is otherwise medically significant
No
Event exempt from requiring 
submission on an SAE Report? 
(as stated in protocol)
Complete SAE Report
Fax Report to Leeds CTRU 
within 24 hours of becoming 
aware of the event
Complete CRF 
(to be submitted at time 
point stated in protocol)
No
Yes
Yes
 
 


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SAE Follow-Up Reports 
All SAEs must be followed-up until resolution and until there are no further queries.  The PI, or other delegated 
site investigator, must provide follow-up SAE Reports if the SAE had not resolved at the time the initial report was 
submitted. 
SAE Processing at LEEDS CTRU 
On receipt of the SAE Report, LEEDS CTRU will check for legibility, completeness, accuracy and consistency.  
Expectedness will be evaluated, to determine whether or not the case qualifies for expedited reporting, using the 
list of expected adverse events in the current Investigator Brochure for Carfilzomib and current SPC for 
Thalidomide and Dexamethasone.  
The CI, or their delegate (e.g. a clinical member of the TMG), will be contacted to review the SAE and to perform 
an evaluation of causality on behalf of LEEDS CTRU.  The CI or delegate will also assign a code to all SAEs using 
the MedDRA Body System Organ Class coding If LEEDS CTRU has considered expectedness difficult to 
determine, the CI, or their delegate, will be consulted for their opinion at this time.   
LEEDS CTRU will report AEs and SAEs in annual line listings in line with the requirements of the MHRA.  
 
13.3  SUSARs 
 
All SARs and SUSARs occurring for all participants from the time of consent until the end of the trial must be 
recorded on the SAE / SUSAR Form and faxed to the CTRU within 24 hours of the research staff becoming aware 
of the event.  
For each SAE / SUSAR, the following information will be collected:  
 full details in medical terms with a diagnosis, if possible  
 its duration (start and end dates if applicable)  
 action taken  
 outcome  
 causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator)*  
 whether or not the event would be considered expected or unexpected*  
 
*Assessment of causality and expectedness must be made by a doctor. If a doctor is unavailable, initial reports 
without causality and expectedness assessment should be submitted to CTRU within 24 hours, but must be 
followed up by medical assessment as soon as possible thereafter.  
Please ensure that each event is reported separately and not combined on one SAE form.  
Any follow-up information should be faxed to the CTRU within 24 hours of the research team becoming aware of 
the information. Events will be followed up until the event has resolved or a final outcome has been reached. 
If the event is evaluated by either the site or LEEDS CTRU as a Suspected Unexpected Serious Adverse Reaction 
(SUSAR), LEEDS CTRU will submit a report to the MHRA (via eSUSAR) and the REC within 7 calendar days 
for fatal/life threatening events, with a follow-up report within a further 8 calendar days, and 15 calendar days for 
all other events.  Where there are conflicting evaluations of causal relationship by the site and LEEDS CTRU/CI, 
both opinions will be reported. 
LEEDS CTRU will submit individual case SUSAR reports to Amgen concurrent with submission to the MHRA 
and the REC. 
Informing Sites of SUSARs 
LEEDS CTRU will inform all PIs of any SUSARs which occur on the trial. All PIs should review the SUSAR when 
received, sign and date as reviewed, and file in their site file.  PIs will receive a quarterly line listing which must be 
processed according to local requirements. 
 


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13.4 Safety Monitoring 
LEEDS CTRU will provide safety information to the TMG and the SRC on a periodic basis for review. Please 
refer also to section 20.0 Monitoring of data. 
 
Trial safety data will be monitored to identify: 
 
new adverse reactions to the trial treatment regimen or individual trial treatments; 
 
a higher incidence in rare adverse events than is stated in the IB or SPCs for a trial treatment; 
 
trial related events that are not considered related to the trial treatment regimen; 
 
Should LEEDS CTRU identify or suspect any issues concerning patient safety at any point throughout the trial, 
the TMG and SRC will be consulted for their opinion.  The SRC will review the safety and ethics of the study by 
regularly reviewing safety data during the dose escalation stage. The decision about whether to expand the cohort 
or open up the next level will be based on the frequency of observed toxicity and the definitions of DLT and MTD 
in Section 8. The Group will meet or communicate via teleconference approximately monthly. 
 
13.5 Pregnancy 
 
Patients taking part in the trial should adhere to the Celgene Pregnancy Prevention Programme for use with 
Thalidomide. The Pregnancy Prevention Programme outlines the risks of pregnancy while taking Thalidomide and 
must be followed at all times.  
 
If a participant or partner of a participant becomes pregnant or is suspected to be pregnant at any point during the 
trial, a completed trial specific Pregnancy Report must be submitted to LEEDS CTRU by fax within 24 hours of 
learning of its occurrence.  Leeds CTRU will notify Amgen Drug Safety within 24 hours of learning of the pregnancy 
or suspected pregnancy.  Any female participant who becomes pregnant, must be withdrawn from trial.   
If the participant is pregnant or is suspected to be pregnant, Carfilzomib, Thalidomide and Dexamethasone must 
be stopped immediately.  
Participants or partner of a participant will be followed through the outcome of the pregnancy. The Investigator 
will be required to report all pregnancies to the Sponsor. 
 
 
All pregnancies must be reported by faxing a completed Pregnancy Report within 24 
hours of becoming aware of the event to LEEDS CTRU 
Fax: 0113 343 4345 
 
 
Sites are also responsible for reporting pregnancies to the MHRA via the yellow card scheme as per standard 
practice. 
13.5.2 SAEs During Pregnancy 
If the outcome of the pregnancy meets a criterion for immediate classification as an SAE - spontaneous abortion 
(any congenital anomaly detected in an aborted foetus is to be documented), stillbirth, neonatal death, or congenital 
anomaly—the Investigator should repeat the procedures for expedited reporting of SAEs as outlined in section 
13.2.2 (Serious Adverse Events (SAEs)).   
13.5.3 Pregnancy Report Processing at LEEDS CTRU 
LEEDS CTRU will fax all Pregnancy Reports concerning exposure to Carfilzomib to Amgen  within 1 business 
day.  
 
LEEDS CTRU will submit a report to the MHRA and the REC should the pregnancy outcome meet the definition 
of a SUSAR. Refer to section 13.3 (SUSARs) for details. 


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13.6 Development Safety Update Reports (DSURs)  
 
Safety data obtained from the trial will be included in DSURs that LEEDS CTRU will submit to the MHRA and 
the REC. 
 
LEEDS CTRU will provide Amgen  with DSURs that include information regarding Carfilzomib. 
 


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14.0 Withdrawal of  patients 
 
In consenting to the trial, patients are consenting to trial treatment, assessments, trial follow-up and data collection.  
 
14.1 
Discontinuation of Trial Treatment  
14.1.1  Withdrawal due to clinical reasons 
The site investigator may withdraw a patient from the trial treatment whenever continued participation is no longer 
in the patient’s best interests, but the reasons for doing so must be recorded.  Reasons for discontinuing treatment 
may include: 
 
• 
Disease progression whilst on therapy 
• 
Unacceptable toxicity 
• 
Intercurrent illness which prevents further treatment 
• 
The patient withdraws consent to further treatment 
• 
Any alterations in the patient’s condition which justifies the discontinuation of treatment in the site 
investigator’s opinion 
 
In these cases patients remain within the trial for the purposes of follow-up and data analysis according to the 
treatment option to which they have been allocated and for allowing existing collected data to be used.  If the 
patient gives a reason for their withdrawal, this should be recorded. 
 
14.1.2 Patient withdrawal from trial treatment 
If a patient expresses their wish to withdraw from trial treatment, sites should explain the importance of remaining 
on trial follow-up, or failing this of allowing routine follow-up data to be used for trial purposes and for allowing 
existing collected data to be used.  If the patient gives a reason for their withdrawal, this should be recorded. 
 
14.2 Future Data Collection 
If a patient explicitly states that they do not wish to contribute further data to the trial their decision must be 
respected, with the exception of safety data, and recorded on the relevant CRF.  In this event details should be 
recorded in the patient’s hospital records, no further CRFs must be completed and no further data other than safety 
data sent to LEEDS CTRU. 
 
14.3 Losses to follow-up 
If a patient moves from the area, every effort should be made for the patient to be followed up at another 
participating trial site and for this new site to take over the responsibility for the patient. Details of participating 
trial sites can be obtained from the LEEDS CTRU trial team who must be informed of the transfer of care and 
follow up arrangements.  
 
 
 


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15.0 Trial Closure  
15.1 
End of Trial 
 
For regulatory purposes the end of the trial is defined as the date of the last participant’s last data item.  At this 
point, the end of trial notification will be submitted to the relevant regulatory authorities (e.g. UK MHRA) and 
ethics committees. 
Following this, LEEDS CTRU will advise sites on the procedure for closing the trial at the site.  
 
15.2 Early discontinuation of trial 
 
The trial may be stopped before completion as an Urgent Safety Measure on the recommendation of the SRC.  
Sites will be informed in writing by LEEDS CTRU of reasons for early closure and the actions to be taken with 
regards the treatment and follow up of patients.   
15.3 Withdrawal from trial participation by sites 
 
Should a site choose to close to recruitment the PI must inform LEEDS CTRU in writing.  Follow up as per 
protocol must continue for all patients recruited into the trial at that site. 
 
15.4 Archiving of Trial Documentation 
 
At the end of the trial, the LEEDS CTRU will archive securely all centrally held trial related documentation for a 
minimum of 15 years.  Arrangements for confidential destruction will then be made.  It is the responsibility of PIs 
to ensure data and all essential documents relating to the trial held at site are retained for a minimum of 15 years 
after the end of the trial, in accordance with national legislation and for the maximum period of time permitted by 
the site.   
 
Essential documents are those which enable both the conduct of the trial and the quality of the data produced to 
be evaluated and show whether the site complied with the principles of Good Clinical Practice and all applicable 
regulatory requirements. 
 
LEEDS CTRU will notify sites when trial documentation held at sites may be archived.  All archived documents 
must continue to be available for inspection by appropriate authorities upon request. 
 
 
 


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16.0  Trial Monitoring and Oversight 
 
Participating sites and PIs must agree to allow trial-related on-site monitoring, Sponsor audits and regulatory 
inspections by providing direct access to source data/documents as required.  Patients are informed of this in the 
patient information sheet and are asked to consent to their medical notes being reviewed by appropriate individuals 
on the consent form. 
LEEDS CTRU will determine the appropriate level and nature of monitoring required for the trial.  Risk will be 
assessed on an ongoing basis and adjustments made accordingly. 
16.1 
Central monitoring 
 
UK NAC will be requested to submit screening logs for the trial to LEEDS CTRU on request.  UK NAC and 
RHC/sites will be requested to submit staff delegation logs for the trial to LEEDS CTRU at the frequency detailed 
in the trial monitoring plan or on request and these logs will be checked for consistency and completeness. Also 
refer to sections 4.2.2 (Required documentation). 
Ensuring patient eligibility is the responsibility of the UK NAC PI and confirmation by the Site (RHC) PI or other 
delegated Investigator(s).  Checks of the criteria listed on the registration form will be undertaken by an 
appropriately trained LEEDS CTRU staff member prior to registration.  Also refer to section 7.1 (Registration). 
UK NAC  will be required to maintain a log of all patient informed consent forms that have been completed at site 
(regardless of whether the patient is subsequently registered to the trial). This log will include details of the versions 
of informed consent form/patient information sheet used, patient completion of the consent form, the name of 
the person taking consent, etc.  A copy of the log must be submitted to LEEDS CTRU at the frequency detailed 
in the trial monitoring plan or on request.  Also refer to section 5 (Informed Consent). 
Copies of completed drug accountability logs will be collected at LEEDS CTRU for all trial patients. Sites will be 
required to submit logs on request.  A proportion of these will be monitored centrally, as per the monitoring plan, 
to ensure completeness and correlation with data captured in the CRF.  Also refer to section 9.3 (pharmacy 
responsibilities). 
Participating RHC/sites (and UK NAC in its role as a RHC/site)  will be requested to conduct quality control 
checks of documentation held within the Investigator Site File and Pharmacy Site File at the frequency detailed in 
the trial monitoring plan. Checklists detailing the current version/date of version controlled documents will be 
provided for this purpose. 
Data received at LEEDS CTRU will be subject to review in accordance with section 12 (Data Management and 
Data Handling Guidelines). 
Where central monitoring of data and/or documentation submitted by sites indicates that a patient may have been 
placed at risk (e.g. evidence of an overdose having been administered, indication that stopping rules for an IMP 
were not observed following an adverse reaction, etc.), the matter will be raised urgently with site staff and escalated 
as appropriate (refer to section 17 (Incident Reporting and Serious Breaches) and 16.2 (‘For cause’ on-site 
monitoring) for further details). 
 
16.2 ’For Cause’ On-Site Monitoring  
On-site monitoring visits may be scheduled where there is evidence or suspicion of non-compliance at a site with 
important aspect(s) of the trial protocol/GCP requirements.  Sites will be sent a letter in advance outlining the 
reason(s) for the visit.  The letter will include a list of the documents that are to be reviewed, interviews that will be 
conducted, planned inspections of the facilities, who will be performing the visit and when the visit is likely to 
occur. 
Following a monitoring visit, the Trial Monitor/Trial Coordinator will provide a report to the site, which will 
summarise the documents reviewed and a statement of findings, deviations, deficiencies, conclusions, actions taken 
and actions required. The PI at each site will be responsible for ensuring that monitoring findings are addressed in 
a timely manner, and by the deadline specified. 


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LEEDS CTRU will assess whether it is appropriate for the site to continue participation in the trial and whether 
the incident(s) constitute a serious breach. Refer to section 17 (Incident Reporting and Serious Breaches) for details. 
 
16.3 Oversight Committees 
16.3.1 Trial Management Group (TMG) 
The TMG will include the Chief Investigator, clinicians and experts from relevant specialities and CATALYST trial 
staff from LEEDS CTRU (see Page 3).  The TMG will be responsible for overseeing the trial.  The group will meet 
regularly and will send updates to PIs (via newsletters and/or at Investigator meetings) and to the NCRI Myeloma 
Clinical Studies Group. 
 
The TMG will review substantial amendments to the protocol prior to submission to the REC and MHRA.  All 
PIs will be kept informed of substantial amendments through their nominated responsible individuals. 
 
Members of the TMG will be asked to sign a TMG charter outlining their duties and responsibilities. 
 
 
The TMG, comprising the Chief Investigator, CTRU team and co-investigators (see page 3) will be assigned 
responsibility for the clinical set-up, on-going management, promotion of the trial, and for the interpretation of 
results. Specifically the TMG will be responsible for (i) protocol completion, (ii) CRF development, (iii) obtaining 
approval from the main REC and supporting applications for Site Specific Assessments, (iv) submitting a CTA 
LRECs, (iv) submitting a DDXt to trial participations by responsible individuals from the research staff or from 
regulatory  application and obtaining approval from the MHRA, (v) completing cost estimates and project initiation, 
(vi) facilitating the Dose Escaltion Review Group, (vii) reporting of serious adverse events, (viii) monitoring of 
screening, recruitment, treatment and follow-up procedures, (ix) auditing consent procedures, data collection, trial 
end-point validation and database development.  During the dose escalation phase, the TMG along with at least 
one investigator from each recruiting site (PI or delegate), a company representative (when available) and non-
recruiting clinician(s) (where available) will review the safety and ethics of the study by regularly reviewing safety 
data during the dose escalation phase. The decision about whether to expand the cohort or open up the next level 
will be based on the frequency of observed toxicity and the definitions of DLT and MTD in section 8. The group 
will meet or communicate via teleconference approximately monthly. 
 
16.3.2 Safety Review Committee 
 
The Safety Review Committee , comprising the Chief Investigator, at least one investigator from each recruiting 
site (PI or delegate), CTRU statistician(s), Senior Trial Co-ordinator, a company representative (when available) 
non-recruiting clinician(s) will regularly review the safety and ethics of the study during the dosae escalaltion phase 
to provide independent advice on data and safety aspects of the trial.   The decision about whether to expand the 
cohort or open up the next level will be based on the frequency of observed toxicity and the definitions of DLT 
and MTD in Section 8. The Group will meet or communicate via teleconference approximately monthly.  
Additionally, the Group will periodically review safety reports throughout the dose expansion phase of the trial. 
Members of the IDMC will be asked to sign a SRC charter outlining their duties and responsibilities. 
 
16.3.3 Role of LEEDS CTRU 
 
The CTRU will provide set-up and monitoring of trial conduct to CTRU SOPs, and the GCP Conditions and 
Principles as detailed in the UK Medicines for Human Use (Clinical Trials) Regulations including, registration design 
and service, database development and provision, protocol development, CRF design, trial design, source data 
verification, monitoring schedule and statistical analysis for the trial. In addition the CTRU will support IRAS and 
NIHR CSP submissions and clinical set-up, ongoing management including training, monitoring reports and 
promotion of the trial. The CTRU will be responsible for the day to day running of the trial including trial 
administration, database administrative functions, data management, safety reporting and all statistical analyses. 
 
 


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17.0 Incident Reporting and Serious Breaches 
 
17.1 
Incident Reporting 
The trial will be conducted in accordance with the principles of Good Clinical Practice in clinical trials, as applicable 
under UK regulations, the NHS Research Governance Framework (and Scottish Executive Health Department 
Research Governance Framework for Health and Social Care 2006 for studies conducted in Scotland), and through 
adherence to CTRU Standard Operating Procedures (SOPs). 
 
Organisations must notify LEEDS CTRU of all deviations from the protocol or GCP immediately.  LEEDS CTRU 
may require a report on the incident(s) and a form will be provided if the organisation does not have an appropriate 
document (e.g. Trust Incident Form for UK sites). 
If site staff are unsure whether a certain occurrence constitutes a deviation from the protocol or GCP, the LEEDS 
CTRU trial team can be contacted immediately to discuss. 
LEEDS CTRU will assess all incidents to see if they meet the definition of a serious breach.  
Each site must also report according to their trust incidence reporting policies. 
17.2 Serious Breaches  
CTRU and Sponsor have systems in place to ensure that serious breaches of GCP or the trial protocol are picked 
up and reported. Investigators are required to promptly notify the CTRU of a serious breach (as defined by 
Regulation 29A of the Medicines for Human Use (Clinical Trials) Regulations 2004 [Statutory Instrument 
2004/1031], as amended by Statutory Instrument 2006/1928) that they become aware of. A “serious breach” is a 
breach which is likely to effect to a significant degree –  
 
 
the safety or physical or mental integrity of the participants of the trial; or  
 
the scientific value of the trial. 
 
For further information, the Investigator should contact the CTRU. 
 
Systematic or persistent non-compliance by a site with GCP and/or the protocol, including failure to report SAEs 
occurring on trial within the specified timeframe, may be deemed a serious breach. 
In cases where an actual serious breach has been identified, LEEDS CTRU will inform the MHRA within 7 calendar 
days of becoming aware of the breach. 
Sites must notify the CTRU of serious breaches (MHRA Guidance on the Notification of Serious Breaches).  The 
CTRU will notify the sponsor of all serious breaches.   
Leeds CTRU will use an organisation’s history of non-compliance to make decisions on future collaborations. 
 
 
 


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18.0 Endpoints 
18.1 
Primary endpoints 
 
Dose-Limiting Toxicities (Dose escalation phase), between the time of receiving the first registered dose of 
Carfilzomib in cycle 1 and day 1 cycle 2, in order to establish the Maximum Tolerated Dose (MTD) and 
recommended dose (RD) of Carfilzomib in combination with Thalidomide and Dexamethasone. 
 
Proportion of patients treated who experience any grade 3 or 4 CTCAE toxicity throughout all treatment cycles 
 
18.2 Secondary endpoints 
 
 
Clonal response rate within 3m, at 3m, within 6m and at 6m  
 
Amyloidotic organ response rate within 3m and 6m 
 
Time to amyloidotic organ response 
 
Number of deaths at 6 months 
 
Number of patients progression free at 6 months 
 
Maximum response  
 
Time to maximum response 
 
Number of patients withdrawing from treatment 
 
Number of patients experiencing dose delays, and compliance profile of KTD. 
 
Relative Dose intensity 
 
Exploratory 
 
Additional exploratory endpoints may be collected; any additional endpoints will be fully detailed in the statistical 
analysis plan. 
18.3 Endpoint definitions  
 
 
DLT and MTD are defined in section 8.1.4 and 8.1.5 
 
 
The proportion of patients treated who experience any grade 3 or 4 CTCAE toxicity will be calculated as 
number of patients who experience any grade 3 or 4 CTCAE toxicity throughout their treatment cycle. 
 
 
Clonal response rate (based on paraprotein and FLCs) is defined as the proportion of patients who achieve 
at least a PR within 3 months, at 3 months, within 6 months and at 6 months after trial registration. 
 
 
Amyloidotic organ response rate is defined as the proportion of patients who achieve organ response 
within 3 months and within 6 months of trial registration. 
 
 
Time to Amyloidotic organ response is defined as the time from the dose allocation to first achieving organ 
response.  
 
 
 
The number of patients experiencing dose delays will be defined as the number of patients experiencing 
delays in treatment with any of the study treatments. 
 
 
KTD compliance: Patients will be regarded as compliant to treatment where treatment is received as per 
protocol until withdrawal from treatment and have no more than 1 dose omission of Carfilzomib, 5 of 
Thalidomide or 1 of Dexamethasone during each cycle.  
 
 
Relative Dose intensity will be calculated as the percentage ratio between the received and planned dose 
intensities, where dose intensity is the cumulative dose divided by the duration of treatment.    


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19.0 Statistical considerations 
 
19.1 
Sample size 
 
In the dose escalation phase of this study, a minimum of 6 (3 at dose level 0 and 3 at dose level -1) and a 
maximum of 18 (6 at dose level 0 1 and 2) patients will recruited in a 3+3 design with cohorts of between 3 and 
6 patients, in order to determine maximum tolerated dose and recommended dose.  
 
At the recommended dose level identified, a further 20 patients will be recruited to further assess safety and 
toxicities at the RD. 
 
 
The secondary objective of assessing activity will be primarily assessed by the clonal response rate.  
19.2 General Considerations 
 
Statistical analysis of clinical endpoint data is the responsibility of the CTRU Statistician. A full statistical analysis 
plan will be written before any analyses are undertaken. The analysis plan will be written in accordance with current 
CTRU standard operating procedures and will be finalised and agreed by the following people: the trial statistician 
and supervising statistician, the Chief Investigator, the CTRU Delivery and Scientific Leads and the Senior Trial 
Manager. Any changes to the finalised analysis plan, and reasons for changes, will be documented.   
 
All patients that receive at least one dose of Carfilzomib and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set. 
 
The per protocol set will include all patients with at least one post baseline efficacy assessment who receive at least 
one dose of Carfilzomib and have no protocol deviations with relevant impact on efficacy.   
 
Determination of the MTD in the dose escalation phase of the trial will be based on those patients who have 
received at least one cycle KTD and will be evaluated between the time of receiving the first dose of Carfilzomib 
in cycle 1 and the first dose of treatment in cycle 2. The safety review committee will review each DLT and attribute 
the DLT to the loading dose or the registered dose; any DLT attributed to the loading dose will be excluded when 
determining the MTD. 
 
KTD Patients who do not receive one complete cycle due to experiencing a DLT will be included in the analysis; 
patients who do not receive at least one complete cycle for reasons other than toxicity, without experiencing a DLT, 
and who miss a dose of Carfilzomib, more than 14 doses Thalidomide or 2 doses of Dexamethasone in the first 
cycle, will be replaced. Evaluability will be considered by the safety review committee on an individual basis to 
account for attributing DLTs and missed doses to the loading or the registered dose.   
 
The RD cohort will include all patients who are registered to receive and receive at least one dose of Carfilzomib 
at the RD. This cohort will include patients from the dose escalation and dose expansion phases of the study. All 
patients who do not fulfil these criteria will be included in the non-RD cohort.    
 
Statistical analysis will be descriptive for all endpoints, and will be summarised overall and by dose cohort. All safety 
analyses will be based upon the safety analysis set; safety data from patients not included in this analysis set will be 
listed separately. All efficacy analyses will be based upon the per protocol set. Patients who do meet the criteria to 
be included in each of analysis sets will have the reasons for emission listed. A sensitivity analysis on the efficacy 
endpoints may be considered if the total number of patients in each of the analysis sets differs by more than 3 
patients.   
19.3 Primary Endpoint Analysis  
 
The number of patients experiencing DLTs within the first cycle of KTD will be presented, with descriptive 
summaries of the specific DLTs observed. Summaries will be presented for each dose level. This data will be 
presented for patients registered to the dose escalation phase of the study only.   


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Further summaries of longer-term tolerability will also be presented for patients registered to the dose escalation 
phase to include the maximum toxicity grade experienced within the first three cycles of treatment, overall and by 
cycle. Individual listings of the toxicities, grade and cycle of all toxicities experienced within the first three cycles 
will be presented.   
 
The number of patients experiencing any grade 3 or 4 CTCAE toxicity within all cycles of treatment will be 
summarised. This will be presented overall and by dose cohort, across all cycles as well as by each cycle. 
 
 
19.4 Secondary Endpoint Analysis  
 
Safety and toxicity profiles for each cycle and cohort: data will be summarised descriptively, including the 
proportion of patients experiencing at least one SAE, the number of SAEs experienced per participant, and the 
number of SAEs experienced according to seriousness criteria, causality, and body system; Toxicity will be 
summarised according to CTCAE grades and will be summarised as the maximum grade toxicity experienced within 
each cycle, and overall. 
 
The proportion of patients achieving at least a PR (clonal response) within 3m, at 3m, within 6m and at 6m and the 
proportion of patients achieving an amyloidotic organ response within 3m and 6m will be presented in tabulated 
form. Corresponding 90% and 95% confidence intervals will also be presented. Responses at 3 and 6 months will 
be broken down by response achieved, and by organ (for organ response). 
 
 
Time to amyloidotic organ response and time to maximum response will be calculated using the Kaplan Meier 
method. Median time to amyloidotic organ response and median time to maximum response will be presented, 
with corresponding 95% confidence intervals. 
 
The proportion and number of patients alive at 6 months and patients progression free at 6months will be presented 
with corresponding 90% and 95% confidence intervals. If the data warrants Kaplan Meier curves for progression 
free survival may be explored.     
 
Each patient will be assessed for their maximum clonal response; the number and proportion of participants in 
each response category within 6 cycles of treatment will be presented with corresponding 95% confidence intervals. 
Patients who do not achieve a maximum response will be summarised as, “no maximum response”. 
 
Feasibility of delivering treatment according to protocol schedule will be summarised descriptively to include the 
number of patients requiring dose delays and/or reductions, the number of patients withdrawing from treatment, 
and reasons for dose delays / reductions and withdrawals. Time on treatment and reasons for stopping treatment 
will also be presented. The number of doses missed will be summarised overall and by cycle. 
 
The following definitions will be used: 
% of intended dose = 100*(dose received / planned dose) 
To represent delays in cycles and reduced dose: 
Dose intensity (DI) = Cumulative Dose / Duration 
Relative Dose intensity (RDI) = Actual DI / Planned DI  
Summaries will be produced at each cycle, for each treatment and overall.  
 
19.5 Frequency of Analyses 
 
During the Dose Escalation Phase, recruitment will be halted after each group of three patients have completed at 
least one cycle of KTD, to allow safety data to be assessed.  CTRU will produce a summary of DLTs at each dose 
level, detailed safety listings, and recruitment figures for consideration by the Safety Review Committee.   
 
No formal analyses are planned until after the trial is closed to recruitment and the required number of patients has 
been recruited. Final analysis will be carried out when the required number of patients has been recruited and all 
patients have been followed up for at least 6 months from registration.   


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20.0 Data Monitoring 
 
20.1 Safety Review Committee 
The Safety Review Committee (SRC) will review the safety and ethics of the trial by reviewing interim data after 
each cohort of treatment during recruitment to the Dose Escalation Cohort. The SRC will meet or communicate 
via teleconference at least after each dose level in the Dose Escalation Cohort has recruited at least 3 patients and 
they have received their first cycle of treatment, to review safety. 
 
Safety reports will be periodically reviewed for the trial unless otherwise requested to determine patterns and trends 
of events, or to identify safety issues, which would not be apparent on an individual case basis. Detailed reports 
containing safety summaries will be prepared by the CTRU for the SRC every 3 months.  
 
20.2 Trial Steering Committee (during the dose expansion phase only):  
The Trial Steering Committee will  review safety data and liaise with the SRC regarding safety issues, and periodically 
reviewing efficacy data in the dose expansion phase. 
 
 
20.3 Data Monitoring 
Data will be monitored for quality and completeness by the CTRU.  Missing data will be chased until it is received, 
confirmed as not available or the trial is at analysis.  The CTRU will reserve the right to intermittently conduct 
source data verification exercises on a sample of patients, which will be carried out by staff from the CTRU.  Source 
data verification will involve direct access to participant medical records at the participating centres, and the central 
collection of copies of consent forms and other relevant investigation reports.  A Trial Monitoring Plan will be 
developed and a Meeting Group Monitoring Schedule including primary endpoint and safety data will be defined 
and agreed by the Trial Management Group (TMG), if necessary. 
 
 
20.4 Clinical Governance Issues 
To ensure responsibility and accountability for the overall quality of care received by patients during the trial period, 
clinical governance issues pertaining to all aspects of routine management will be brought to the attention of the 
SRC, sponsor and, where applicable, to individual NHS Trusts.  
 


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21.0 Ethical and Regulatory Approvals 
In conducting the trial, the Sponsor, LEEDS CTRU and sites shall comply with all laws and statutes, as 
amended from time to time, applicable to the performance of clinical trials including, but not limited to: 
• the principles of ICH Harmonised Tripartite Guideline for Good Clinical Practice (CPMP/ICH/135/95) 
as set out in Schedule 1 (Conditions and Principles of Good Clinical Practice and for the Protection of 
Clinical Trial Subjects) of the Medicines for Human Use (Clinical Trials) Regulations 2004 and the GCP 
Directive 2005/28/EC, as set out in SI 2006/1928 
• 
Human Rights Act 1998 
• 
Data Protection Act 1998 
• 
Freedom of Information Act 2000 
• 
Human Tissue Act 2004 
• 
Human Tissue Act (Scotland) 2006 
• 
Medicines Act 1968  
• 
Medicines for Human Use (Clinical Trials) UK Regulations SI 2004/1031, and subsequent amendments  
• 
Good Manufacturing Practice  
• 
the Research Governance Framework for Health and Social Care, issued by the UK Department of Health 
(Second Edition 2005) or the Scottish Health Department Research Governance Framework for Health 
and Community Care (Second Edition 2006) 
21.1 
Ethical Approval 
The trial will be conducted in accordance with the World Medical Association Declaration of Helsinki entitled 
‘Ethical Principles for Medical Research Involving Human Subjects’ (1996 version) and in accordance with the 
terms and conditions of the ethical approval given to the trial. 
LEEDS CTRU will submit an application for favourable ethical opinion and will subsequently submit Annual 
Progress Reports to the REC, which will commence one year from the date of ethical approval for the trial. 
21.2 Regulatory Approval  
The trial will be conducted at approved trial sites in accordance with the trial protocol and the terms of the CTA 
granted by the MHRA. 
21.3 Site Approvals 
Local governance checks will be undertaken by local CLRNs associated with individual trial sites. 
Evidence of approval from the Trust R&D for a trial site must be provided to LEEDS CTRU.  Sites will only be 
activated when all necessary local approvals for the trial have been obtained.   
21.4 Protocol Amendments 
LEEDS CTRU will be responsible for gaining ethical and regulatory approvals, as appropriate, for amendments 
made to the protocol and other trial-related documents.  Once approved, LEEDS CTRU will ensure that all 
amended documents are distributed to sites and CLRNs as appropriate. 
Site staff will be responsible for acknowledging receipt of documents and for implementing all amendments.  
21.5   Patient Confidentiality & Data Protection 
Patient identifiable data, including date of birth, patient initials and NHS number will be required for the 
registration process and will be provided to LEEDS CTRU.  
LEEDS CTRU will preserve patient confidentiality and will not disclose or reproduce any information by which 
patients could be identified.  Data will be stored in a secure manner and LEEDS CTRU trials are registered in 
accordance with the Data Protection Act 1998 with the Data Protection Officer at UCL. 
The CTRU will comply with all aspects of the 1998 Data Protection Act and operationally this will include: 


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 
consent from participants to record personal details including name, date of birth, NHS ID, hospital ID  
 
appropriate storage, restricted access and disposal arrangements for participant personal and clinical details 
 
consent from participants for access to their medical records by responsible individuals from the research staff 
or from regulatory authorities, where it is relevant to trial participation 
 
consent from participants for the data collected for the trial to be used to evaluate safety and develop new 
research. 
 
participant name will be collected on the consent form when a participant is registered into the trial, but all 
other data collection forms that are transferred to or from the CTRU will be coded with a trial number and 
will include two participant identifiers, usually the participant’s initials and date of birth. 
 
where central monitoring of source documents by CTRU (or copies of source documents) is required (such as 
scans or local blood results), the participant’s name must be obliterated by site before sending 
 
where anonymisation of documentation is required, sites are responsible for ensuring only the instructed 
identifiers are present before sending to CTRU 
 
If a participant withdraws consent from further trial treatment and / or further collection of data, their data and 
samples will remain on file and will be included in the final trial analysis. 
 
The trial staff at the participating site will be responsible for ensuring that any data / documentation sent to the 
CTRU is appropriately anonymised as per instructions given by CTRU in accordance with the trial procedures to 
conform with the 1998 Data Protection Act. 
22.0  Sponsorship and Indemnity 
 
22.1 Sponsor Details: 
 
Sponsor Name: 
 
Address: 
University College London 
 
Joint Research Office 
Gower Street 
London 
WC1E 6BT 
 
Contact: 
 
Telephone: 
 
Tendai Nelson, Regulatory Advisor 
0207 679 6492 
Fax: 
020 3108 2312 
 
 
 
22.2 Indemnity 
 
University College London holds insurance against claims from patients for injury caused by their participation in 
the clinical trial. Patients may be able to claim compensation if they can prove that UCL has been negligent. 
However, as this clinical trial is being carried out in a hospital, the hospital continues to have a duty of care to the 
participant of the clinical trial. University College London does not accept liability for any breach in the hospital’s 
duty of care, or any negligence on the part of hospital employees. This applies whether the hospital is an NHS 
Trust or otherwise.  
 


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Patients may also be able to claim compensation for injury caused by participation in this clinical trial without the 
need to prove negligence on the part of University College London or another party. Patients who sustain injury 
and wish to make a claim for compensation should do so in writing in the first instance to the Chief Investigator, 
who will pass the claim to the Sponsor’s Insurers, via the Sponsor’s office.  
 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover for harm caused 
by their employees and a copy of the relevant insurance policy or summary shall be provided to University College 
London, upon request. 
 
23.0  Funding 
 
Carfilzomib is provided free of charge for the trial duration by Amgen . 
 
24.0  Publication Policy 
 
All publications and presentations relating to the trial will be authorised by the Trial Management Group.  The 
TMG will form the basis of the writing committee and advise on the nature of publications.  Contributing site 
investigators in this trial will also be acknowledged.  Data from all sites will be analysed together and published as 
soon as possible.  Participating sites may not publish trial results prior to the first publication by the TMG or 
without prior written consent from the TMG.  The trial data is owned by UCL.  However, drug companies who 
have provided grants towards the trial will be permitted to see the draft manuscripts and make comments at least 
prior to submission for publication as detailed in the trial drug supply agreement.  The ISRCTN number allocated 
to this trial will be quoted in any publications resulting from this trial. 
 
The trial will be registered with an authorised registry, according to ICMJE Guidelines, prior to the start of 
recruitment. 
 
The success of the trial depends upon the collaboration of all patients. For this reason, credit for the main results 
will be given to all those who have collaborated in the trial, through authorship and contributor ship. Uniform 
requirements for authorship for manuscripts submitted to medical journals will guide authorship decisions. These 
state that authorship credit should be based only on substantial contribution to:  
 
conception and design, or acquisition of data, or analysis and interpretation of data 
 
drafting the article or revising it critically for important intellectual content 
 
and final approval of the version to be published 
 
and that all these conditions must be met (www.icmje.org). 
 
In light of this the Chief Investigator and relevant senior CTRU staff will be named as authors in any publication. 
Dependent on the number of participating centres and journal restrictions, wherever possible all Principal 
Investigators and at least two CTRU staff will be named as authors.   
 
Publication of emerging safety data in the form of abstracts for oral or poster presentation, or journal letters is 
permitted. However no formal manuscript publication is permitted until the final analysis of the trial data has been 
completed. All abstracts and letters must be reviewed by at least the Chief Investigator and CTRU trial statistician. 
The release of any data prior to the end of the trial must be approved by the Safety Review Committee. Amgen  
will review any resulting publications prior to submission as detailed in the contract. 


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25.0  References 
 
 
1. 
Kyle G, et. al. . Criteria for the classification of monoclonal gammopathies, multiple myeloma 
and related disorders: a report of the International Myeloma Working Group. British journal of 
haematology. 2003 Jun;121(5):749-57. PubMed PMID: 12780789. 
2. 
Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, et al. New criteria 
for response to treatment in immunoglobulin light chain amyloidosis based on free light chain 
measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012 Dec 
20;30(36):4541-9. PubMed PMID: 23091105. 
3. 
Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin 
Oncol. 2011 May 10;29(14):1924-33. PubMed PMID: 21483018. Pubmed Central PMCID: 
3138545. 
4. 
Cordes S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Dingli D, et al. Ten-year survival 
after autologous stem cell transplantation for immunoglobulin light chain amyloidosis. Cancer. 
2012 Dec 15;118(24):6105-9. PubMed PMID: 22707405. Epub 2012/06/19. eng. 
5. 
Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, et al. Consensus 
guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. 
Leukemia. 2012 Nov;26(11):2317-25. PubMed PMID: 22475872. 
6. 
Gertz M, Lacy M, Dispenzieri A, Hayman S, Kumar S, Buadi F, et al. Troponin T level as an 
exclusion criterion for stem cell transplantation in light-chain amyloidosis. Leukemia & 
lymphoma. 2008 Jan;49(1):36-41. PubMed PMID: 18203009. 
7. 
Gertz MA, Lacy MQ, Dispenzieri A, Kumar SK, Dingli D, Leung N, et al. Refinement in patient 
selection to reduce treatment-related mortality from autologous stem cell transplantation in 
amyloidosis. Bone marrow transplantation. 2013 Apr;48(4):557-61. PubMed PMID: 
22964596. 
8. 
Sanchorawala V, Skinner M, Quillen K, Finn KT, Doros G, Seldin DC. Long-term outcome of 
patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. 
Blood. 2007 Nov 15;110(10):3561-3. PubMed PMID: 17673601. Pubmed Central PMCID: 
2077307. Epub 2007/08/04. eng. 
9. 
Madan S, Kumar SK, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. High-dose 
melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with 
cardiac involvement. Blood. 2012 Feb 2;119(5):1117-22. PubMed PMID: 22147893. Pubmed 
Central PMCID: 3277349. 
10. 
Tsai SB, Seldin DC, Quillen K, Berk JL, Ruberg FL, Meier-Ewert H, et al. High-dose melphalan 
and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related 
mortality over the past 17 years at a single referral center. Blood. 2012 Nov 
22;120(22):4445-6. PubMed PMID: 23175664. 
11. 
Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, et al. Bortezomib and 
Dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation 
for patients with newly diagnosed light-chain amyloidosis. Leukemia : official journal of the 
Leukemia Society of America, Leukemia Research Fund, UK. 2013 Apr;27(4):823-8. PubMed 
PMID: 23014566. Epub 2012/09/28. eng. 
12. 
Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, et al. Association of 
melphalan and high-dose Dexamethasone is effective and well tolerated in patients with AL 
(primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 
15;103(8):2936-8. PubMed PMID: 15070667. 
13. 
Palladini G, Russo P, Nuvolone M, Lavartelli F, Perfetti V, Obici L, et al. Treatment with oral 
melphalan plus Dexamethasone produces long-term remissions in AL amyloidosis. Blood. 
2007 Jul 15;110(2):787-8. PubMed PMID: WOS:000248112400044. English. 
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Gertz MA. I don't know how to treat amyloidosis. Blood. 2010 Jul 29;116(4):507-8. PubMed 
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Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and 
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Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, et al. The activity 
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amyloidosis. Blood. 2007 Jan 15;109(2):465-70. PubMed PMID: WOS:000243416600016. 
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18. 
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combination with melphalan and Dexamethasone in patients with newly diagnosed AL 
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2;116(23):4777-82. PubMed PMID: 20724537. 
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Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, et al. Durable 
hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 
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20. 
Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, 
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Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, et al. Lenalidomide, 
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23. 
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25. 
Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, et al. Weekly 
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2009/06/06. eng. 
26. 
Bockorny M, Chakravarty S, Schulman P, Bockorny B, Bona R. Severe Heart Failure after 
Bortezomib Treatment in a Patient with Multiple Myeloma: A Case Report and Review of the 
Literature. Acta Haematol-Basel. 2012;128(4):244-7. PubMed PMID: WOS:000311278000007. 
English. 
27. 
Dubrey SW, Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, et al. Bortezomib 
in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall 
effects. QJM : monthly journal of the Association of Physicians. 2011 Nov;104(11):957-70. 
PubMed PMID: 21752867. Epub 2011/07/15. eng. 
28. 
Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Blade J, et al. Efficacy and 
safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL 
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WOS:000293221700012. English. 
29. 
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Cyclophosphamide-bortezomib-Dexamethasone (CyBorD) produces rapid and complete 
hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. 
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Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L, Goy A. Phase 1 single agent antitumor 
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patients (pts) with relapsed and refractory multiple myeloma (MM). J Clin Oncol. 2009 May 
20;27(15). PubMed PMID: WOS:000276606605414. English. 
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Siegel D, Wang LH, Orlowski RZ, Kaufman JL, Stewart AK, Kukreti V, et al. PX-171-004, An 
Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with 
Relapsed or Refractory Myeloma (MM); Updated Results From the Bortezomib-Treated 
Cohort. Blood. 2009 Nov 20;114(22):128-. PubMed PMID: WOS:000272725800304. English. 
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Wang L, Siegel D, Kaufman JL, Stewart AK, Jakubowiak AJ, Alsina M, et al. Updated Results 
of Bortezomib-Naive Patients in PX-171-004, An Ongoing Open-Label, Phase II Study of 
Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM). ASH 
Annual Meeting Abstracts. 2009 November 20, 2009;114(22):302-. 
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Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, et al. A phase 2 single-
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multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. PubMed PMID: 
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Multicenter Dose Escalation Study of Carfilzomib Plus Lenalidomide and Low Dose 
Dexamethasone (CRd) in Relapsed and Refractory Multiple Myeloma (MM). Blood. 2009 Nov 
20;114(22):128-9. PubMed PMID: WOS:000272725800305. English. 
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Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et al. A phase 1/2 
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cyclophosphamide, and Dexamethasone in patients with newly diagnosed multiple myeloma: 
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Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, et al. Phase 
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39. 
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase II study (PX-171-
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40. 
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, et al. Carfilzomib, 
lenalidomide, and Dexamethasone for relapsed multiple myeloma. The New England journal 
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Cohen AD, Scott EC, Liedtke M, Kaufman JL, Landau H, Vesole DH, et al. A Phase I Dose-
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Papadopoulos KP, Siegel DS, Vesole DH, Lee P, Rosen ST, Zojwalla N, et al. Phase I Study of 
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Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma. Journal of 
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Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, et al. Carfilzomib in multiple 
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APPENDIX 1: 
ABBREVIATIONS 
 
 
ABPI 
Association of British Pharmaceutical Industry 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AL 
Refers to the serum free light chain fibrils that are produced in this type of Amyloidosis 
ALP 
Alkaline phosphatase 
ALT 
AML 
Alanine transaminase 
Acute Myeloid Leukaemia 
ANC 
APTT 
Absolute Neutrophil Count 
Activate partial thromboplastin time 
AR 
Adverse Reaction 
ASCT 
Autologous stem cell transplantation 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
Bcl 
BUN 
B-cell lymphoma 
Blood urea nitrogen 
CAM 
CD 
Cell Adhesion Molecule 
Cluster of differentation 
CEA 
Carcinoembryonic Antigen 
CI 
CLRN 
Chief Investigator 
Comprehensive local research network 
CR 
CrCl 
CRd 
Complete response 
Creatinine clearance 
A chemotherapy regimen of Carfilzomib, lenalidomide, and Dexamethasone 
CRF 
Case Report Form 
CR UK 
Cancer Research UK 
CT 
Computerised Tomography 
CTA 
Clinical Trial Authorisation 
CTAAC 
Clinical Trials Advisory & Awards Committee 
CTCAE 
see NCI CTCAE 
CTD 
Chemotherapy regimen containing cyclophosphamide, Thalidomide & Dexamethasone 
CTDa 
CTRU 
Attenuated CTD 
Clinical Trials Research Unit 
CTSA 
Clinical Trial Site Agreement 
CVD 
Chemotherapy regimen containing Bortezomib, Cyclophosphamide & Dexamethasone 
CXR 
Chest X-Ray 
DFS 
DH 
DI 
Disease Free Survival 
Department of Health 
Dose intensity 
DLT 
DOR 
DPA 
Dose Limiting Toxicity 
Duration of Response 
Data Protection Act 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
eGFR 
Ethylene Diamine Tetra Acetate 
Estimated glomerular filtration rate 
EudraCT 
European Clinical Trials Database 
FBC 
Full Blood Count 
FLC 
Free Light Chain 
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
GI 
GGT 
Glomerular Filtration Rate 
Gastro-intestinal 
Gamma glutamyl-transpeptidase/transferase 
Hb 
HIV 
HL 
Haemoglobin 
Human Immunodeficiency Virus 
Hodgkin’s lymphoma 


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HUS 
Haemolytic uraemic syndrome 
IκBα 
Inhibitor protein: I kappa B alpha-assocaited protein kinase 
IB 
Investigator’s Brochure 
ICH GCP 
International Conference of Harmonisation-Good Clinical Practice 
IDMC 
Independent Data Monitoring Committee 
IDMD 
Intermediate dose melphalan and Dexamethasone 
IL 
Interleukin 
ImiD 
Immunomodulatory Drug 
IMP 
Investigational Medicinal Product 
IMWG 
International Myeloma Working Group 
INR 
International Normalised Ratio 
ISRCTN 
International Standard Randomised Controlled Trial Number 
IUD 
IUS 
Intrauterine Device 
Intrauterine System 
IV 
Intravenous 
KTD 
LDH 
Chemotherapy regimen containing Carfilzomib, Thalidomide & Dexamethasone 
Lactate Dehydrogenase 
LFT 
Liver Function Tests 
LLN 
LVEF 
MDS 
Lower Limit of Normal 
Left ventricular ejection fraction 
Myelodysplastic Syndrome 
MM 
Multiple Myeloma 
MP 
MR 
Melphalan & Prednisolone 
Maximum response 
MRC 
Medical Research Council 
MTD 
REC 
Maximum Tolerated Dose 
Research Ethics Committee 
MRI 
Magnetic Resonance Image 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NAC 
See UK NAC 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
nCR 
Near Complete Response 
NCRI 
National Cancer Research Institute 
NCRN 
NHL 
National Cancer Research Network 
Non-Hodgkin’s lymphoma 
NICE 
NIHR 
National Institute of Clinical Excellence 
National Institute for Health Research 
NF-κB 
Nuclear Factor-κB 
NR 
Not meeting Free Light Chain criteria for Complete Response (CR) or Partial Response 
(PR)  
NRES 
NT-proBNP 
NYHA 
National Research Ethics Service 
N-terminal prohormone of brain natriuretic peptide 
New York Heart Association 
ORR 
Overall response rates 
OS 
Overall Survival 
PA 
Posteroanterior 
PAD 
Chemotherapy regimen containing Bortexomib, Doxorubicin & Dexamethasone 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
By mouth 
PR 
PRES 
PT 
Partial Response 
Posterior reversible encephalopathy syndrome 
Prothrombin time 
RD 
RDI 
REC 
Recommended Dose 
Relative dose intensity 
Research Ethics Committee 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RHC 
Regional Haematology Centre (Site) 


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RPLS 
R/RMM 
Reversible posterior leukoencephalopathy syndrome 
Relapsed/refractory multiple myeloma 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
SC 
SCC 
Serum Amyloid Protein 
Subcutaneous 
Stem cell collection 
SD 
SOP 
Stable Disease 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SRC 
SSA 
Safety Review Committee 
Site Specific Assessment 
SUSAR 
TLS 
Suspected Unexpected Serious Adverse Reaction  
Tumour lysis syndrome 
TMF 
Trial Master File  
TMG 
Trial Management Group 
TRM 
Treatment Related Mortality 
TSC 
Trial Steering Committee 
TTP 
Time to progression 
UCL 
University College London 
U&E 
Urea and Electrolyte 
UK NAC 
UK National Amyloidosis Centre (Royal Free Hospital) 
ULN 
Upper Limit of Normal 
VAD 
Chemotherapy regimen containing vincristine, doxorubicin and Dexamethasone 
VGPR 
Very Good Partial Response 
WBC 
White Blood Cells 


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APPENDIX 2: 
DEFINITION OF AMYLOIDOSIS, MYELOMA AND RELATED 
DISEASES  
 
Amyloid 
 
Tissue biopsy showing red-green birefringence in cross polarised light when stained with Congo red by 
Puchtler’s method 
 
 
Overt Non-Amyloid manifestations of Multiple Myeloma  
 
Lytic bony lesions (>4 if limited to skull only) 
 
Hypercalcaemia, hyperviscosity or plasmacytomata 
 
 
 
Amyloid-related organ involvement causing organ dysfunction 
 
For details please refer to Gertz et al. Definition of organ involvement and treatment response in immunoglobulin 
light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and 
Amyloidosis. Am J Hematol. 2005 Aug;79(4):319-28. 
 
Defining organ involvement  
Kidney 
24-hour urine protein >0.5 g per day, predominantly albumin 
 
Heart 
Echo: mean left ventricular wall thickness >12 mm, no other cardiac cause 
or severe diastolic dysfunction in presence of NT-ProBNP >150 pMol/L 
and low voltage complexes on ECG without any other cause for these 
anormalities 
 
Liver 
 
Total liver span >15 cm in the absence of heart failure or alkaline 
phosphatase >1.5 times institutional upper limit of normal 
 
Gastrointestinal tract 
Symptomatic GI disturbance with or without direct biopsy verification with 
 
Nerve 
Peripheral: clinical; symmetric lower extremity sensorimotor peripheral 
neuropathy 
Autonomic: gastric-emptying disorder, pseudo-obstruction, voiding 
dysfunction not related to direct organ infiltration, postural hypotension 
 
Soft tissue 
Tongue enlargement, clinical 
Arthropathy 
Myopathy by biopsy or pseudohypertrophy 
Lymph node enlargement 
 
 
Number of organs involved by amyloid 
 
One to 5 of the following organ systems could be involved by amyloid; 
 
Renal 
 
Gastro-intestinal (including liver) 
 
Cardiac 
 
Nerves (peripheral and/or autonomic) 
 
Miscellaneous (e.g. significant soft tissue, factor X deficiency, adrenal insufficiency) 


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APPENDIX 3: 
ECOG GRADES OF PERFORMANCE STATUS AND NYHA 
CLASS 
 
Grade 
Summary 
Description 
 
0 
 
Normal 
 
Able to carry out all normal activity without restriction 
 
1 
 
With effort 
 
Restricted in physically strenuous activity; ambulatory, can do 
light work 
 
2 
 
Restricted 
 
Ambulatory and capable of all self-care but unable to carry out 
any work; up and about more than 50% of waking hours 
 
3 
 
Dependent 
 
Capable of only limited self-care; confined to bed or chair for 
more than 50% of waking hours 
 
4 
 
Immobile 
 
Completely disabled; cannot carry out any self-care; totally 
confined to bed or chair  
 
 
 
NYHA CLASS 
 
Class I 
Patients with no limitation of activities; they suffer no symptoms from ordinary activities. 
Class II 
Patients with slight, mild limitation of activity; they are comfortable with rest or with mild 
exertion. 
Class III 
Patients with marked limitation of activity; they are comfortable only at rest. 
Class IV 
Patients who should be at complete rest, confined to bed or chair; any physical activity brings 
on discomfort and symptoms occur at rest. 
 


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APPENDIX 4: 
DEFINITIONS OF RESPONSE  
 
(based on IMWG criteria 2006 and amyloidosis consensus criteria 2005) 
 
Haematological Response: 
 
CR 
Negative immunofixation of serum and urine (serum alone in anuric patients) 
AND 
Normal FLC concentration and kappa/lambda FLC ratio (FLC ratio alone in 
renal failure)  
AND 
≤5% plasma cells in bone marrowa without clonality by immunohistochemistry 
or immunofluorescencea  
VGPRb  
 
 
>90% reduction in serum paraprotein or abnormal component of FLC  
 
 
 
            or dFLC over the starting value or dFLC <40mg/L 
PR 
≥50% decrease in aberrant FLC concentration or dFLC (or ≥50% decrease in 
dFLC  if renal failure) or serum paraprotein but not fulfilling criteria for CR or 
VGPR 
MR 
>25% but <50% decrease in aberrant FLC or dFLC or paraprotein  
NR 
Not meeting FLC criteria for CR, PR or MR  
 
 
Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; NR, no response. 
 
Plateau 
2 consecutive FLC samples or serum paraprotein (at least 2 weeks apart) showing 
the aberrant (monoclonal) light chain concentration to be abnormal but stable 
(within 20% of each other).  In the context of progressive renal impairment, the 
/ ratio or dFLC rather than absolute FLC concentration should remain stable 
(i.e. within 20%).   
 
a Confirmation with repeat bone marrow biopsy only if done, not mandatory.  Presence/absence of clonal cells is 
based upon the k/ ratio.  An abnormal k/ ratio by immunohistochemistry and/or immunofluorescence requires 
a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting presence of an abnormal clone is k/ of 
>4:1 or <1:2.  Alternatively, the absence of clonal plasma cells can be defined based on the investigation of 
phenotypically aberrant PC.  The sensitivity level is 10-3 (less than one phenotypically aberrant PC within a total of 
1000 PC).  Examples of aberrant phenotypes include (1) CD38 +dim and CD56+ strong and CD19- and CD45-; (2) 
CD38+dim and CD138+ and CD56++ and CD28+; (3) CD138+, CD19- CD56++, CD117+. 
 
 
APPENDIX 4 CONTINUED OVERLEAF..... 
 
 


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APPENDIX 4   
CONTINUED FROM PREVIOUS PAGE 
 
 
Haematological Relapse:  
 
From CR 
Increase in the aberrant serum free light chain concentration to outside the 
normal range and by a factor of ≥2 from that at the time of CR or re-appearance 
of the original paraprotein  
 
From PR or VGPR: 
Increase in the aberrant free light chain concentration by a factor of ≥2 from that 
at the time of PR (≥50% change in ratio away from normal in patients with renal 
failure) or doubling of the serum paraprotein level (if starting >5g/L) or doubling 
and increase of serum paraprotein to >5g/L (if starting <5g/L) 
 
 
 
Organ Response: 
 
Heart  
Interventricular septal thickness decreased by 2 mm or 10% improvement in 
ejection fraction or a 30% and 35 pMol/L reduction in NT-ProBNP (only 
applicable if there is no change or <25% improvement in renal function) or 
significant improvement in lateral wall TDI S wave and E/E’ ratio 
 
Kidney  
50% decrease (at least 0.5 g/day) in 24-hr urinary protein loss (urine protein must 
be>0.5 g/day pretreatment) without fall in creatinine clearance of ≥25% from 
baseline 
 
Liver  
50% decrease in abnormal alkaline phosphatase value or a decrease in liver size 
radiographically by at least 2 cm 
 
Nerve  
Improvement in electromyogram nerve conduction velocity (rare) 
 
Soft tissue 
Definite clinical and/or radiographic improvement with associated functional 
improvement in affected tissue 
 
 
 
 
 
Organ Progression: 
 
Heart  
Interventricular septal thickness increased by >2 mm compared with baseline or 
20% decline in ejection fraction 
 
Kidney  
50% increase (at least 1 g/day) in 24-hr urinary protein loss to >1 g/day  
OR 
Sustained fall in creatinine clearance of ≥25% from baseline 
 
Liver   
 
 
50% increase of alkaline phosphatase from the lowest value 
 
Nerve  
Progressive neuropathy by electromyography or nerve conduction velocity 
 
Soft tissue 
Definite clinical and/or radiographic deterioration with associated functional 
deterioration in affected tissue 
 
 


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APPENDIX 5: 
TOXICITY CRITERIA 
 
NCI CTCAE Toxicity Criteria (V4.03). For full list see:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
 
 
Toxicity 
1 
2 
3 
4 
CONSTIPATION 
Occasional or intermittent 
symptoms; occasional use of 
stool softeners, laxatives, dietary 
modification, or enema 
Persistent symptoms with regular use 
of laxatives or enemas; limiting 
instrumental ADL 
Obstipation with manual evacuation 
indicated; limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
DIARRHOEA (patients 
without colostomy) 
Increase of <4 stools per day 
over baseline; mild increase in 
ostomy output compared to 
baseline 
Increase of 4 - 6 stools per day over 
baseline; moderate increase in ostomy 
output compared to baseline 
Increase of 7 stools per day over 
baseline; incontinence; hospitalization 
indicated; severe increase in ostomy 
output compared to baseline; limiting 
self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
FATIGUE 
Fatigue relieved by rest 
Fatigue not relieved by rest; limiting 
instrumental ADL 
Fatigue not relieved by rest, limiting 
self care ADL 
- 
HYPOTENSION 
Asymptomatic, intervention not 
indicated 
Non-urgent medical intervention 
indicated 
Medical intervention or hospitalization 
indicated 
Life-threatening and urgent 
intervention indicated 
INFECTION WITH 
NORMAL ANC 
Asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated 
Moderate; minimal, local or 
noninvasive intervention indicated; 
limiting ageappropriate instrumental 
ADL 
Severe or medically significant but not 
immediately lifethreatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
LETHARGY 
Mild symptoms; reduced 
alertness and awareness 
Moderate symptoms; limiting 
instrumental ADL 
- 
- 
MUCOSITIS: 
 
 
 
 
ANAL MUCOSITIS 
Asymptomatic or mild 
symptoms; intervention not 
indicated 
Symptomatic; medical intervention 
indicated; limiting instrumental ADL 
Severe symptoms; limiting self care 
ADL 
Life-threatening consequences; 
urgent intervention indicated 
ORAL MUCOSITIS 
Asymptomatic or mild 
symptoms; intervention not 
indicated 
Moderate pain; not interfering with 
oral intake; modified diet indicated 
Severe pain; interfering with oral 
intake 
Life-threatening consequences; 
urgent intervention indicated 
SMALL INTESTINAL 
MUCOSITIS 
Asymptomatic or mild 
symptoms; intervention not 
indicated 
Moderate pain; not interfering with 
oral intake; modified diet indicated 
Severe pain; interfering with oral 
intake; tube feeding, TPN or 
hospitalization indicated; limiting self 
care ADL 
Life-threatening consequences; 
urgent intervention indicated 
LARYNGEAL 
MUCOSITIS 
Endoscopic findings only; mild 
discomfort with normal intake 
Moderate discomfort; altered oral 
intake 
Severe pain; severely altered 
eating/swallowing; medical 
intervention indicated 
Life-threatening airway 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation) 
PHARYNGEAL 
MUCOSTIS 
Endoscopic findings only; 
minimal symptoms with normal 
oral intake; mild pain but 
analgesics not indicated 
Moderate pain and analgesics 
indicated; altered oral intake; limiting 
instrumental ADL 
Severe pain; unable to adequately 
aliment or hydrate orally; limiting self 
care ADL 
Life-threatening consequences; 
urgent intervention indicated 
TRACHEAL MUCOSITIS 
Endoscopic findings only; 
minimal hemoptysis, pain, or 
respiratory symptoms 
Moderate symptoms; medical 
intervention indicated; limiting 
instrumental ADL 
Severe pain; hemorrhage or respiratory 
symptoms; limiting self care ADL 
Life-threatening consequences; 
urgent intervention indicated 
PERIPHERAL MOTOR 
NEUROPATHY 
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated 
Moderate symptoms; limiting 
instrumental ADL 
Severe symptoms; limiting self care 
ADL; assistive device indicated 
Life-threatening consequences; 
urgent intervention indicated 
PERIPHERAL SENSORY 
NEUROPATHY 
Asymptomatic; loss of deep 
tendon reflexes or paresthesia 
Moderate symptoms; limiting 
instrumental ADL 
Severe symptoms; limiting self care 
ADL 
Life-threatening consequences; 
urgent intervention indicated 
RASH MACULO-
PAPULAR 
Macules/papules covering 
<10% BSA with or without 
symptoms (e.g., pruritus, 
burning, tightness) 
Macules/papules covering 10 
- 30% BSA with or without 
symptoms (e.g., pruritus, 
burning, tightness); limiting 
instrumental ADL 
Macules/papules covering 
>30% BSA with or without 
associated symptoms; limiting 
self care ADL 
 
NEUTROPHILS COUNT 
DECREASED 
<LLN - 1500/mm3; <LLN - 
1.5 x 10e9 /L 
<1500 - 1000/mm3; <1.5 - 1.0 x 10e9 
/L 
<1000 - 500/mm3; <1.0 - 0.5 x 10e9 
/L 
<500/mm3; <0.5 x 10e9 /L 
SOMNOLENCE 
Mild but more than usual 
drowsiness or sleepiness 
Moderate sedation; limiting 
instrumental ADL 
Obtundation or stupor 
Life-threatening consequences; 
urgent intervention indicated 
THROMBOEMBOLIC 
EVENT 
Venous thrombosis (e.g., 
superficial thrombosis) 
Venous thrombosis (e.g., 
uncomplicated deep vein thrombosis), 
medical intervention indicated 
Thrombosis (e.g., uncomplicated 
pulmonary embolism [venous], 
nonembolic cardiac mural [arterial] 
thrombus), medical intervention 
indicated 
Life-threatening (e.g., 
pulmonary embolism, 
cerebrovascular event, arterial 
insufficiency); hemodynamic or 
neurologic instability; urgent 
intervention indicated 
RESTRICTIVE 
CARDIOMYOPATHY 
- 
- 
Symptomatic heart failure or other 
cardiac symptoms, responsive to 
intervention 
Refractory heart failure or other 
poorly controlled cardiac 
symptoms 
HAEMORRHAGE (GI) 
Mild; intervention not indicated 
Moderate symptoms; medical 
intervention or minor cauterization 
indicated 
Transfusion, radiologic, endoscopic, or 
elective operative intervention 
indicated 
Life-threatening consequences; 
urgent intervention indicated 
HAEMORRHAGE 
(OTHER) 
Mild; intervention not indicated 
Symptomatic; medical intervention 
indicated  
Transfusion indicated 
Life-threatening consequences; 
urgent intervention indicated 
PAIN 
Mild pain 
Moderate pain; limiting instrumental 
ADL 
Severe pain; limiting self care ADL 
- 
 


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APPENDIX 6: 
DETAILS OF INVESTIGATIONS AND THEIR TIMINGS 
 
PLEASE ALSO SEE PROTOCOL SECTION 11 
 
PLEASE NOTE – prior to starting each treatment cycle at RHC a 5ml serum sample must be collected 
and sent to UK NAC (see protocol section 1 for contacts). 
 
Clinical Assessments to be performed at the following timepoints: 
- 
Baseline at UK NAC 
- 
Re-confirmation of Eligibility at RHC 
- 
Prior to each cycle at RHC 
- 
UK NAC visit following 3rd cycle of study treatment 
- 
UK NAC visit 7.5 months after start of treatment or 1 month after the end of study treatment if 6 cycles 
given. 
 
 
Medical History at baseline 
 
Physical examination 
 
Weight 
 
Lying blood pressure 
 
5 minute standing blood pressure 
 
ECOG Performance Status 
 
 
NYHA heart failure class 
 
Haematology to be performed at the following timepoints: 
- 
Baseline at UK NAC 
- 
Re-confirmation of Eligibility at RHC 
- 
Prior to each cycle at RHC and at day 8 and 15 
- 
UK NAC visit following 3rd cycle of study treatment 
- 
UK NAC visit 7.5 months after start of treatment or 1 month after the end of study treatment if 6 cycles 
given. 
 
 
Haemoglobin 
 
White blood count (including differential) 
 
Platelets 
 
PT 
 
APTT 
 
Factor X (if indicated) 
 
Biochemistry to be performed at the following timepoints: 
- 
Baseline at UK NAC 
- 
Re-confirmation of Eligibility at RHC 
- 
Prior to each cycle at RHC 
- 
UK NAC visit following 3rd cycle of study treatment 
- 
UK NAC visit 7.5 months after start of treatment or 1 month after the end of study treatment if 6 cycles 
given. 
 
 
Urea 
 
Creatinine (to be checked at day 8 & day 15 of 
each cycle) 
 
eGFR (to be calculated as per local 
biochemistry laboratory standard protocol) 
 
Calcium 
 
Phosphate 
 
CRP 
 
ALP 
 
GGT 
 
AST 
 
ALT 
 
Bilirubin 
 
Potassium 
 
Albumin 
 
Sodium 
 
APPENDIX 6 CONTINUED OVERLEAF..... 


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APPENDIX 6  CONTINUED FROM PREVIOUS PAGE 
 
 
Other investigations to be performed at UK NAC at the following timepoints: 
 
- 
PLEASE NOTE – prior to starting each cycle at RHC a 5ml serum sample must be collected and sent to 
UK NAC 
 
- 
* Baseline at UK NAC, at UK NAC visit following 3rd cycle of study treatment, at UK NAC visit 6 
months after registration or 1 month after the end of study treatment if 6 cycles given and on posted 
serum samples and on each posted sample sent by RHC as defined in protocol  
- 
** Baseline visit to UK NAC and at UK NAC visit 6 months after registration or 1 month after the 
end of study treatment if 6 cycles given. Bone marrow tests will be done at these time points only if 
clinically indicated. 
- 
*** Baseline at UK NAC, at UK NAC visit following 3rd cycle of study treatment, at UK NAC visit 6 
months after start of treatment or 1 month after the end of study treatment if 6 cycles given. At RHC 
ECHO will be done at end of cycle 2 only. Echocardiogram to be repeated at any cycle if clinically 
indicated for unexpected worsening of cardiac function. 
- 
**** Baseline at UK NAC, 1st cycle of treatment at day 1, 8 & 15 at RHC, day 1 of every subsequent 
cycle at RHC, at UK NAC visit following 3rd cycle of study treatment, at RHC at end of treatment, 
visit, at UK NAC visit 6 months after registration or or 1 month after the end of study treatment if 6 
cycles given. 
 
 
Serum Free Light Chains* 
 
Bone marrow aspirate & trephine 
plasmacytosis**  
 
NT-ProBNP**** 
 
24 hour urinary light chain type and 
quantification** 
 
Echocardiography *** 
 
Serum monoclonal protein* 
 


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APPENDIX 7: 
AMYLOID STAGE 
 
The amyloid stage definition will be based on the report published by Dispenzieri et al 2004. The stages will be 
classified as follows:  
 
Stage I: Both NT-proBNP and cardiac troponin-T normal defined as NT-proBNP ≤36 pMol/L and cardiac 
troponin T ≤0.03 ng/ml (or cardiac high sensitivity troponin T ≤ 0.05 µg/L) 
 
Stage II: Either one of NT-proBNP or cardiac troponin T abnormal defined as: NT-proBNP>36 pMol/L or 
cardiac troponin T >0.03 ng/ml (or cardiac high sensitivity troponin T >0.05 µg/L) 
 
Stage III: Both NT-proBNP and cardiac troponin T abnormal defined as: NT-proBNP >36 pMol/L and cardiac 
troponin T >0.03 ng/ml (or cardiac high sensitivity troponin T >0.05 µg/L) 
 
 
 
 
 
 


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APPENDIX 8: 
POSSIBLE RISKS AND DISCOMFORTS WITH CARFILZOMIB 
 
Carfilzomib Risks 
Carfilzomib (KyprolisTM) is approved by the U.S. Food and Drug Administration (FDA) to be used only in certain 
U.S. patients with relapsed and refractory multiple myeloma that have tried and failed other therapies. It has not 
been approved to be used for any other disease or condition. In this study, Carfilzomib is an investigational study 
drug because it is not approved for use in all patients in the United States, and it is not approved by some regulatory 
authorities (the agencies that are responsible for approving the use of a medicine in a country such as the European 
Medicines Agency and Health Canada). You will be told about the known risks, which are the side effects reported 
previously by others who took Carfilzomib. However, your doctors do not know all the side effects that you may 
experience. As with all investigational drugs, all risks may not have been identified at this time. There may be serious 
unexpected or unforeseen risks while taking Carfilzomib, including death. It is known that nearly everyone who 
takes Carfilzomib will have some side effects while on the drug. Many of these side effects may be mild but some 
side effects can be serious and even fatal.  
Everyone taking part in the study will be watched carefully for any side effects. You should talk to your study doctor 
about any side effects that you have while taking part in the study.   
If side effects occur, your health care team may give you medicines to help lessen side effects. Your doctor may 
have you stop taking Carfilzomib or take a lower dose of Carfilzomib because of the side effects, or the side effects 
may go away on their own even if you continue to take Carfilzomib.   
Information provided below is based on data from approximately 800 patients who took Carfilzomib while taking 
part in clinical studies over the past 6 years. During this time period the following side effects have been observed 
and may be due to Carfilzomib. 
 
 
Likely Side Effects:  those occurring in more than 20% of patients (or more than 20 out of 100 persons) who 
received Carfilzomib: 
• 
Fatigue (tiredness) 
• 
Fever  
• 
Headache 
• 
Cough 
• 
Shortness of breath (at rest or with exertion) which in rare cases may be life-threatening or resulting in 
death  
• 
Nausea 
• 
Vomiting 
• 
Diarrhea  
• 
Constipation 
• 
Decreased red blood cell count which may lead to feeling tired 
• 
Decreased platelet counts which may lead to increase bleeding or bruising 
• 
Decreased white blood cell count which may decrease your ability to fight infection 
• 
Upper respiratory tract infection 
• 
Mild decreases in kidney function which are generally reversible 
• 
Swelling of the arms or legs 
• 
Back pain 
 
 
Less Likely Side Effects:  those occurring in 5-20% of patients (or 5 to 20 out of 100 persons) who received 
Carfilzomib: 
• 
Flu-like symptoms such as fever, chills, or shaking that may occur at any time but are more likely to occur 
on the day of or the day after Carfilzomib infusion.  
• 
Loss of or decreased appetite which may lead to weight loss 
• 
Insomnia (difficulty sleeping) 
• 
Anxiety 
• 
Dizziness 
• 
Confusion or changes in mental state 
• 
Blurred or double vision 
• 
Numbness, tingling, or decreased sensation in hands and/or feet  
• 
Blood chemistry and electrolyte alterations 
 
APPENDIX 8 CONTINUED OVERLEAF..... 
 
 


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• 
Rash and/or itching, or dry skin 
• 
Pain, burning, or irritation at the infusion site 
• 
Generalized pain  
• 
Pain in the bones or joint pain 
• 
Muscle spasm, pain, or weakness 
• 
General weakness, or lack of energy or strength 
• 
Abdominal pain, discomfort, or swelling 
• 
Indigestion (upset stomach) 
• 
Inflammation of the liver (mild, reversible changes in liver function tests) 
• 
Increase or decrease in blood pressure 
• 
Pneumonia or other lower respiratory tract infections 
• 
Urinary tract infection  
• 
Nosebleeds 
• 
Dehydration 
• 
Sore throat, inflammation of the nose and throat, runny nose or nasal congestion 
 
 
Rare and/or Potentially Serious Side Effects: those occurring in less than 5% of patients (or in less than 5 out 
of 100 persons) who received Carfilzomib; side effects can be serious enough to be life-threatening or even fatal in 
rare cases: 
• 
Infusion reactions (which can occur during or shortly after Carfilzomib infusion) including flushing or 
feeling hot, fever, shakes, nausea, vomiting, weakness, shortness of breath, swelling of the face, pain in the 
muscles or joints, tightness or pain in the chest, and low blood pressure 
• 
Allergic reaction including total body rash, hives, and difficulty breathing 
• 
Inflammation of the pancreas (pancreatitis) 
• 
Kidney failure which can lead to dialysis  
• 
Worsening liver function up to and including liver failure  
• 
Decreased or worsening of heart function including chest pain, abnormal heart rhythm, heart attack, and 
heart failure  
• 
Increase in the blood pressure in the arteries of the lungs 
• 
Blood clots in the leg or lungs  
• 
Infections in the blood  
• 
Tumor lysis syndrome (TLS) 
• 
Tumor lysis syndrome is caused by rapid killing of tumor cells during treatment.  When the tumor cells 
die, they release their contents into the bloodstream.  If cell killing is very rapid, this can affect blood 
chemistries and the kidneys.  In severe cases, this can lead to shutdown of kidney function requiring dialysis.   
• 
Myelodysplastic syndromes (MDS)/ Acute Myeloid Leukemia (AML) 
• 
Myelodysplastic syndromes refers to  disorders that develops when the cells in the bone marrow (the soft 
inner part of the bones, where new blood cells are made) do not work properly and have problems making 
new blood cells.  A person with MDS may experience no symptoms or may experience fatigue, infection, 
easy bruising or bleeding.  MDS can turn into a cancer of bone marrow cells called acute myeloid leukemia 
(AML).   
• 
Posterior reversible encephalopathy syndrome (PRES) 
• 
Posterior reversible encephalopathy syndrome (PRES) is a rare condition that causes swelling of the brain 
and affects how it functions. A person with PRES may experience headaches, confusion, loss or decreased 
level of consciousness, blurred vision or blindness, seizures, and possibly death. If caught early and treated, 
PRES may be reversed.  
 
You should seek medical care immediately if you develop any of the following symptoms: severe shortness of 
breath, chest pain, fevers, chills, shaking with fever, vomiting, muscle weakness or cramping, seizures, confusion, 
severe headaches, fainting, blurred vision or blindness, and/or significantly decreased urine output. 
Carfilzomib may impair ability to operate a car, other motorized vehicle, or machinery because of tiredness, 
dizziness, changes in blood pressure, or fainting. 
Hydration Risks (Prevention of TLS) 
 
There may be risks associated with over hydrating (having too much fluid in your body) so it is important to follow 
your doctor’s instructions regarding how much water or other fluids you should drink.  Over hydration may 
negatively affect the heart, lungs, and kidneys. 

SAP_001.pdf: 
Anl_Plan_V1.0 May 2019                                                                                                   Page 1 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
 
 
 
 
CLINICAL TRIALS RESEARCH UNIT 
(CTRU) 
UNIVERSITY OF LEEDS 
 
 
 
 
FINAL 
STATISTICAL ANALYSIS PLAN 
 
CATALYST 
 
 
 
 
 
 
 
 
V1.0 
 
MAY 2019 
 
 
 
  
Trial Statistician: Alexandra Pitchford 
Supervising Statistician: Andrew Hall 
 
 
 
CTRU Scientific Lead: Sarah Brown 
 
 
Senior Trial Co-ordinator: Jamie Oughton 
 
CTRU Project Delivery Lead: Louise Flanagan  
Chief Investigator: Ashutosh Wechalekar 
 
 
 
 
 
 
 
 


Anl_Plan_V1.0 May 2019                                                                                                   Page 2 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
 


Anl_Plan_V1.0 May 2019                                                                                                   Page 3 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
Table of Contents 
 
 
Amendments ................................................................................................................................................... 4 
1. 
Introduction ............................................................................................................................................ 4 
1.1 
Background ..................................................................................................................................... 4 
1.2 
Design ............................................................................................................................................. 4 
1.3 
Aims ................................................................................................................................................. 5 
1.4 
Sample size and expected accrual ................................................................................................. 5 
1.5 
Planned analyses ............................................................................................................................ 5 
2. 
Endpoints ................................................................................................................................................ 5 
2.1 
Primary endpoint ............................................................................................................................. 5 
2.2 
Secondary endpoints ....................................................................................................................... 6 
2.3 
Derivation of endpoints .................................................................................................................... 6 
2.3.1  
Primary endpoints ................................................................................................................... 6 
2.3.2  
Secondary endpoints .............................................................................................................. 6 
3. 
Analysis Sets .......................................................................................................................................... 7 
3.1 
Eligibility........................................................................................................................................... 7 
3.2 
Safety analysis set .......................................................................................................................... 7 
3.3 
Per protocol set ............................................................................................................................... 7 
3.4 
Evaluability for determining the MTD .............................................................................................. 7 
3.5 
Dose Cohorts .................................................................................................................................. 7 
4. 
Data Handling ......................................................................................................................................... 8 
4.1 
Data monitoring ............................................................................................................................... 8 
4.2 
Data validation ................................................................................................................................. 8 
5. 
Data Analysis.......................................................................................................................................... 9 
5.1 
General calculations ........................................................................................................................ 9 
5.2 
Analysis ........................................................................................................................................... 9 
5.3.1     Baseline characteristics .............................................................................................................. 9 
5.3.2     Primary endpoints ....................................................................................................................... 9 
5.3.2     Secondary endpoints .................................................................................................................. 9 
6. 
Reporting and Dissemination of the Results .................................................................................... 10 
6. 
References ............................................................................................................................................ 10 
Approval of Analysis Plan ........................................................................................................................... 11 
 
 
 


Anl_Plan_V1.0 May 2019                                                                                                   Page 4 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
Amendments 
 
None 
 
 
1. 
Introduction 
 
1.1 
Background 
 
Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, 
insoluble fibrils that progressively disrupt tissue structure and impair function.  Systemic AL amyloidosis, which 
is the commonest amyloid type, is a malignant disorder occurring in a small proportion of individuals with 
monoclonal B cell dyscrasias and AL amyloidosis is a myeloma defining criteria according to the international 
working group definition of myeloma 2003  (Kyle 2003). AL amyloidosis occurs at an incidence of 3-5 cases 
per million population and is the cause of death of between 0.5-1 per thousand individuals in the UK. AL fibrils 
are derived from monoclonal immunoglobulin light chains which are unique in each patient underlying the 
remarkably heterogeneous clinical picture in this particular form of amyloidosis; virtually any organ or 
combination of organs other than the brain may be affected.    Treatment in AL amyloidosis is aimed at 
suppression of the underlying B cell dyscrasia using chemotherapy regimens based on those used for multiple 
myeloma.  Without therapy it is inexorably progressive and until recently the median survival was just 6-15 
months.  Survival for patients who achieve a less than VGPR or refractory patients is even poorer (Palladini, 
Dispenzieri et al. 2012). 
 
Many studies have demonstrated a link between hematologic responses and improved organ function and 
survival. Stopping the production of the toxic light chain species can translate into significant benefit for most 
patients except those with most advanced organ involvement, while stable hematologic disease despite 
therapy means it is likely that the effects of the toxic light chain species will continue. Consensus criteria for 
hematologic and cardiac response have been recently developed and validated (Palladini, Dispenzieri et al. 
2012). Advanced cardiac and extensive organ involvement limit benefits that can be derived from treatment 
including eligibility for autologous stem cell transplantation (ASCT) and can shorten survival despite treatment 
(Merlini, Seldin et al. 2011, Cordes, Dispenzieri et al. 2012). Another treatment limitation is related to the type 
of organ involvement predisposing patients to the adverse effects of specific drugs. In AL amyloidosis clinical 
trials, it has been a challenge to distinguish drug-specific side effects from disease-mediated organ dysfunction  
(Comenzo, Reece et al. 2012) 
 
Carfilzomib (PR-171) is a tetrapeptide ketoepoxide-based inhibitor specific for the chymotrypsin-like active site 
of the 20S proteasome.  Carfilzomib is structurally and mechanistically distinct from the dipeptide boronic acid 
proteasome inhibitor bortezomib (Velcade®).  In addition, when measured against a broad panel of proteases 
including metallo, aspartyl, and serine proteases, carfilzomib demonstrated less reactivity against non-
proteasomal proteases when compared to bortezomib. There is limited data on the use of carfilzomib in AL 
amyloidosis, we therefore propose a gradual dose escalation study. There is an ongoing study of carfilzomib 
in AL amyloidosis.  
 
Proteasome inhibitors are associated with highest response rates in AL amyloidosis.  Bortezomib has toxicity 
and limitations in AL amyloidosis.  In particular, the high specificity of carfilzomib for proteosome inhibition and 
it’s favorable toxicity profile makes it very appealing in AL amyloidosis.   For instance, toxicities which 
commonly complicate Bortezomib use, such as autonomic and peripheral neuropathy, appear uncommon with 
carfilzomib. Combination of proteosome inhibitors with Immunomodulatory Drug (IMiDs) appears to be 
synergistic in myeloma and the phase II data using carfilzomib with lenalidomide or thalidomide appears 
promising.  In the UK, we have extensive experience using thalidomide in the treatment of patients with AL 
amyloidosis.  Combining carfilzomib with thalidomide offers an attractive treatment option for patients with 
relapsed refractory disease due to their non-overlapping toxicity profile.  Low dose thalidomide is generally 
well tolerated by patients with AL amyloidosis but as single agent has limited efficacy.  However, in combination 
with other agents, response rates are high as we have documented by using risk adapted CTD regime.  This 
study is designed to improve the response rates seen with CTD protocol by using carfilzomib in combination 
with thalidomide and dexamethasone.  
 
1.2 
Design 
 
 
This will be a single arm open label multicentre phase Ib dose escalation study with expansion phases.  


Anl_Plan_V1.0 May 2019                                                                                                   Page 5 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
Patients will receive treatment with Carfilzomib in escalating dose cohorts along with a fixed dose of 
Dexamethasone and Thalidomide (KTD).  The dose escalation phase of the study will use a 3+3 dose 
escalation design. Cohorts of 3-6 participants will be treated with KTD as outlined in the Section 8. Carfilzomib 
doses will be increased between cohorts until the occurrence of dose limiting toxicities (DLTs) define the MTD.  
The Safety Review Committee will review the safety and ethics of the trial by reviewing interim data after each 
cohort of treatment during recruitment to the Dose Escalation Cohort.  Once the MTD and/or RD has been 
established a maximum of 20 participants will be recruited for entry into the expansion phase of the study at 
the RD.  
 
1.3 
Aims 
 
The Catalyst (Carfil-thal-Dex in AL treatment) Trial aims to assess the safety and tolerability of KTD 
(Carfilzomib-thalidomide-dexamethasone) using the phase 1 dose escalating component to define the 
maximum tolerated dose (MTD) and recommended dose (RD) and the expansion cohort to further assess the 
safety and tolerability and to gain an understating of efficacy to allow design for further trials.  
 
Primary:  
Dose escalation 
To define the MTD and RD of Carfilzomib used in combination with Thalidomide and Dexamethasone 
in patients with relapsed or refractory AL amyloidosis 
Dose expansion 
To further assess the safety and tolerability of KTD at the RD of Carfilzomib identified in the dose 
escalation phase  
 
Secondary: 
 
To make a preliminary assessment of the activity of KTD in patients with relapsed refractory AL 
amyloidosis  
 
1.4 
Sample size and expected accrual 
 
In the dose escalation phase of this study, a minimum of 6 (3 at dose level 0 and 3 at dose level -1) and a 
maximum of 18 (6 at dose level 0 1 and 2) patients will recruited in a 3+3 design with cohorts of between 3 
and 6 patients, in order to determine maximum tolerated dose and recommended dose.  
 
At the recommended dose level identified, a further 20 patients will be recruited to further assess safety and 
toxicities at the RD. 
 
The study will run in 15 UK centres. The study duration is expected to be approximately 42 months – including 
6 months of set up, 24 months of recruitment, 6 months of follow-up and 6 months of analysis/write-up. 
 
1.5 
Planned analyses 
 
During the Dose Escalation Phase, recruitment will be halted after each group of three patients have completed 
at least one cycle of KTD, to allow safety data to be assessed.  CTRU will produce a summary of DLTs at each 
dose level, detailed safety listings, and recruitment figures for consideration by the Safety Review Group.   
 
No formal analyses are planned until after the trial is closed to recruitment and the required number of patients 
has been recruited. Final analysis will be carried out when the required number of patients has been recruited 
and all patients have been followed up for at least 6 months from registration.   
 
2. 
Endpoints 
 
 
2.1 
Primary endpoint 
 
Dose-Limiting Toxicities (Dose escalation phase), between the time of receiving the first registered dose of 
Carfilzomib in cycle 1 and day 1 cycle 2, in order to establish the Maximum Tolerated Dose (MTD) and 
recommended dose (RD) of Carfilzomib in combination with Thalidomide and Dexamethasone. 
 
Proportion of patients treated who experience any grade 3 or 4 CTCAE toxicity throughout all treatment cycles. 


Anl_Plan_V1.0 May 2019                                                                                                   Page 6 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
 
2.2 
Secondary endpoints 
 
 
Clonal response rate within 3m, at 3m, within 6m and at 6m  
 
Amyloidotic organ response rate within 3m and 6m 
 
Time to amyloidotic organ response 
 
Number of deaths at 6 months 
 
Number of patients progression free at 6 months 
 
Maximum response  
 
Time to maximum response 
 
Number of patients withdrawing from treatment 
 
Number of patients experiencing dose delays, and compliance profile of KTD. 
 
Relative Dose intensity 
 
 
2.3 
Derivation of endpoints 
 
2.3.1  
Primary endpoints 
 
Dose limiting toxicities (DLTs) will be collected from the time of receiving the first dose of Carfilzomib in cycle 1 
up to the first dose of treatment administered in cycle 2. Only DLTs that are attributed to the registered dose 
of Carfilzomib will be included when determining the MTD. A DLT will be defined as any of the following events 
that are determined to be related to trial drug administration: 
 
1. 
Any non-haematological toxicity ≥ Grade 3 according to NCI CTCAE Version 4.03 which fails to 
return to ≤Grade 1 or baseline after 7 days. Nausea, vomiting, diarrhoea and electrolyte imbalances 
will be considered DLTs only if they reach ≥ Grade 3 severity despite adequate supportive care 
measures. Similarly, fluid retention or worsening symptoms of heart failure will be considered as 
DLTs if they are persistent ≥Grade 3 despite increase in oral diuretics or there is an increase in 
dyspnoea by ≥ 2 NYHA grades within 12 hours of administration of Carfilzomib which persists for > 
6 hours or needs hospital admission 
2. 
Grade 4 neutropenia lasting > 7 days or Grade 4 neutropenia with sepsis despite adequate 
supportive measures. 
3. 
Any grade 4 thrombocytopenia which fails to return to Grade 2 within 7 days without platelet support 
4. 
Delay of >8 days within cycle 1 or delay of commencement of 2nd cycle by more than 14 days, due 
to significant toxicity or tolerability issue* 
5. 
Any other event which, in the opinion of the Safety Review Committee, is considered to be clinically 
significant and related to treatment 
 
The MTD is defined as the highest dose level at which no more than 1 patient experiences a DLT, from the 
time of receiving the first registered dose of Carfilzomib in cycle 1 up to the first dose of treatment administered 
in cycle 2, i.e. the dose level below that at which 2 or more patients experiences a DLT.  If no more than one 
patient experiences a DLT at the highest dose level then this will be considered as the MTD. 
 
Once the MTD has been established, a minimum of 6 patients will be treated at this dose level in order to 
establish the RD. The RD is the dose which will be used in the dose expansion phase of the study to evaluate 
activity. 
 
The proportion of patients treated who experience any grade 3 or 4 CTCAE toxicity will be calculated as 
number of patients who experience any grade 3 or 4 CTCAE toxicity throughout their treatment cycle. 
 
* This will not be defined as a DLT if the delay is due to one of the other specified DLT criteria. 
 
 
 
2.3.2  
Secondary endpoints 
 
Clonal response rate (based on paraprotein and FLCs) is defined as the proportion of patients who achieve at 
least a PR within 3 months, at 3 months, within 6 months and at 6 months after trial registration. 
 
Amyloidotic organ response rate is defined as the proportion of patients who achieve organ response within 3 


Anl_Plan_V1.0 May 2019                                                                                                   Page 7 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
months and within 6 months of trial registration. 
 
Time to Amyloidotic organ response is defined as the time from the dose allocation to first achieving organ 
response.  
 
The number of patients experiencing dose delays will be defined as the number of patients experiencing delays 
in treatment with any of the study treatments. 
 
KTD compliance: Patients will be regarded as compliant to treatment where treatment is received as per 
protocol until withdrawal from treatment and have no more than 1 dose omission of Carfilzomib, 5 of 
Thalidomide or 1 of Dexamethasone during each cycle.  
 
Relative Dose intensity will be calculated as the percentage ratio between the received and planned dose 
intensities, where dose intensity is the cumulative dose divided by the duration of treatment.    
 
3. 
Analysis Sets 
 
Statistical analysis will be descriptive for all endpoints, and will be summarised overall and by dose cohort. All 
safety analyses will be based upon the safety analysis set; safety data from patients not included in this 
analysis set will be listed separately. All efficacy analyses will be based upon the per protocol set. Patients 
who do meet the criteria to be included in each of analysis sets will have the reasons for emission listed. A 
sensitivity analysis on the efficacy endpoints may be considered if the total number of patients in each of the 
analysis sets differs by more than 3 patients.   
 
 
3.1 
Eligibility 
 
Participants considered eligible for the study are those that fulfil all the inclusion and none of the exclusion 
criteria noted in the protocol. All participants in the analysis population should remain in the trial after 
registration unless they explicitly withdraw consent. If a participant is found to be ineligible after registration 
they will be included in the analysis population as appropriate unless written informed consent has not been 
obtained. If a participant withdraws consent from further trial treatment and / or further collection of data their 
samples will remain on file. 
 
3.2 
Safety analysis set 
 
All patients that receive at least one dose of Carfilzomib and with no protocol deviations with relevant impact 
on safety will be included in the safety analysis set. 
 
3.3 
Per protocol set 
 
The per protocol set will include all patients with at least one post baseline efficacy assessment who receive 
at least one dose of Carfilzomib and have no protocol deviations with relevant impact on efficacy.   
 
3.4 
Evaluability for determining the MTD 
 
Determination of the MTD in the dose escalation phase of the trial will be based on those patients who have 
received at least one cycle KTD and will be evaluated between the time of receiving the first dose of Carfilzomib 
in cycle 1 and the first dose of treatment in cycle 2. The safety review committee will review each DLT and 
attribute the DLT to the loading dose or the registered dose; any DLT attributed to the loading dose will be 
excluded when determining the MTD. KTD Patients who do not receive one complete cycle due to experiencing 
a DLT will be included in the analysis; patients who do not receive at least one complete cycle for reasons 
other than toxicity, without experiencing a DLT, and who miss a dose of Carfilzomib, more than 14 doses 
Thalidomide or 2 doses of Dexamethasone in the first cycle, will be replaced. Evaluability will be considered 
by the safety review committee on an individual basis to account for attributing DLTs and missed doses to the 
loading or the registered dose. 
 
 3.5 
Dose Cohorts 
  
The RD cohort will include all patients who are registered to receive and receive at least one dose of 
Carfilzomib at the RD. This cohort will include patients from the dose escalation and dose expansion phases 


Anl_Plan_V1.0 May 2019                                                                                                   Page 8 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
of the study. All patients who do not fulfil these criteria will be included in the non-RD cohort.    
 
 
4. 
Data Handling 
 
4.1 
Data monitoring 
 
Data will be monitored for quality and completeness by the CTRU.  Missing data will be chased until it is 
received, confirmed as not available or the trial is at analysis.  The CTRU will reserve the right to intermittently 
conduct source data verification exercises on a sample of participants, which will be carried out by staff from 
the CTRU.  Source data verification will involve direct access to participant notes at the participating hospital 
sites and the collection of copies of consent forms and other relevant investigation reports.  A Trial Monitoring 
Plan will be developed and a Meeting Group Monitoring Schedule including primary endpoint and safety data 
will be defined and agreed by the Trial Management Group (TMG) if necessary. 
 
The Safety Review Committee will be acting as the data monitoring ethics committee and will review safety 
and ethics of the trial as described in the protocol. 
 
The following will also be examined continuously during the course of the trial: 
 
Accrual 
 
Data quality 
 
Consent 
 
DLTs/SAEs/SUSARs 
 
Withdrawal from the trial 
 
Pregnancy  
 
Protocol deviations 
 
4.2 
Data validation 
 
The Data Manager will carry out initial validation of the forms in accordance with the guidelines developed for 
the study. This will ensure that data is complete, consistent and up-to-date. Reasons should be obtained when 
data is unobtainable.  
 
The database will also validate most dates and data in line with the pre-programmed validation rules in real 
time, as data is entered. Periodic batch validation will also be carried out to detect any data queries that may 
be missed if CRFs are entered in an order that does not allow the real time validation checks to work. 
 
Key data items required are those for the primary endpoints and for withdrawal information. All key data items 
will be checked manually by the data managers (or their delegate) at the time of final analysis. Key data items 
include: 
 
 
Date of randomisation/registration  
 
Registered dose level 
 
Cycle number  
 
Drug compliance in first cycle to confirm evaluability for determining the MTD and analysis sets 
 
SAE/AE data 
 
Additionally, data regarding withdrawal of consent is also classed as key data: 
 
Withdrawal of consent and date 
  
In addition the statistician will validate the data to be used in the analysis in the following steps: 
 
The data will be read into permanent SAS data sets using the SAS data views procedure; the names 
and contents of the datasets can be found on the final database specification reports in the database 
documentation folder.  
 
SAS will also be used to further validate the data and identify any missing or inconsistent data. Checks to be 
performed include: 
 
Eligibility checks (if not data management validations) 
 
Sequential dates (if not data management validations) 
 
Checks for unusual and outlying data (if not database validations) 
 
Checks for missing data (are there items of data which are systematically missing/do specific variables 


Anl_Plan_V1.0 May 2019                                                                                                   Page 9 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
have a large amount of missing data etc) (if not database validations) 
 
Checks for inconsistencies in safety data 
 
Other checks as deemed appropriate 
 
Any inconsistent data will be noted and an e-mail sent to the data manager responsible for the study (or their 
delegate). A copy of this e-mail will be kept in the statistician’s trial file. All queries will be resolved, if possible 
in time for final analysis and the outcome documented. 
 
5. 
Data Analysis 
 
5.1 
General calculations 
 
Unless otherwise stated, percentages will be calculated using the total number of patients in the appropriate 
population as the denominator (i.e. including all patients with missing data for that variable). All analyses will 
be carried out using SAS unless stated otherwise. 
 
All percentages and means will be rounded to 1 decimal place and standard deviations to 2 decimal places. 
Values that are below the limit of detection and therefore non-quantifiable will be summarised using the limit 
of quantification value. For listings, if required, the non-quantifiable value would be reported as an inequality. 
 
Summaries are divided into those participants treated at the recommended dose either during the dose 
escalation phase (prior to the identification of the recommended dose) or during the dose expansion phase 
(RD population), and all other participants treated during the dose escalation phase at dose levels other than 
the recommended dose (Non-RD population). The non-RD population will be split by dose level. 
 
5.2 
Analysis 
 
As defined in Section 3, data will be summarised using descriptive summary statistics only and no formal 
statistical testing will be carried out on any of the study endpoints. 
 
 
5.3.1     Baseline characteristics 
 
Baseline characteristics will be tabulated for all registered eligible patients using summary statistics overall 
and by dose. 
 
 
5.3.2     Primary endpoints 
 
The number of patients experiencing DLTs within the first cycle of KTD will be presented, with descriptive 
summaries of the specific DLTs observed. Summaries will be presented for each dose level. This data will be 
presented for patients registered to the dose escalation phase of the study only.   
 
Further summaries of longer-term tolerability will also be presented for patients registered to the dose 
escalation phase to include the maximum toxicity grade experienced within the first three cycles of treatment, 
overall and by cycle. Individual listings of the toxicities, grade and cycle of all toxicities experienced within the 
first three cycles will be presented.   
 
The number of patients experiencing any grade 3 or 4 CTCAE toxicity within all cycles of treatment will be 
summarised. This will be presented overall and by dose cohort, across all cycles as well as by each cycle. 
 
 
5.3.2     Secondary endpoints 
 
Safety and toxicity profiles for each cycle and cohort: data will be summarised descriptively, including the 
proportion of patients experiencing at least one SAE, the number of SAEs experienced per participant, and 
the number of SAEs experienced according to seriousness criteria, causality, and body system. Toxicity will 
be summarised according to CTCAE grades and will be summarised as the maximum grade toxicity 
experienced within each cycle, and overall. 
 
The proportion of patients achieving at least a PR (clonal response) within 3m, at 3m, within 6m and at 6m and 
the proportion of patients achieving an amyloidotic organ response within 3m and 6m will be presented in 
tabulated form. Corresponding 90% and 95% confidence intervals will also be presented. Responses at 3 and 
6 months will be broken down by response achieved, and by organ (for organ response). 


Anl_Plan_V1.0 May 2019                                                                                                   Page 10 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
 
Time to amyloidotic organ response and time to maximum response will be calculated using the Kaplan Meier 
method. Median time to amyloidotic organ response and median time to maximum response will be presented, 
with corresponding 95% confidence intervals. 
 
The proportion and number of patients alive at 6 months and patients progression free at 6 months will be 
presented with corresponding 90% and 95% confidence intervals. If appropriate, Kaplan Meier curves for 
progression free survival may be explored.    
 
Each patient will be assessed for their maximum clonal response; the number and proportion of participants 
in each response category within 6 cycles of treatment will be presented with corresponding 95% confidence 
intervals. Patients who do not achieve a maximum response will be summarised as, “no maximum response”. 
 
Feasibility of delivering treatment according to protocol schedule will be summarised descriptively to include 
the number of patients requiring dose delays and/or reductions, the number of patients withdrawing from 
treatment, and reasons for dose delays / reductions and withdrawals. Time on treatment and reasons for 
stopping treatment will also be presented. The number of doses missed will be summarised overall and by 
cycle. 
 
 
 
6. 
Reporting and Dissemination of the Results 
 
Final analysis will be carried out after the last participant’s last data item. 
 
After the analysis is complete, the results will be presented to the project team who will discuss them and 
decide if any further analysis or investigation is required.  After this, members of the project team will write up 
the results with a view to submitting a manuscript to a peer-reviewed scientific journal. The results will also be 
submitted as abstracts to appropriate conferences for either poster or oral presentation.  All abstracts and 
manuscripts must be reviewed by each member of the project team and an external referee if appropriate, 
before submission. 
 
7. 
References 
 
Comenzo, R. L., D. Reece, G. Palladini, D. Seldin, V. Sanchorawala, H. Landau, R. Falk, K. Wells, A. Solomon, 
A. Wechalekar, J. Zonder, A. Dispenzieri, M. Gertz, H. Streicher, M. Skinner, R. A. Kyle and G. Merlini (2012). 
"Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis." 
Leukemia 26(11): 2317-2325. 
Cordes, S., A. Dispenzieri, M. Q. Lacy, S. R. Hayman, F. K. Buadi, D. Dingli, S. K. Kumar, W. J. Hogan and 
M. A. Gertz (2012). "Ten-year survival after autologous stem cell transplantation for immunoglobulin light chain 
amyloidosis." Cancer 118(24): 6105-6109. 
Kyle, G., et. al. (2003). "Criteria for the classification of monoclonal gammopathies, multiple myeloma and 
related disorders: a report of the International Myeloma Working Group." Br J Haematol 121(5): 749-757. 
Merlini, G., D. C. Seldin and M. A. Gertz (2011). "Amyloidosis: pathogenesis and new therapeutic options." J 
Clin Oncol 29(14): 1924-1933. 
Palladini, G., A. Dispenzieri, M. A. Gertz, S. Kumar, A. Wechalekar, P. N. Hawkins, S. Schonland, U. 
Hegenbart, R. Comenzo, E. Kastritis, M. A. Dimopoulos, A. Jaccard, C. Klersy and G. Merlini (2012). "New 
criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain 
measurement and cardiac biomarkers: impact on survival outcomes." J Clin Oncol 30(36): 4541-4549. 
 
 
 
 
 


Anl_Plan_V1.0 May 2019                                                                                                   Page 11 of 11  Copyright © 2007 CTRU, 
University of Leeds. All rights reserved. 
 
Approval of Analysis Plan 
 
Clinical Trials Research Unit (CTRU) 
 
The following Final analysis plan V1.0, May 2019, for the Catalyst study has been approved by the following 
personnel. Protocol version at time of writing is 3.0. Any signed amendments to the plan will be filed with this 
document. 
 
Trial Statistician (Alexandra Pitchford): __________________________________________________ 
 
Date: ____________________________________________________________________________ 
 
 
Supervising statistician (Andrew Hall): __________________________________________________ 
 
Date: ____________________________________________________________________________ 
 
 
Scientific lead (Sarah Brown): _________________________________________________________ 
 
Date: ____________________________________________________________________________ 
 
 
Senior Trial Co-ordinator (Jamie Oughton ):______________________________________________ 
 
Date: ____________________________________________________________________________ 
 
 
CTRU Delivery lead (Louise Flanagan): _________________________________________________ 
 
Date: ____________________________________________________________________________ 
 
 
Chief Investigator (Ashutosh Wechalekar): ______________________________________________ 
 
Date: ____________________________________________________________________________ 
 
 
Additional information: